THERAPEUTIC METHODS EMPLOYING NORIBOGAINE AND RELATED COMPOUNDS

METHODES THERAPEUTIQUES FAISANT INTERVENIR DE LA NORIBOGAINE ET DES COM OSES APPARENTES

English Abstract

This invention is directed to the use of noribogaine, noribogaine derivative,
or a
pharmaceutically acceptable salt and/or solvate thereof at a dosage that
provides a therapeutic
serum concentration for treating a disease or disorder as described herein in
a patient.

Claims

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What is claimed is:
1. A method for treating opioid or opioid-like drug abuse in a human
patient addicted
thereto, comprising administering to the patient a therapeutic dosage of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt or solvate
thereof, such that the
therapeutic dosage provides an average serum concentration of about 50 ng/mL
to about
180 ng/rnL, said concentration being sufficient to inhibit or ameliorate said
abuse while
maintaining a QT interval of less than about 500 ms during said treatment.
2. The method of claim 1, comprising:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of about 50 ng/mL to about 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of about 50 ng/mL to
about 180
ng/mL for a period of time.
3. The method of claim 1, further comprising selecting an addicted patient
who is
prescreened to evaluate tolerance for prolongation of QT interval.
4. The method of claim 1 wherein the maximum serum concentration is between
about 40 ng/mL and about 250 ng/mL.
5. The method of claim 1 wherein the serum concentration of noribogaine is
between
about 1000 ng*hr/mL and about 5800 ng*hr/mL.
6. A method for treating opioid or opioid-like drug abuse in a human
patient addicted
thereto, comprising administering to the patient a dosage of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof that
provides an average
serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration
being
sufficient to inhibit or ameliorate said abuse while maintaining a QT interval
prolongation
of less than about 20 ms during said treatment.
7. A method for treating nicotine addiction in a patient in need thereof,
comprising
administering to the patient a therapeutically effective amount of
noribogaine, noribogaine
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derivative, or a pharmaceutically acceptable salt thereof, wherein said
therapeutically
effective amount is from about 50 ng to less than 101.1g per kg body weight
per day.
8. A method for preventing a nicotine craving in a patient in need thereof,
comprising
administering to the patient a prophylactically effective amount of
noribogaine,
noribogaine derivative, or a pharmaceutically acceptable salt thereof, wherein
said
prophylactically effective amount is from about 50 ng to less than 10 lug per
kg body
weight per day.
9. The method of claim 8, wherein the patient is no longer physically
addicted to
nicotine.
10. A method for treating alcohol dependence in a human patient suffering
therefrom,
comprising administering to the patient a dosage of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt and/or solvate thereof that provides an
average serum
concentration of about 50 ng/mL to about 500 ng/mL, said concentration being
sufficient
to ameliorate said dependence while maintaining a QT interval of less than
about 500 ms
during said treatment.
11. The method of claim 10, wherein the aggregate dosage of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof is from
about 1.3
mg/kg to about 4 mg/kg per day.
12. A method for treating substance abuse in a human patient addicted
thereto,
comprising administering to the patient a dosage of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt and/or solvate thereof that provides an
average serum
concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to
inhibit or
ameliorate said abuse while maintaining a QT interval of less than about 500
ms during
said treatment.
13. The method of claim 12, comprising:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of 50 ng/mL to 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
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additional dose maintains the average serum concentration of 50 ng/mL to 180
ng/mL for
a period of time.
14. A method for treating substance abuse in a human patient addicted
thereto,
comprising administering to the patient a dosage of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt and/or solvate thereof that provides an
average serum
concentration of 50 ng/mL to 1 8 0 ng/mL, said concentration being sufficient
to inhibit or
ameliorate said abuse while maintaining a QT interval prolongation of less
than about 20
ms during said treatment.
15. .. The method of claim 14, comprising:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of 50 ng/mL to 1 8 0 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of 50 ng/mL to 180
ng/mL for
a period of time.
16. A method for treating pain in a patient, comprising administering to
the patient a
dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable
salt and/or
solvate thereof that provides an average serum concentration of 50 ng/mL to
180 ng/mL ,
said concentration being sufficient to alleviate and/or inhibit said pain
while maintaining a
QT interval of less than about 500 ms during said treatment.
17. The method of claim 16, comprising:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of 50 ng/mL to 1 8 0 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of 50 ng/mL to 180
ng/mL for
a period of time.
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18. A method for treating pain in a patient, comprising administering to
the patient a
dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable
salt and/or
solvate thereof that provides an average serum concentration of 50 ng/mL to
180 ng/mL ,
said concentration being sufficient to alleviate and/or inhibit said pain
while maintaining a
QT interval prolongation of less than about 20 ms during said treatment.
19. A method for treating migraine headache and/or symptoms thereof in a
patient in
need thereof comprising administering to the patient a therapeutically
effective amount of
noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt
thereof.
20. The method of claim 19, wherein the therapeutically effective amount is
from
about 50 ng to about 10 g per kg body weight per day.
21. A method for preventing migraine headache and/or symptoms thereof in a
patient
in need thereof, comprising administering to the patient a prophylactically
effective
amount of noribogaine, noribogaine derivative, or a pharmaceutically
acceptable salt
thereof.
22. The method of claim 21, wherein said prophylactically effective amount
is from
about 50 ng to about 10 g per kg body weight per day.
23. A method for treating a condition in a patient which is treatable with
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof
while
maintaining an acceptable QT interval prolongation in said patient, the method

comprising:
a) administering to the patient an initial unit dose of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof wherein
said unit dose
provides a therapeutic average serum concentration of 50 ng/mL to 180 ng/mL
which
serum concentration imparts an acceptable QT interval in said patient; and
b) maintaining said serum concentration by periodically administering at
least one
additional dose of noribogaine, noribogaine derivative, or pharmaceutically
acceptable salt
or solvate thereof such that the at least one additional dose maintains the
therapeutic
average serum concentration of 50 ng/mL to 180 ng/mL during treatment;
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wherein said additional dose or doses are continued as necessary to treat said
condition,
and further wherein said acceptable QT interval is no longer than 500 ms.
24. The method of claim 24, wherein the QT interval is prolonged by less
than 50 ms,
or by less than 20 ms.
25. A method for treating a condition in a patient which is treatable with
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof
while
maintaining an acceptable QT interval prolongation in said patient, the method

comprising:
a) administering to the patient an initial unit dose of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, wherein
said unit dose
provides a therapeutic average serum concentration of 50 ng/mL to 180 ng/mL
which
serum concentration imparts an acceptable QT interval prolongation in said
patient; and
b) maintaining said serum concentration by periodically administering at
least one
additional dose of noribogaine, noribogaine derivative, or pharmaceutically
acceptable salt
or solvate thereof, such that the at least one additional dose maintains the
therapeutic
average serum concentration of 50 ng/mL to 180 ng/mL during treatment;
wherein said additional dose or doses are continued as necessary to treat said
condition,
and further wherein said acceptable QT interval prolongation is no longer than
50 ms.
26. The method of claim 25, wherein the QT interval prolongation is less
than 20 ms.
27. A method for modulating tolerance to an opioid analgesic in a patient
undergoing
opioid analgesic therapy, the method comprising interrupting or administering
concurrently with said opioid analgesic therapy an amount of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof that
provides an
average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being

sufficient to re-sensitize the patient to the opioid as an analgesic while
maintaining a QT
interval of less than about 500 ms during said treatment.
28. The method of claim 27, further comprising interrupting the dosage of
the
analgesic.
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29. The method of claim 27, further comprising administering noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt and/or solvate
thereof
concurrently with the analgesic.
30. A method for modulating tolerance to an opioid analgesic in a patient
undergoing
opioid analgesic therapy, the method comprising interrupting or administering
concurrently with said opioid analgesic therapy an amount of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof that
provides an
average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being

sufficient to re-sensitize the patient to the opioid as an analgesic while
maintaining a QT
interval prolongation of less than about 20 ms during said treatment.
31. The method of any one of clairns 27-30, wherein the opioid analgesic is
selected
from the group consisting of fentanyl, hydrocodone, hydromorphone, morphine,
oxycodone, buprenorphine, codeine, thebaine, buprenorphine, methadone,
meperidine,
tramadol, tapentadol, levorphanol, sufentanil, pentazocine, and oxymorphone.
32. A method for treating depression and/or posttraumatic stress disorder
in a patient
in need thereof, comprising administering to the patient a therapeutically
effective amount
of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt
and/or
solvate thereof, wherein the patient is not addicted to cocaine or an opiate,
and further
wherein the therapeutically effective amount provides an efficacious average
noribogaine
serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a
QT
interval of less than about 500 ms during said treatment.
33. A method for treating depression and/or posttraumatic stress disorder
in a patient
in need thereof, comprising administering to the patient a therapeutically
effective amount
of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt
and/or
solvate thereof, wherein the patient is not addicted to cocaine or an opiate,
and further
wherein the therapeutically effective amount provides an efficacious average
noribogaine
serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a
QT
interval prolongation of less than about 20 ms during said treatment.
34. A method for treating an anxiety-related disorder in a patient in need
thereof,
comprising administering to the patient a therapeutically effective amount of
noribogaine,
noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate
thereof,
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wherein the patient is not addicted to cocaine or an opiate, and further
wherein the
therapeutically effective amount provides an efficacious average noribogaine
serum level
of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval
of less
than about 500 ms during said treatment.
35. A method for treating an impulse control disorder in a patient in need
thereof,
comprising administering to the patient a therapeutically effective amount of
noribogaine,
noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate
thereof,
wherein the patient is not addicted to cocaine or an opiate, and further
wherein the
therapeutically effective amount provides an efficacious average noribogaine
serum level
of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval
of less
than about 500 ms during said treatment.
36. A method for regulating food intake and/or attenuating food craving in
a patient in
need thereof, comprising administering to the patient a therapeutically
effective amount of
noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt
and/or solvate
thereof, wherein the patient is not addicted to cocaine or an opiate, and
further wherein the
therapeutically effective amount provides an efficacious average noribogaine
serum level
of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval
of less
than about 500 ms during said treatment.
37. A method for treating an anger-related disorder in a patient in need
thereof,
comprising administering to the patient a therapeutically effective amount of
noribogaine,
noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate
thereof, and
further wherein the therapeutically effective amount provides an efficacious
average
noribogaine serum level of between about 50 ng/mL and about 180 ng/mL while
maintaining a QT interval of less than about 500 rns during said treatment.
38. A method for screening an opioid-addicted patient to determine the
patient's
tolerance for a therapeutic dose of noribogaine or pharmaceutically acceptable
salt and/or
solvate thereof, the method comprising:
measuring the patient's pre-administration QT interval;
administering to the patient a sub-therapeutic dose of noribogaine or
pharmaceutically acceptable salt thereof., and
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measuring the patient's post-administration QT interval.
39. The method of claim 38, further comprising one or more of:
determining the difference between pre-administration QT interval and post-
administration QT interval to determine a first prolongation;
estimating a second prolongation based on the first prolongation, wherein the
second prolongation is the estimated QT interval prolongation expected to be
observed in
the patient upon administration of a therapeutic dose of noribogaine;
determining the patient's tolerance for the therapeutic dose of noribogaine;
and
administering to the patient the therapeutic dose of noribogaine or
discontinuing
noribogaine treatment, wherein a therapeutic dose is administered if the
second
prolongation is estimated to be less than about 50 ms.
40. The method of claim 39, wherein the therapeutic dose provides an
average serum
concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to
inhibit or
ameliorate opioid addiction while resulting in prolongation of the patient's
QT interval of
less than about 50 ms.
41. The method of claim 39, further comprising:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of 50 ng/mL to 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative,
or pharmaceutically acceptable salt or solvate thereof, such that the at least
one additional
dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a
period of
time.
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Description

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WO 2015/126836
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THERAPEUTIC METHODS EMPLOYING NORIBOGAINE AND RELATED
COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application Nos.
61/941,387
filed February 18, 2014; 61/945,746 filed February 27, 2014; 61/941,390 filed
February
18, 2014; 62/035,335 filed August 8,2014; 61/952,731 filed March 13, 2014;
61/952,727
filed March 13, 2014; 62/005,851 filed May 30, 2014; 61/952,733 filed March
13, 2014;
62/005,847 filed May 30, 2014; 61/952,738 filed March 13, 2014; 62/005,855
filed May
30, 2014; 61/952,741 March 13, 2014; 62/005,841 filed May 30, 2014; 61/952,744
March
13, 2014; 62/005,858 filed May 30, 2014; 62/007,346 filed June 3, 2014;
62/024,388 filed
July 14, 2014; and 62/033,538 filed August 5, 2014; and U.S. Application Nos.
14/195,822 filed March 3, 2014, 14/292,632 filed May 30, 2014 and 14/485,514
filed
September 12, 2014; and PCT Application No. PCT/US14/19692 filed February 28,
2014,
each of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention is directed to the use of noribogaine, noribogaine
derivative, or a
pharmaceutically acceptable salt and/or solvate thereof at a dosage that
provides a
therapeutic serum concentration for treating a disease or disorder in a
patient.
STATE OF THE ART
[0003] Noribogaine is sometimes referred to as 12-hydroxyibogaine. US Patent
No.
2,813,873 claims noribogaine albeit as "12-0-demethylibogaine" while providing
an
incorrect structural formula for ibogaine. Noribogaine can be depicted by the
following
formula:
HO C2H 5
[0004] Noribogaine and its pharmaceutically acceptable salts have recently
received
significant attention as a non-addictive alkaloid useful in treating drug
dependency (U.S.
Patent No. 6,348,456) and as a potent analgesic (U.S. Patent No. 7,220,737).
Such
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treatment generally requires administration of high doses of noribogaine,
typically 0.1 mg
to 100 mg per kg body weight.
[0005] Noribogaine is a metabolite of ibogaine found in human, dog, rat and
monkey.
While the prior art suggests that ibogaine at higher doses is useful as a
treatment for
addiction, use of ibogaine is associated with hallucinations and other
negative side effects.
In the United States, ibogaine is classified as a Schedule I controlled
substance.
Noribogaine has been suggested to have a greater and longer lasting activity
in humans
than ibogaine for reducing craving for addictive substances and treating
chemical
dependency. U.S. Patent No. 6,348,456, incorporated by reference herein in its
entirety,
discloses highly purified noribogaine and teaches that it should be provided
at dosages
from about 0.01 to about 100 mg per kg body weight per day to treat addiction,
although
no human data was provided showing an effective dose to treat drug addiction.
[0006] The therapeutic dosing of noribogaine for long-term treatment in humans
has not
previously been addressed, especially as it relates to dosing protocols that
are effective, as
well as safe. Indeed, prior to the instant invention, it was uncertain as to
whether
noribogaine could be administered at a dose which was therapeutic while at the
same time
safe for patients.
Addiction
[0007] Nicotine addiction relates generally to smoking, although other forms
of nicotine
addiction are common (e.g., chewing tobacco). Smoking and other forms of
nicotine use
pose a serious threat to global health. In the United States alone, annual
mortality from
smoking (including environmental exposure, i.e. "second-hand smoke") is
greater than
440,000. Costs associated with smoking-related illness in the United States
total $96
billion in medical costs and $97 billion in lost productivity each year.
Furthermore,
smoking significantly increases the risk of a number of diseases, including
coronary artery
disease, stroke, lung cancer and other cancers, and chronic obstructive
pulmonary disease.
An estimated 46 million people in the United States are smokers, 20.6 percent
of the US
population.
[0008] More than 40 percent of existing smokers attempt to quit smoking
annually.
Various approved therapies (varenicline, bupropion, nicotine patch/gum,
nicotine nasal
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spray/inhaler, hypnotherapy, biofeedback) have long been in clinical use to
treat nicotine
dependence. Current therapies directed toward smoking cessation tend to focus
on
counseling, behavioral treatment such as hypnosis, ancUor pharmaceutical
therapies.
Quitting smoking is difficult and may require multiple attempts, with success
rates of 4%
to 25% depending on the technique used. Users often relapse because of stress,
weight
gain, and withdrawal symptoms. Furthermore, nicotine replacement therapies
(e.g.,
nicotine patch, nicotine gum, nicotine nasal spray, or nicotine inhaler) do
not directly treat
nicotine addiction, as the patient remains addicted to nicotine throughout
treatment.
[0009] A nicotine addict in remission may exhibit psychological symptoms of
nicotine
addiction long after the physical symptoms of nicotine addiction are gone.
Many ex-
smokers relapse due to a trigger, such as stress or environmental cues. For
example,
approximately 50% of relapses occur when the ex-smoker has been drinking
alcohol.
[0010] Given the immense harm of smoking and other forms of nicotine use to
the
human body, the high degree of cost to the health care system, the addictive
nature of
nicotine use, and the difficulty in quitting even when using conventional
therapy, there
remains an acute need for effective strategies for treating nicotine
addiction. There also
remains an acute need for effective strategies for preventing relapse of
nicotine addiction
in nicotine addicts who are in remission.
[0011] Alcohol dependence (also referred to alcohol abuse, alcohol addiction,
or
alcoholism) is also serious public health problem throughout the world. As
many as 140
million people worldwide have an alcohol abuse problem, although only a small
fraction
of those receive treatment. Alcohol abuse can cause damage to almost every
organ in the
body, including the brain. Long-term alcohol abuse is known to cause or
contribute to
numerous diseases, including cirrhosis of the liver, pancreatitis, epilepsy,
dementia, heart
disease, peptic ulcers, damage to the central and/or peripheral nervous
system, cancer,
polyneuropathy, nutritional deficiencies, and death.
[0012] Complicating the treatment of alcohol dependence, alcohol-dependent
patients
generally experience significant, potentially fatal, withdrawal symptoms while
attempting
to quit using alcohol. Acute withdrawal lasts one to three weeks after
cessation of alcohol
consumption. Acute withdrawal symptoms include anxiety, seizures, delirium
tremens,
hallucinations, shakes, and heart failure. Post-acute withdrawal can last
significantly
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longer, with symptoms such as anxiety, depression, sleep disturbance, fatigue,
and tension
being common.
[0013] Treatment for alcohol dependence generally includes detoxification
followed by
individual and/or group therapy. Detoxification may include treatment with
medications
(such as benzodiazepines) that reduce the symptoms of withdrawal. However,
drugs such
as benzodiazepines have numerous negative side effects, including adverse
psychological
effects and physical dependence. Benzodiazepines are also known to increase
alcohol
cravings in alcohol dependent people, and are thus not suitable for long-term
treatment of
alcohol dependence/addiction. Alcohol-dependent patients have a high rate of
relapse.
[0014] Alcohol consumption has been shown to stimulate the release of
endogenous
opioids in the brains of both humans and experimental animals. Alcohol's
effects on the
opioid system are believed to be central to drug-induced reward and relapse to
alcohol use,
as well as sensitivity to alcohol.
[0015] Due to the severity and duration of withdrawal symptoms, alcohol-
dependent
patients have a high rate of relapse. There is a significant need for
effective, non-addictive
treatment for acute and post-acute withdrawal symptoms, as well as a method
for
preventing relapse to alcohol use by a detoxified patient.
[0016] Alcohol consumption has been shown to stimulate the release of
endogenous
opioids in the brains of both humans and experimental animals. Alcohol's
effects on the
opioid system are believed to be central to drug-induced reward and relapse to
alcohol use,
as well as sensitivity to alcohol.
[0017] Substance addiction is a serious public health problem throughout the
world. As
many as 23.5 million people in the US have a drug or alcohol abuse problem,
although
only a small fraction of those receive treatment.
100181 Complicating the treatment of drug addiction, drug-addicted patients
generally
experience significant withdrawal symptoms while attempting to quit using the
drug.
Acute withdrawal from drug dependence is characterized by dramatic and
traumatic
symptoms, including sweating, racing heart, palpitations, muscle tension,
tightness in the
chest, difficulty breathing, tremor, nausea, vomiting, diarrhea, grand mal
seizures, heart
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attacks, strokes, hallucinations and delirium tremens (DTs). Withdrawal
symptoms can
also include severe cravings for the drug, fatigue, lack of pleasure, anxiety,
irritability,
sleepiness, suicidal thoughts, and sometimes agitation or extreme suspicion or
paranoia.
Once acute withdrawal symptoms have subsided, post-acute withdrawal syndrome
can last
for months or years. Post-acute withdrawal symptoms include physical,
emotional, and
psychological symptoms, such as fatigue, depression, lack of motivation, and
increased
pain sensitivity. Acute and post-acute withdrawal symptoms are the primary
reason drug-
addicted patients return to using the drug after treatment, even when the
patient has been
drug-free for a significant amount of time.
[0019] Although treatments have been developed in attempts to ameliorate acute
and
post-acute withdrawal symptoms, such treatments do not work for all types of
drugs. In
addition, treatment of withdrawal may require use of other addictive
substances (e.g.,
morphine, buprenorphine, or methadone). Due to the severity and duration of
withdrawal
symptoms, addicted patients have a high rate of relapse. There is a
significant need for
effective, non-addictive treatment for acute and post-acute withdrawal
symptoms.
[0020] While the prior art suggests that ibogaine at higher doses is useful as
a treatment
for addiction, use of ibogaine is associated with hallucinations and other
negative side
effects. In the United States, ibogaine is classified as a Schedule I
controlled substance.
Pain and Migraine
[0021] Pain is broadly defined as an unpleasant sensory experience associated
with
actual or potential tissue damage, or described in terms of such damage. The
interpretation
of sensory pain occurs when peripheral nerve endings called nociceptors are
stimulated
and subsequently transmit signals through sensory neurons in the spinal cord.
The signals
are then transmitted to the brain, at which point the individual becomes aware
of the pain.
[0022] There are a number of pain categories and classifications, which for
example, can
be grouped into four categories according to the source and related
nociceptors: (1)
cutaneous pain; (2) somatic pain; (3) visceral pain; and (4) neuropathic pain.
Other pain
classifications include acute pain and chronic pain. Acute pain is defined as
short-term
pain or pain with an easily identifiable cause. Acute pain indicates present
damage to
tissue or disease and may be "fast" and "sharp" followed by aching pain. Acute
pain is
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centralized in one area before becoming somewhat spread out. Acute pain
generally
responds well to medications (e.g., morphine).
[0023] Chronic pain may be medically defined as pain that has lasted six
months or
longer. This constant or intermittent pain has often outlived its purpose
because it does not
help the body to prevent injury. It is often more difficult to treat than
acute pain. Expert
care is generally necessary to treat any pain that has become chronic. In
addition, stronger
medications are typically used for extended periods in an attempt to control
the pain. This
can lead to drug dependency. For example, opioids are used in some instances
for
prolonged periods to control chronic pain. Drug tolerance, chemical
dependency, and even
psychological addiction may occur.
[0024] Debilitating chronic pain affects tens of millions of people annually
and costs
hundreds of millions of dollars in terms of medication, physical therapy, and
lost
production. Numerous treatments have been developed in attempts to ameliorate
pain in its
various categories. The current methods for treating chronic pain have a
limited success
rate and in some cases may result in chemical dependency.
[0025] Migraine headaches (also referred to as "headaches") are a neurological
disorder
whose symptoms include headaches of moderate to severe intensity, which may be

accompanied by nausea, vomiting, sensitivity to sensatory inputs (light,
sound, and/or
smell), fatigue, irritability, and/or auras. Migraines can last for prolonged
periods of time,
usually between 4 and 72 hours. Migraines affect approximately 15% of the
human
population, with up to 2.2% of the population experiencing chronic migraines.
Costs
associated with migraines (e.g., patient care, lost productivity, etc.) in the
U.S. are
estimated to be up to $17 billion per year.
[0026] Migraines are generally managed by trigger avoidance, control of
symptoms, and
prevention using pharmacologic agents. Acupuncture, acupressure, massage, and
relaxation may also be used. Biofeedback, neurostimulators, or migraine
surgery may be
used in more severe cases, especially those that do not respond to other
treatments. Given
the prevalence of migraines and the difficulty in treatment and/or prevention,
there
remains an acute need for effective strategies for treating and preventing
migraines and
symptoms thereof.
6
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Depression, Anxiety, Psychiatric Disorders, and Related Disorders
[0027] The CDC estimates that about 1 in 10 adults in the United States suffer
from
depression. High levels of depression correlate with high rates of other
diseases, including
obesity, heart disease, and stroke.
[0028] Similarly, anxiety-related disorders are prevalent in the United
States. Anxiety-
related disorders include obsessive-compulsive disorder, panic disorder,
social anxiety
disorder, and generalized anxiety disorder.
[0029] PTSD affects approximately 8% of Americans at some point in their
lives. More
strikingly, up to 30% of people, including veterans, who spend time in war
zones develop
PTSD. PTSD is increasingly recognized as a major issue for U.S. troops
returning from
Iraq and Afghanistan, as well as those who served in previous wars, and is a
potential
contributor to the high rate of suicide among veterans.
[0030] Impulse control disorder is a class of psychiatric disorders involving
the failure to
resist a temptation, urge, or impulse (impulsivity) where such impulse is
potentially
harmful to the patient and/or others. The American Psychiatric Association's
DSM-5
(May 2013) includes impulse control disorders "characterized by problems in
emotional
and behavioral self-control". These include borderline personality disorder,
conduct
disorder, antisocial personality disorder, attention deficit hyperactivity
disorder (ADHD),
schizophrenia, mood disorders, pathological gambling, pyromania, intermittent
explosive
disorder, kleptomania, sexual compulsion, paraphilia, interne addiction,
trichotillomania,
pathological skin picking, and compulsive shopping. Impulse control disorder
may be
related to anxiety disorder and/or OCD.
[0031] Violence and anger, particularly when out of proportion to a stimulus
and/or a
result of pathological anger, are associated with a number of mental
disorders. These
include oppositional defiant disorder, attention-deficit/hyperactivity
disorder and conduct
disorder (in children and adolescents), psychotic disorder, bipolar disorder,
antisocial,
borderline, paranoid and narcissistic personality disorders, adjustment
disorder with
disturbance of conduct, and intermittent explosive disorder. Pathological
anger and
violence account for a significant portion of violent crimes, including many
high-profile
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crimes involving multiple victims. Highly volatile individuals are over-
represented in the
prison system in the United States.
Food Intake
[0032] Over 2/3 of adults in the U.S. are overweight, with about half of those
being
obese. The U.S. weight loss market is estimated to be worth over $60 billion;
diet pills
alone account for around $1 billion. However, many diet pills contain
ingredients that are
at best of dubious efficacy and at worst dangerous. Obesity greatly increases
a person's
risk for a variety of diseases, including coronary heart disease, high blood
pressure, stroke,
type 2 diabetes, abnormal levels of blood fats, metabolic syndrome, cancer,
osteoarthritis,
sleep apnea, reproductive issues, and gallstones.
Opioid Analgesic Tolerance
[0033] Addictive opioid analgesic agents such as morphine are well-known and
exceptionally potent analgesics. Such opioids operate as mu receptor agonists.
Upon
administration, opioids initiate a cascade of biological events including
increased
serotonin and dopamine expression. As is well known, continued use of many
such
opioids (especially at high doses) carries a significant risk of
dependency/addiction.
Indeed, potential addiction to such opioids is a serious issue that limits the
therapeutic use
of addictive opioids as analgesic agents. For example, the use of morphine as
an analgesic
is common among end stage patients suffering from serious pain where addiction
is no
longer a concern.
[0034] Drug tolerance to opioid analgesics is common, and may be psychological
and/or
physiological. A patient who has developed tolerance to the opioid analgesic
is not
necessarily addicted to or misusing the analgesic. Drug tolerance occurs when
the patient's
reaction to the drug is reduced, requiring an increase in dose to achieve the
same desired
effect. There are several potential methods for how tolerance develops,
including receptor
desensitization, receptor phosphorylation, receptor internalization or down-
regulation, and
up-regulation of inhibitory pathways.
[0035] Drug tolerance requires that the dosage of analgesic be increased in
order to
provide sustained analgesic effect. However, high doses of opioids may lead to
serious
complications and side effects, including physical dependence, addiction,
respiratory
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depression, nausea, sedation, euphoria or dysphoria, decreased
gastrointestinal motility,
and itching.
[0036] Noribogaine is a metabolite of ibogaine found in human, dog, rat and
monkey.
The therapeutic dosing of noribogaine for treating drug addiction and other
diseases in
humans has not previously been addressed, especially as it relates to dosing
protocols that
are effective, as well as safe. Indeed, prior to the instant invention, it was
uncertain as to
whether noribogaine could be administered at a dose which was therapeutic
while at the
same time safe for patients.
Depression
[0037] Noribogaine is a well-known member of the ibogaine family of alkaloids
and is
sometimes referred to as 12-hydroxyibogaine. U.S. Patent No. 2,813,873 claims
noribogaine, albeit as "12-0-demethylibogaine," while providing an incorrect
structural
formula for ibogaine. The structure of noribogaine has now been thoroughly
evaluated
and is found to combine the features of tryptamine, tetrahydrohavaine and
indolazepines.
Noribogaine can be depicted by the following formula:
HO C2H5
[0038] Depressive disorders include major depressive disorder and dysthymic
disorder
(American Psychiatric Association, 1994a; American Psychiatric Association,
1994b).
Major depressive disorder is characterized by the occurrence of one or more
major
depressive episodes without manic or hypomanic episodes. A major depressive
episode is
defined as a prominent and relatively persistent depressed or dysphoric mood
that usually
interferes with daily functioning (nearly every day for at least 2 weeks); it
can include at
least 4 of the following 8 symptoms: change in appetite, change in sleep,
psychomotor
agitation or retardation, loss of interest in usual activities or decrease in
sexual drive,
increased fatigue, feelings of guilt or worthlessness, slowed thinking or
impaired
concentration, and a suicide attempt or suicidal ideation. Dysthymic disorder
involves a
type of depression that is not severe enough to be called a major depressive
episode, but
that lasts much longer than major depressive disorder, without high phases.
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[0039] Post-traumatic stress disorder (PTSD), as defined by DSM-111-R/IV
(American
Psychiatric Association, 1987; American Psychiatric Association, 1994a),
requires
exposure to a traumatic event that involved actual or threatened death or
serious injury, or
threat to the physical integrity of self or others, and a response which
involves intense fear,
helplessness, or horror. Although PTSD is classified as an anxiety disorder,
PTSD is
unique from other anxiety disorders because of the requirement of exposure to
a traumatic
event.
[0040] Symptoms that occur as a result of exposure to the traumatic event
include re-
experiencing of the event in the form of intrusive thoughts, flashbacks or
dreams, and
intense psychological distress and physiological reactivity on exposure to
cues to the
event; avoidance of situations reminiscent of the traumatic event, inability
to recall details
of the event, and/or numbing of general responsiveness manifested as
diminished interest
in significant activities, estrangement from others, restricted range of
affect, or sense of
foreshortened future; and symptoms of autonomic arousal including
hypervigilance,
exaggerated startle response, sleep disturbance, impaired concentration, and
irritability or
outbursts of anger. A PTSD diagnosis requires that the symptoms are present
for at least a
month and that they cause clinically significant distress or impairment in
social,
occupational, or other important areas of functioning.
[0041] Given the prevalence and impact of depression and PTSD, there is a need
for
treatments that address these issues. Prior to the embodiments described
herein, the
therapeutic dosing of noribogaine and its derivatives for treating depression
and/or PTSD
in humans at an acceptable QT interval prolongation has not previously been
addressed,
especially as it relates to dosing protocols that are effective, as well as
safe.
SUMMARY
[0042] While noribogaine has been disclosed for treatment of substance
addiction, its
use in humans is complicated by the fact that the ranges in the prior art are
exceptionally
broad (0.01 to 1000 mg/kg body weight). Furthermore, human clinical studies
demonstrate that the lower dosing of noribogaine has minimal impact on
withdrawal
symptoms in addicted patients. Thus, the previously disclosed broad range has
now been
found to be insufficient for some human therapies at the lower end of this
range.
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[0043] Moreover, the use of noribogaine imparts a dose-dependent prolongation
of the
treated patient's QT interval, rendering higher dosing of noribogaine
unacceptable. A
prolonged QT interval is a marker of potential Torsades de Pointes, a serious
arrhythmia
that can result in death.
[0044] The current invention is predicated, in part, on the surprising
discovery that
treatment with a narrow dosage range of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt and/or solvate thereof, between about 1 mg/kg
body
weight and about 4 mg/kg body weight, provides a therapeutic reduction in
withdrawal
symptoms and/or an increase in time to resumption of opioid use in opioid-
addicted
patients. Preferably, the dose range that provide both therapeutic results and
an acceptable
QT interval prolongation of less than about 50 milliseconds in opioid and
opioid-like drug
addicted humans is between about 1.3 mg per kg body weight and no more than
about 4
mg per kg body weight and, more preferably between about 1.3 mg per kg body
weight
and no more than about 3 mg per kg body weight, or any subrange or subvalue
within the
aforementioned ranges. Opioid-like drugs, including cocaine, ketamine, and
methamphetamine, are not opioids but act through the opioid receptors, and
thus addiction
to these drugs also can be treated with noribogaine.
[0045] In some embodiments, the unit dose that provides both therapeutic
results and an
acceptable QT interval prolongation of less than about 50 milliseconds in
opioid and
opioid-like drug addicted humans is between about 60 mg and about 150 mg. In
some
embodiments, the unit dose that provides both therapeutic results and an
acceptable QT
interval prolongation of less than about 50 milliseconds in opioid and opioid-
like drug
addicted humans is about 120 mg. In some embodiments, the unit dose that
provides both
therapeutic results and an acceptable QT interval prolongation of less than
about 50
milliseconds in opioid and opioid-like drug addicted humans is about 2 mg/kg
body
weight.
[0046] In some embodiments, the patient is administered an initial dose of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt and/or solvate
thereof,
followed by one or more additional doses. In one embodiment, the initial dose
is from
about 50 mg to about 120 mg. In one embodiment, the one or more additional
doses are
lower than the initial dose. In one embodiment, the one or more additional
doses are from
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about 5 mg to about 50 mg. In one embodiment, such a dosing regimen provides
an
average serum concentration of noribogaine of about 50 ng/mL to about 180
ng/mL. In
one embodiment, the one or more additional doses maintain an average serum
concentration of about 50 ng/mL to about 180 ng/mL over a period of time. In
one
embodiment, the one or more additional doses are administered periodically.
[0047] In a preferred embodiment, the narrow therapeutic doses of noribogaine,

noribogaine derivative, or pharmaceutically acceptable salt or solvate
described above
unexpectedly do not prolong the QT interval to unacceptable levels in human
addicted
patients. It is expected that opioid or opioid-like drug addicted patients
will be
administered therapeutic doses of noribogaine, noribogaine derivative, or
pharmaceutically acceptable salt or solvate thereof in a clinical setting with
cardiac
monitoring. In some embodiments, the patient will be pre-screened to evaluate
tolerance
for prolongation of QT interval, e.g., to determine whether the patient has
any pre-existing
cardiac conditions which would disqualify them from treatment with
noribogaine.
[0048] Some aspects of the current invention are further predicated on the
discovery that
even lower doses of noribogaine, noribogaine derivative, or pharmaceutically
acceptable
salt and/or solvate thereof, for example approximately 80% or less of the
therapeutic dose,
may be effective for prevention of relapse of opioid (or opioid-like drug) use
in an opioid-
addicted patient treated to ameliorate their opioid use. That is, a lower dose
of noribogaine
can prevent a patient who is no longer physically addicted to opioid from
relapsing to
opioid use. Without being bound by theory, it is believed that a patient who
is no longer
physically addicted to opioids or opioid-like drug requires less noribogaine
to prevent
relapse because the opioid or opioid-like drug does not compete with
noribogaine for
receptor binding, and/or because desensitization of one or more receptors in
the brain by
the opioid or opioid-like drug is reversed when the patient ceases to take the
drug. This
lower, maintenance dose of noribogaine results in a QT interval prolongation
that does not
require clinical cardiac monitoring.
[0049] In some embodiments, the maintenance dose of noribogaine is about 5 mg
to
about 100 mg. In some embodiments, the maintenance dose of noribogaine is
about 1.5
mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is
about
1 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine
is
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about 0.9 mg/kg body weight. In some embodiments, the maintenance dose of
noribogaine
is about 0.8 mg/kg body weight. In some embodiments, the maintenance dose of
noribogaine is about 0.7 mg/kg body weight. In some embodiments, the
maintenance dose
of noribogaine is about 0.6 mg/kg body weight. In some embodiments, the
maintenance
dose of noribogaine is about 0.5 mg/kg body weight. In some embodiments, the
maintenance dose of noribogaine is about 0.4 mg/kg body weight. In some
embodiments,
the maintenance dose of noribogaine is about 0.3 mg/kg body weight. In some
embodiments, the maintenance dose of noribogaine is about 0.2 mg/kg body
weight. In
some embodiments, the maintenance dose of noribogaine is about 0.1 mg/kg body
weight.
[0050] In some embodiments, the therapeutic dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof
administered to the
patient is sufficient to provide a serum concentration of about 1000 to about
6000
ng*hour/mL. In some embodiments the therapeutic dose of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof
administered to the
patient is sufficient to provide a maximum serum concentration (Cmax) of less
than about
250 ng/mL. In a preferred embodiment, the therapeutic dose provides a Cmax of
about
100 ng/mL to about 200 ng/mL.
[0051] In some embodiments, the therapeutic dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof
administered to the
patient is sufficient to provide an average serum concentration of about 50
ng/mL to about
180 ng/mL, or any subrange or subvalue there between. In a preferred
embodiment, the
dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable
salt or solvate
thereof administered to the patient provides an average serum concentration of
about 80
ng/mL to about 100 ng/ml.
[0052] In some embodiments, the patient is administered a high (therapeutic)
dose of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate thereof
for a period of time to ameliorate the most significant withdraw symptoms, and
then is
administered a lower (maintenance) dose to prevent relapse to opioid or opioid-
like drug
use. In some embodiments, the patient is administered a therapeutic dose of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof
for a period
of time to ameliorate the most significant withdrawal symptoms, and then is
administered
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a decreasing (tapered) amount of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof over time until the maintenance dose is
reached. In some
embodiments, a high initial therapeutic dose is administered, followed by
administration
of a lower therapeutic dose. In some embodiments, the dose of noribogaine is
tapered over
time from the high therapeutic dose to a lower therapeutic dose.
[0053] In some embodiments, the dose of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt or solvate thereof that provides an average
serum
concentration of about 50 ng/mL to about 180 ng/mL is administered as a single
dose. In
some embodiments, the dose of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof that provides an average serum
concentration of about 50
ng/mL to about 180 ng/mL is administered as multiple doses. In an embodiment,
the
aggregate dose of noribogaine, noribogaine derivative, or pharmaceutically
acceptable salt
or solvate thereof is from about 1 mg/kg to about 3 mg/kg. In another
preferred
embodiment, the aggregate dose of noribogaine, noribogaine derivative, or
pharmaceutically acceptable salt or solvate thereof is from about 1 mg/kg to
about 2.5
mg/kg.
[0054] In some embodiments, the serum concentration is sufficient to inhibit
or
ameliorate said abuse while maintaining a QT interval of less than about 500
milliseconds
(ms) during said treatment. In a preferred embodiment, the serum concentration
is
sufficient to inhibit or ameliorate said abuse while maintaining a QT interval
of less than
about 450 ms during said treatment.
[0055] In some embodiments, the therapeutic dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof provides
prolongation of
the QT interval of less than about 80 ms. In an embodiment, the maintenance
dose of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate thereof
provides prolongation of the QT interval of less than about 50 ms. In some
embodiments,
the maintenance dose or therapeutic dose of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt or solvate thereof provides prolongation of
the QT
interval of less than about 30 ms. In a preferred embodiment, the maintenance
dose of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate thereof
provides prolongation of the QT interval of less than about 20 ms. In one
embodiment, the
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QT prolongation is equivalent to or less than that observed in patients
receiving
methadone treatment. In a preferred embodiment, the patient is tested to
determine QT
interval before treatment with noribogaine, and if clinician determines that
the QT
prolongation would be unacceptable risk, noribogaine therapy will be
contraindicated.
[0056] In another embodiment, noribogaine or a pharmaceutically acceptable
salt thereof
is administered.
Opioid or Opioid Like Drug Abuse
[0057] In one aspect, provided herein is a method for treating opioid or
opioid-like drug
abuse in a human patient addicted thereto, comprising administering to the
patient a
therapeutic dosage of noribogaine, noribogaine derivative, or pharmaceutically
acceptable
salt or solvate thereof, such that the therapeutic dosage provides an average
serum
concentration of about 50 ng/mL to about 180 ng/mL, said concentration being
sufficient
to inhibit or ameliorate said abuse while maintaining a QT interval of less
than about 500
ms during said treatment.
[0058] In one embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof is administered as a single dose or
multiple doses. In
another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of about 50 ng/mL to about 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of about 50 ng/mL to
about 180
ng/mL for a period of time.
[0059] In another embodiment, the initial dose is from about 75 mg to about
120 mg. In
another embodiment, the at least one additional dose is from about 5 mg to
about 25 mg.
In another embodiment, the at least one additional dose is administered from
about 6 hours
to about 24 hours after the initial dose. In another embodiment, at least two
additional
doses are administered, and further wherein the additional doses are
administered from
about 6 hours to about 24 hours after the previous dose. In another
embodiment, the
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method further comprises selecting an addicted patient who is prescreened to
evaluate
tolerance for prolongation of QT interval. In another embodiment, the maximum
serum
concentration is between about 40 ng/mL and about 250 ng/mL. In another
embodiment,
the serum concentration of noribogaine is between about 1000 ng*hr/mL and
about 5800
ng*hr/mL .
[0060] In another aspect, provided herein is a method for treating opioid or
opioid-like
drug abuse in a human patient addicted thereto, comprising administering to
the patient a
dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable
salt or
solvate thereof that provides an average serum concentration of about 50 ng/mL
to about
180 ng/mL, said concentration being sufficient to inhibit or ameliorate said
abuse while
maintaining a QT interval prolongation of less than about 20 ms during said
treatment.
[0061] In one embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof is administered as a single dose or
multiple doses.
[0062] In another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of about 50 ng/mL to about 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of about 50 ng/mL to
about 180
ng/mL for a period of time.
[0063] In another embodiment, the initial dose is from about 75 mg to about
120 mg. In
another embodiment, the at least one additional dose is from about 5 mg to
about 25 mg.
In another embodiment, the at least one additional dose is administered from
about 6 hours
to about 24 hours after the initial dose. In another embodiment, at least two
additional
doses are administered, and further wherein the additional doses are
administered from
about 6 hours to about 24 hours after the previous dose.
[0064] In another aspect, provided herein is a method for attenuating
withdrawal
symptoms in a human patient susceptible to such symptoms due to opioid or
opioid-like
drug addiction, comprising administering to the patient a dosage of
noribogaine,
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noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof
that provides
an average serum concentration of about 50 ng/mL to about 180 ng/mL, said
concentration
being sufficient to attenuate said symptoms while maintaining a QT interval of
less than
about 500 ms during said treatment.
[0065] In one embodiment, the withdrawal symptoms are due to acute withdrawal.
In
another embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof is administered as a single dose or
multiple doses. In
another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of about 50 ng/mL to about 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of about 50 ng/mL to
about 180
ng/mL for a period of time.
[0066] In another embodiment, the initial dose is from about 75 mg to about
120 mg. In
another embodiment, the at least one additional dose is from about 5 mg to
about 25 mg.
In another embodiment, the at least one additional dose is administered from
about 6 hours
to about 24 hours after the initial dose. In another embodiment, at least two
additional
doses are administered, and further wherein the additional doses are
administered from
about 6 hours to about 24 hours after the previous dose.
[0067] In another aspect, provided herein is a method to prevent relapse of
opioid or
opioid-like drug abuse in a patient previously treated to ameliorate said
abuse, said method
comprising periodically administering to said patient a maintenance dosage of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate thereof,
wherein the patient is no longer abusing the opioid or opioid-like drug,
wherein the dosage
is less than about 70% of a therapeutic dose, and further wherein the
prolongation of the
QT interval is no greater than about 30 ms.
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[0068] In one embodiment, the aggregate dosage of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof is from
about 5 mg to
about 100 mg per day.
Nicotine
[0069] This invention is based, in part, on the discovery that at very low
doses, direct
blood stream delivery of noribogaine reduces the desire to smoke. Such dosing
is well
below that previously described. Direct blood stream delivery of noribogaine
enhances the
amount of noribogaine delivered to the brain, because noribogaine so
administered does
not initially pass through the liver before reaching the brain as it does when
ingested.
Direct blood stream delivery of noribogaine includes sublingual, pulmonary and
intranasal
delivery where the noribogaine is absorbed directly into the blood stream and
then into the
brain. The rapid delivery of noribogaine into the brain causes a significant
reduction in
the craving to smoke on a rapid basis, typically less than 5 minutes after
administration.
[0070] Noribogaine is believed to bind to several receptors in the brain,
including
nicotinic acetylcholine receptors (nAChRs) and opiod receptors (e.g., vi-opiod
receptors).
Without being bound by theory, it is believed that the nAChR has a greater
binding
affinity for noribogaine than other receptors in the brain. This allows
treatment of nicotine
addiction and/or nicotine cravings using much lower doses of noribogaine than
are
currently used for the treatment of other conditions, such as opiod
withdrawal.
Furthermore, a nicotine addict in remission may not exhibit physical symptoms
of
addiction, but rather may have psychological cravings for cigarettes or other
forms of
nicotine, or may anticipate such cravings in certain situations. As such, and
without being
bound by theory, it is expected that lower amounts of noribogaine are required
to treat or
prevent nicotine cravings in such situations than would be required in a
patient who is
currently addicted to nicotine.
[0071] In one aspect, this invention relates to methods of treating nicotine
addiction or
preventing relapse of nicotine use, comprising administration of a therapeutic
amount of
noribogaine. As used herein, unless specified otherwise, noribogaine includes
to
noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt
of each
thereof.
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[0072] In one aspect, this invention relates to treating nicotine addiction in
a patient in
need thereof comprising administering to the patient by direct blood stream
delivery a
therapeutically effective amount of noribogaine. In one aspect, a
therapeutically effective
amount of noribogaine or derivative is from about 50 ng to less than 10 lig
per kg of body
weight. In some embodiments, the therapeutically effective amount of
noribogaine or
noribogaine derivative is administered once a day, twice a day, or more than
twice a day.
[0073] In another aspect, this invention provides a method for treating
nicotine addiction
in a patient in need thereof comprising administering to the patient a
therapeutic amount of
noribogaine or a noribogaine derivative or pharmaceutically acceptable salt
thereof,
wherein the noribogaine or derivative or pharmaceutically acceptable salt
thereof is
administered by sublingual, intranasal, or intrapulmonary delivery.
[0074] In one aspect, this invention relates to methods of preventing relapse
of nicotine
use, comprising administration of a prophylactic amount of noribogaine to
inhibit a
behavioral craving for nicotine. As used herein, unless specified otherwise,
noribogaine
includes to noribogaine, a noribogaine derivative, or a pharmaceutically
acceptable salt of
each thereof.
[0075] In one aspect, this invention relates to preventing relapse of nicotine
use in a
patient in need thereof comprising administering to the patient by direct
blood stream
delivery a prophylactically effective amount of noribogaine. In one aspect, a
prophylactically effective amount of noribogaine is from about 50 ng to less
than 10 pg
per kg of body weight. In some embodiments, the prophylactically effective
amount of
noribogaine or noribogaine derivative is administered once a day, twice a day,
or more
than twice a day. In some embodiments, the prophylactically effective amount
is
administered when the patient feels a craving, or anticipates feeling a
craving, for nicotine.
[0076] In another aspect, this invention provides a method for preventing
relapse of
nicotine use in a patient in need thereof comprising administering to the
patient a
prophylactically effective amount of noribogaine, a noribogaine derivative, or
a
pharmaceutically acceptable salt thereof, wherein the noribogaine, derivative,
or salt
thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
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[0077] In one aspect, provided herein is a a method for treating nicotine
addiction in a
patient in need thereof, comprising administering to the patient a
therapeutically effective
amount of noribogaine, noribogaine derivative, or a pharmaceutically
acceptable salt
thereof, wherein said therapeutically effective amount is from about 50 ng to
less than 10
g per kg body weight per day.
[0078] In one embodiment, the therapeutically effective amount is from about
50 ng to
about 1 jig per kg body weight per day. In another embodiment, the
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt thereof is
administered by
sublingual, intranasal, or intrapulmonary delivery. In another embodiment, the

therapeutically effective amount is administered once a day. In another
embodiment, the
therapeutically effective amount is administered two or more times per day.
[0079] In one aspect, provided herein is a method for preventing a nicotine
craving in a
patient in need thereof, comprising administering to the patient a
prophylactically effective
amount of noribogaine, noribogaine derivative, or a pharmaceutically
acceptable salt
thereof, wherein said prophylactically effective amount is from about 50 ng to
less than 10
1.1g per kg body weight per day.
[0080] In one embodiment, the patient is no longer physically addicted to
nicotine. In
another embodiment, the prophylactically effective amount is from about 50 ng
to about 1
jig per kg body weight per day. In another embodiment, the noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt thereof is administered by
sublingual,
intranasal, or intrapulmonary delivery. In another embodiment, the
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt thereof is
administered on an
as-needed basis as determined by the subject. In another embodiment, the
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt thereof is
administered before
the nicotine craving occurs. In another embodiment, the noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt thereof is administered after
the nicotine
craving occurs.
Alcohol Dependence
[0081] While noribogaine has been disclosed for treatment of alcohol
dependence, its
use in humans is complicated by the fact that the ranges in the prior art are
exceptionally
broad (0.01 to 1000 mg/kg body weight). Furthermore, human clinical studies
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demonstrate that the lower dosing of noribogaine has minimal impact on
withdrawal
symptoms in addicted patients. Thus, the previously disclosed broad range has
now been
found to be insufficient for human therapy at the lower end of this range.
[0082] The current invention is predicated, in part, on the surprising
discovery that
treatment with a narrow dosage range of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt and/or solvate thereof, between greater than
about 1
mg/kg body weight and about 8 mg/kg body weight, provides a therapeutic
reduction in
withdrawal symptoms in alcohol dependent patients. Preferably, the dose range
that
provide both therapeutic results and an acceptable QT interval prolongation of
less than 50
milliseconds in addicted humans is between about 1.3 mg per kg body weight and
no more
than about 4 mg per kg body weight and, more preferably between about 1.3 mg
per kg
body weight and no more than about 3 mg per kg body weight, or any subrange or

subvalue within the aforementioned ranges.
[0083] In a preferred embodiment, the narrow therapeutic doses of noribogaine,

noribogaine derivative, or pharmaceutically acceptable salt and/or solvate
described
above do not prolong the QT interval to unacceptable levels in human patients.
It is
expected that alcohol dependent patients will be administered therapeutic
doses of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof in a clinical setting with cardiac monitoring. In some embodiments,
the patient will
be pre-screened to evaluate tolerance for prolongation of QT interval, e.g.,
to determine
whether the patient has any pre-existing cardiac conditions or other
indicators which
would disqualify them from treatment with noribogaine. In one embodiment, a
patient
who exhibits a QT interval prolongation of less than about 20 ms after
treatment with one
or more therapeutic doses of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof will not require further clinical
monitoring.
[0084] Some aspects of the current invention are further predicated on the
discovery that
even lower doses of noribogaine, noribogaine derivative, or pharmaceutically
acceptable
salt and/or solvate thereof, for example approximately 80% or less of the
therapeutic dose,
may be effective for prevention of relapse of alcohol use in an addicted
patient treated to
ameliorate their alcohol dependence. That is, a lower dose of noribogaine can
prevent a
patient who is no longer physically dependent on alcohol from relapsing to use
thereof.
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Without being bound by theory, it is believed that a patient who is no longer
physically
dependent on alcohol requires less noribogaine to prevent relapse at least in
part because
the changes made to the brain by alcohol dependence at least partially reverse
when the
patient detoxifies from alcohol. This lower, maintenance dose of noribogaine
results in a
QT interval prolongation that does not require clinical cardiac monitoring.
[0085] In some embodiments, the therapeutic dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof
administered to the
patient is sufficient to provide an average serum concentration of about 50
ng/mL to about
850 ng/mL, or any subrange or subvalue there between. In a preferred
embodiment, the
dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable
salt and/or
solvate thereof administered to the patient provides an average serum
concentration of
about 50 ng/mL to about 400 ng/mL.
[0086] In some embodiments, the patient is administered a high (therapeutic)
dose of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof for a period of time to ameliorate the most significant withdraw
symptoms, and
then is administered a lower (maintenance) dose to prevent relapse to alcohol
use. In some
embodiments, the patient is administered a therapeutic dose of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof for a
period of time
to ameliorate the most significant withdraw symptoms, and then is administered
a
decreasing (tapered) amount of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof over time until the maintenance dose is
reached. In
some embodiments, a high initial therapeutic dose is administered, followed by

administration of a lower therapeutic dose. In some embodiments, the dose of
noribogaine
is tapered over time from the high therapeutic dose to a lower therapeutic
dose.
[0087] In some embodiments, the dose of noribogaine, noribogaine derivative,
or
phatmaceutically acceptable salt and/or solvate thereof that provides an
average serum
concentration of about 50 ng/mL to about 850 ng/mL is administered as a single
dose. In
some embodiments, the dose of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof that provides an average serum
concentration of
about 50 ng/mL to about 850 ng/mL is administered as multiple doses. In some
embodiments, the aggregate dose of noribogaine, noribogaine derivative, or
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pharmaceutically acceptable salt and/or solvate thereof is from greater than
about 1 mg/kg
to about 8 mg/kg. In a preferred embodiment, the aggregate dose of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt and/or solvate
thereof is from
greater than about 1 mg/kg to about 4 mg/kg. In another preferred embodiment,
the
aggregate dose of noribogaine, noribogaine derivative, or pharmaceutically
acceptable
salt and/or solvate thereof is from greater than about 1 mg/kg to 3 mg/kg.
[0088] In some embodiments, the serum concentration of noribogaine is
sufficient to
inhibit or ameliorate said dependence while maintaining a QT interval of less
than 500
milliseconds (ms) during said treatment. In some embodiments, the therapeutic
dose of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof provides prolongation of the QT interval of less than 80 ms. In one
embodiment,
the maintenance dose of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt ancUor solvate thereof provides prolongation of the QT
interval of less than
50 ms. In some embodiments, the maintenance dose or therapeutic dose of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt and/or solvate
thereof
provides prolongation of the QT interval of less than 30 ms. In a preferred
embodiment,
the maintenance dose of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof provides prolongation of the QT
interval of less than
20 ms. In a preferred embodiment, the patient is tested to determine QT
interval before
treatment with noribogaine, and if clinician determines that the QT
prolongation would be
unacceptable risk, noribogaine therapy will be contraindicated.
[0089] In one aspect, provided herein is a method for treating alcohol
dependence in a
human patient suffering therefrom, comprising administering to the patient a
dosage of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof that provides an average serum concentration of about 50 ng/mL to
about 500
ng/mL, said concentration being sufficient to ameliorate said dependence while

maintaining a QT interval of less than about 500 ms during said treatment.
[0090] In one embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically acceptable salt and/or solvate thereof is administered as a
single dose or
multiple doses. In another embodiment, the aggregate dosage of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof is from
about 1.3
mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of
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noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof is from about 1.5 mg/kg to about 3 mg/kg per day. In another
embodiment, the
aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically
acceptable
salt and/or solvate thereof is from about 2 mg/kg to about 4 mg/kg per day. In
another
embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or
pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg
to about 3
mg/kg per day. In another embodiment, the aggregate dosage of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof is
about 2 mg/kg per
day. In another embodiment, the dosage of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt and/or solvate thereof provides an average
serum
concentration of about 50 ng/mL to about 200 ng/mL. In another embodiment, the
QT
interval is less than about 470 ms. In another embodiment, the QT interval is
less than
about 450 ms. In another embodiment, the method further comprises selecting an
addicted
patient who is prescreened to evaluate tolerance for prolongation of QT
interval. In
another embodiment, the prescreening step comprises ascertaining that
noribogaine
treatment will not result in a QT interval greater than about 500 ms. In
another
embodiment, the prescreening step comprises ascertaining that noribogaine
treatment will
not result in a QT interval greater than about 470 ms. In another embodiment,
the
prescreening step comprises ascertaining that noribogaine treatment will not
result in a QT
interval greater than about 450 ms.
[0091] In another aspect, provided herein is a method for attenuating
withdrawal
symptoms in a human patient susceptible to such symptoms due to alcohol
dependence,
comprising administering to the patient a dosage of noribogaine, noribogaine
derivative,
or pharmaceutically acceptable salt and/or solvate thereof that provides an
average serum
concentration of about 50 ng/mL to about 400 ng/mL, said concentration being
sufficient
to attenuate said symptoms while maintaining a QT interval of less than about
500 ms
during said treatment.
[0092] In one embodiment, the withdrawal symptoms are due to acute withdrawal.
In
another embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof is administered as a single dose or
multiple doses. In
another embodiment, the aggregate dosage of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt and/or solvate thereof is from about 1.3
mg/kg to about 4
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mg/kg per day. In another embodiment, the aggregate dosage of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof is from
about 1.5
mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of

noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment,
the
aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically
acceptable
salt and/or solvate thereof is from about 2 mg/kg to about 3 mg/kg per day. In
another
embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or
pharmaceutically acceptable salt and/or solvate thereof is about 2 mg/kg per
day. In
another embodiment, the QT interval is less than about 470 ms. In another
embodiment,
the QT interval is less than about 450 ms.
[0093] In one aspect, provided herein is a method to prevent relapse of
alcohol abuse in
a patient treated to ameliorate said abuse, said method comprising
periodically
administering to said patient a maintenance dosage of noribogaine, noribogaine
derivative,
or pharmaceutically acceptable salt and/or solvate thereof, wherein the
patient is no longer
physically dependent on alcohol.
[0094] In one embodiment, the maintenance dosage is less than about 70% of a
therapeutic dose, and further wherein the prolongation of the QT interval is
no greater than
about 30 ms. In another embodiment, the dosage is less than about 70% of the
therapeutic
dose, and further wherein the prolongation of the QT interval is no greater
than about 20
ms. In another embodiment, noribogaine or a pharmaceutically acceptable salt
and/or
solvate thereof is administered.
Drug Addiction
[0095] While noribogaine has been disclosed for treatment of substance
addiction, its
use in humans is complicated by the fact that the ranges in the prior art are
exceptionally
broad (0.01 to 1000 mg/kg body weight). Furthermore, human clinical studies
demonstrate that the lower dosing of noribogaine has minimal impact on
withdrawal
symptoms in addicted patients. Thus, the previously disclosed broad range has
now been
found to be insufficient for human therapy at the lower end of this range.
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[0096] The current invention is predicated, in part, on the surprising
discovery that
treatment with a narrow dosage range of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt and/or solvate thereof; between 1 mg/kg body
weight and
4 mg/kg body weight, provides a therapeutic reduction in withdrawal symptoms
and/or an
increase in time to resumption of drug use in addicted patients. Preferably,
the dose range
that provide both therapeutic results and an acceptable QT interval
prolongation of less
than 50 milliseconds in addicted humans is between 1.3 mg per kg body weight
and no
more than 4 mg per kg body weight and, more preferably between 1.3 mg per kg
body
weight and no more than 3 mg per kg body weight, or any subrange or subvalue
within the
aforementioned ranges.
[0097] In some embodiments, the dose that provides both therapeutic results
and an
acceptable QT interval prolongation of less than 50 milliseconds in drug
addicted humans
is about 120 mg. In some embodiments, the dose that provides both therapeutic
results and
an acceptable QT interval prolongation of less than 50 milliseconds in drug
addicted
humans is about 2 mg/kg body weight.
[0098] In some embodiments, the patient is administered an initial dose of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt or solvate
thereof, followed by
one or more additional doses. In one embodiment, the initial dose is from 75
mg to 120
mg. In one embodiment, the one or more additional doses are lower than the
initial dose.
In one embodiment, the one or more additional doses are from 5 mg to 50 mg. In
one
embodiment, such a dosing regimen provides an average serum concentration of
noribogaine of 50 ng/mL to 180 ng/mL. In one embodiment, the one or more
additional
doses maintain an average serum concentration of 50 ng/mL to 180 ng/mL over a
period
of time. In one embodiment, the one or more additional doses are administered
periodically.
[0099] In some embodiments, the narrow therapeutic doses of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate described above

unexpectedly do not prolong the QT interval to unacceptable levels in human
addicted
patients. It is expected that drug-addicted patients will be administered
therapeutic doses
of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof in a clinical setting with cardiac monitoring. In some embodiments,
the patient will
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be pre-screened to evaluate tolerance for prolongation of QT interval, e.g.,
to determine
whether the patient has any pre-existing cardiac conditions which would
disqualify them
from treatment with noribogaine.
[0100] Some aspects of the current invention are further predicated on the
discovery that
even lower doses of noribogaine, noribogaine derivative, or pharmaceutically
acceptable
salt and/or solvate thereof, for example approximately 80% or less of the
therapeutic dose,
may be effective for prevention of relapse of drug use in an addicted patient
treated to
ameliorate their substance abuse. That is, a lower dose of noribogaine can
prevent a
patient who is no longer physically addicted to an addictive substance from
relapsing to
use thereof. Without being bound by theory, it is believed that a patient who
is no longer
physically addicted to the drug requires less noribogaine to prevent relapse
because the
drug does not compete with noribogaine for receptor binding, and/or because
desensitization of one or more receptors in the brain by the drug is reversed
when the
patient ceases to take the drug. This lower, maintenance dose of noribogaine
results in a
QT interval prolongation that does not require clinical cardiac monitoring.
[0101] In some embodiments, the maintenance dose of noribogaine is 5 mg to 100
mg.
In some embodiments, the maintenance dose of noribogaine is about 1.5 mg/kg
body
weight. In some embodiments, the maintenance dose of noribogaine is about 1
mg/kg
body weight. In some embodiments, the maintenance dose of noribogaine is about
0.9
mg,/kg body weight. In some embodiments, the maintenance dose of noribogaine
is about
0.8 mg/kg body weight. In some embodiments, the maintenance dose of
noribogaine is
about 0.7 mg/kg body weight. In some embodiments, the maintenance dose of
noribogaine
is about 0.6 mg/kg body weight. In some embodiments, the maintenance dose of
noribogaine is about 0.5 mg/kg body weight. In some embodiments, the
maintenance dose
of noribogaine is about 0.4 mg/kg body weight. In some embodiments, the
maintenance
dose of noribogaine is about 0.3 mg/kg body weight. In some embodiments, the
maintenance dose of noribogaine is about 0.2 mg/kg body weight. In some
embodiments,
the maintenance dose of noribogaine is about 0.1 mg/kg body weight.
[0102] In some embodiments, the therapeutic dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof
administered to the
patient is sufficient to provide an average serum concentration of 50 ng/mL to
400 ng/mL ,
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or any subrange or subvalue there between. In a preferred embodiment, the dose
of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof administered to the patient provides an average serum concentration of
50 ng/mL
to 180 ng/mL.
[0103] In some embodiments, the patient is administered a high (therapeutic)
dose of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof for a period of time to ameliorate the most significant withdrawal
symptoms, and
then is administered a lower (maintenance) dose to prevent relapse to drug
use. In some
embodiments, the patient is administered a therapeutic dose of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof for a
period of time
to ameliorate the most significant withdrawal symptoms, and then is
administered a
decreasing (tapered) amount of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof over time until the maintenance dose is
reached. In
some embodiments, a high initial therapeutic dose is administered, followed by

administration of a lower therapeutic dose. In some embodiments, the dose of
noribogaine
is tapered over time from the high therapeutic dose to a lower therapeutic
dose.
[0104] In some embodiments, the dose of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt and/or solvate thereof that provides an
average serum
concentration of 50 ng/mL to 180 ng/mL is administered as a single dose. In
some
embodiments, the dose of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof that provides an average serum
concentration of 50
ng/mL to 180 ng/mL is administered as multiple doses. In an embodiment, the
aggregate
dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable
salt and/or
solvate thereof is from 1 mg/kg to 3 mg/kg. In another embodiment, the
aggregate dose of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof is from 1 mg/kg to 2.5 mg/kg.
[0105] In some embodiments, the serum concentration is sufficient to inhibit
or
ameliorate said abuse while maintaining a QT interval of less than 500
milliseconds (ms)
during said treatment. In some embodiments, the therapeutic dose of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt and/or solvate
thereof provides
prolongation of the QT interval of less than 80 ms. In one embodiment, the
maintenance
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dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable
salt and/or
solvate thereof provides prolongation of the QT interval of less than 50 ms.
In some
embodiments, the maintenance dose or therapeutic dose of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof
provides
prolongation of the QT interval of less than 30 ms. In an embodiment, the
maintenance
dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable
salt and/or
solvate thereof provides prolongation of the QT interval of less than 20 ms.
In one
embodiment, the QT prolongation is equivalent to or less than that observed in
patients
receiving methadone treatment. In a preferred embodiment, the patient is
tested to
determine QT interval before treatment with noribogaine, and if clinician
determines that
the QT prolongation would be unacceptable risk, noribogaine therapy will be
contraindicated.
[0106] In another aspect, provided herein is a method for treating substance
abuse in a
human patient addicted thereto, comprising administering to the patient a
dosage of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL
, said
concentration being sufficient to inhibit or ameliorate said abuse while
maintaining a QT
interval of less than about 500 ms during said treatment.
[0107] In one embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof is administered as a single dose or
multiple doses. In
another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of 50 ng/mL to 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of 50 ng/mL to 180
ng/mL for
a period of time.
[0108] In another embodiment, the initial dose is from 75 mg to 120 mg. In
another
embodiments, the at least one additional dose is from 5 mg to 25 mg. In
another
embodiment, the at least one additional dose is administered from 6 hours to
24 hours after
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the initial dose. In another embodiment, at least two additional doses are
administered,
and further wherein the additional doses are administered from 6 hours to 24
hours after
the previous dose. In another embodiment, the method further comprising
selecting an
addicted patient who is prescreened to evaluate tolerance for prolongation of
QT interval.
[0109] In another aspect, provided herein is a a method for treating substance
abuse in a
human patient addicted thereto, comprising administering to the patient a
dosage of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL
, said
concentration being sufficient to inhibit or ameliorate said abuse while
maintaining a QT
interval prolongation of less than about 20 ms during said treatment.
[0110] In one embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof is administered as a single dose or
multiple doses. In
another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of 50 ng/mL to 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of 50 ng/mL to 180
ng/mL for
a period of time.
[0111] In another embodiment, the initial dose is from 75 mg to 120 mg. In
another
embodiment, the at least one additional dose is from 5 mg to 25 mg. In another

embodiment, the at least one additional dose is administered from 6 hours to
24 hours after
the initial dose. In another embodiment, at least two additional doses are
administered,
and further wherein the additional doses are administered from 6 hours to 24
hours after
the previous dose.
[0112] In another aspect, provided herein is a method for attenuating
withdrawal
symptoms in a human patient susceptible to such symptoms due to drug
addiction,
comprising administering to the patient a dosage of noribogaine, noribogaine
derivative,
or pharmaceutically acceptable salt and/or solvate thereof that provides an
average serum
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concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to
attenuate
said symptoms while maintaining a QT interval of less than about 500 ms during
said
treatment.
[0113] In another embodiment, the withdrawal symptoms are due to acute
withdrawal.
In another embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof is administered as a single dose or
multiple doses. In
another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of 50 ng/mL to 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of 50 ng/mL to 180
ng/mL for
a period of time.
[0114] In another embodiment, the initial dose is from 75 mg to 120 mg. In
another
embodiment, the at least one additional dose is from 5 mg to 25 mg. In another

embodiment, the at least one additional dose is administered from 6 hours to
24 hours after
the initial dose. In another embodiment, at least two additional doses are
administered,
and further wherein the additional doses are administered from 6 hours to 24
hours after
the previous dose.
[0115] In another aspect, provided herein is a method to prevent relapse of
drug abuse in
a patient treated to ameliorate said abuse, said method comprising
periodically
administering to said patient a maintenance dosage of noribogaine, noribogaine
derivative,
or pharmaceutically acceptable salt and/or solvate thereof, wherein the
patient is no longer
abusing the drug, wherein the dosage is less than about 70% of the therapeutic
dose, and
further wherein the prolongation of the QT interval is no greater than about
30 ms.
[0116] In another embodiment, the aggregate dosage of noribogaine, noribogaine

derivative, or pharmaceutically acceptable salt or solvate thereof is from 50
mg to 100 mg
per day.
Pain
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[0117] In some embodiments, the current invention is predicated on the
surprising
discovery that treatment with a narrow dosage range of ibogaine between
greater than
about 0.1 mg/kg body weight and about 8 mg/kg body weight, provides a
therapeutic
alleviation of pain. Preferably, the dose range that provides both therapeutic
results and an
acceptable QT interval prolongation of less than 50 milliseconds in humans is
between
about 0.1 mg per kg body weight and no more than about 3 mg per kg body weight
and,
more preferably between about 0.7 mg per kg body weight and no more than about
2 mg
per kg body weight, or any subrange or subvalue within the aforementioned
ranges.
[0118] In some embodiments, the narrow therapeutic doses of ibogaine described
above
do not prolong the QT interval to unacceptable levels in human patients. In
some
embodiments, patients are administered therapeutic doses of ibogaine in a
clinical setting
with cardiac monitoring. In some embodiments, the patient will be pre-screened
to
evaluate tolerance for prolongation of QT interval, e.g., to determine whether
the patient
has any pre-existing cardiac conditions which would disqualify them from
treatment with
ibogaine. In one embodiment, a patient who exhibits a QT interval prolongation
of less
than about 20 ms after treatment with one or more therapeutic doses of
ibogaine will not
require further clinical monitoring. In one embodiment, the patient is not
monitored after
administration of ibogaine.
[0119] In some embodiments, the therapeutic dose of ibogaine administered to
the
patient is sufficient to provide an average serum concentration of about 50
ng/mL to about
850 ng/mL, or any subrange or subvalue there between. In a preferred
embodiment, the
dose of ibogaine administered to the patient provides an average serum
concentration of
about 50 ng/mL to about 400 ng/mL.
[0120] In some embodiments, the dose of ibogaine that provides an average
serum
concentration of about 50 ng/mL to about 850 ng/mL is administered as a single
dose. In
some embodiments, the dose of ibogaine that provides an average serum
concentration of
about 50 ng/mL to about 850 ng/mL is administered as multiple doses. In some
embodiments, the aggregate dose of ibogaine is from about 0.1 mg/kg to about 8
mg/kg. In
one embodiment, the aggregate dose of ibogaine is from about 0.1 mg/kg to
about 3
mg/kg. In another embodiment, the aggregate dose of ibogaine is from about 0.7
mg/kg to
1.5 mg/kg.
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[0121] In one aspect, provided herein is a method for treating pain in a
patient,
comprising administering to the patient a dosage of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt and/or solvate thereof that provides an
average serum
concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to
alleviate
and/or inhibit said pain while maintaining a QT interval of less than about
500 ms during
said treatment.
[0122] In one embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof is administered as a single dose or
multiple doses. In
one embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of 50 ng/mL to 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of 50 ng/mL to 180
ng/mL for
a period of time.
[0123] In another embodiment, the initial dose is from 75 mg to 120 mg. In
another
embodiment, the at least one additional dose is from 5 mg to 25 mg. In another

embodiment, the at least one additional dose is administered from 6 hours to
24 hours after
the initial dose. In another embodiment, at least two additional doses are
administered,
and further wherein the additional doses are administered from 6 hours to 24
hours after
the previous dose. In another embodiment, the method further comprises
selecting an
addicted patient who is prescreened to evaluate tolerance for prolongation of
QT interval.
In another embodiment, the aggregate dosage of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt or solvate thereof is from 70 mg to 150 mg
per day.
[0124] In another aspect, provided herein is a method for treating pain in a
patient,
comprising administering to the patient a dosage of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt ancUor solvate thereof that provides an
average serum
concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to
alleviate
and/or inhibit said pain while maintaining a QT interval prolongation of less
than about 20
ms during said treatment.
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[0125] In one embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof is administered as a single dose or
multiple doses. In
another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of 50 ng/mL to 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of 50 ng/mL to 180
ng/mL for
a period of time.
[0126] In another embodiment, the initial dose is from 75 mg to 120 mg. In
another
embodiment, the at least one additional dose is from 5 mg to 25 mg. In another

embodiment, the at least one additional dose is administered from 6 hours to
24 hours after
the initial dose. In another embodiment, at least two additional doses are
administered,
and further wherein the additional doses are administered from 6 hours to 24
hours after
the previous dose.
[0127] In another aspect, provided herein is a method for alleviating pain
symptoms in a
human patient susceptible to such symptoms, comprising administering to the
patient a
dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable
salt and/or
solvate thereof that provides an average serum concentration of 50 ng/mL to
180 ng/mL,
said concentration being sufficient to attenuate said symptoms while
maintaining a QT
interval of less than about 500 ms during said treatment.
[0128] In another embodiment, the pain symptoms are due to chronic pain. In
another
embodiment, the noribogaine, noribogaine derivative, or pharmaceutically
acceptable salt
and/or solvate thereof is administered as a single dose or multiple doses. In
another
embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of 50 ng/mL to 180 ng/mL; and
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b) administering at least one additional dose of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of 50 ng/mL to 180
ng/mL for
a period of time.
[0129] In another embodiment, the initial dose is from 75 mg to 120 mg. In
another
embodiment, the at least one additional dose is from 5 mg to 25 mg. In another

embodiment, the at least one additional dose is administered from 6 hours to
24 hours after
the initial dose. In another embodiment, at least two additional doses are
administered,
and further wherein the additional doses are administered from 6 hours to 24
hours after
the previous dose.
Migraine
[0130] The current invention is predicated, in part, on the surprising
discovery that
treatment with a narrow dosage range of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt and/or solvate thereof, of between about 1
mg/kg body
weight and about 4 mg/kg body weight, provides a therapeutic alleviation of
migraine
headaches. Preferably, the dose provides both therapeutic results and an
acceptable QT
interval prolongation of less than about 50 milliseconds (ms) in humans.
[0131] This invention is based, in part, on the discovery that noribogaine
reduces
frequency, severity, and/or length of headaches, and particularly migraine
headaches. This
invention is further based on the discovery that at very low doses, direct
blood stream
delivery of noribogaine can treat and/or prevent migraine headaches. Direct
blood stream
delivery of noribogaine enhances the amount of noribogaine delivered to the
brain,
because noribogaine so administered does not initially pass through the liver
before
reaching the brain as it does when ingested. Direct blood stream delivery of
noribogaine
includes sublingual, buccal, pulmonary and intranasal delivery, where the
noribogaine is
absorbed directly into the blood stream for delivery into the brain. The rapid
delivery of
noribogaine into the brain may cause a significant reduction in the symptoms
of migraine,
typically less than 15 minutes after administration.
[0132] Migraine headaches may contain four phases, although not all phases are

experienced in all cases. The first phase is the prodrome phase, wherein the
patient
experiences irritability, altered mood, depression or euphoria, fatigue, food
cravings,
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muscle stiffness, constipation or diarrhea, and sensitivity to smells and/or
noise. The
second phase is the aura phase, characterized by visual, sensory, or motor
effects. Only a
subset of migraines include auras. The third phase is the pain phase; pain is
often
accompanied by nausea, vomiting, sensitivity to sensory input, fatigue,
irritability, vertigo,
light-headedness, confusion, blurred vision, nasal stuffiness, diarrhea,
frequent urination,
pallor, or sweating. The final phase is the postdrome phase, and may include a
sore feeling
at the site of the migraine, impaired thinking, fatigue, head pain, mood
changes,
gastrointestinal symptoms, and weakness.
[0133] The cause of migraines is unclear, but migraines can be brought on by
triggers,
including hormone changes, stress, hunger, fatigue, certain smells, foods,
poor air quality,
etc. Migraine may also be affected by genetic factors.
[0134] In one aspect, this invention relates to methods of treating or
preventing
migraines and/or symptoms thereof, comprising administration of a therapeutic
amount of
noribogaine. As used herein, unless specified otherwise, noribogaine includes
noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt
of each
thereof. In one embodiment, the patient is co-administered a therapeutic
amount of an
agent known to treat migraines in addition to noribogaine. In a preferred
embodiment, the
co-treatment does not result in a QT interval prolongation of greater than 50
ms. In one
embodiment, both compounds are administered at the same time. In one
embodiment, the
compounds are administered at different times (e.g., sequentially).
[0135] In one aspect, this invention relates to treating migraines and/or
symptoms
thereof in a patient in need thereof, comprising administering to the patient
by direct blood
stream delivery a therapeutically effective amount of noribogaine or
derivative. In one
aspect, a therapeutically effective amount of noribogaine or derivative is
from about 50 ng
to about 10 lag per kg of body weight. In some embodiments, the
therapeutically effective
amount of noribogaine or noribogaine derivative is administered once a day,
twice a day,
or more than twice a day. In one embodiment, an agent known to treat and/or
prevent
migraines is also administered.
[0136] In another aspect, this invention provides a method for treating
migraines and/or
symptoms thereof in a patient in need thereof, comprising administering to the
patient a
therapeutic amount of noribogaine or a noribogaine derivative or
pharmaceutically
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acceptable salt thereof, wherein the noribogaine or derivative or
pharmaceutically
acceptable salt thereof is administered by sublingual, intranasal, buccal, or
intrapulmonary
delivery.
[0137] This invention relates to methods of preventing migraines and/or
symptoms
thereof, comprising administration of a prophylactic amount of noribogaine to
prevent or
ameliorate migraine and/or symptoms thereof. As used herein, unless specified
otherwise,
noribogaine includes noribogaine, a noribogaine derivative, or a
pharmaceutically
acceptable salt of each thereof. In one embodiment, an agent known to treat
and/or prevent
migraines is also administered.
[0138] In one aspect, this invention relates to preventing migraines and/or
symptoms
thereof in a patient in need thereof, comprising administering to the patient
by direct blood
stream delivery a prophylactically effective amount of noribogaine. In one
aspect, a
prophylactically effective amount of noribogaine is from about 1 mg to about 2
mg per kg
of body weight. In one aspect, a prophylactically effective amount of
noribogaine is from
about 50 ng to about 10 lig per kg of body weight. In some embodiments, the
prophylactically effective amount of noribogaine or noribogaine derivative is
administered
once a day, twice a day, or more than twice a day. In some embodiments, the
prophylactically effective amount is administered regularly (e.g., every day).
In some
embodiments, the prophylactically effective amount is administered prior to,
concurrent
with, or immediately after potential triggers for migraine. In some
embodiments, the
prophylactically effective amount is administered when the patient feels the
onset of at
least one symptom of migraine. In one embodiment, an agent known to treat
and/or
prevent migraines is also administered.
[0139] In another aspect, this invention provides a method for preventing
migraines
and/or symptoms thereof in a patient in need thereof, comprising administering
to the
patient a prophylactically effective amount of noribogaine, a noribogaine
derivative, or a
pharmaceutically acceptable salt or solvate thereof, wherein the noribogaine,
derivative, or
salt thereof is administered by sublingual, intranasal, buccal, or
intrapulmonary delivery.
[0140] As will be apparent to the skilled artisan upon reading this
disclosure, this
invention, in one aspect, provides a method for treating or preventing
migraines and/or
symptoms thereof in a subject, comprising administering to the patient in need
thereof a
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therapeutically effective amount of noribogaine, a noribogaine derivative, a
noribogaine
prodrug, or a pharmaceutically acceptable salt of each thereof. In one
embodiment, the
method further comprises administering at least one agent known to treat or
prevent
migraines and/or symptoms thereof.
[0141] In another aspect, this invention provides a composition for treating
and/or
preventing migraines, comprising a therapeutic or prophylactic amount of
noribogaine, a
noribogaine derivative, or a pharmaceutically acceptable salt or solvate
thereof, at least
one agent that is known to treat ancUor prevent migraines, and optionally a
pharmaceutically acceptable excipient.
[0142] In another aspect, provided herein is a method for treating migraine
headache
and/or symptoms thereof in a patient in need thereof, comprising administering
to the
patient a therapeutically effective amount of noribogaine, noribogaine
derivative, or a
phatmaceutically acceptable salt thereof.
[0143] In one embodiment, the therapeutically effective amount is from about
50 ng to
about 10 i.tg per kg body weight per day. In another embodiment, the
therapeutically
effective amount is from about 1 mg to about 4 mg per kg body weight per day.
In
another embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt thereof is administered by sublingual, buccal, intranasal, or
intrapulmonary
delivery. In another embodiment, the therapeutically effective amount is
administered
once a day. In another embodiment, the therapeutically effective amount is
administered
two or more times per day.
[0144] In another aspect, provided herein is a method for preventing migraine
headache
and/or symptoms thereof in a patient in need thereof, comprising administering
to the
patient a prophylactically effective amount of noribogaine, noribogaine
derivative, or a
pharmaceutically acceptable salt thereof.
[0145] In one embodiment, the prophylactically effective amount is from about
50 ng to
about 10 lag per kg body weight per day. In another embodiment, the
prophylactically
effective amount is less than about 90% of the therapeutically effective
amount. In
another embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt thereof is administered by sublingual, intranasal, buccal, or
intrapulmonary
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delivery. In another embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically acceptable salt thereof is administered on an as-needed basis
as
determined by the subject. In another embodiment, the patient's QT interval is
not
prolonged by more than about 30 ms. In another embodiment, the method further
comprises administering at least one agent known to treat and/or prevent
migraine and/or
symptoms thereof. In another embodiment, the at least one agent is selected
from the
group consisting of: an analgesic, a triptan, an ergotamine, and
dexamethasone.
Reducing Tolerance To Opioid Analgesics
[0146] This invention is directed, in part, to the use of noribogaine to
modulate tolerance
to addictive opioid analgesic agents in a patient who has developed or is at
risk of
developing a tolerance for the analgesic. In such methods, effective analgesia
can be
achieved in a patient while resensitizing the patient to the addictive opioid
analgesic. The
term "resensitizing the patient" is used herein to refer to reducing,
relieving, attenuating,
and/or reversing tolerance to the analgesic. In one aspect, the resensitized
patient obtains
therapeutic effect from a lower dose of the opioid analgesic than before
resensitization. In
one aspect, the resensitized patient obtains improved therapeutic effect from
the same dose
of the opioid analgesic compared to before resensitization.
[0147] In one embodiment, noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof is administered concurrently with the
opioid
analgesic. In one embodiment, noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof is administered after administration of
the analgesic,
for example one, two, three, four, eight, ten, twelve, 24 hours or more after
administration
of the analgesic. In one embodiment, one dose of noribogaine is administered.
In one
embodiment, two or more doses of noribogaine are administered. In one
embodiment, the
opioid analgesic is interrupted for a period of time while noribogaine is
administered. In
one embodiment, a non-opioid analgesic is administered while the opioid
analgesic is
interrupted. In one embodiment, noribogaine acts as an analgesic. In one
embodiment, the
opioid analgesic is not interrupted during noribogaine treatment.
[0148] In some embodiments, the unit dose that provides both therapeutic
results and an
acceptable QT interval prolongation of less than 50 milliseconds in opioid-
tolerant humans
is about 120 mg. In some embodiments, the unit dose that provides both
therapeutic results
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and an acceptable QT interval prolongation of less than 50 milliseconds in
opioid-tolerant
humans is 2 mg/kg body weight.
[0149] In one aspect, provided herein is a method for modulating tolerance to
an opioid
analgesic in a patient undergoing opioid analgesic therapy, the method
comprising
interrupting or administering concurrently with said opioid analgesic therapy
an amount of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL
said
concentration being sufficient to re-sensitize the patient to the opioid as an
analgesic while
maintaining a QT interval of less than about 500 ms during said treatment.
[0150] In one embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof is administered as a single dose or
multiple doses.
In another embodiment, the method further comprises interrupting the dosage of
the
analgesic. In another embodiment, the method further comprises administering
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof concurrently with the analgesic. In another embodiment, during
concurrent
administration, the dose of opioid analgesic is reduced. In another
embodiment, the
method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of 50 ng/mL to 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of 50 ng/mL to 180
ng/mL for
a period of time.
[0151] In another embodiment, the initial dose is from 75 mg to 120 mg. In
another
embodiment, the at least one additional dose is from 5 mg to 25 mg. In another

embodiment, the at least one additional dose is administered from 6 hours to
24 hours after
the initial dose. In another embodiment, at least two additional doses are
administered,
and further wherein the additional doses are administered from 6 hours to 24
hours after
the previous dose. In another embodiment, the method further comprises
selecting an
addicted patient who is prescreened to evaluate tolerance for prolongation of
QT interval.
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[0152] In one aspect, provided herein is a method for modulating tolerance to
an opioid
analgesic in a patient undergoing opioid analgesic therapy, the method
comprising
interrupting or administering concurrently with said opioid analgesic therapy
an amount of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL,
said
concentration being sufficient to re-sensitize the patient to the opioid as an
analgesic while
maintaining a QT interval prolongation of less than about 20 ms during said
treatment.
[0153] In one embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof is administered as a single dose or
multiple doses.
In another embodiment, the method further comprising interrupting the dosage
of the
analgesic. In another embodiment, the method further comprises administering
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof concurrently with the analgesic. In another embodiment, during
concurrent
administration, the dose of opioid analgesic is reduced. In another
embodiment, the
method further comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of 50 ng/mL to 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of 50 ng/mL to 180
ng/mL for
a period of time.
[0154] In another embodiment, the initial dose is from 75 mg to 120 mg. In
another
embodiment, the at least one additional dose is from 5 mg to 25 mg. In another

embodiment, the at least one additional dose is administered from 6 hours to
24 hours after
the initial dose. In another embodiment, at least two additional doses are
administered,
and further wherein the additional doses are administered from 6 hours to 24
hours after
the previous dose. In another embodiment, the method further comprises
selecting an
addicted patient who is prescreened to evaluate tolerance for prolongation of
QT interval.
[0155] In another embodiment, the opioid analgesic is selected from the group
consisting of fentanyl, hydrocodone, hydromorphone, morphine, oxycodone,
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buprenorphine, codeine, thebaine, buprenorphine, methadone, meperidine,
tramadol,
tapentadol, levorphanol, sufentanil, pentazocine, and oxymorphone. In another
embodiment, the opioid analgesic is morphine.
Depression
[0156] There are certain properties of noribogaine that present this compound
as a very
attractive candidate for the treatment of depression and/or postraumatic
stress disorder
(PTSD). These include the interaction of noribogaine with a variety of
receptors in the
brain, including nicotinic acetylcholine receptors (nAChRs) and opioid
receptors (e.g., -
opiod receptors). Further, noribogaine elevates brain serotonin levels by
blocking synaptic
reuptake via the SERT transporter. As such, this invention relates to methods
of treating
depression and/or PTSD, or symptoms thereof, comprising administering to a
patient
noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt
and/or solvate
thereof.
[0157] At very low doses, direct blood stream delivery of noribogaine may
reduce
symptoms of depression and/or PTSD. Such dosing is well below that previously
described. Direct blood stream delivery of noribogaine enhances the amount of
noribogaine delivered to the brain, because noribogaine does not pass through
the liver as
it does when ingested. Direct blood stream delivery of noribogaine includes
sublingual,
pulmonary and intranasal delivery where the noribogaine is absorbed directly
into the
blood stream and then into the brain. The rapid delivery of noribogaine into
the brain, e.g.
less than 15 minutes, may cause a significant reduction in symptoms of
depression and/or
PTSD.
[0158] In one aspect, this invention relates to treating depression and/or
PTSD in a
patient in need thereof comprising administering to the patient a
therapeutically effective
amount of noribogaine, noribogaine derivative, solvate, or pharmaceutically
acceptable
salt and/or solvate thereof. In one embodiment, this invention treats
depression. In
another embodiment, this invention treats PTSD. In a preferred embodiment, the
patient is
not addicted to cocaine or an opiate. Unlike PTSD, conventional anxiety
disorders are not
within the scope of this invention.
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[0159] In some embodiments, the therapeutic dose of noribogaine or
pharmaceutically
acceptable salt and/or solvate thereof administered to the patient is
sufficient to provide an
average serum concentration of 50 ng/mL to 180 ng/mL, or any subrange or
subvalue
there between. In one embodiment, the dose of noribogaine or phatinaceutically

acceptable salt and/or solvate thereof administered to the patient provides an
average
serum concentration of 50 ng/mL to 150 ng/mL. In one embodiment, the dose of
noribogaine or pharmaceutically acceptable salt and/or solvate thereof
administered to the
patient provides an average serum concentration of 80 ng/mL to 100 ng/mL.
[0160] In some embodiments, the serum concentration is sufficient to inhibit
or
ameliorate symptoms of depression and/or PTSD while maintaining a QT interval
of less
than 500 milliseconds (ms) during said treatment. In some embodiments, the
dose of
noribogaine or pharmaceutically acceptable salt and/or solvate thereof
provides
prolongation of the QT interval of less than 50 ms. In some embodiments, the
dose of
noribogaine or pharmaceutically acceptable salt and/or solvate thereof
provides
prolongation of the QT interval of less than 30 ms. In a preferred embodiment,
the dose of
noribogaine or pharmaceutically acceptable salt and/or solvate thereof
provides
prolongation of the QT interval of less than 20 ms. In a preferred embodiment,
the patient
is tested to determine QT interval before treatment with noribogaine, and if
clinician
determines that the QT prolongation would be an unacceptable risk, noribogaine
therapy
will be contraindicated.
[0161] In another aspect, this invention provides a method for treating
depression and/or
PTSD in a patient in need thereof comprising administering to the patient
noribogaine or a
noribogaine derivative in a sustained release manner such that the
concentration of
noribogaine, noribogaine derivative, pharmaceutically acceptable salt and/or
solvate
thereof is maintained at a therapeutically effective amount for period of
about 6 hours,
about 12 hours, about 18 hours, about 24 hours, about 36 hours, about 48
hours, about 72
hours, about 96 hours, or a period of time between any two of these durations.
[0162] In another aspect, provided herein is a method for treating depression
and/or
posttraumatic stress disorder in a patient in need thereof, comprising
administering to the
patient a therapeutically effective amount of noribogaine, noribogaine
derivative, or a
pharmaceutically acceptable salt and/or solvate thereof, wherein the patient
is not addicted
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to cocaine or an opiate, and further wherein the therapeutically effective
amount provides
an efficacious average noribogaine serum level of between about 50 ng/mL and
about 180
ng/mL while maintaining a QT interval of less than about 500 ms during said
treatment.
[0163] In another aspect, provided herein is a method for treating depression
and/or
posttraumatic stress disorder in a patient in need thereof, comprising
administering to the
patient a therapeutically effective amount of noribogaine, noribogaine
derivative, or a
pharmaceutically acceptable salt and/or solvate thereof, wherein the patient
is not addicted
to cocaine or an opiate, and further wherein the therapeutically effective
amount provides
an efficacious average noribogaine serum level of between about 50 ng/mL and
about 180
ng/mL while maintaining a QT interval prolongation of less than about 20 ms
during said
treatment.
[0164] In one embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof is administered as a single dose or
multiple doses.
[0165] In another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of 50 ng/mL to 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of 50 ng/mL to 180
ng/mL for
a period of time.
[0166] In another embodiment, the initial dose is from 75 mg to 120 mg. In
another
embodiment, the at least one additional dose is from 5 mg to 25 mg. In another

embodiment, the at least one additional dose is administered from 6 hours to
24 hours after
the initial dose. In another embodiment, at least two additional doses are
administered,
and further wherein the additional doses are administered from 6 hours to 24
hours after
the previous dose. In another embodiment, the method further comprises
selecting a
patient who is prescreened to evaluate tolerance for prolongation of QT
interval. In
another embodiment, depression is treated. In another embodiment,
posttraumatic stress
disorder is treated.
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Anxiety
[0167] There are certain properties of noribogaine that present this compound
as a very
attractive candidate for the treatment of anxiety disorders, impulse control
disorder,
anger/violence-related disorders, or regulation of food intake. These include
the
interaction of noribogaine with a variety of receptors in the brain, including
nicotinic
acetylcholine receptors (nAChRs) and opioid receptors (e.g., -opiod
receptors). Further,
noribogaine elevates brain serotonin levels by blocking synaptic reuptake via
the SERT
transporter. As such, this invention relates to methods of treating anxiety
disorders,
impulse control disorder, anger/violence-related disorders, or symptoms
thereof; or
regulation of food intake, comprising administering to a patient noribogaine,
a noribogaine
derivative, or a pharmaceutically acceptable salt and/or solvate thereof.
[0168] At very low doses, direct blood stream delivery of noribogaine may
reduce
symptoms of anxiety disorders, impulse control disorder, anger/violence-
related disorders,
or provide regulation of food intake. Such dosing is well below that
previously described.
Direct blood stream delivery of noribogaine enhances the amount of noribogaine
delivered
to the brain, because noribogaine does not pass through the liver as it does
when ingested.
Direct blood stream delivery of noribogaine includes sublingual, pulmonary and
intranasal
delivery where the noribogaine is absorbed directly into the blood stream and
then into the
brain. The rapid delivery of noribogaine into the brain, e.g. less than about
15 minutes,
may cause a significant reduction in symptoms of anxiety disorders, impulse
control
disorder, anger/violence-related disorders, or food cravings.
[0169] In one aspect, this invention relates to treating anxiety disorders,
impulse control
disorder, anger/violence-related disorders, or regulation of food intake in a
patient in need
thereof comprising administering to the patient a therapeutically effective
amount of
noribogaine, noribogaine derivative, solvate, or pharmaceutically acceptable
salt and/or
solvate thereof. In one embodiment, this invention treats an anxiety disorder.
In one
embodiment, this invention treats OCD. In one embodiment, this invention
treats
generalized anxiety disorder. In one embodiment, this invention treats social
anxiety
disorder. In one embodiment, this invention treats panic disorder. In another
embodiment,
this invention treats impulse control disorder. In another embodiment, this
invention treats
pathological anger and/or violence. In another embodiment, this invention
treats
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anger/violence-related disorders. In another embodiment, this invention
reduces
pathological anger in a patient. In another embodiment, this invention reduces
violent
outbursts in a patient. In another embodiment, this invention regulates food
intake. In one
embodiment, food consumption is reduced. In one embodiment, food cravings are
reduced. In a preferred embodiment, the patient is not addicted to cocaine or
an opiate.
[0170] In some embodiments, the therapeutic dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof
administered to the
patient is sufficient to provide an average serum concentration of about 50
ng/mL to about
180 ng/mL, or any subrange or subvalue there between. In a preferred
embodiment, the
dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof

administered to the patient provides an average serum concentration of about
50 ng/mL to
about 110 ng/mL. In one embodiment, the dose of noribogaine or
pharmaceutically
acceptable salt and/or solvate thereof administered to the patient provides an
average
serum concentration of about 50 ng/mL to about 100 ng/mL. In one embodiment,
the dose
of noribogaine or pharmaceutically acceptable salt and/or solvate thereof
administered to
the patient provides an average serum concentration of less than about 50
ng/mL.
[0171] In some embodiments, the serum concentration is sufficient to inhibit
or
ameliorate symptoms of anxiety disorders, impulse control disorder,
anger/violence-
related disorders, or to regulate food intakewhile maintaining a QT interval
of less than
about 500 milliseconds (ms) during said treatment. In some embodiments, the
dose of
noribogaine or pharmaceutically acceptable salt and/or solvate thereof
maintains a QT
interval of less than about 450 ms. In some embodiments, the dose of
noribogaine or
pharmaceutically acceptable salt and/or solvate thereof maintains a QT
interval of less
than about 420 ms.
[0172] In some embodiments, the dose of noribogaine or pharmaceutically
acceptable
salt and/or solvate thereof provides prolongation of the QT interval of less
than about 50
ms. In some embodiments, the dose of noribogaine or pharmaceutically
acceptable salt
and/or solvate thereof provides prolongation of the QT interval of less than
about 30 ms.
In a preferred embodiment, the dose of noribogaine or pharmaceutically
acceptable salt
and/or solvate thereof provides prolongation of the QT interval of less than
about 20 ms.
In a preferred embodiment, the patient is tested to determine QT interval
before treatment
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with noribogaine, and if clinician determines that the QT prolongation would
be an
unacceptable risk, noribogaine therapy will be contraindicated.
[0173] In another aspect, this invention provides a method for treating
anxiety disorders,
impulse control disorder, anger/violence-related disorders, or regulating food
intakein a
patient in need thereof comprising administering to the patient noribogaine or
a
noribogaine derivative in a sustained release manner such that the
concentration of
noribogaine, noribogaine derivative, pharmaceutically acceptable salt and/or
solvate
thereof is maintained at a therapeutically effective amount for period of
about 6 hours,
about 12 hours, about 18 hours, about 24 hours, about 36 hours, about 48
hours, about 72
hours, about 96 hours, or a period of time between any two of these durations.
[0174] In one aspect, provided herein is a method for treating an anxiety-
related disorder
in a patient in need thereof, comprising administering to the patient a
therapeutically
effective amount of noribogaine, noribogaine derivative, or a pharmaceutically
acceptable
salt and/or solvate thereof, wherein the patient is not addicted to cocaine or
an opiate, and
further wherein the therapeutically effective amount provides an efficacious
average
noribogaine serum level of between about 50 ng/mL and about 180 ng/mL while
maintaining a QT interval of less than about 500 ms during said treatment.
[0175] In one embodiment, the anxiety-related disorder is selected from the
group
consisting of generalized anxiety disorder, panic disorder, obsessive-
compulsive disorder,
and social anxiety disorder.
[0176] In one aspect, provided herein is a method for treating an impulse
control
disorder in a patient in need thereof, comprising administering to the patient
a
therapeutically effective amount of noribogaine, noribogaine derivative, or a
pharmaceutically acceptable salt and/or solvate thereof, wherein the patient
is not addicted
to cocaine or an opiate, and further wherein the therapeutically effective
amount provides
an efficacious average noribogaine serum level of between about 50 ng/mL and
about 180
ng/mL while maintaining a QT interval of less than about 500 ms during said
treatment.
[0177] In one embodiment, the impulse control disorder is selected from the
group
consisting of borderline personality disorder, conduct disorder, antisocial
personality
disorder, attention deficit hyperactivity disorder, attention deficit
disorder, schizophrenia,
mood disorders, pathological gambling, pyromania, intermittent explosive
disorder,
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kleptomania, sexual compulsion, paraphilia, intemet addiction,
trichotillomania,
pathological skin picking, and compulsive shopping.
[0178] In one aspect, provided herein is a method for regulating food intake
and/or
attenuating food craving in a patient in need thereof, comprising
administering to the
patient a therapeutically effective amount of noribogaine, noribogaine
derivative, or a
pharmaceutically acceptable salt and/or solvate thereof, wherein the patient
is not addicted
to cocaine or an opiate, and further wherein the therapeutically effective
amount provides
an efficacious average noribogaine serum level of between about 50 ng/mL and
about 180
ng/mL while maintaining a QT interval of less than about 500 ms during said
treatment.
[0179] In one aspect, provided herein is a method for treating an anger-
related disorder
in a patient in need thereof, comprising administering to the patient a
therapeutically
effective amount of noribogaine, noribogaine derivative, or a pharmaceutically
acceptable
salt and/or solvate thereof, and further wherein the therapeutically effective
amount
provides an efficacious average noribogaine serum level of between about 50
ng/mL and
about 180 ng/mL while maintaining a QT interval of less than about 500 ms
during said
treatment.
[0180] In one embodiment, the method, comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of about 50 ng/mL to about 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
the at least one
additional dose maintains the average serum concentration of about 50 ng/mL to
about 180
ng/mL for a period of time.
[0181] In another embodiment, the initial dose is from about 75 mg to about
120 mg. In
another embodiment, the at least one additional dose is from about 5 mg to
about 25 mg.
In another embodiment, the at least one additional dose is administered from
about 6 hours
to about 24 hours after the initial dose. In another embodiment, at least two
additional
doses are administered, and further wherein the additional doses are
administered from
about 6 hours to about 24 hours after the previous dose. In another
embodiment, the QT
interval is less than about 450 ms. In another embodiment, the method further
comprises
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selecting a patient who is prescreened to evaluate tolerance for prolongation
of QT
interval. In another embodiment, the noribogaine, noribogaine derivative, or
pharmaceutically acceptable salt and/or solvate thereof is administered by
sublingual,
buccal, intranasal, or intrapulmonary delivery.
[0182] Noribogaine induces side effects in some patients. Methods are needed
for pre-
screening an opioid-addicted patient to determine the patient's tolerance for
a therapeutic
dose of noribogaine.
[0183] Noribogaine is administered to ameliorate acute and post-acute
withdrawal
symptoms. In particular, initial testing of noribogaine therapy with methadone
addicted
patients indicates that a single 120 mg dosing of noribogaine generally
provides a
meaningful therapeutic response, whereas a single 60 mg dosing of noribogaine
generally
does not provide a meaningful therapeutic response. It follows that a single
90 mg dose of
noribogaine shows some therapy but is sub-therapeutic for commercial purposes.
[0184] Unexpectedly, it was discovered that noribogaine behaves in a linear
pattern
regarding QT interval prolongation. For example, doubling the dose of
noribogaine will
result in about a doubling of the QT interval prolongation in the patient. As
such, QT
interval and QT interval prolongation data obtained from a sub-therapeutic
dose of less
than 120 mg of noribogaine, such as about 90 mg, can be used as a predictor of
the
patient's tolerance for therapeutic noribogaine treatment at the therapeutic
dose of 120 mg.
This is possible because the QT interval and QT interval prolongation data
obtained from
a sub-therapeutic dose of less than 120 mg of noribogaine can be accurately
extrapolated
for a dose of 120 mg noribogaine without subjecting the patient to a
potentially life-
threatening side effect at the therapeutic dosage.
[0185] As initially noted above, opioid-addicted patients treated with 120 mg
noribogaine exhibit a significantly longer time to resumption of opioid
substitution therapy
than patients treated with 60 mg. Patients receiving 120 mg noribogaine also
exhibit
variable QT interval prolongation with an average prolongation of
approximately 38
milliseconds (ms). Some patients exhibit QT interval prolongation of greater
than 50 ms,
or a QT interval of greater than 500 ms. A patient with a QT interval that is
greater than
500 ms, or is prolonged more than 50 ms, is at high risk of ventricular
tachyarrhythmia
and possibly death.
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[0186] Provided is a pre-screening method for predicting which patients are
eligible for
noribogaine therapy based on those who exhibit an unacceptable QT interval
prolongation
or a QT interval of over 500 milliseconds when treated with noribogaine. This
method for
predicting either an unacceptable QT interval prolongation of greater than 50
milliseconds
or a QT interval of greater than 500 milliseconds can be used as a means of
using sub-
therapeutic doses (less than 120 mg) of noribogaine to screen out such
patients before
therapeutic doses (120 mg) of noribogaine therapy are initiated.
Patient Pre-screening [0187] As will be apparent to the skilled artisan upon
reading
this disclosure, the present invention provides a method for pre-screening an
opioid-
addicted patient, or another patient in need of treatment or prevention as
provided herein,
to determine the patient's tolerance for a therapeutic dose of noribogaine.
[0188] In one aspect, provided is a method for screening an opioid-addicted
patient, or
another patient in need of treatment or prevention as provided herein, to
determine the
patient's tolerance for a therapeutic dose of noribogaine or pharmaceutically
acceptable
salt and/or solvate thereof, the method comprising:
measuring the patient's pre-administration QT interval;
administering to the patient a sub-therapeutic dose of noribogaine or
pharmaceutically
acceptable salt thereof; and
measuring the patient's post-administration QT interval.
[0189] In some embodiments, the method further comprises one or more of:
determining the difference between pre-administration QT interval and post-
administration QT interval to determine a first prolongation;
estimating a second prolongation based on the first prolongation, wherein the
second
prolongation is the estimated QT interval prolongation expected to be observed
in the
patient upon administration of a therapeutic dose of noribogaine;
determining the patient's tolerance for the therapeutic dose of noribogaine;
and
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administering to the patient the therapeutic dose of noribogaine or
discontinuing
noribogaine treatment, wherein a therapeutic dose is administered if the
second
prolongation is estimated to be less than about 50 ms.
[0190] In one embodiment, provided is a method for screening an opioid-
addicted patient
to determine the patient's tolerance for a therapeutic dose of noribogaine or
pharmaceutically acceptable salt and/or solvate thereof, the method
comprising:
measuring the patient's pre-administration QT interval;
administering to the patient a sub-therapeutic dose of noribogaine or
pharmaceutically
acceptable salt thereof;
measuring the patient's post-administration QT interval;
determining the difference between pre-administration QT interval and post-
administration QT interval to determine a first prolongation;
estimating a second prolongation based on the first prolongation, wherein the
second
prolongation is the estimated QT interval prolongation expected to be observed
in the
patient upon administration of a therapeutic dose of noribogaine;
determining the patient's tolerance for the therapeutic dose of noribogaine;
and
administering to the patient the therapeutic dose of noribogaine or
discontinuing
noribogaine treatment, wherein a therapeutic dose is administered if the
second
prolongation is estimated to be less than about 50 ms.
[0191] In one embodiment, a therapeutic dose is administered if the second
prolongation
is estimated to be less than about 40 ms. In one embodiment, a therapeutic
dose is
administered if the second prolongation is estimated to be less than about 30
ms. In one
embodiment, a therapeutic dose is administered if the second prolongation is
estimated to
be less than about 20 ms. In one embodiment, a therapeutic dose is
administered if the
second prolongation is estimated to be less than about 10 ms.
[0192] In one embodiment, the therapeutic dose provides an average serum
concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to
inhibit or
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ameliorate opioid addiction while resulting in prolongation of the patient's
QT interval of
less than a threshold, for example about 50 ms.
[0193] In a preferred embodiment, the therapeutic dose is about 120 mg
noribogaine. In
another embodiment, the therapeutic dose is between 70-120 mg noribogaine. In
another
embodiment, the therapeutic dose is between 100-150 mg noribogaine. In another

embodiment, the therapeutic dose is more than 150 mg noribogaine. In one
embodiment,
the therapeutic dose is between 1 mg per kg body weight and 4 mg per kg body
weight.
[0194] In one embodiment, the therapeutic dose is administered in one or more
dosings,
such as one, two, three, four, five or more dosings over one or more days.
[0195] In one embodiment, the sub-therapeutic dose is administered in one or
more
dosings, such as one, two, three, four, five or more dosings over one or more
days.
[0196] In one embodiment, the sub-therapeutic dose of noribogaine may be e.g.,
80%,
70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective
dose (e.g.,
120 mg) of noribogaine, or any subvalue or subrange there between.
[0197] In one embodiment, the sub-therapeutic dose of noribogaine may be e.g.,
110 mg,
100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 30 mg, 20 mg, 10 mg, 5 mg, 2
mg, 1
mg of noribogaine, or any subvalue or subrange there between.
[0198] In one embodiment, where the second prolongation is estimated to be
greater
than a threshold QT interval prolongation, the patient is administered a sub-
therapeutic
dose of noribogaine.
[0199] In one embodiment, where the second prolongation is estimated to be
greater
than a threshold QT interval prolongation, the patient is administered a
therapeutic dose of
noribogaine in multiple administrations. For example, where the therapeutic
dose is 120
mg per day, 60 mg may be given every 12 hours. Without being limited by
theory, it is
believed that multiple administrations will lower the maximum serum
concentration of
noribogaine experienced by the patient, thereby reducing QT interval
prolongation.
[0200] In one embodiment, where the second prolongation is estimated to be
greater
than a threshold QT interval prolongation, the patient is administered an
initial dose of
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noribogaine, followed by one or more additional doses. In one embodiment, the
initial
dose is from 75 mg to 120 mg. In one embodiment, the one or more additional
doses are
lower than the initial dose. In one embodiment, the one or more additional
doses are from
mg to 50 mg. In one embodiment, such a dosing regimen provides an average
serum
concentration of noribogaine of 50 ng/mL to 180 ng/mL. In one embodiment, such
a
dosing regimen provides an average serum concentration of noribogaine of 80
ng/mL to
100 ng/mL. In one embodiment, the one or more additional doses maintain an
average
serum concentration of 50 ng/mL to 180 ng/mL over a period of time. In one
embodiment,
the one or more additional doses maintain an average serum concentration of 80
ng/mL to
100 ng/mL over a period of time. In one embodiment, the one or more additional
doses are
administered periodically, such as every 4 hours, every 6 hours, every 8
hours, every 12
hours, or every 24 hours.
[0201] In one embodiment, the threshold QT interval prolongation is 50 ms. In
one
embodiment, the threshold QT interval prolongation is 40 ms. In one
embodiment, the
threshold QT interval prolongation is 30 ms. In one embodiment, the threshold
QT interval
prolongation is 20 ms. In one embodiment, the threshold QT interval
prolongation is 10
ms.
[0202] In one embodiment, the therapeutic amount of noribogaine is sufficient
to
provide an average serum concentration of noribogaine from 50 ng/mL to 180
ng/mL, or
60 ng/mL to 180 ng/mL. In one embodiment, the therapeutic amount of
noribogaine is
sufficient to provide an average serum concentration of noribogaine from 50
ng/mL to 150
ng/mL, or 60 ng/mL to 150 ng/mL. In one embodiment, the therapeutic amount of
noribogaine is sufficient to provide an average serum concentration of
noribogaine from
50 ng/mL to 100 ng/mL, or 60 ng/mL to 100 ng/mL. In one embodiment, the
therapeutic
amount of noribogaine is sufficient to provide an average serum concentration
of
noribogaine from 80 ng/mL to 100 ng/mL The ranges include both extremes as
well as any
subranges between.
[0203] In one aspect, provided herein is a method for screening an opioid-
addicted
patient to determine the patient's tolerance for a therapeutic dose of
noribogaine or
pharmaceutically acceptable salt and/or solvate thereof, the method
comprising:
measuring the patient's pre-administration QT interval;
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administering to the patient a sub-therapeutic dose of noribogaine or
pharmaceutically
acceptable salt thereof; and
measuring the patient's post-administration QT interval.
[0204] In one embodiment, the method further comprises one or more of:
determining the difference between pre-administration QT interval and post-
administration QT interval to determine a first prolongation;
estimating a second prolongation based on the first prolongation, wherein the
second
prolongation is the estimated QT interval prolongation expected to be observed
in the
patient upon administration of a therapeutic dose of noribogaine;
determining the patient's tolerance for the therapeutic dose of noribogaine;
and
administering to the patient the therapeutic dose of noribogaine or
discontinuing
noribogaine treatment, wherein a therapeutic dose is administered if the
second
prolongation is estimated to be less than about 50 ms.
[0205] In another embodiment, the therapeutic dose provides an average serum
concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to
inhibit or
ameliorate opioid addiction while resulting in prolongation of the patient's
QT interval of
less than about 50 ms.
[0206] In another embodiment, the method further comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the initial dose
provides an
average serum concentration of 50 ng/mL to 180 ng/mL; and
b) administering at least one additional dose of noribogaine, noribogaine
derivative,
or pharmaceutically acceptable salt or solvate thereof, such that the at least
one additional
dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a
period of
time.
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[0207] In another embodiment, the therapeutic dose is administered in one or
more
dosings. In another embodiment, the sub-therapeutic dose is administered in
one or more
dosings. In another embodiment, the sub-therapeutic dose is 80% or less than
the
therapeutic dose. In another embodiment, the sub-therapeutic dose is 70% or
less than the
therapeutic dose. In another embodiment, the sub-therapeutic dose is between
60 mg and
100 mg. In another embodiment, the sub-therapeutic dose is about 90 mg.
Sustained Treatment
[0208] In one aspect, the current invention is predicated on the surprising
discovery that
treatment with a narrow dosage range of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt or solvate thereof provides a therapeutic
blood serum
concentration in treated patients.
[0209] In some aspects the present invention provides a method for treating a
condition
in a patient which is treatable with noribogaine, noribogaine derivative, or
pharmaceutically acceptable salt or solvate thereof, while maintaining an
acceptable QT
interval prolongation in said patient, the method comprising:
a) administering to the patient an initial unit dose of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, wherein
said unit dose
provides a therapeutic average serum concentration of 50 ng/mL to 180 ng/mL
which
serum concentration imparts minimal QT interval prolongation; and
b) maintaining said serum concentration by periodically administering at
least
one additional dose of noribogaine, noribogaine derivative, or
pharmaceutically acceptable
salt or solvate thereof, such that the at least one additional dose maintains
the average
serum concentration of 50 ng/mL to 180 ng/mL during treatment wherein said
additional
dose or doses are continued as necessary to treat said condition.
[0210] In one embodiment, the therapeutic blood serum concentration is between
50
ng/mL and 180 ng/mL. In a preferred embodiment, the therapeutic serum
concentration is
80 ng/mL to 100 ng/mL. In one embodiment, the dose range provides both
therapeutic
results and an acceptable QT interval prolongation of less than 50
milliseconds in a
patient. In one embodiment, an initial unit dose of noribogaine, noribogaine
derivative, or
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pharmaceutically acceptable salt or solvate thereof is administered. In one
embodiment,
the initial unit dose provides the therapeutic blood serum concentration with
minimal QT
interval prolongation. In one embodiment, the QT interval is not prolonged by
more than
20 ms.
[0211] In some embodiments, the patient is administered an initial unit dose
of
noribogaine, noribogaine derivative, or phat tnaceutically acceptable salt
or solvate thereof,
followed by one or more additional doses. In one embodiment, the initial unit
dose is from
50 mg to 120 mg. In one embodiment, the one or more additional doses are lower
than the
initial dose. In one embodiment, the one or more additional doses are from 5
mg to 50 mg.
In one embodiment, such a dosing regimen provides a therapeutic average serum
concentration of noribogaine of 50 ng/mL to 180 ng/mL. In one embodiment, the
one or
more additional doses maintain a therapeutic average serum concentration of 50
ng/mL to
180 ng/mL over a period of time. In one embodiment, the one or more additional
doses are
administered periodically. In one embodiment, the at least one additional dose
is
administered between about 6 hours and about 24 hours after administration of
the initial
unit dose. In one embodiment, the at least one additional dose is administered
between
about 6 hours and about 24 hours after administration of the previous dose. In
one
embodiment, one or more doses are administered as a controlled release
formulation.
[0212] In one embodiment, the narrow therapeutic doses of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt or solvate described above
unexpectedly do
not prolong the QT interval to unacceptable levels in human patients. In some
embodiments, the patient will be pre-screened to evaluate tolerance for
prolongation of QT
interval, e.g., to determine whether the patient has any pre-existing cardiac
conditions
which would disqualify them from treatment with noribogaine. In some
embodiments, the
patient undergoes cardiac monitoring during a portion of the treatment. In a
preferred
embodiment, cardiac monitoring is not required. In one embodiment, the patient
is tested
to determine QT interval before treatment with noribogaine, and if clinician
determines
that the QT prolongation would be unacceptable risk, noribogaine therapy will
be
contraindicated.
[0213] In one aspect, provided herein is a method for treating a condition in
a patient
which is treatable with noribogaine, noribogaine derivative, or
pharmaceutically
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acceptable salt or solvate thereof while maintaining an acceptable QT interval

prolongation in said patient, the method comprising:
a) administering to the patient an initial unit dose of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, wherein
said unit dose
provides a therapeutic average serum concentration of 50 ng/mL to 180 ng/mL
which
serum concentration imparts an acceptable QT interval in said patient; and
b) maintaining said serum concentration by periodically administering at
least
one additional dose of noribogaine, noribogaine derivative, or
pharmaceutically acceptable
salt or solvate thereof, such that the at least one additional dose maintains
the therapeutic
average serum concentration of 50 ng/mL to 180 ng/mL during treatment;
wherein said additional dose or doses are continued as necessary to treat said

condition, and further wherein said acceptable QT interval is no longer than
500 ms.
102141 In one embodiment, the QT interval is prolonged by less than 50 ms. In
another
embodiment, the QT interval is prolonged by less than 20 ms. In another
embodiment,
the initial unit dose is higher than any of the at least one additional dose.
In another
embodiment, the initial unit dose and at least one additional dose are
incorporated into a
single controlled release formulation. In another embodiment, the initial unit
dose is
administered as subunit doses, which subunit doses are administered serially
until the unit
dose level is achieved, wherein the aggregate of subunit doses provides the
initial unit
dose and further provides the therapeutic average serum concentration. In
another
embodiment, the initial unit dose is from 75 mg to 120 mg. In another
embodiment, the at
least one additional dose is from 5 mg to 25 mg. In another embodiment, the at
least one
additional dose is administered from 6 hours to 24 hours after the initial
dose. In another
embodiment, at least two additional doses are administered, and further
wherein the
additional doses are administered from 6 hours to 24 hours after the previous
dose. In
another embodiment, the method further comprises selecting an addicted patient
who is
prescreened to evaluate tolerance for prolongation of QT interval.
102151 In another aspect, provided herein is a method for treating a condition
in a patient
which is treatable with noribogaine, noribogaine derivative, or
pharmaceutically
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acceptable salt or solvate thereof while maintaining an acceptable QT interval

prolongation in said patient, the method comprising:
a) administering to the patient an initial unit dose of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, wherein
said unit dose
provides a therapeutic average serum concentration of 50 ng/mL to 180 ng/mL
which
serum concentration imparts an acceptable QT interval prolongation in said
patient; and
b) maintaining said serum concentration by periodically administering at
least
one additional dose of noribogaine, noribogaine derivative, or
pharmaceutically acceptable
salt or solvate thereof, such that the at least one additional dose maintains
the therapeutic
average serum concentration of 50 ng/mL to 180 ng/mL during treatment;
wherein said additional dose or doses are continued as necessary to treat said

condition, and further wherein said acceptable QT interval prolongation is no
longer than
50 ms.
[0216] In one embodiment, the QT interval prolongation is less than 20 ms. In
another
embodiment, the initial unit dose is higher than any of the at least one
additional dose. In
another embodiment, the initial unit dose and at least one additional dose are
incorporated
into a single controlled release formulation. In another embodiment, the
initial unit dose is
administered as subunit doses, which subunit doses are administered serially
until the unit
dose level is achieved, wherein the aggregate of subunit doses provides the
initial unit
dose and further provides the therapeutic average serum concentration. In
another
embodiment, the initial unit dose is from 75 mg to 120 mg. In another
embodiment, the at
least one additional dose is from 5 mg to 25 mg. In another embodiment, the at
least one
additional dose is administered from 6 hours to 24 hours after the initial
dose. In another
embodiment, at least two additional doses are administered, and further
wherein the
additional doses are administered from 6 hours to 24 hours after the previous
dose. In
another embodiment, the method further comprises selecting an addicted patient
who is
prescreened to evaluate tolerance for prolongation of QT interval.
[0217] In another embodiment, noribogaine or a pharmaceutically acceptable
salt and/or
solvate thereof is administered.
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Formulations
[0218] In another aspect, provided herein is a pharmaceutically acceptable
formulation
comprising a unit dose of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof, wherein the amount of noribogaine is
sufficient to
provide a serum concentration of about 50 ng/mL to about 180 ng/mL when
administered
to a patient. In one embodiment, the unit dose of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt or solvate thereof is administered in one or
more dosings.
In another embodiment, the unit dose of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt or solvate thereof is from about 20 mg to
about 120 mg.
BRIEF DESCRIPTION OF THE FIGURES
[0219] FIG. 1 represents mean noribogaine concentration-time profiles in
healthy
patients after single oral dosing with 3, 10, 30 or 60 mg doses. Inset:
Individual
concentration-time profiles from 0-12 h after a 10 mg dose.
[0220] FIG. 2 represents mean plasma noribogaine glucuronide concentration-
time
profiles in healthy patients after single oral 30 or 60 mg doses.
[0221] FIG. 3 illustrates the mean noribogaine concentration-time profile in
opioid-
addicted patients after a single oral 60 mg (diamonds), 120 mg (squares), or
180 mg
(triangles) dose of noribogaine.
[0222] FIG. 4 illustrates hours to resumption of opioid substitution treatment
(OST) for
each patient given placebo (circles), or a single oral dose of noribogaine (60
mg, squares;
120 mg, triangles; 180 mg, inverted triangles). Center horizontal line
represents mean.
Error bars represent standard deviation.
[0223] FIG. 5 illustrates results of noribogaine treatment on final COWS
scores before
resumption of OST. Boxes include values representing 25% ¨ 75% quartiles.
Diamonds
represent the median, crossbars represent mean. Whiskers represent values
within one
standard deviation of mid-quartiles. No outliers were present.
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[0224] FIG. 6A illustrates of the mean change in total COWS scores over the
first 6
hours following dosing of noribogaine (60 mg, squares; 120 mg, triangles; 180
mg,
diamonds) or placebo (circles). Data is given relative to baseline COWS score.
[0225] FIG. 6B illustrates the mean area under the curve (AUC) over the
initial 6 hour
period after administration of noribogaine or placebo, based on the COWS score
data
given in Figure 6A. A negative change in score indicates that withdrawal
symptoms
subsided over the period.
[0226] FIG. 7A illustrates of the mean change in total 0OWS scores over the
first 6
hours following dosing of noribogaine (60 mg, squares; 120 mg, triangles; 180
mg,
diamonds) or placebo (circles). Data is given relative to baseline 0OWS score.
[0227] FIG. 7B illustrates the mean area under the curve (AUC) over the
initial 6 hour
period after administration of noribogaine or placebo, based on the 0OWS score
data
given in Figure 7A. A negative change in score indicates that withdrawal
symptoms
subsided over the period.
[0228] FIG. 8A illustrates of the mean change in total SOWS scores over the
first 6
hours following dosing of noribogaine (60 mg, squares; 120 mg, triangles; 180
mg,
diamonds) or placebo (circles). Data is given relative to baseline SOWS score.
[0229] FIG. 8B illustrates the mean area under the curve (AUC) over the
initial 6 hour
period after administration of noribogaine or placebo, based on the SOWS score
data
given in Figure 8A. A negative change in score indicates that withdrawal
symptoms
subsided over the period.
[0230] FIG. 9A illustrates the average change in QT interval (AQTc1) for each
cohort
(60 mg, squares; 120 mg, triangles; 180 mg, diamonds) or placebo (circles)
over the first
24 hours post administration.
[0231] FIG. 9B illustrates the correlation between serum noribogaine
concentration and
AQTcl for each patient over time. The equation of the line is given.
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[0232] FIG. 10A represents the effects of noribogaine and varenicline in
nicotine
dependent rats. Data represent mean + standard error of the mean (SEM).
#P<0.10;
***P<0.001 compared to vehicle or saline treatment.
[0233] FIG. 10B represents the effects of noribogaine and varenicline on
percentage of
inactive lever press during nicotine self-administration. Data represent mean
+ SEM.
[0234] FIG. 11 represents the effects of noribogaine on general motor activity
of
zebrafish during nicotine withdrawal. Behavioral endpoints examined include,
latency to
upper half of tank (panel A), transitions to upper half of tank(panel B),
transitions to upper
half of tank per minute (panel C), time in upper half of tank (panel D), time
in upper half
of tank per minute (panel E), average entry duration (panel F), and average
entry duration
per minute (panel G).
[0235] FIG. 12 represents effects of noribogaine on general motor activity of
zebrafish
during nicotine withdrawal. Behavioral endpoints examined include, distance
moved
(panel A), velocity (panel B), rotation angle (panel C), number of rotation
events (panel
D), change in direction of body/heading (panel E), change in direction of
movement per
distance moved/meander total (panels F and G).
[0236] FIG. 13 depicts effects of noribogaine on freezing bouts frequency
(panel A) and
duration of freezing bouts (panels B and C).
[0237] FIG. 14 depicts effects of noribogaine treatment on movement mobility.
Immobile (dark squares) was used to express the frequency of episodes with
degree of
movement independent of spatial displacement (duration of immobility). Mobile
(medium
gray squares) reflects overall locomotor activity. Hi-mobile (light gray
squares) reflects
bouts of accelerated swimming (>60 % of individual average).
[0238] FIG. 15 shows representative traces of control, chronic nicotine,
repeated
nicotine withdrawal (WD), and WD + 1 mg/L noribogaine treatment (from top to
bottom),
recorded in the 5 minute novel tank test (NTT) by Ethovision XT8.5 software.
[0239] FIG. 16 shows the effects of noribogaine treatment (at 1-, 5- and 10-
mg/L doses)
on general motor activity of zebrafish. Behavioral endpoints examined include:
latency to
upper half of tank (panel A), transitions to upper half of tank (panel B),
transitions to
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upper half of tank per minute (panel C), time in upper half of tank (panel D),
time in upper
half of tank per minute (panel E), average entry duration (panel F), and
average entry
duration per minute (panel G).
[0240] FIG. 17 shows the effects of noribogaine treatment (at 1-, 5- and 10-
mg/L doses)
on general motor activity of zebrafish. Behavioral endpoints examined include:
distance
moved (panel A), velocity (panel B), rotation angle (panel C), number of
rotation events
(panel D), change in direction of body/heading (panel E), change in direction
of movement
per distance moved/meander total (panels F and G).
[0241] FIG. 18 depicts effects of noribogaine (at 1-, 5- and 10-mg/L doses) on
freezing
bouts frequency (panel A) and duration of freezing bouts (panel B).
[0242] FIG. 19 depicts effects of noribogaine treatment on movement mobility,
including percentage of events per animal (panel A) and duration (panel B).
"Immobile"
(high frequency "HF" or low frequency "LF") was used to express the frequency
of
episodes with degree of movement independent of spatial displacement (duration
of
immobility). Mobile (HF or LF) reflects frequency of episodes of moderate
locomotor
activity. Hi-mobile (HF and LF) reflects bouts of accelerated velocity (>60 %
of
individual average).
[0243] FIG. 20 shows representative traces of control (top row) and
noribogaine-treated
fish (1, 5 and 10 mg/L, from top to bottom), recorded in the 5 minute novel
tank test
(NTT) by Ethovision XT8.5 software.
DETAILED DESCRIPTION
[0244] It is to be understood that this invention is not limited to particular
embodiments
described, as such may, of course, vary. It is also to be understood that the
terminology
used herein is for the purpose of describing particular embodiments only, and
is not
intended to be limiting, since the scope of this invention will be limited
only by the
appended claims.
[0245] The detailed description of the invention is divided into various
sections only for
the reader's convenience and disclosure found in any section may be combined
with that
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in another section. Unless defined otherwise, all technical and scientific
terms used herein
have the same meaning as commonly understood by one of ordinary skill in the
art to
which this invention belongs.
[0246] It must be noted that as used herein and in the appended claims, the
singular
forms "a", "an", and "the" include plural referents unless the context clearly
dictates
otherwise. Thus, for example, reference to "a compound" includes a plurality
of
compounds.
I. Definitions
[0247] Unless defined otherwise, all technical and scientific terms used
herein have the
same meaning as commonly understood by one of ordinary skill in the art to
which this
invention belongs. As used herein the following terms have the following
meanings.
[0248] The term "about" when used before a numerical designation, e.g.,
temperature,
time, amount, concentration, and such other, including a range, indicates
approximations
which may vary by ( + ) or ( -) 20%, 10 %, 5 %,1 %, or any subrange or
subvalue there
between. Preferably, the term "about" when used with regard to a dose amount
means that
the dose may vary by +1- 20%. For example, "about 2 mg/kg noribogaine"
indicates that a
patient may be administered a dose of noribogaine between 1.6 mg/kg and 2.4
mg/kg. In
another example, about 120 mg per unit dose of noribogaine indicates that the
unit dose
may range from 96 mg to 144 mg.
[0249] "Administration" refers to introducing an agent, such as noribogaine,
into a
patient. Typically, an effective amount is administered, which amount can be
determined
by the treating physician or the like. Any route of administration, such as
oral, topical,
subcutaneous, peritoneal, intra-arterial, inhalation, vaginal, rectal, nasal,
introduction into
the cerebrospinal fluid, or instillation into body compartments can be used.
The agent,
such as noribogaine may be administered by direct blood stream delivery, e.g.
sublingual,
buccal, intranasal, or intrapulmonary administration.
[0250] The related terms and phrases "administering" and "administration of',
when
used in connection with a compound or pharmaceutical composition (and
grammatical
equivalents) refer both to direct administration, which may be administration
to a patient
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by a medical professional or by self-administration by the patient, and/or to
indirect
administration, which may be the act of prescribing a drug. For example, a
physician who
instructs a patient to self-administer a drug and/or provides a patient with a
prescription
for a drug is administering the drug to the patient.
[0251] "Periodic administration" or "periodically administering" refers to
multiple
treatments that occur on a daily, weekly, or monthly basis. Periodic
administration may
also refer to administration of an agent, such as noribogaine one, two, three,
or more times
per day. Administration may be via transdermal patch, gum, lozenge, sublingual
tablet,
intranasal, intrapulmonary, oral administration, or other administration.
[0252] "Comprising" or "comprises" is intended to mean that the compositions
and
methods include the recited elements, but not excluding others. "Consisting
essentially
of' when used to define compositions and methods, shall mean excluding other
elements
of any essential significance to the combination for the stated purpose. Thus,
a
composition consisting essentially of the elements as defined herein would not
exclude
other materials or steps that do not materially affect the basic and novel
characteristic(s) of
the claimed invention. "Consisting of' shall mean excluding more than trace
elements of
other ingredients and substantial method steps. Embodiments defined by each of
these
transition terms are within the scope of this invention.
[0253] As used herein, the term "alkyl" refers to monovalent saturated
aliphatic
hydrocarbyl groups having from Ito 12 carbon atoms, 1 to 10 carbon atoms,
preferably 1
to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. This term
includes, by way
of example, linear and branched hydrocarbyl groups such as methyl (CH3-),
ethyl
(CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-
),
isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-
pentyl
(CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). The term "C, alkyl" refers to
an
alkyl group having x carbon atoms, wherein x is an integer, for example, C3
refers to an
alkyl group having 3 carbon atoms.
[0254] "Alkenyl" refers to straight or branched hydrocarbyl groups having from
2 to 6
carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and
preferably from
to 2 sites of vinyl (>C=C<) unsaturation. Such groups are exemplified, for
example, by
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vinyl, allyl, and but-3-en-1-yl. Included within this term are the cis and
trans isomers or
mixtures of these isomers.
[0255] "Alkynyl" refers to straight or branched monovalent hydrocarbyl groups
having
from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at
least 1 and
preferably from 1 to 2 sites of acetylenic
unsaturation. Examples of such alkynyl
groups include acetylenyl (-CECH), and propargyl (-CH2CCH).
[0256] "Substituted alkyl" refers to an alkyl group having from 1 to 5,
preferably 1 to 3,
or more preferably 1 to 2 substituents selected from the group consisting of
alkoxy,
substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino,
aminocarbonyl,
aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy,
aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,
substituted aryl,
aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,
carboxyl ester,
(carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted
cycloalkyl,
cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted
cycloalkylthio,
cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted
cycloalkenyloxy,
cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted
guanidino, halo,
hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted
heteroaryloxy,
heteroarylthio, substituted heteroarylthio, heterocyclic, substituted
heterocyclic,
heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted
heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl,
thiol, alkylthio,
and substituted alkylthio, wherein said substituents are defined herein.
[0257] "Substituted alkenyl" refers to alkenyl groups having from 1 to 3
substituents,
and preferably 1 to 2 substituents, selected from the group consisting of
alkoxy,
substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino,
aminocarbonyl,
aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy,
aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,
substituted aryl,
aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,
carboxyl ester,
(carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted
cycloalkyl,
cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted
cycloalkylthio,
cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted
cycloalkenyloxy,
cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted
guanidino, halo,
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hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted
heteroaryloxy,
heteroarylthio, substituted heteroarylthio, heterocyclic, substituted
heterocyclic,
heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted
heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl,
thiol, alkylthio,
and substituted alkylthio, wherein said substituents are defined herein and
with the proviso
that any hydroxy or thiol substitution is not attached to a vinyl
(unsaturated) carbon atom.
[0258] "Substituted alkynyl" refers to alkynyl groups having from 1 to 3
substituents,
and preferably 1 to 2 substituents, selected from the group consisting of
alkoxy,
substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino,
aminocarbonyl,
aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy,
aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl,
substituted aryl,
aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,
carboxyl ester,
(carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted
cycloalkyl,
cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted
cycloalkylthio,
cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted
cycloalkenyloxy,
cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted
guanidino, halo,
hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted
heteroaryloxy,
heteroarylthio, substituted heteroarylthio, heterocyclic, substituted
heterocyclic,
heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted
heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl,
thiol, alkylthio,
and substituted alkylthio, wherein said substituents are defined herein and
with the proviso
that any hydroxy or thiol substitution is not attached to an acetylenic carbon
atom.
[0259] "Alkoxy" refers to the group -0-alkyl wherein alkyl is defined herein.
Alkoxy
includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,

t-butoxy, sec-butoxy, and n-pentoxy.
[0260] "Substituted alkoxy" refers to the group -0-(substituted alkyl) wherein

substituted alkyl is defined herein.
[0261] "Acyl" refers to the groups H-C(0)-, alkyl-C(0)-, substituted alkyl-
C(0)-,
alkenyl-C(0)-, substituted alkenyl-C(0)-, alkynyl-C(0)-, substituted alkynyl-
C(0)-,
cycloalkyl-C(0)-, substituted cycloalkyl-C(0)-, cycloalkenyl-C(0)-,
substituted
cycloalkenyl-C(0)-, aryl-C(0)-, substituted aryl-C(0)-, heteroaryl-C(0)-,
substituted
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heteroaryl-C(0)-, heterocyclic-C(0)-, and substituted heterocyclic-C(0)-,
wherein alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,
substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
are as defined
herein. Acyl includes the "acetyl" group CH3C(0)-.
[0262] "Acylamino" refers to the groups -NR38C(0)alkyl, -NR38C(0)substituted
alkyl, -NR38C(0)cycloalkyl, -NR38C(0)substituted
cycloalkyl, -NeC(0)cycloalkenyl, -NR38C(0)substituted
cycloalkenyl, -NR38C(0)alkenyl, -NeC(0)substituted
alkenyl, -NR38C(0)alkynyl, -NR38C(0)substituted
alkynyl, -NR38C(0)aryl, -NR38C(0)substituted
aryl, -NR38C(0)heteroaryl, -NR38C(0)substituted heteroaryl, -
NR38C(0)heterocyclic,
and -NR38C(0)substituted heterocyclic wherein R38 is hydrogen or alkyl and
wherein
alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
alkynyl,
cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
aryl, substituted
aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted
heterocyclic are as
defined herein.
[0263] "Acyloxy" refers to the groups alkyl-C(0)O-, substituted alkyl-C(0)O-,
alkenyl-C(0)O-, substituted alkenyl-C(0)O-, alkynyl-C(0)O-, substituted
alkynyl-C(0)O-, aryl-C(0)O-, substituted aryl-C(0)O-, cycloalkyl-C(0)O-,
substituted
cycloalkyl-C(0)O-, cycloalkenyl-C(0)O-, substituted cycloalkenyl-C(0)O-,
heteroaryl-C(0)O-, substituted heteroaryl-C(0)O-, heterocyclic-C(0)O-, and
substituted
heterocyclic-C(0)0- wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl, alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted
cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic, and
substituted heterocyclic are as defined herein.
[0264] "Amino" refers to the group -NH2.
[0265] "Substituted amino" refers to the group -NR39R4 where R39 and R4 are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,
substituted
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heteroaryl, heterocyclic, substituted heterocyclic, -S02-alkyl, -S02-
substituted
alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-
substituted
cylcoalkyl, -S02-cycloalkenyl, -S02-substituted cylcoalkeny1,-S02-aryl, -S02-
substituted
aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, and -
S02-substituted
heterocyclic and wherein R39 and R4 are optionally joined, together with the
nitrogen
bound thereto to form a heterocyclic or substituted heterocyclic group,
provided that R39
and R4 are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl,
substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl,
substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl,
heterocyclic, and substituted heterocyclic are as defined herein. When R39 is
hydrogen
and R4 is alkyl, the substituted amino group is sometimes referred to herein
as
alkylamino. When R39 and R4 are alkyl, the substituted amino group is
sometimes
referred to herein as dialkylamino. When referring to a monosubstituted amino,
it is
meant that either R39 or R4 is hydrogen but not both. When referring to a
disubstituted
amino, it is meant that neither R39 nor R4 are hydrogen.
102661 "Aminocarbonyl" refers to the group -C(0)NR41R42 where R41 and R42 are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R41 and R42
are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or
substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted
cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic, and
substituted heterocyclic are as defined herein.
102671 "Aminothiocarbonyl" refers to the group -C(S)NR41R42 where R4' and R42
are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where WI and R42
are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or
substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl,
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alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted
cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic, and
substituted heterocyclic are as defined herein.
[0268] "Aminocarbonylamino" refers to the group -NR38C(0)NR41R42 where R38 is
hydrogen or alkyl and R41 and R42 are independently selected from the group
consisting of
hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted
alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted
cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted heterocyclic
and where R41- and R42 are optionally joined together with the nitrogen bound
thereto to
form a heterocyclic or substituted heterocyclic group, and wherein alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,
heteroaryl,
substituted heteroaryl, heterocyclic, and substituted heterocyclic are as
defined herein.
[0269] "Aminothiocarbonylamino" refers to the group -NR38C(S)NR41R42 where R"
is
hydrogen or alkyl and R41 and R42 are independently selected from the group
consisting of
hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted
alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted
cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted heterocyclic
and where R41 and R42 are optionally joined together with the nitrogen bound
thereto to
form a heterocyclic or substituted heterocyclic group, and wherein alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,
heteroaryl,
substituted heteroaryl, heterocyclic, and substituted heterocyclic are as
defined herein.
[0270] "Aminocarbonyloxy" refers to the group -O-C(0)NR41R42 where R41 and R42
are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R41 and R42
are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or
substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted
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cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic, and
substituted heterocyclic are as defined herein.
[0271] "Aminosulfonyl" refers to the group -S02NR41R42 where R41 and R42 are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R4' and R42
are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or
substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted
cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic, and
substituted heterocyclic are as defined herein.
[0272] "Aminosulfonyloxy" refers to the group -0-S02NR41K'-'42 where R41 and
R42 are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R41- and R42
are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or
substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted
cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic, and
substituted heterocyclic are as defined herein.
[0273] "Aminosulfonylamino" refers to the group -NR38-S02NR41R42 where R38 is
hydrogen or alkyl and R41 and R42 are independently selected from the group
consisting of
hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted
alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted
cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted heterocyclic
and where R4I and R42 are optionally joined together with the nitrogen bound
thereto to
form a heterocyclic or substituted heterocyclic group, and wherein alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted
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cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,
heteroaryl,
substituted heteroaryl, heterocyclic, and substituted heterocyclic are as
defined herein.
[0274] "Amidino" refers to the group -C(=NR43)NR41R42 where R41, R42, and R43
are
independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,
substituted
heteroaryl, heterocyclic, and substituted heterocyclic and where R41 and R42
are optionally
joined together with the nitrogen bound thereto to form a heterocyclic or
substituted
heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted
alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted
cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic, and
substituted heterocyclic are as defined herein.
[0275] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of
from 6 to 14
carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings
(e.g.,
naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g.,
2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like) provided
that the
point of attachment is at an aromatic carbon atom. Preferred aryl groups
include phenyl
and naphthyl.
[0276] "Substituted aryl" refers to aryl groups which are substituted with 1
to 5,
preferably 1 to 3, or more preferably 1 to 2 substituents selected from the
group consisting
of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl,
alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted
amino,
aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,
aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino,
amidino, aryl,
substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted
arylthio, carboxyl,
carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl,
substituted
cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio,
substituted
cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy,
substituted
cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino,
substituted
guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy,
substituted
heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic,
substituted
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heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio,
substituted
heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl,
thiol, alkylthio,
and substituted alkylthio, wherein said substituents are defined herein.
[0277] "Aryloxy" refers to the group -0-aryl, where aryl is as defined herein,
that
includes, by way of example, phenoxy and naphthoxy.
[0278] "Substituted aryloxy" refers to the group -0-(substituted aryl) where
substituted
aryl is as defined herein.
[0279] "Arylthio" refers to the group -S-aryl, where aryl is as defined
herein.
[0280] "Substituted arylthio" refers to the group -S-(substituted aryl), where
substituted
aryl is as defined herein.
[0281] "Carbonyl" refers to the divalent group -C(0)- which is equivalent to -
C(=0)-.
[0282] "Carboxy" or "carboxyl" refers to -COOH or salts thereof.
[0283] "Carboxyl ester" or "carboxy ester" refers to the
groups -C(0)0-alkyl, -C(0)0-substituted alkyl, -C(0)0-alkenyl, -C(0)0-
substituted
alkenyl, -C(0)0-alkynyl, -C(0)0-substituted alkynyl, -C(0)0-aryl, -C(0)0-
substituted
aryl, -C(0)0-cycloalkyl, -C(0)0-substituted
cycloalkyl, -C(0)0-cycloalkenyl, -C(0)0-substituted
cycloalkenyl, -C(0)0-heteroaryl, -C(0)0-substituted heteroaryl, -C(0)0-
heterocyclic,
and -C(0)0-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl,
substituted
alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl,
substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl,
heterocyclic, and substituted heterocyclic are as defined herein.
[0284] "(Carboxyl ester)amino" refers to the
group -NR38-C(0)0-alkyl, -NR38-C(0)0-substituted
alkyl, -NR38-C(0)0-alkenyl, -NR38-C(0)0-substituted
alkenyl, -NR38-C(0)0-alkynyl, -NR38-C(0)0-substituted
alkynyl, -NR38-C(0)0-aryl, -NR38-C(0)0-substituted
aryl, -NR38-C(0)0-cycloalkyl, -Nle-C(0)0-substituted
cycloalkyl, -NR38-C(0)0-cycloalkenyl, -NR38-C(0)0-substituted
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cycloalkenyl, -Ne-C(0)0-heteroaryl, -NR38-C(0)0-substituted
heteroaryl, -NR38-C(0)0-heterocyclic, and -NR38-C(0)0-substituted heterocyclic
wherein
R38 is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl,
substituted alkenyl,
alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted
cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic, and
substituted heterocyclic are as defined herein.
[0285] "(Carboxyl ester)oxy" refers to the group -0-C(0)0-alkyl,
substituted -0-C(0)0-alkyl, -0-C(0)0-alkenyl, -0-C(0)0-substituted
alkenyl, -0-C(0)0-alkynyl, -0-C(0)0-substituted
alkynyl, -0-C(0)0-aryl, -0-C(0)0-substituted
aryl, -0-C(0)0-cycloalkyl, -0-C(0)0-substituted
cycloalkyl, -0-C(0)0-cycloalkenyl, -0-C(0)0-substituted
cycloalkenyl, -0-C(0)0-heteroaryl, -0-C(0)0-substituted
heteroaryl, -0-C(0)0-heterocyclic, and -0-C(0)0-substituted heterocyclic
wherein alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,
substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
are as defined
herein.
[0286] "Cyano" refers to the group -CN.
[0287] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms
having
single or multiple cyclic rings including fused, bridged, and Spiro ring
systems. One or
more of the rings can be aryl, heteroaryl, or heterocyclic provided that the
point of
attachment is through the non-aromatic, non-heterocyclic ring carbocyclic
ring. Examples
of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl,
cyclobutyl,
cyclopentyl, and cyclooctyl. Other examples of cycloalkyl groups include
bicycle[2,2,2,]octanyl, norbornyl, and spirobicyclo groups such as
spiro[4.5]dec-8-yl.
[0288] "Cycloalkenyl" refers to non-aromatic cyclic alkyl groups of from 3 to
10 carbon
atoms having single or multiple cyclic rings and having at least one >C=C
ring
unsaturation and preferably from 1 to 2 sites of >C=C ring unsaturation.
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[0289] "Substituted cycloalkyl" and "substituted cycloalkenyl" refers to a
cycloalkyl or
cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents
selected from the
group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl,
substituted alkenyl,
alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino,
acyloxy, amino,
substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,
aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy,
aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted
aryloxy, arylthio,
substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino,
(carboxyl ester)oxy,
cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted
cycloalkyloxy,
cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted
cycloalkenyl,
cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted
cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl,
substituted
heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio,
substituted
heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,
substituted
heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H,
substituted
sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,
wherein said
substituents are defined herein.
[0290] "Cycloalkyloxy" refers to -0-cycloalkyl.
[0291] "Substituted cycloalkyloxy" refers to -0-(substituted cycloalkyl).
[0292] "Cycloalkylthio" refers to -S-cycloalkyl.
[0293] "Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl).
[0294] "Cycloalkenyloxy" refers to -0-cycloalkenyl.
[0295] "Substituted cycloalkenyloxy" refers to -0-(substituted cycloalkenyl).
[0296] "Cycloalkenylthio" refers to -S-cycloalkenyl.
[0297] "Substituted cycloalkenylthio" refers to -S-(substituted cycloalkenyl).
[0298] "Guanidino" refers to the group -NHC(=NH)NH2.
[0299] "Substituted guanidino" refers to -NR44q_NR44)N(R44)2 where each R44 is

independently selected from the group consisting of hydrogen, alkyl,
substituted alkyl,
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aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted
heterocyclic and two R44 groups attached to a common guanidino nitrogen atom
are
optionally joined together with the nitrogen bound thereto to form a
heterocyclic or
substituted heterocyclic group, provided that at least one R44 is not
hydrogen, and wherein
said substituents are as defined herein.
[0300] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and
preferably is
fluoro or chloro.
[0301] "Haloalkyl" refers to alkyl groups substituted with 1 to 5, 1 to 3, or
1 to 2 halo
groups, wherein alkyl and halo are as defined herein.
[0302] "Haloalkoxy" refers to alkoxy groups substituted with 1 to 5, 1 to 3,
or 1 to 2
halo groups, wherein alkoxy and halo are as defined herein.
[0303] "Haloalkylthio" refers to alkylthio groups substituted with 1 to 5, 1
to 3, or 1 to 2
halo groups, wherein alkylthio and halo are as defined herein.
[0304] "Hydroxy" or "hydroxyl" refers to the group -OH.
[0305] "Heteroaryl" refers to an aromatic group of from 1 to 10 carbon atoms
and 1 to 4
heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur
within the
ring. Such heteroaryl groups can have a single ring (e.g., pyridyl, pyridinyl
or furyl) or
multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the
condensed rings
may or may not be aromatic and/or contain a heteroatom provided that the point
of
attachment is through an atom of the aromatic heteroaryl group. In one
embodiment, the
nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally
oxidized to
provide for the N-oxide (N¨>0), sulfinyl, and/or sulfonyl moieties. Preferred
heteroaryls
include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
[0306] "Substituted heteroaryl" refers to heteroaryl groups that are
substituted with from
1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected
from the group
consisting of the same group of substituents defined for substituted aryl.
[0307] "Heteroaryloxy" refers to -0-heteroaryl.
[0308] "Substituted heteroaryloxy" refers to the group -0-(substituted
heteroaryl).
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[0309] "Heteroarylthio" refers to the group -S-heteroaryl.
[0310] "Substituted heteroarylthio" refers to the group -S-(substituted
heteroaryl).
[0311] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocycly1"
refers to
a saturated or partially saturated, but not aromatic, group having from 1 to
10 ring carbon
atoms and from 1 to 4 ring heteroatoms selected from the group consisting of
nitrogen,
sulfur, or oxygen. Heterocycle encompasses single ring or multiple condensed
rings,
including fused bridged and Spiro ring systems. In fused ring systems, one or
more the
rings can be cycloalkyl, aryl, or heteroaryl provided that the point of
attachment is through
the non-aromatic heterocyclic ring. In one embodiment, the nitrogen and/or
sulfur atom(s)
of the heterocyclic group are optionally oxidized to provide for the N-oxide,
sulfinyl,
and/or sulfonyl moieties.
[0312] "Substituted heterocyclic" or "substituted heterocycloalkyl" or
"substituted
heterocycly1" refers to heterocyclyl groups that are substituted with from 1
to 5 or
preferably 1 to 3 of the same substituents as defined for substituted
cycloalkyl.
[0313] "Heterocyclyloxy" refers to the group -0-heterocycyl.
[0314] "Substituted heterocyclyloxy" refers to the group -0-(substituted
heterocycyl).
[0315] "Heterocyclylthio" refers to the group -S-heterocycyl.
[0316] "Substituted heterocyclylthio" refers to the group -S-(substituted
heterocycyl).
[0317] Examples of heterocycle and heteroaryls include, but are not limited
to, azetidine,
pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,
indolizine,
isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline,
quinoline,
phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,
carbazole,
carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine,
isoxazole,
phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine,
piperazine, indoline,
phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-
tetrahydrobenzo[b]thiophene,
thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl,
thiomorpholinyl (also
referred to as thiamorpholinyl), 1,1-dioxothiomotpholinyl, piperidinyl,
pyrrolidine, and
tetrahydrofuranyl.
[0318] "Nitro" refers to the group -NO2.
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[0319] "Oxo" refers to the atom (-0) or (-0).
[0320] "Spiro ring systems" refers to bicyclic ring systems that have a single
ring carbon
atom common to both rings.
[0321] "Sulfonyl" refers to the divalent group -S(0)2-.
[0322] "Substituted sulfonyl" refers to the group -S02-alkyl, -S02-substituted

alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-
substituted
cylcoakl, -S02-cycloalkenyl, -S02-substituted cylcoalkenyl, -S02-aryl, -S02-
substituted
aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S02-
substituted
heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl,
substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
substituted
cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,
heterocyclic, and
substituted heterocyclic are as defined herein. Substituted sulfonyl includes
groups such as
methyl-S02-, phenyl-S02-, and 4-methylphenyl-S02-. The term "alkylsulfonyl"
refers
to -502-alkyl. The term "haloalkylsulfonyl" refers to -502-haloallcyl where
haloallcyl is
defined herein. The term "(substituted sulfonyl)amino" refers to -
NH(substituted
sulfonyl), and the term "(substituted sulfonyl)aminocarbonyl" refers to -
C(0)NH(substituted sulfonyl), wherein substituted sulfonyl is as defined
herein.
[0323] "Sulfonyloxy" refers to the group -0502-alkyl, -0S02-substituted
alkyl, -0S02-alkenyl, -0S02-substituted alkenyl, -0S02-cycloalkyl, -0S02-
substituted
cylcoalkyl, -0502-cycloalkenyl, -0502-substituted
cylcoalkeny1,-0S02-aryl, -0S02-substituted aryl, -0S02-heteroaryl, -0S02-
substituted
heteroaryl, -0S02-heterocyclic, -0502-substituted heterocyclic, wherein alkyl,
substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,
substituted
cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl,
heteroaryl,
substituted heteroaryl, heterocyclic, and substituted heterocyclic are as
defined herein.
[0324] "Thioacyl" refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-
C(S)-,
alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-
C(S)-,
cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-,
substituted
cycloalkenyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-,
substituted
heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-,
wherein alkyl,
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substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
cycloalkyl,
substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,
substituted aryl,
heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic
are as defined
herein.
[0325] "Thiol" refers to the group -SH.
[0326] "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent
to -C(=S)-.
[0327] "Thione" refers to the atom (=S).
[0328] "Alkylthio" refers to the group -S-alkyl wherein alkyl is as defined
herein.
[0329] "Substituted alkylthio" refers to the group -S-(substituted alkyl)
wherein
substituted alkyl is as defined herein.
[0330] "Compound" or "compounds" as used herein is meant to include the
stereoiosmers and tautomers of the indicated formulas.
[0331] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the
chirality
of one or more stereocenters. Stereoisomers include enantiomers and
diastereomers.
[0332] "Tautomer" refer to alternate forms of a compound that differ in the
position of a
proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms
of
heteroaryl groups containing a ring atom attached to both a ring -NH- moiety
and a ring
=N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and
tetrazoles.
[0333] As used herein, the term "phosphate ester" refers to any one of the
mono-, di- or
triphosphate esters of noribogaine, wherein the mono-, di- or triphosphate
ester moiety is
bonded to the 12-hydroxy group and/or the indole nitrogen of noribogaine.
[0334] As used herein, the term "phosphate ester" refers to any one of the
mono-, di- or
triphosphate esters of noribogaine, wherein the mono-, di- or triphosphate
ester moiety is
bonded to the 12-hydroxy group and/or the indole nitrogen of noribogaine.
[0335] As used herein, the term "monophosphate" refers to the group
¨P(0)(OH)2.
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[0336] As used herein, the term "diphosphate" refers to the group ¨P(0)(OH)-
0P(0)(OH)2.
[0337] As used herein, the term "triphosphate" refers to the group ¨P(0)(OH)-
(0P(0)(OH))20H.
[0338] As used herein, the term "ester" as it refers to esters of the mono-,
di- or
triphosphate group means esters of the monophosphate can be represented by the
formula
¨P(0)(0R45)2, where each R45 is independently hydrogen, C1-C12 alkyl, C3-Cio
cycloalkyl,
C6-C14 aryl, heteroaryl of 1 to 10 carbon atoms and 1 to 4 optionally oxidized
heteroatoms
selected from the group consisting of oxygen, nitrogen, and sulfur and the
like, provided
that at least one R45 is not hydrogen. Likewise, exemplary esters of the di-
or triphosphate
can be represented by the formulas ¨P(0)(0R45)-0P(0)(0R45)2
and -P(0)(0R45)-(0P(0)(0R45))20R45, where R45 is as defined above.
[0339] As used herein, the term "hydrolyzable group" refers to a group that
can be
hydrolyzed to release the free hydroxy group under hydrolysis conditions.
Examples of
hydrolysable group include, but are not limited to those defined for R above.
Preferred
hydrolysable groups include carboxyl esters, phosphates and phosphate esters.
The
hydrolysis may be done by chemical reactions conditions such as base
hydrolysis or acid
hydrolysis or may be done in vivo by biological processes, such as those
catalyzed by a
phosphate hydrolysis enzyme. Nonlimiting examples of hydrolysable group
include
groups linked with an ester-based linker (-C(0)0- or -0C(0)-), an amide-based
linker
(-C(0)NR46- or ¨NR46C(0)-), or a phosphate-linker (-P(0)(0R46)-0-, -0-
P(S)(0R46)-0-, -
0-P(S)(SR46)-0-, -S-P(0)(0R46)-0-, -0-P(0)(0R46)-S-, -S-P(0)(0R46)-S-
, -0-P(S)(0R46)-S-, -S-P(S)(0R46)-0-, -0-P(0)(R46)-0-, -0-P(S)(R46)-0-
, -S-P(0)(R46)-0-, -S-P(S)(R46)-0-, -S-P(0)(R46)-S-, or -0-P(S)(R46)-S-) where
R46 can be
hydrogen or alkyl.
[0340] Substituted groups of this invention, as set forth above, do not
include polymers
obtained by an infinite chain of substituted groups. At most, any substituted
group can be
substituted up to five times.
[0341] "Noribogaine" refers to the compound:
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HO C2H 5
as well as noribogaine derivatives or pharmaceutically acceptable salts and
pharmaceutically acceptable solvates thereof. It should be understood that
where
"noribogaine" is mentioned herein, one more polymorphs of noribogaine can be
utilized
and are contemplated. In some embodiments, noribogaine is noribogaine
glucuronide.
[0342] Noribogaine can be prepared by demethylation of naturally occurring
ibogaine:
H3C0 C2 H5
which is isolated from Tabernanth iboga, a shrub of West Africa. Demethylation
may be
accomplished by conventional techniques such as by reaction with boron
tribromide/methylene chloride at room temperature followed by conventional
purification.
See, for example, Huffman, et al., J. Org. Chem. 50:1460 (1985), which
incorporated
herein by reference in its entirety. Noribogaine can be synthesized as
described, for
example in U.S. Patent Pub. Nos. 2013/0165647, 2013/0303756, and 2012/0253037,
PCT
Patent Publication No. WO 2013/040471 (includes description of making
noribogaine
polymorphs), and U.S. Patent App. No. 13/593,454, each of which is
incorporated herein
by reference in its entirety.
[0343] "Noribogaine derivatives" refer to, without limitation, esters or 0-
carbamates of
noribogaine, or pharmaceutically acceptable salts and/or solvates of each
thereof. Also
encompassed within this invention are derivatives of noribogaine that act as
prodrug forms
of noribogaine. A prodrug is a pharmacological substance administered in an
inactive (or
significantly less active) form. Once administered, the prodrug is metabolized
in vivo into
an active metabolite. Noribogaine derivatives include, without limitation,
those
compounds set forth in US Patent Nos. 6,348,456 and 8,362,007; as well as in
US Patent
Application Serial No. 13/165,626; and US Patent Application Publication Nos.
U52013/0131046; U52013/0165647; U52013/0165425; and U52013/0165414; all of
which are incorporated herein by reference. Non-limiting examples of
noribogaine
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derivatives encompassed by this invention are given in more detail in the
"Compositions"
section below.
[0344] In some embodiments, the methods of the present disclosure entail the
administration of a prodrug of noribogaine that provides the desired maximum
serum
concentrations and efficacious average noribogaine serum levels. A prodrug of
noribogaine refers to a compound that metabolizes, in vivo, to noribogaine. In
some
embodiments, the prodrug is selected to be readily cleavable either by a
cleavable linking
arm or by cleavage of the prodrug entity that binds to noribogaine such that
noribogaine is
generated in vivo. In one preferred embodiment, the prodrug moiety is selected
to
facilitate binding to the and/or lc receptors in the brain either by
facilitating passage
across the blood brain barrier or by targeting brain receptors other than the
i and/or
receptors. Examples of prodrugs of noribogaine are provided in United States
Patent
Application Serial No. 13/165,626, the entire content of which is incorporated
herein by
reference.
[0345] This invention is not limited to any particular chemical form of
noribogaine or
noribogaine derivative, and the drug may be given to patients either as a free
base, solvate,
or as a pharmaceutically acceptable acid addition salt. In the latter case,
the hydrochloride
salt is generally preferred, but other salts derived from organic or inorganic
acids may also
be used. Examples of such acids include, without limitation, those described
below as
"pharmaceutically acceptable salts" and the like.
[0346] "Pharmaceutically acceptable composition" refers to a composition that
is
suitable for administration to a mammal, preferably a human. Such compositions
include
various excipients, diluents, carriers, and such other inactive agents well
known to the
skilled artisan.
[0347] "Pharmaceutically acceptable salt" refers to pharmaceutically
acceptable salts,
including pharmaceutically acceptable partial salts, of a compound, which
salts are derived
from a variety of organic and inorganic counter ions well known in the art and
include, by
way of example only, hydrochloric acid, hydrobromic acid, phosphoric acid,
sulfuric acid,
methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic
acid, tartaric
acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid,
aconitic acid, salicylic
acid, thalic acid, embonic acid, enanthic acid, oxalic acid and the like, and
when the
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molecule contains an acidic functionality, include, by way of example only,
sodium,
potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like.
[0348] A "pharmaceutically acceptable solvate" or "hydrate" of a compound of
the
invention means a solvate or hydrate complex that is pharmaceutically
acceptable and that
possesses the desired pharmacological activity of the parent compound, and
includes, but
is not limited to, complexes of a compound of the invention with one or more
solvent or
water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or
4, solvent or
water molecules.
[0349] As used herein the term "solvate" is taken to mean that a solid-form of
a
compound that crystallizes with one or more molecules of solvent trapped
inside. A few
examples of solvents that can be used to create solvates, such as
pharmaceutically
acceptable solvates, include, but are certainly not limited to, water,
methanol, ethanol,
isopropa,nol, butanol, C1-C6 alcohols in general (and optionally substituted),

tetrahydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid,
formic acid,
water, and solvent mixtures thereof. Other such biocompatible solvents which
may aid in
making a pharmaceutically acceptable solvate are well known in the art and
applicable to
the present invention. Additionally, various organic and inorganic acids and
bases can be
added or even used alone as the solvent to create a desired solvate. Such
acids and bases
are known in the art. When the solvent is water, the solvate can be referred
to as a hydrate.
Further, by being left in the atmosphere or recrystallized, the compounds of
the present
invention may absorb moisture, may include one or more molecules of water in
the formed
crystal, and thus become a hydrate. Even when such hydrates are formed, they
are
included in the term "solvate". Solvate also is meant to include such
compositions where
another compound or complex co-crystallizes with the compound of interest. The
term
"solvate" as used herein refers to complexes with solvents in which
noribogaine is reacted
or from which noribogaine is precipitated or crystallized. For example, a
complex with
water is known as a "hydrate". Solvates of noribogaine are within the scope of
the
invention. It will be appreciated by those skilled in organic chemistry that
many organic
compounds can exist in more than one crystalline form. For example,
crystalline form may
vary based on the solvate used. Thus, all crystalline forms of noribogaine or
the
pharmaceutically acceptable solvates thereof are within the scope of the
present invention.
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[0350] "Therapeutically effective amount" or "therapeutic amount" refers to an
amount
of a drug or an agent that, when administered to a patient suffering from a
condition, will
have the intended therapeutic effect, e.g., alleviation, amelioration,
palliation or
elimination of one or more manifestations of the condition in the patient. The

therapeutically effective amount will vary depending upon the patient and the
condition
being treated, the weight and age of the subject, the severity of the
condition, the salt,
solvate, or derivative of the active drug portion chosen, the particular
composition or
excipient chosen, the dosing regimen to be followed, timing of administration,
the manner
of administration and the like, all of which can be determined readily by one
of ordinary
skill in the art. The full therapeutic effect does not necessarily occur by
administration of
one dose, and may occur only after administration of a series of doses. Thus,
a
therapeutically effective amount may be administered in one or more
administrations. For
example, and without limitation, a therapeutically effective amount of
noribogaine, in the
context of treating opioid or opioid-like drug dependency, refers to an amount
of
noribogaine that attenuates the dependency and/or symptoms of acute withdrawal
for at
least about 2 hours beyond control (placebo), at least about 5 hours beyond
control, and
preferably at least about 10 hours beyond control. For example, and without
limitation, a
therapeutically effective amount of an agent, such as noribogaine, in the
context of treating
nicotine dependency, refers to an amount of the agent that attenuates the
dependency
and/or statistically presents little or no risk of relapse to nicotine use.
For example, and
without limitation, a therapeutically effective amount of noribogaine, in the
context of
treating alcohol dependency, refers to an amount of noribogaine that
attenuates the
dependency and/or symptoms of acute withdrawal for at least 2 hours beyond
control
(placebo), at least 5 hours beyond control, and preferably at least 10 hours
beyond control.
For example, and without limitation, a therapeutically effective amount of
noribogaine, in
the context of treating drug dependency, refers to an amount of noribogaine
that attenuates
the dependency and/or symptoms of acute withdrawal for at least 2 hours beyond
control
(placebo), at least 5 hours beyond control, and preferably at least 10 hours
beyond control.
For example, and without limitation, a therapeutically effective amount of
noribogaine, in
the context of modulating opioid analgesic tolerance, refers to an amount of
noribogaine
that resensitizes the patient to the opioid analgesic therapy.
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[0351] The therapeutically effective amount of the compound may be higher or
lower,
depending on the route of administration used. For example, when direct blood
administration (e.g., sublingual, pulmonary and intranasal delivery) is used,
a lower dose
of the compound may be administered. In one aspect, a therapeutically
effective amount of
noribogaine or derivative is from about 50 ng to less than 100 i.tg per kg of
body weight.
Where other routes of administration are used, a higher dose of the compound
may be
administered. In one embodiment, the therapeutically effective amount of the
compound
is from greater than about 1 mg to about 8 mg per kg of body weight per day.
[0352] A "therapeutic level" of a drug is an amount of noribogaine,
noribogaine
derivative, or pharmaceutical salt or solvate thereof that is sufficient to
treat a disease or
disorder or symptoms of a disease or disorder or to treat, prevent, or
attenuate a disease or
disorder or symptoms of a disease or disorder but not high enough to pose any
significant
risk to the patient. Therapeutic levels of drugs can be determined by tests
that measure the
actual concentration of the compound in the blood of the patient. This
concentration is
referred to as the "serum concentration." Where the serum concentration of
noribogaine is
mentioned, it is to be understood that the term "noribogaine" encompasses any
form of
noribogaine, including derivatives thereof.
[0353] A "sub-therapeutic level" of noribogaine or pharmaceutical salt and/or
solvate
thereof that is less than the therapeutic level described above. For example,
the sub-
therapeutic level of noribogaine may be e.g., 80%, 70%, 60%, 50%, 40%, 30%,
20%, or
10% less than a therapeutically effective amount (e.g., 120 mg) of
noribogaine, or any
subvalue or subrange there between. Sub-therapeutic levels of noribogaine may
coincide
with "maintenance amounts" of noribogaine which are amounts, less than the
therapeutically effective amount, that provide some attenuation and/or
prevention of post-
acute withdrawal syndrome in a patient. The maintenance amount of the compound
is
expected to be less than the therapeutically effective amount because the
level of
inhibition does not need to be as high in a patient who is no longer
physically addicted to
opioid or opioid-like drug.
[0354] As defined herein, a "prophylactically effective amount" of a drug is
an amount,
typically less than the therapeutically effective amount, that provides
attenuation and/or
prevention of a disease or disorder or symptoms of a disease or disorder in a
patient. For
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example, the prophylactically effective amount of the compound is expected to
be less
than the therapeutically effective amount because the level of inhibition does
not need to
be as high in a patient who no longer has a disease or disorder or symptoms of
a disease or
disorder (e.g., no longer physically addicted to nicotine). For example, a
prophylactically
effective amount is preferably 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%
less
than a therapeutically effective amount. However, a prophylactically effective
amount
may be the same as the therapeutically effective amount, for example when a
patient who
is physically addicted to nicotine is administered noribogaine to attenuate
cravings for a
period of time when nicotine use is not feasible. The prophylactically
effective amount
may vary for different a diseases or disorders or symptoms of different
diseases or
disorders.
[0355] As defined herein, a "maintenance amount" of a drug or an agent is an
amount,
typically less than the therapeutically effective amount that provides
attenuation and/or
prevention of syndrome disease or disorder or symptoms of a disease or
disorder in a
patient. The maintenance amount of the compound is expected to be less than
the
therapeutically effective amount because the level of inhibition does not need
to be as high
in a patient who is no longer physically manifests a disease or disorder or
symptoms of a
disease or disorder. For example, a maintenance amount is preferably 90%, 80%,
70%,
60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount,
or any
subvalue or subrange there between.
[0356] "Treatment," "treating," and "treat" are defined as acting upon a
disease,
disorder, or condition with an agent, such as noribogaine to reduce or
ameliorate harmful
or any other undesired effects of the disease, disorder, or condition and/or
its symptoms.
"Treatment," as used herein, covers the treatment of a human patient, and
includes: (a)
reducing the risk of occurrence of the condition in a patient determined to be
predisposed
to the condition but not yet diagnosed as having the condition, (b) impeding
the
development of the condition, and/or (c) relieving the condition, i.e.,
causing regression of
the condition and/or relieving one or more symptoms of the condition.
"Treating" or
"treatment of' a condition or patient refers to taking steps to obtain
beneficial or desired
results, including clinical results such as the reduction of symptoms. For
purposes of this
invention, beneficial or desired clinical results include, but are not limited
to: treating
nicotine addiction; treating, preventing, and/or attenuating cravings for
nicotine; and
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preventing relapse of nicotine use. This includes reducing or eliminating
smoking in the
patient, and/or reducing or eliminating symptoms of withdrawal, cravings, and
the like.
For some purposes of this invention, beneficial or desired clinical results
include, but are
not limited to: treating substance addiction; treating, preventing, and/or
attenuating acute
withdrawal symptoms; treating, preventing, and/or attenuating long-term (post-
acute)
withdrawal symptoms; and preventing relapse of substance use. For purposes of
certain
aspects of this invention, beneficial or desired clinical results include, but
are not limited
to: pain relief in all categories and classifications of pain; treating,
alleviating and/or
preventing acute and/or chronic pain; treating, alleviating and/or preventing
cutaneous,
somatic, visceral and/or neuropathic pain; and preventing the recurrence of
long-term pain.
[0357] As used herein, the term "patient" refers to mammals and includes
humans and
non-human mammals.
[0358] As used herein, the term "opiate" refers to naturally-occurring
alkaloids found in
the opium poppy. These include codeine, morphine, oripavine, pseudomorphine,
and
thebaine. Also included are opium, opium poppy, poppy straw, and extracts and
concentrates thereof.
[0359] As used herein, the term "opioid" refers to naturally-occurring opiates
and
synthetic or semi-synthetic opioids that have psychoactive effects. Non-
limiting examples
include acetyl-alpha-methylphentanyl, acetylmethadol, alfentanil,
allylprodine,
alphacetylmethadol, alphamethadol, alpha-methylfentanyl, alpha-
methylthiofentanyl,
alphaprodine, anileridine, benzylmorphine, benzethidine, betacetylmethadol,
beta-
hydroxyfentanyl, beta-hydroxy-3-methylfentanyl, betameprodine,
betacetylmethadol,
beta-hydroxyfentanyl, beta-hydroxy-3-methylfentanyl, betameprodine,
betamethadol,
betaprodine, bezitramide, buprenorphine, butorphanol, carfentanil,
clonitazene, codeine,
desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide,
diamorphone, diethylthiambutene, dihydrocodeine, dihydroetorphine,
dihydromorphine,
dimenoxadol, dimepheptanol, dimethyl- thiambutene, dioxaphetyl butyrate,
diphenoxylate,
difenoxin, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,
ethylmorphine,
etonitazene, etorphine, etoxeridine, fentanyl, furethidine, heroin,
hydrocodone,
hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levo-
alphacetylmethadol, levomethorphan, levorphanol, levophenacylmorphan,
levomoramide,
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lofentanil, loperamide, laudanum, meperidine, meptazinol, metazocine,
methadone, 3-
methylfentanyl, 3-methylthiofentanyl, metopon, morphine, morpheridine, MPPP (1-

methy1-4-pheny1-4-propionoxypiperidine), myrophine, narceine, nicomorphine,
noracymethadol, norlevorphanol, normethadone, nalorphine, nalbuphene,
normorphine,
norpipanone, opium, oxycodone, oxymorphone, papaveretum, para-fluorofentanyl,
paregoric, PEPAP (1+2-phenethyl)-4-phenyl-4-acetoxypiperidine), pentazocine,
phenadoxone, phenampromide, phenomorphan, phenazocine, phenoperidine,
piminodine,
piritramide, propheptazine, promedol, properidine, propiram, propoxyphene,
racemoramide, racemethorphan, racemorphan, remifentanil, sufentanil,
tapentadol,
thebaine, thiofentanyl, tilidine, tramadol, trimeperidine, mixtures of any of
the foregoing,
salts of any of the foregoing, derivatives of any of the foregoing, and the
like. The term
opioids also encompasses opioid intermediates, including 4-cyano-2-
dimethylamino-4,4-
diphenyl butane, 2-methy1-3-morpholino-1,1-diphenylpropane-carboxylic acid, 4-
cyano-1-
methy1-4-phenylpiperidine, ethyl-4-phenylpiperidine-4-carboxylate, and 1-
methy1-4-
phenylpiperidine-4-carboxylic acid. Many opioids are Schedule I or Schedule II
drugs in
the US. Certain preferred examples of opioids include, without limitation,
buprenorphine,
codeine, heroine, hydrocodone, oxycodone, morphine, thebaine, and their
derivatives,
which will be well known to the skilled artisan.
[0360] As used herein, the term "opioid-like drug" refers to any illicit drug
that binds to
one or more opioid receptor and causes opioid-like addiction. Acute and long-
term
withdrawal symptoms from cessation of use of such drugs may be similar to
those from
cessation of opioids. Opioid-like drugs include amphetamine, methamphetamine,
ketamine, and cocaine.
[0361] As used herein, the term "QT interval" refers to the measure of the
time between
the start of the Q wave and the end of the T wave in the electrical cycle of
the heart.
Prolongation of the QT interval refers to an increase in the QT interval.
[0362] As used herein, the terms "addiction," "abuse" and "dependence" are
used
interchangeably to refer to the patient's inability to stop using the opioid
or opioid-like
drug, nicotine, alcohol, addictive substance, or the like, even when it would
be in his/her
best interest to stop. The DSMIV-TR criteria for dependency include:
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Dependence or significant impairment or distress, as manifested by 3 or
more of the following during a 12 month period:
1. Tolerance or markedly increased amounts of the substance to
achieve intoxication or desired effect or markedly diminished effect with
continued use of the same amount of substance;
2. Withdrawal symptoms or the use of certain substances to avoid
withdrawal symptoms;
3. Use of a substance in larger amounts or over a longer period than
was intended;
4. Persistent desire or unsuccessful efforts to cut down or control
substance use;
5. Involvement in chronic behavior to obtain the substance, use the
substance, or recover from its effects;
6. Reduction or abandonment of social, occupational or recreational
activities because of substance use;
7. Use of substances even though there is a persistent or recurrent
physical or psychological problem that is likely to have been caused or
exacerbated by the substance.
103631 As used herein, the term "nicotine addict in remission" refers to any
patient who
has quit using nicotine for a period of time. As used herein, a nicotine
addict in remission
includes any person who was previously addicted to nicotine in any form,
including but
not limited to cigarettes, electronic cigarettes or vaporizers ("vaping"),
chewing tobacco,
cigars, snuff, pipes, hookahs, and the like. The period of time since the
nicotine addict in
remission quit using nicotine may be short, for example one day to a few
weeks, or longer-
term, for example months or years. Preferably, the patient has quit using
nicotine long
enough to no longer exhibit physical symptoms of nicotine addiction. The
patient may
exhibit psychological symptoms of nicotine addiction. In some embodiments, the
patient
does not exhibit psychological symptoms of nicotine addiction.
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[0364] As used herein, the terms "addictive substance", "drug", "addictive
drug" and the
like refer to drugs and other substances whose use results in addiction in at
least a subset
of individuals who use them. Addictive substances include, without limitation,

benzodiazepines (including chlordiazepoxide, clorazepate, diazepam,
flurazepam,
halazepam, prazepam, lorazepam, lormetazepam, oxazepam, temazepam, clonazepam,

flunitrazepam, nimetazepam, nitrazepam, adinazolam, alprazolam, estazolam,
triazolam,
climazolam, loprazolam, and midazolam), cannabinoids and synthetic
cannabinoids,
stimulants (including amphetamine, methylphenidate, dexmethylphenidate,
dextroamphetamine, mixed amphetamine salts, dextromethamphetamine,
lisdexamfetamine, modafinil, adrafinil, armodafinil, caffeine, ephedrine,
methylenedioxymethamphetamine, methylenedioxypyrovalerone, mephedrone,
phenylpropanolamine, propylhexadrine, pseudoephedrine, and khat), barbiturates

(including allobarbital, amobarbital, aprobarbital, alphenal, barbital,
brallobarbital,
pentobarbital, phenobarbital, and secobarbital), gamma-hydroxybutyrate (GHB),
ketamine, opiate, opioid, opioid-like drug, PCP, dextromethorphan (DXM),
lysergic acid
diethylamide (LSD), mescaline, anabolic steroids, and derivatives of each
thereof.
Addictive substances may be illicit drugs, prescription drugs prone to abuse,
or other legal
drugs prone to abuse.
[0365] Obsessive compulsive disorder (OCD) is characterized by recurrent and
persistent ideas, thoughts, impulses or images (obsessions) that are ego-
dystonic and/or
repetitive, purposeful and intentional behaviors (compulsions) that are
recognized by the
person as excessive or unreasonable (American Psychiatric Association, 1994a).
The
obsessions or compulsions cause marked distress, are time-consuming, and/or
significantly
interfere with social or occupational functioning.
[0366] Panic disorder is characterized by recurrent unexpected panic attacks
and
associated concern about having additional attacks, worry about the
implications or
consequences of the attacks, and/or a significant change in behavior related
to the attacks
(American Psychiatric Association, 1994a). A panic attack is defined as a
discrete period
of intense fear or discomfort in which four (or more) of the following
symptoms develop
abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart,
or
accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations
of shortness
of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort;
(7) nausea or
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abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9)
derealization
(feelings of unreality) or depersonalization (being detached from oneself);
(10) fear of
losing control; (11) fear of dying; (12) paresthesias (numbness or tingling
sensations); (13)
chills or hot flushes. Panic disorder may or may not be associated with
agoraphobia, or an
irrational and often disabling fear of being out in public.
[0367] Social anxiety disorder, also known as social phobia, is characterized
by a
marked and persistent fear of one or more social or performance situations in
which the
person is exposed to unfamiliar people or to possible scrutiny by others
(American
Psychiatric Association, 1994a). Exposure to the feared situation almost
invariably
provokes anxiety, which may approach the intensity of a panic attack. The
feared
situations are avoided or endured with intense anxiety or distress. The
avoidance, anxious
anticipation, or distress in the feared situation(s) int' erferes
significantly with the person's
normal routine, occupational or academic functioning, or social activities or
relationships,
or there is marked distress about having the phobias. Lesser degrees of
performance
anxiety or shyness generally do not require psychopharmacological treatment.
[0368] Generalized anxiety disorder is characterized by excessive anxiety and
worry
(apprehensive expectation) that is persistent for at least 6 months and which
the person
finds difficult to control (American Psychiatric Association, 1994a). It must
be associated
with at least 3 of the following 6 symptoms: restlessness or feeling keyed up
or on edge,
being easily fatigued, difficulty concentrating or mind going blank,
irritability, muscle
tension, and sleep disturbance. The diagnostic criteria for this disorder are
described in
further detail in DSM-IV, which is incorporated herein by reference (American
Psychiatric
Association, 1994a).
[0369] Impulse control disorder is a class of psychiatric disorders involving
the failure to
resist a temptation, urge, or impulse (impulsivity) where such impulse is
potentially
harmful to the patient and/or others. The American Psychiatric Association's
DSM-5
(May 2013) includes impulse control disorders "characterized by problems in
emotional
and behavioral self-control". These include borderline personality disorder,
conduct
disorder, antisocial personality disorder, attention deficit hyperactivity
disorder (ADHD),
schizophrenia, mood disorders, pathological gambling, pyromania, intermittent
explosive
disorder, kleptomania, sexual compulsion, paraphilia, interne addiction,
trichotillomania,
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pathological skin picking, and compulsive shopping. Impulse control disorder
may be
related to anxiety disorder and/or OCD.
[0370] Violence and anger, particularly when out of proportion to a stimulus
and/or a
result of pathological anger, are associated with a number of mental
disorders. These
include oppositional defiant disorder, attention-deficit/hyperactivity
disorder and conduct
disorder (in children and adolescents), psychotic disorder, bipolar disorder,
antisocial,
borderline, paranoid and narcissistic personality disorders, adjustment
disorder with
disturbance of conduct, and intermittent explosive disorder. Pathological
anger and
violence account for a significant portion of violent crimes, including many
high-profile
crimes involving multiple victims. Highly volatile individuals are over-
represented in the
prison system in the United States.
[0371] As used herein, the term "pain" refers to all categories and
classifications of pain,
which are summarized below for purposes of illustration. First, cutaneous pain
is caused
by injury to the skin or superficial tissues. Cutaneous nociceptors terminate
just below the
skin, and due to the high concentration of nerve endings, produce a well-
defined, localized
pain of short duration. Example injuries that produce cutaneous pain include
paper cuts,
minor burns (e.g., first degree burns) and superficial lacerations.
[0372] Second, somatic pain originates from ligaments, tendons, bones, blood
vessels,
and even nerves themselves, and is detected with somatic nociceptors. The
scarcity of
nociceptors in these areas produces a sharp, aching, pain of longer duration
than cutaneous
pain and somewhat less localized. Examples include a sprained ankle or broken
bones.
[0373] Third, visceral pain originates from body organs. Visceral nociceptors
are located
within body organs and internal cavities. Similar to somatic pain, a scarcity
of nociceptors
in these areas produces a pain usually more aching and of a longer duration
than somatic
pain. Visceral pain may be more difficult to localize. Injuries to visceral
tissue may exhibit
"referred" pain, where the sensation is localized to an area completely
unrelated to the site
of injury. Myocardial ischaemia (i.e., the loss of blood flow to a part of the
heart muscle
tissue) is an example of referred pain; the sensation can occur in the upper
chest as a
restricted feeling, or as an ache in the left shoulder, arm, or hand. Another
example of
referred pain is phantom limb pain. Phantom limb pain is the sensation of pain
from a limb
that a person no longer has or from which the person no longer receives
physical signals.
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This phenomena _______________________________________ also known as
deafferentation pain is almost universally reported by
amputees and quadriplegics.
[0374] Fourth, neuropathic pain (e.g., "neuralgia") can occur as a result of
injury or
disease to the nerve tissue itself. The injury or disease can disrupt the
ability of the sensory
nerves to transmit correct information to the thalamus or cortex.
Consequently, the brain
interprets painful stimuli even though there is no obvious or documented
physiologic
cause for the pain.
[0375] Other pain classifications include acute pain and chronic pain. Acute
pain is
defined as short-term pain or pain with an easily identifiable cause. Acute
pain indicates
present damage to tissue or disease and may be "fast" and "sharp" followed by
aching
pain. Acute pain is centralized in one area before becoming somewhat spread
out. Acute
pain generally responds well to medications (e.g., morphine).
[0376] Chronic pain may be medically defined as pain that has lasted six
months or
longer. This constant or intermittent pain has often outlived its purpose
because it does not
help the body to prevent injury. It is often more difficult to treat than
acute pain. Expert
care is generally necessary to treat any pain that has become chronic. In
addition, stronger
medications are typically used for extended periods in an attempt to control
the pain. This
can lead to drug dependency. For example, opioids are used in some instances
for
prolonged periods to control chronic pain. Drug tolerance, chemical
dependency, and even
psychological addiction may occur.
[0377] "Nociceptive pain" refers to pain that is sensed by nociceptors, which
are the
nerves that sense and respond to parts of the body suffering from a damage.
The
nociceptors can signal tissue irritation, impending injury, or actual injury.
When
activated, they transmit pain signals (via the peripheral nerves as well as
the spinal cord)
to the brain. Nociceptive pain is typically well localized, constant, and
often has an aching
or throbbing quality. A subtype of nociceptive pain includes visceral pain and
involves
the internal organs. Visceral pain tends to be episodic and poorly localized.
Nociceptive
pain may be time limited; when the tissue damage heals, the pain typically
resolves.
However, nociceptive pain related to arthritis or cancer may not be time
limited.
Nociceptive pain tends to respond to treatment with opiate analgesics, such
as, for
example, buprenorphin, codeine, hydrocodone, oxycodone, morphine, and the
like.
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Examples of nociceptive pain include, without limitation, pains from sprains,
bone
fractures, burns, bumps, bruises, inflammatory pain from an infection or
arthritic disorder,
pains from obstructions, cancer pain, and myofascial pain related to abnormal
muscle
stresses.
[0378] "Neuropathic pain" refers to chronic pain, often due to tissue injury.
Neuropathic
pain is generally caused by injury or damage to nerve fibers. It may include
burning or
coldness, "pins and needles" sensations, numbness and/or itching. It may be
continuous
and/or episodic. Neuropathic pain is difficult to treat, but opioids,
including, without
limitation, methadone, tramadol, tapentadol, oxycodone, methadone, morphine,
levorphanol, and the like. Causes of neuropathic pain include, without
limitation,
alcoholism; amputation; back, leg, and hip problems; chemotherapy; diabetes;
facial nerve
problems; HIV/AIDS; multiple sclerosis; shingles; spine surgery; trigeminal
neuralgia;
fibromyalgia; and the like. In some cases, the cause of neuropathic pain may
be unclear or
unknown.
[0379] "Addictive" refers to a compound that, when administered to a mammal
over a
period of time, creates dependency in the mammal to that compound. The
dependence can
be physiological and/or psychological. A therapeutic effect of an addictive
compound on
a mammal may decrease with prolonged administration of the addictive compound,
which
is a non-limiting example of a physiological dependence. When administered to
a
mammal, an addictive compound may also create a craving in the mammal for more
of it,
which is a non-limiting example of a psychological dependence. Examples of
addictive
compounds include, without limitation, addictive opioids, and the like.
[0380] "Analgesic" and "analgesic agent" refer to a compound that is capable
of
inhibiting and/or reducing pain in mammals. Pain may be inhibited and/or
reduced in the
mammal by the binding of the opioid analgesic agent to the mu receptor. When
analgesia
is effected through the mu receptor, the analgesic agent is referred to as a
mu receptor
agonist. Certain analgesic agents are capable of inhibiting nociceptive and/or
neuropathic
pain including, by way of example, morphine, codeine, hydromorphone,
oxycodone,
hydrocodone, buprenorphin, and the like.
[0381] The term "tolerance" as used herein refers to the psychological and/or
physiologic process wherein the patient adjusts to the frequent presence of a
substance
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such that a higher dose of the substance is required to achieve the same
effect. Tolerance
may develop at different times for different effects of the same drug (e.g.,
analgesic effect
versus side effects). The mechanisms of tolerance are not entirely understood,
but they
may include receptor down-regulation or desensitization, inhibitory pathway up-

regulation, increased metabolism, and/or changes in receptor processing (e.g.,

phosphorylation).
103821 The term "dose" refers to a range of noribogaine, noribogaine
derivative, or
pharmaceutical salt or solvate thereof that provides a therapeutic serum level
of
noribogaine when given to a patient in need thereof. The dose is recited in a
range, for
example from about 20 mg to about 120 mg, and can be expressed either as
milligrams or
as mg/kg body weight. The attending clinician will select an appropriate dose
from the
range based on the patient's weight, age, degree of addiction, health, and
other relevant
factors, all of which are well within the skill of the art.
103831 The term "unit dose" refers to a dose of drug that is given to the
patient to
provide therapeutic results, independent of the weight of the patient. In such
an instance,
the unit dose is sold in a standard form (e.g., 20 mg tablet). The unit dose
may be
administered as a single dose or a series of subdoses. In some embodiments,
the unit dose
provides a standardized level of drug to the patient, independent of weight of
patient.
Many medications are sold based on a dose that is therapeutic to all patients
based on a
therapeutic window. In such cases, it is not necessary to titrate the dosage
amount based
on the weight of the patient.
Compositions
103841 As will be apparent to the skilled artisan upon reading this
disclosure, this
invention provides compositions for treating or preventing diseases or
disorders or
symptoms of diseases or disorders described herein, comprising noribogaine,
noribogaine
derivatives, prodrugs of noribogaine, pharmaceutically acceptable salts and/or
solvates of
each thereof. This invention further provides compositions for treating,
attenuating, or
preventing symptoms of diseases or disorders described herein, comprising
noribogaine,
noribogaine derivatives, prodrugs of noribogaine, pharmaceutically acceptable
salts and/or
solvates of each thereof.
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[0385] In some embodiments, the composition is formulated for oral,
transdermal,
internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous,
intraarterial,
intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery. In
one
embodiment, the therapeutically effective amount of the compound is from about
1 mg to
about 4 mg per kg body weight per day. In another embodiment, the
therapeutically
effective amount of the compound is from about 1 mg to about 3 mg per kg body
weight
per day. In another embodiment, the therapeutically effective amount of the
compound is
from about lmg to about 2 mg per kg body weight per day. In another
embodiment, the
therapeutically effective amount of the compound is from about 1.3 mg to about
3 mg per
kg body weight per day. In another embodiment, the therapeutically effective
amount of
the compound is from about 1.5 mg to about 3 mg per kg body weight per day. In
another
embodiment, the therapeutically effective amount of the compound is from about
1.3 mg
to about 4 mg per kg body weight per day. In another embodiment, the
therapeutically
effective amount of the compound is from about 1.5 mg to about 4 mg per kg
body weight
per day. The ranges include both extremes as well as any subranges there
between.
[0386] In one embodiment, the therapeutically effective amount of the compound
is
from about 1 mg to about 8 mg per kg body weight per day. In another
embodiment, the
therapeutically effective amount of the compound is from about 1.3 mg to about
7 mg per
kg body weight per day. In another embodiment, the therapeutically effective
amount of
the compound is from about 1.3 mg to about 6 mg per kg body weight per day. In
another
embodiment, the therapeutically effective amount of the compound is from about
1.3 mg
to about 5 mg per kg body weight per day. In another embodiment, the
therapeutically
effective amount of the compound is from about 1.3 mg to about 4 mg per kg
body weight
per day. In another embodiment, the therapeutically effective amount of the
compound is
from about 1.3 mg to about 2 mg per kg body weight per day. In another
embodiment, the
therapeutically effective amount of the compound is from about 1.5 mg to about
3 mg per
kg body weight per day. In another embodiment, the therapeutically effective
amount of
the compound is from about 1.7 mg to about 3 mg per kg body weight per day. In
another
embodiment, the therapeutically effective amount of the compound is from about
2 mg to
about 4 mg per kg body weight per day. In another embodiment, the
therapeutically
effective amount of the compound is from about 2 mg to about 3 mg per kg body
weight
per day.
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[0387] In one embodiment, the therapeutically effective amount of the compound
is
about 8 mg/kg body weight per day. In one embodiment, the therapeutically
effective
amount of the compound is about 7 mg/kg body weight per day. In one
embodiment, the
therapeutically effective amount of the compound is about 6 mg/kg body weight
per day.
In one embodiment, the therapeutically effective amount of the compound is
about 5
mg/kg body weight per day. In one embodiment, the therapeutically effective
amount of
the compound is about 4 mg/kg body weight per day. In one embodiment, the
therapeutically effective amount of the compound is about 3 mg/kg body weight
per day.
In one embodiment, the therapeutically effective amount of the compound is
about 2
mg/kg body weight per day. In one embodiment, the therapeutically effective
amount of
the compound is about 1 mg/kg body weight per day.
[0388] In one embodiment, the therapeutically effective amount of the compound
is
about 4 mg/kg body weight per day. In one embodiment, the therapeutically
effective
amount of the compound is about 3 mg/kg body weight per day. In another
embodiment,
the therapeutically effective amount of the compound is about 2 mg per kg body
weight
per day. In another embodiment, the therapeutically effective amount of the
compound is
about 1.7 mg per kg body weight per day. In another embodiment, the
therapeutically
effective amount of the compound is about 1.5 mg per kg body weight per day.
In another
embodiment, the therapeutically effective amount of the compound is about 1.2
mg per kg
body weight per day. In another embodiment, the therapeutically effective
amount of the
compound is about 1 mg per kg body weight per day.
[0389] In one aspect, the invention provides a pharmaceutical composition
comprising a
therapeutically or prophylactically effective amount of noribogaine and a
pharmaceutically
acceptable excipient, wherein the therapeutically or prophylactically
effective amount of
noribogaine is an amount that delivers an aggregate amount of noribogaine of
about 50 ng
to less than 10 g per kg body weight per day. In some aspects, the
therapeutically or
prophylactically effective amount of noribogaine is an amount that delivers an
aggregate
amount of noribogaine of about 50 ng to about 5 g per kg body weight per day.
In some
aspects, the therapeutically or prophylactically effective amount of
noribogaine is an
amount that delivers an aggregate amount of noribogaine of about 50 ng to
about 1 jig per
kg body weight per day. In some aspects, the composition is formulated for
administration
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once per day. In some aspects, the composition is formulated for
administration two or
more times per day.
[0390] In some embodiments, the composition is formulated for sublingual,
intranasal,
or intrapulmonary delivery. In one aspect, the invention provides a
pharmaceutical
composition comprising a pharmaceutically effective amount of noribogaine and
a
pharmaceutically acceptable excipient, wherein the therapeutically effective
amount of
noribogaine is an amount that delivers an aggregate amount of noribogaine of
50 ng to less
than 100 g per kg body weight per day. In some aspects, the therapeutically
effective
amount of noribogaine is an amount that delivers an aggregate amount of
noribogaine of
50 ng to 50 lag per kg body weight per day. In some aspects, the
therapeutically effective
amount of noribogaine is an amount that delivers an aggregate amount of
noribogaine of
50 ng to 10 jig per kg body weight per day. In some aspects, the
therapeutically effective
amount of noribogaine is an amount that delivers an aggregate amount of
noribogaine of
50 ng to 1 jig per kg body weight per day. In some aspects, the composition is
formulated
for administration once per day. In some aspects, the composition is
formulated for
administration two or more times per day. The ranges include both extremes as
well as any
subranges there between.
[0391] In another embodiment, the therapeutically effective amount of the
compound is
from 1.3 mg to 4 mg per kg body weight per day. In another embodiment, the
therapeutically effective amount of the compound is from 1.5 mg to 3 mg per kg
body
weight per day. In another embodiment, the therapeutically effective amount of
the
compound is from 1.7 mg to 3 mg per kg body weight per day. In another
embodiment,
the therapeutically effective amount of the compound is from 2 mg to 4 mg per
kg body
weight per day. In another embodiment, the therapeutically effective amount of
the
compound is from 2 mg to 3 mg per kg body weight per day.
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COMPOUNDS UTILIZED
[0392] In one embodiment, the noribogaine derivative is represented by Formula
I:
411 N
CH2CH3
or a pharmaceutically acceptable salt and/or solvate thereof,
wherein R is hydrogen or a hydrolyzable group such as hydrolyzable esters of
from about
1 to 12 carbons.
[0393] Generally, in the above formula, R is hydrogen or a group of the
formula:
0
II
¨C
wherein X is a C1-C12 group, which is unsubstituted or substituted. For
example, X may be
a linear alkyl group such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-
hexyl, n-heptyl, n-
octyl, n-nonyl, n -decyl, n-undecyl or n-dodecyl, or a branched alkyl group,
such as i-
propyl or sec-butyl. Also, X may be a phenyl group or benzyl group, either of
which may
be substituted with lower alkyl groups or lower alkoxy groups. Generally, the
lower alkyl
and/or alkoxy groups have from 1 to about 6 carbons. For example, the group R
may be
acetyl, propionyl or benzoyl. However, these groups are only exemplary.
[0394] Generally, for all groups X, they may either be unsubstituted or
substituted with
lower alkyl or lower alkoxy groups. For example, substituted X may be o-, m-
or p-methyl
or methoxy benzyl groups.
[0395] CI-Cu groups include Ci-C12 alkyl, C3-C12 cycloalkyl, C6-C12 aryl, C7-
C12
arylalkyl, wherein Cx indicates that the group contains x carbon atoms. Lower
alkyl refers
to Ci-C4 alkyl and lower alkoxy refers to C1-C4 alkoxy.
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[0396] In one embodiment, the noribogaine derivative is represented by Formula
II:
R1
L¨ R5
R4
R3
or a pharmaceutically acceptable salt ancUor solvate thereof,
wherein
is a single or double bond;
R' is halo, OR2, or C1-C12 alkyl optionally substituted with 1 to 5 Rm;
R2 is hydrogen or a hydrolysable group selected from the group consisting of -

C(0)1V, -C(0)0Rx and -C(0)N(R)2 where each 12_8 is selected from the
group consisting of C1-C6 alkyl optionally substituted with 1 to 5 le , and
each RY is independently selected from the group consisting of hydrogen,
C1-C6 alkyl optionally substituted with 1 to 5 RI , C6-C14 aryl optionally
substituted with 1 to 5 Rm, C3-C10 cycloalkyl optionally substituted with 1
to 5 Rl , C1-C10 heteroaryl having 1 to 4 heteroatoms and which is
optionally substituted with 1 to 5 RI , C1-C10 heterocyclic having 1 to 4
heteroatoms and which is optionally substituted with 1 to 5 RI , and where
each RY, together with the nitrogen atom bound thereto form a C1-C6
heterocyclic having 1 to 4 heteroatoms and which is optionally substituted
with 1 to 5 RR' or a C1-C6 heteroaryl having 1 to 4 heteroatoms and which is
optionally substituted with 1 to 5 R16;
R3 is selected from the group consisting of hydrogen, Ci-C 12 alkyl optionally

substituted with 1 to 5 le , aryl optionally substituted with 1 to 5 Rm, -
C(0)R6, -C(0)NR6R6 and -C(0)0R6;
R4 is selected from the group consisting of hydrogen, -(CH2).0R8, -
CR7(OH)R8, -(CH2)õ,CN, -(CH2)6,COR8, -(CH2).0O2R8, -(CH2),X(0)NR7
R8, -(CH2)6,C(0)NR7NR8R8, -(CH2),X(0)NR7NR8C(0)R9,
and -(CH2).NR7R8;
m is 0, 1, or 2;
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L is a bond or Ci-C12 alkylene;
R5 is selected from the group consisting of hydrogen, Ci-C12 alkyl substituted
with
1 to 5 Rim, C1-C12 alkenyl substituted with 1 to 5 R19, -X1-R7, -(X1-Y)õ-X1-
R7, -SO2NR7R8, -0-C(0)R9, -C(0)0R8, -C(0)NR7R8, -NR7R8, -
NHC(0)R9, and -NR7C(0)R9;
each R6 is independently selected from the group consisting of hydrogen, CI-Cu

alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-Clo aryl, C1-C6 heteroaryl having 1
to 4 heteroatoms, and C1-C6 heterocycle having 1 to 4 heteroatoms, and
wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are
optionally substituted with 1 to 5 R19;
X1 is selected from the group consisting of 0 and S;
Y is C1-C4 alkylene or C6-C10 arylene, or a combination thereof;
n is 1, 2, or 3;
R7 and R8 are each independently selected from the group consisting of
hydrogen,
CI-Cu alkyl optionally substituted with 1 to 5 R19, CI-C6 heterocycle
having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5
RIO,
C10 cycloalkyl optionally substituted with 1 to 5 R19, C6-Clo aryl
optionally substituted with 1 to 5 R19 and C1-C6 heteroaryl having 1 to 4
heteroatoms optionally substituted with 1 to 5 R19;
R9 is selected from the group consisting of CI-Cu alkyl optionally substituted
with
1 to 5 R19, C1-C6 heterocycle having 1 to 4 heteroatoms optionally
substituted with 1 to 5 R19, C3-Clo cycloalkyl optionally substituted with 1
to 5 R19, C6-C10 aryl optionally substituted with 1 to 5 R19 and C1-C6
heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R16;
Rim is selected from the group consisting of CI-C4 alkyl, phenyl, halo, -OR", -

CN, -COR11, -CO2R11, -C(0)NHRI 15 -NR"
R", _C(0)NR11Rii, _c(o)Nti-N
HR", -C(0)NR11NHR11, -C(0)NR' 'NR' K _C(0)NFINRUC(0)R11, -C(
0)NHNHC(0)R11, -SO2NR11¨

K11, _C(0)NR11NR11C(C)R11,
and -C(0)NR11NHC(0)R11; and
R" is independently hydrogen or CI-C12 alkyl;
provided that:
when L is a bond, then R5 is not hydrogen;
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when ¨ is a double bond, R1 is an ester hydrolyzable group, R3 and R4 are
both hydrogen, then -L-R5 is not ethyl;
when ¨ is a double bond, R1 is -OH, halo or C1-C12 alkyl optionally
substituted with 1 to 5 R1 , then R4 is hydrogen; and
when is a double bond, R1 is OR2, R4 is hydrogen, -L-R5 is ethyl, then
R2 is
not a hydrolyzable group selected from the group consisting of an ester,
amide, carbonate and carbamate.
[0397] In one embodiment, the noribogaine derivative is represented by Formula
III:
R12 R14
R13
III
or a pharmaceutically acceptable salt and/or solvate thereof,
wherein
¨ is a single or double bond;
R12 is halo, -OH, -SH, -NH2, -S(0)2N(Rt7)2, _Rz_c_R19,
_Rz_c_R20 or _
Rz_c K
_cHR18¨ 195
where It.' is 0, S or NR17;
L1 is alkylene, arylene, -C(0)-alkylene, -C(0)-arylene, -C(0)0-arylene, -C(0)0-

alkylene, -C(0)NR20-alkylene, -C(0)NR20-arylene, -C(NR20)NR20-alkylene
or -C(.,4R20)N¨K 20_
arylene, wherein L1 is configured such that -0-L1-R18 is -
OC(0)-alkylene-R18, -0C(0)0-arylene-R18, -0C(0)0-alkylene-R18, -
OC(0)-arylene-R18, -0C(0)NR20-alkylene-R18, -0C(0)NR20-arylene-R18, -
0C(NR20)N- 20_
alkylene-R" or -0C(NR20)NR20-arylene-R18, and wherein
the alkylene and arylene are optionally substituted with 1 to 2 R16;
R13 is hydrogen, -S(0)20R20, -S(0)2R20, -C(0)R15, -C(0)NR15R15, -C(0)0R15,
C12 alkyl optionally substituted with 1 to 5 R16, C1-C12 alkenyl optionally
substituted with 1 to 5 R16, or aryl optionally substituted with 1 to 5 R16;
R14 is hydrogen, halo, -0R17, -CN, CI-Cu alkyl, CI-Cu alkoxy, aryl or aryloxY,

where the alkyl, alkoxy, aryl, and aryloxy are optionally substituted with 1
to 5 R16;
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each R15 is independently selected from the group consisting of hydrogen, C1-
C12
alkyl, C2-C12 alkenyl, C2-C12 alkynyl, aryl, heteroaryl, and heterocycle, and
wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are
optionally substituted with 1 to 5 R16;
R16 is selected from the group consisting of phenyl, halo, -0R17, -
CN, -COR17, _co2R17, _NR17R17, _NR17c(o)R17, _NR17s02K 17,
C(0)NR17
R17, -C(0)NR17NR17R17, -SO2NR17R17 and -C(0)NR17NR17C(0)R17;
each R17 is independently hydrogen or C1-C12 alkyl optionally substituted with

from 1 to 3 halo;
R18 is hydrogen, -C(0)R20,

-C(0)0R20, -C(0)N(R20)2 or -N(R20)C(0)R20;
R19 is hydrogen, -
N(R20)2, C(0)N(R20)2, 2, ) _c(NR2o)N(R2o),
C(NSO2R20)N(R20, 2,
NR26 C (0)
N(R20) 2,
NR20C(S)N(R20)2, (NR20)N (R20 2,
) NR26C(NSO2R26)1\1(R2
0)2 or tetrazole; and
each R2 is independently selected from the group consisting of hydrogen, C1-
C12
alkyl and aryl;
provided that:
when - is a double bond and R13 and R14 are hydrogen, then R12 is not
hydroxy;
when - is a double bond, R14 is hydrogen, R12 is -0-L1-R18, -0-L1-R19, -0-L1-
R20, and L1 is alkylene, then -O-L'-R'8, -O-L'-R'9, -O-L'-R2
are not
methoxy;
when - is a double bond, R14 is hydrogen, Rz is 0, L1 is -C(0)-
alkylene, -C(0)-arylene, -C(0)0-arylene, -C(0)0-alkylene, -C(0)NR20-
alkylene, or -C(0)NR20-arylene, then none of R18, R19 or R2 are hydrogen.
[0398] In one embodiment, the noribogaine derivative is represented by Formula
IV:
R210 C2H5
--R22 IV
or a pharmaceutically acceptable salt and/or solvate thereof,
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wherein
R2' is selected from the group consisting of hydrogen, a hydrolysable group
selected from the group consisting of-C(0)R23, -C(0)NR24¨ 25
K and -C(0)0R26, where R23
is selected from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl,
substituted alkenyl, alkynyl and substituted alkynyl, R24 and R25 are
independently
selected from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
heteroaryl,
substituted heteroaryl, heterocyclic and substituted heterocyclic, R26 is
selected from the
group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,
alkynyl,
substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, heterocyclic
and substituted heterocyclic, provided that R2' is not a saccharide or an
oligosaccharide;
L2 is selected from the group consisting of a covalent bond and a cleavable
linker
group;
R22 is selected from the group consisting of hydrogen, alkyl, substituted
alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted
aryl, cycloalkyl,
substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and
substituted
heterocyclic, provided that R is not a saccharide or an oligosaccharide;
provided that when L2 is a covalent bond and R22 is hydrogen, then R2' is
selected
from the group consisting of -C(0)NR24R25 and -C(0)0R26; and
further provided that when R2' is hydrogen or -C(0)R23 and L2 is a covalent
bond,
then R22 is not hydrogen.
[0399] In one embodiment, the noribogaine derivative is represented by Formula
V:
,0
R27
28
V
or a pharmaceutically acceptable salt and/or solvate thereof,
wherein:
refers to a single or a double bond provided that when is a single bond,
Formula V refers to the corresponding dihydro compound;
R27 is hydrogen or S020R29;
R28 is hydrogen or S020R29;
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R29 is hydrogen or C1 - C6 alkyl;
provided that at least one of R27 and R28 is not hydrogen.
[0400] In one embodiment, the noribogaine derivative is represented by Formula
VI:
,0
R3
R31
VI
or a pharmaceutically acceptable salt and/or solvate thereof,
wherein:
refers to a single or a double bond provided that when is a single bond,
Formula VI refers to the corresponding vicinal dihydro compound;
R3 is hydrogen, a monophosphate, a diphosphate or a triphosphate; and
R31 is hydrogen, a monophosphate, a diphosphate or a triphosphate;
provided that both R3 and R31 are not hydrogen;
wherein one or more of the monophosphate, diphosphate and triphosphate groups
of R3
and R31 are optionally esterified with one or more Ci-C6 alkyl esters.
[0401] Noribogaine as utilized herein, can be replaced by a noribogaine
derivative or a
salt of noribogaine or the noribogaine derivative or a solvate of each of the
foregoing.
[0402] In a preferred embodiment, the compound utilized herein is noribogaine
or a salt
thereof. In a more preferred embodiment, the compound utilized herein is
noribogaine.
III. Methods of the Invention
[0403] As will be apparent to the skilled artisan upon reading this
disclosure, the present
invention provides a method for treating disases treatable by administering
noribogaine, as
described herein, comprising administering to the patient a dosage of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt or solvate
thereof.
Nicotine Addiction
[0404] As will be apparent to the skilled artisan upon reading this
disclosure, this
invention provides a method for treating nicotine addiction in a subject,
comprising
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administering to the patient in need thereof a therapeutically effective
amount of
noribogaine, a noribogaine derivative, a noribogaine prodrug, or a
pharmaceutically
acceptable salt of each thereof. This invention further provides a method for
treating,
attenuating, or preventing nicotine cravings in a subject, comprising
administering to the
patient in need thereof a therapeutically or prophylactically effective amount
of
noribogaine, a noribogaine derivative, a noribogaine prodrug, or a
pharmaceutically
acceptable salt of each thereof.
[0405] In some embodiments, the invention provides for a method for treating
nicotine
addiction in a subject, comprising administering to the patient in need
thereof a
therapeutically effective amount of noribogaine, a noribogaine derivative, or
a
pharmaceutically acceptable salt of each thereof.
[0406] The subject or patient may be any patient who uses nicotine in any
form,
including cigarettes, electronic cigarettes or vaporizers ("vaping"), chewing
tobacco,
cigars, snuff, pipes, hookahs, and the like. In some embodiments, the patient
is addicted to
nicotine. In some embodiments, the patient is physically addicted to nicotine.
In some
embodiments, the patient is psychologically addicted to nicotine.
[0407] In some embodiments, the therapeutically effective amount of the
compound is
from about 50 ng to less than 10 ps per kilogram body weight per day. In
another
embodiment, the therapeutically effective amount of the compound is from about
50 ng to
about 5 jig per kilogram body weight per day. In another embodiment, the
therapeutically
effective amount of the compound is from about 50 ng to about 1 jig per
kilogram body
weight per day. In another embodiment, the therapeutically effective amount of
the
compound is from about 50 ng to about 1 jig per kilogram body weight per day.
In yet
another embodiment, the therapeutically effective amount of the compound is
from about
500 ng to less than 10 jig per kilogram body weight per day. In yet another
embodiment,
the therapeutically effective amount of the compound is from about 1 lug to
less than 10
jig per kilogram body weight per day. In yet another embodiment, the
therapeutically
effective amount of the compound is about 50 ng, about 100 ng, about 150 ng,
about 200
ng, about 250 ng, about 300 ng, about 350 ng, about 400 ng, about 450 ng,
about 500 ng,
about 550 ng, about 600 ng, about 650 ng, about 700 ng, about 750 ng, about
800 ng,
about 850 ng, about 900 ng, about 950 ng, about 1 lug, about 2 lug, about 3
lug, about 3
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jig, about 4 pig, about 5 pig, about 6 jig, about 7 jig, about 8 jig, about 9
jig, about 10 jug
per kilogram body weight per day. The therapeutically effective amount of the
compound
may be any amount within any of these ranges, including endpoints.
[0408] In some embodiments, the therapeutically effective amount of
noribogaine,
derivative, prodrug, or salt thereof is administered once a day. In some
embodiments, the
therapeutically effective amount is administered twice per day. In some
embodiments, the
therapeutically effective amount is administered more than two times per day.
[0409] Where the therapeutically effective amount is administered more than
one time
per day, a portion of the total therapeutically effective amount is
administered at each
time. For example, an 90 kg patient taking 1 jig noribogaine per kg body
weight per day
would take 90 pig once a day, 45 lag twice a day, or 30 pig three times a day,
etc.
[0410] In some embodiments, the therapeutically effective amount of
noribogaine,
derivative, prodrug, or salt thereof is administered once when needed, e.g.,
when the
patient has a craving for nicotine or anticipates to have a craving for
nicotine as described
herein.
[0411] In some embodiments, the noribogaine or noribogaine derivative is
administered
sublingually, intrapulmonary, or intranasally. These routes of administration
are discussed
in further detail below in the subsection titled "Dosage and Routes of
Administration."
Preventing relapse of nicotine use
[0412] In some embodiments, the invention provides for a method for treating,
preventing, or attenuating nicotine cravings in a subject, comprising
administering to the
patient in need thereof a prophylactically effective amount of noribogaine, a
noribogaine
derivative, or a pharmaceutically acceptable salt of each thereof. In some
embodiments,
the invention provides for a method for preventing recurrence of nicotine
addiction in a
subject, comprising administering to the patient in need thereof a
prophylactically
effective amount of noribogaine, a noribogaine derivative, or a
pharmaceutically
acceptable salt of each thereof.
[0413] In some situations, a patient who has not ceased nicotine use
nonetheless is
unable to use nicotine for an extended amount of time. For example, most
airplane flights
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no longer allow smoking, and have banned vaporizers and e-cigarettes, as well.
Other
places and situations where nicotine use is not feasible or is difficult
include movie
theaters, other entertainment venues (including theater, opera, concerts, and
the like), and
even workplaces, notably hospitals and schools where smoking may not be
allowed
anywhere on the property. In some embodiments, a prophylactically effective
amount of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
thereof is
administered before and/or during a period of time when the patient expects to
be unable
to use nicotine, wherein the noribogaine, derivative, or salt prevents,
interrupts, or
attenuates cravings for nicotine. In some embodiments, nicotine cravings are
attenuated,
interrupted, or prevented for at least 2, 3, 4, 5, 6, 7, 8, 10, 15, or 24
hours.
[0414] In some embodiments, the noribogaine is administered on an as-needed
basis by
the patient. In some embodiments, the noribogaine may be administered before
the
nicotine craving occurs. For example, the patient may take a dose of
noribogaine in
anticipation of cravings, such as before drinking alcohol, before a stressful
situation
occurs, or when facing another trigger for nicotine use. In some embodiments,
the patient
takes a dose of noribogaine after the nicotine craving occurs, for example
during the
craving, in order to reduce or eliminate the craving. In some embodiments, the
dose of
noribogaine is low enough that a patient can take one dose before a craving
occurs, and
another later the same day if he/she feels or anticipates another craving.
[0415] In one embodiment, the prophylactically effective amount of the
compound is
from about 50 ng to less than 10 jig per kilogram body weight per day. In
another
embodiment, the prophylactically effective amount of the compound is from
about 50 ng
to about 5 jig per kilogram body weight per day. In another embodiment, the
prophylactically effective amount of the compound is from about 50 ng to about
1 jig per
kilogram body weight per day. In yet another embodiment, the prophylactically
effective
amount of the compound is from about 500 ng to less than 10 mg per kilogram
body
weight per day. In yet another embodiment, the prophylactically effective
amount of the
compound is from about 1 jig to less than 10 jig per kilogram body weight per
day. The
prophylactically effective amount of the compound may be any amount within any
of
these ranges, including endpoints.
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[0416] In some embodiments, the prophylactically effective amount of
noribogaine,
derivative, prodrug, or salt thereof is administered once a day. In some
embodiments, the
prophylactically effective amount is administered twice per day. In some
embodiments,
the prophylactically effective amount is administered more than two times per
day.
[0417] Where the prophylactically effective amount of noribogaine is
administered more
than one time per day, a portion of the total prophylactically effective
amount is
administered at each time. For example, an 90 kg patient taking 1 jig
noribogaine per kg
body weight per day would take 90 jig once a day, 45 jig twice a day, or 30
lug three times
a day, etc.
[0418] In some embodiments, the noribogaine or noribogaine derivative is
administered
sublingually, intrapulmonary, or intranasally. These routes of administration
are discussed
in further detail in the subsection titled "Dosage and Routes of
Administration."
Opioid or Opioid-Like Drug Addiction
[0419] In one aspect, this invention relates to treatment of acute withdrawal
from an
opioid or opioid-like drug in an addicted patient comprising administration of
a
therapeutically effective amount of noribogaine, noribogaine derivative, or
pharmaceutically acceptable salt or solvate thereof.
[0420] In one aspect, this invention relates to a method for treating opioid
or opioid-like
drug abuse in an addicted patient, comprising administering to the patient a
dosage of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate thereof
that provides an average serum concentration of about 50 ng/mL to about 180
ng/mL, said
concentration being sufficient to inhibit or ameliorate said abuse while
maintaining a QT
interval of less than about 500 ms during said treatment.
[0421] In one aspect, this invention relates to a method for attenuating
withdrawal
symptoms in a human patient susceptible to such symptoms due to opioid or
opioid-like
drug addiction, comprising administering to the patient a dosage of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof
that provides
an average serum concentration of about 80 ng/mL to about 100 ng/mL, said
concentration
being sufficient to attenuate said symptoms while maintaining a QT interval of
less than
about 500 ms during said treatment. In some embodiments, the concentration is
sufficient
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to attenuate said symptoms while maintaining a QT interval of less than about
470 ms
during treatment. Preferably, the concentration is sufficient to attenuate
said symptoms
while maintaining a QT interval of less than about 450 ms during treatment. In
one
embodiment, the concentration is sufficient to attenuate said symptoms while
maintaining
a QT interval of less than about 420 ms during treatment. In one embodiment,
the
withdrawal symptoms are symptoms of acute withdrawal.
104221 In one embodiment, the QT interval is not prolonged more than about 50
ms. In
one embodiment, the QT interval is not prolonged more than about 40 ms. In one

embodiment, the QT interval is not prolonged more than about 30 ms. In one
embodiment,
the QT interval is not prolonged more than about 20 ms. In one embodiment, the
QT
interval is not prolonged more than about 10 ms.In one embodiment,
prolongation of the
QT interval is equivalent to or less than the prolongation observed for
methadone-treated
patients.
104231 In one aspect, this invention relates to a method for attenuating
withdrawal
symptoms in a human patient susceptible to such symptoms due to opioid or
opioid-like
drug addiction, comprising administering to the patient a dosage of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof
that provides
an average serum concentration of about 60 ng/mL to about 180 ng/mL, said
concentration
being sufficient to attenuate said symptoms while maintaining a QT interval of
less than
about 500 ms during said treatment. In some embodiments, the concentration is
sufficient
to attenuate said symptoms while maintaining a QT interval of less than about
470 ms
during treatment. Preferably, the concentration is sufficient to attenuate
said symptoms
while maintaining a QT interval of less than about 450 ms during treatment. In
one
embodiment, the concentration is sufficient to attenuate said symptoms while
maintaining
a QT interval of less than about 420 ms during treatment. In one embodiment,
the
withdrawal symptoms are symptoms of acute withdrawal.
[0424] In one embodiment, the average serum concentration of noribogaine is
from
about 50 ng/mL to about 180 ng/mL, or about 60 ng/mL to about 180 ng/mL. In
one
embodiment, the average serum concentration of noribogaine is from about 50
ng/mL to
about 150 ng/mL, or about 60 ng/mL to about 150 ng/mL. In one embodiment, the
average
serum concentration of noribogaine is from about 50 ng/mL to about 100 ng/mL,
or about
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60 ng/mL to about 100 ng/mL. In one embodiment, the average serum
concentration of
noribogaine is from about 80 ng/mL to about 150 ng/mL. In one embodiment, the
average
serum concentration of noribogaine is from about 80 ng/mL to about 100 ng/mL.
The
ranges include both extremes as well as any subranges between.
[0425] In one embodiment, the dosage of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt or solvate thereof provides a serum
concentration of
between about 1000 ng*hr/mL and about 6000 ng*hr/mL. In one embodiment, the
dosage
of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate
thereof provides a serum concentration of between about 1200 ng*hr/mL and
about 5800
ng*hr/mL. In one embodiment, the dosage of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt or solvate thereof provides a serum
concentration of
between about 1200 ng*hr/mL and about 5500 ng*hr/mL. The ranges include both
extremes as well as any subranges between.
[0426] In one embodiment, the dosage of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt or solvate thereof provides a maximum serum
concentration (Cmax) of less than about 250 ng/mL. In one embodiment, the
dosage of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate thereof
provides a Cmax between about 40 ng/mL and about 250 ng/mL. In a preferred
embodiment, the dosage of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof provides a Cmax between about 60 ng/mL and
about 200
ng/mL. In one embodiment, the dosage of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt or solvate thereof provides a Cmax between
about 100
ng/mL and about 180 ng/mL.
[0427] In one embodiment, the dosage or aggregate dosage of noribogaine,
noribogaine
derivative, or salt or solvate thereof is from about 1 mg/kg to about 4 mg/kg
body weight
per day. The aggregate dosage is the combined dosage, for example the total
amount of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate thereof
administered over a 24-hour period where smaller amounts are administered more
than
once per day. In one embodiment, the dosage or aggregate dosage of
noribogaine,
noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to
about 4 mg/kg
body weight. In one embodiment, the dosage or aggregate dosage of noribogaine,
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noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to
about 3 mg/kg
body weight. In one embodiment, the dosage or aggregate dosage of noribogaine,

noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to
about 2 mg/kg
body weight. In one embodiment, the dosage or aggregate dosage of noribogaine,

noribogaine derivative, or salt or solvate thereof is from about 1.5 mg/kg to
about 3 mg/kg
body weight. In one embodiment, the dosage or aggregate dosage of noribogaine,

noribogaine derivative, or salt or solvate thereof is from about 1.7 mg/kg to
about 3 mg/kg
body weight. In one embodiment, the dosage or aggregate dosage of noribogaine,

noribogaine derivative, or salt or solvate thereof is from about 2 mg/kg to
about 4 mg/kg
body weight. In one embodiment, the dosage or aggregate dosage of noribogaine,

noribogaine derivative, or salt or solvate thereof is from about 2 mg/kg to
about 3 mg/kg
body weight. In one embodiment, the dosage or aggregate dosage of noribogaine,

noribogaine derivative, or salt or solvate thereof is about 2 mg/kg body
weight. The ranges
include both extremes as well as any subranges there between.
[0428] In one embodiment, the dosage or aggregate dosage of noribogaine,
noribogaine
derivative, or salt or solvate thereof is about 4 mg/kg body weight per day.
In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt or solvate thereof is about 3 mg/kg body weight per day. In one
embodiment, the
dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or
solvate
thereof is about 2 mg/kg body weight per day. In one embodiment, the dosage or

aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate
thereof is about
1.9 mg/kg body weight per day. In one embodiment, the dosage or aggregate
dosage of
noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.8
mg/kg body
weight per day. In one embodiment, the dosage or aggregate dosage of
noribogaine,
noribogaine derivative, or salt or solvate thereof is about 1.7 mg/kg body
weight per day.
In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or salt or solvate thereof is about 1.6 mg/kg body weight per day.
In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt or solvate thereof is about 1.5 mg/kg body weight per day. In one
embodiment, the
dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or
solvate
thereof is about 1.4 mg/kg body weight per day. In one embodiment, the dosage
or
aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate
thereof is about
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1.3 mg/kg body weight per day. In one embodiment, the dosage or aggregate
dosage of
noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.2
mg/kg body
weight per day. In one embodiment, the dosage or aggregate dosage of
noribogaine,
noribogaine derivative, or salt or solvate thereof is about 1.1 mg/kg body
weight per day.
In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or salt or solvate thereof is about 1 mg/kg body weight per day.
[0429] In one embodiment, the dosage or aggregate dosage of noribogaine,
noribogaine
derivative, or salt or solvate thereof is between about 70 mg and about 150
mg. In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt or solvate thereof is between about 75 mg and about 150 mg. In one
embodiment, the
dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or
solvate
thereof is between about 80 mg and about 140 mg. In one embodiment, the dosage
or
aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate
thereof is
between about 90 mg and about 140 mg. In one embodiment, the dosage or
aggregate
dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is
between about
90 mg and about 130 mg. In one embodiment, the dosage or aggregate dosage of
noribogaine, noribogaine derivative, or salt or solvate thereof is between
about 100 mg
and about 130 mg. In one embodiment, the dosage or aggregate dosage of
noribogaine,
noribogaine derivative, or salt or solvate thereof is between about 110 mg and
about 130
mg.
[0430] In another embodiment, there is provided a unit dose of noribogaine,
noribogaine derivative, or salt or solvate thereof which is about 120 mg per
dose. It being
understood that the term "unit dose" means a dose sufficient to provide
therapeutic results
whether given all at once or serially over a period of time.
[0431] In some embodiments, the patient is administered an initial dose of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt or solvate
thereof, followed by
one or more additional doses. In one embodiment, such a dosing regimen
provides an
average serum concentration of noribogaine of about 50 ng/mL to about 180
ng/mL. In
one embodiment, the one or more additional doses maintain an average serum
concentration of about 50 ng/mL to about 180 ng/mL over a period of time.
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[0432] In some embodiments, the initial dose of noribogaine, noribogaine
derivative, or
salt or solvate thereof is from about 60 mg to about 120 mg. In one
embodiment, the initial
dose is about 75 mg. In one embodiment, the initial dose is about 80 mg. In
one
embodiment, the initial dose is about 85 mg. In one embodiment, the initial
dose is about
90 mg. In one embodiment, the initial dose is about 95 mg. In one embodiment,
the initial
dose is about 100 mg. In one embodiment, the initial dose is about 105 mg. In
one
embodiment, the initial dose is about 110 mg. In one embodiment, the initial
dose is about
115 mg. In one embodiment, the initial dose is about 120 mg.
[0433] In some embodiments, the one or more additional doses are lower than
the initial
dose. In one embodiment, the one or more additional doses are from 5 mg to 50
mg. In one
embodiment, the one or more additional doses may or may not comprise the same
amount
of noribogaine, noribogaine derivative, or salt or solvate thereof. In one
embodiment, at
least one additional dose is about 5 mg. In one embodiment, at least one
additional dose is
about 10 mg. In one embodiment, at least one additional dose is about 15 mg.
In one
embodiment, at least one additional dose is about 20 mg. In one embodiment, at
least one
additional dose is about 25 mg. In one embodiment, at least one additional
dose is about
30 mg. In one embodiment, at least one additional dose is about 35 mg. In one
embodiment, at least one additional dose is about 40 mg. In one embodiment, at
least one
additional dose is about 45 mg. In one embodiment, at least one additional
dose is about
50 mg.
[0434] In one embodiment, the one or more additional doses are administered
periodically. In one embodiment, the one or more additional doses are
administered every
4 hours. In one embodiment, the one or more additional doses are administered
every 6
hours. In one embodiment, the one or more additional doses are administered
every 8
hours. In one embodiment, the one or more additional doses are administered
every 10
hours. In one embodiment, the one or more additional doses are administered
every 12
hours. In one embodiment, the one or more additional doses are administered
every 18
hours. In one embodiment, the one or more additional doses are administered
every 24
hours. In one embodiment, the one or more additional doses are administered
every 36
hours. In one embodiment, the one or more additional doses are administered
every 48
hours.
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[0435] In some embodiments, the therapeutic dose of noribogaine, noribogaine
derivative, or salt or solvate thereof is a tapered dosing over a period of
time, during which
the patient is detoxified, for example, without suffering significant acute
withdrawal
symptoms. Without being bound by theory, it is believed that tapering will
allow the full
therapeutic effect of noribogaine with less prolongation of the QT interval.
Tapering
involves administration of one or more subsequently lower doses of noribogaine
over
time. For example, in some embodiments, the first tapered dose is 50% to 95%
of the first
or original dose. In some embodiments, the second tapered dose is 40% to 90%
of the first
or original dose. In some embodiments, the third tapered dose is 30% to 85% of
the first or
original dose. In some embodiments, the fourth tapered dose is 20% to 80% of
the first or
original dose. In some embodiments, the fifth tapered dose is 10% to 75% of
the first or
original dose.
[0436] In some embodiments, the first tapered dose is given after the first
dose of
noribogaine. In some embodiments, the first tapered dose is given after the
second, third,
or a subsequent dose of noribogaine. The first tapered dose may be
administered at any
time after the previous dose of noribogaine. The first tapered dose can be
given once, for
example, followed by subsequent further tapered doses, or it can be given
multiple times
with or without subsequent, further tapered doses (e.g., second, third,
fourth, etc. tapered
doses), which likewise can be given once or over multiple administrations, for
example. In
some embodiments, the first tapered dose is administered about one hour, 6
hours, 12
hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after the previous dose
of
noribogaine. Similarly, second, third, fourth, etc. tapered doses, if given,
can be given
about one hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or
more after
the previous dose of noribogaine.
[0437] In some embodiments, one tapered dose is given to achieve the desired
lower
therapeutic dose. In some embodiments, two tapered doses are given to achieve
the desired
lower therapeutic dose. In some embodiments, three tapered doses are given to
achieve the
desired lower therapeutic dose. In some embodiments, four or more tapered
doses are
given to achieve the desired lower therapeutic dose. Determination of the
tapered doses,
number of tapered doses, and the like can be readily made a qualified
clinician.
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[0438] In some embodiments, the patient is administered periodically, such as
once,
twice, three times, four times or five times daily with noribogaine,
noribogaine derivative,
or a pharmaceutically acceptable salt or solvate thereof. In some embodiments,
the
administration is once daily, or once every second day, once every third day,
three times a
week, twice a week, or once a week. The dosage and frequency of the
administration
depends on the route of administration, dosage, age and body weight of the
patient,
condition of the patient, without limitation. Determination of dosage and
frequency
suitable for the present technology can be readily made a qualified clinician.
[0439] Noribogaine, noribogaine derivative, or a pharmaceutically acceptable
solvate or
salt thereof, suitable for administration in accordance with the methods
provide herein, can
be suitable for a variety of delivery modes including, without limitation,
oral,transdermal,
sublingual, buccal, intrapulmonary or intranasal delivery. Compositions
suitable for
internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intra-
arterial,
intramuscular, intraperitoneal, intracutaneous and subcutaneous routes may
also be used.
Possible dosage forms include tablets, capsules, pills, powders, aerosols,
suppositories,
parenterals, and oral liquids, including suspensions, solutions and emulsions.
Sustained
release dosage forms may also be used. All dosage forms may be prepared using
methods
that are standard in the art (see e.g., Remington's Pharmaceutical Sciences,
16th ed., A.
Oslo editor, Easton Pa. 1980).
[0440] In a preferred embodiment, noribogaine, noribogaine derivative, or a
pharmaceutically acceptable salt or solvate thereof is administered orally,
which may
conveniently be provided in tablet, caplet, sublingual, liquid or capsule
form. In certain
embodiments, the noribogaine is provided as noribogaine HCl, with dosages
reported as
the amount of free base noribogaine. In some embodiments, the noribogaine HC1
is
provided in hard gelatin capsules containing only noribogaine HC1 with no
excipients.
[0441] The patient may suffer from addiction to any opioid or opiate or opioid-
like drug.
In a preferred embodiment, the opioid or opioid-like drug is selected from the
group
consisting of heroin, cocaine, opiate, methadone, morphine, codeine,
oxycodone,
hydrocodone, and methamphetamine. In one embodiment, the opioid or opioid-like
drug is
heroin. In one embodiment, the opioid or opioid-like drug is methadone. In one

embodiment, the opioid or opioid-like drug is morphine.
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[0442] In one aspect, this invention relates to treatment or attenuation of
post-acute
withdrawal from opioids or opioid-like drug in an addicted patient with a
maintenance
amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable
salt or
solvate thereof.
[0443] In some aspects, this invention relates to a method to prevent relapse
of opioid or
opioid-like drug abuse in an addicted patient treated to ameliorate said
abuse, said method
comprising periodically administering to said patient a maintenance dosage of
noribogaine.
[0444] In some embodiments, the patient undergoes long-term (e.g., one year or
longer)
treatment with maintenance doses of noribogaine, noribogaine derivative, or
salt or solvate
thereof. In some embodiments, the patient is treated for acute withdrawal with
therapeutic
doses of noribogaine as described above, and then the amount of noribogaine is
reduced to
maintenance levels after acute withdrawal symptoms would be expected to have
subsided.
Acute withdrawal symptoms generally are the most pronounced in the first 48 to
72 hours
after cessation of the drug of addiction, although acute withdrawal may last
as long as a
week or more.
[0445] In some embodiments, the patient is administered a high (therapeutic)
dose of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate thereof
for a period of time to ameliorate the most significant withdraw symptoms, and
then is
administered a lower (maintenance) dose to prevent relapse to opioid or opioid-
like drug
use. In some embodiments, the patient is administered a therapeutic dose of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof
for a period
of time to ameliorate the most significant withdraw symptoms, and then is
administered a
decreasing (tapered) amount of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof over time until the maintenance dose is
reached.
[0446] In some embodiments, the maintenance dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof is 70% of
the therapeutic
dose. In some embodiments, the maintenance dose is 60% of the therapeutic
dose. In some
embodiments, the maintenance dose is 50% of the therapeutic dose. In some
embodiments,
the maintenance dose is 40% of the therapeutic dose. In some embodiments, the
maintenance dose is 30% of the therapeutic dose. In some embodiments, the
maintenance
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dose is 20% of the therapeutic dose. In some embodiments, the maintenance dose
is 10%
of the therapeutic dose.
[0447] In some embodiments, the maintenance average serum level of noribogaine
is
about 70% of the therapeutic average serum level of noribogaine. In some
embodiments,
the maintenance average serum level of noribogaine is about 60% of the
therapeutic
average serum level of noribogaine. In some embodiments, the maintenance
average
serum level of noribogaine is about 50% of the therapeutic average serum level
of
noribogaine. In some embodiments, the maintenance average serum level of
noribogaine is
about 40% of the therapeutic average serum level of noribogaine. In some
embodiments,
the maintenance average serum level of noribogaine is about 30% of the
therapeutic
average serum level of noribogaine. In some embodiments, the maintenance
average
serum level of noribogaine is about 20% of the therapeutic average serum level
of
noribogaine. In some embodiments, the maintenance average serum level of
noribogaine is
about 10% of the therapeutic average serum level of noribogaine.
[0448] In some embodiments, the maintenance Cmax of noribogaine is about 70%
of the
therapeutic Cmax of noribogaine. In some embodiments, the maintenance Cmax of
noribogaine is about 60% of the therapeutic Cmax of noribogaine. In some
embodiments,
the maintenance Cmaxof noribogaine is about 50% of the therapeutic Cmax of
noribogaine. In some embodiments, the maintenance Cmax of noribogaine is about
40%
of the therapeutic Cmax of noribogaine. In some embodiments, the maintenance
Cmax of
noribogaine is about 30% of the therapeutic Cmax of noribogaine. In some
embodiments,
the maintenance Cmax of noribogaine is about 20% of the therapeutic Cmax of
noribogaine. In some embodiments, the maintenance Cmax of noribogaine is about
10%
of the therapeutic Cmax of noribogaine.
[0449] In some embodiments, the maintenance AUC/24 h of noribogaine is about
70%
of the therapeutic AUC/24 h of noribogaine. In some embodiments, the
maintenance
AUC/24 h of noribogaine is about 60% of the therapeutic AUC/24 h of
noribogaine. In
some embodiments, the maintenance AUC/24 h of noribogaine is about 50% of the
therapeutic AUC/24 h of noribogaine. In some embodiments, the maintenance
AUC/24 h
of noribogaine is about 40% of the therapeutic AUC/24 h of noribogaine. In
some
embodiments, the maintenance AUC/24 h of noribogaine is about 30% of the
therapeutic
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AUC/24 h of noribogaine. In some embodiments, the maintenance AUC/24 h of
noribogaine is about 20% of the therapeutic AUC/24 h of noribogaine. In some
embodiments, the maintenance AUC/24 h of noribogaine is about 10% of the
therapeutic
Cma AUC/24 h of noribogaine.
[0450] In one embodiment, the therapeutic dose is tapered over time until the
desired
maintenance dose is reached. For example, in some embodiments, the first
tapered dose is
50% to 95% of the therapeutic dose. In some embodiments, the second tapered
dose is
40% to 90% of the therapeutic dose. In some embodiments, the third tapered
dose is 30%
to 85% of the therapeutic dose. In some embodiments, the fourth tapered dose
is 20% to
80% of the therapeutic dose. In some embodiments, the fifth tapered dose is
10% to 75%
of the therapeutic dose. In some embodiments, one tapered dose is given to
achieve the
maintenance dose. In some embodiments, two tapered doses are given to achieve
the
maintenance dose. In some embodiments, three tapered doses are given to
achieve the
maintenance dose. In some embodiments, four or more tapered doses are given to
achieve
the maintenance dose. Determination of the tapered doses, number of tapered
doses, and
the like can be readily made a qualified clinician.
[0451] In one embodiment, the QT interval is not prolonged more than about 30
ms. In a
preferred embodiment, the QT interval is not prolonged more than about 20 ms.
In one
embodiment, the QT interval is not prolonged more than about 10 ms.
[0452] In one embodiment, the dosage or aggregate dosage of noribogaine,
noribogaine
derivative, or salt or solvate thereof is between about 10 mg and about 100
mg. In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt or solvate thereof is between about 20 mg and about 100 mg. In one
embodiment, the
dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or
solvate
thereof is between about 30 mg and about 100 mg. In one embodiment, the dosage
or
aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate
thereof is
between about 40 mg and about 100 mg. In one embodiment, the dosage or
aggregate
dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is
between about
50 mg and about 100 mg. In one embodiment, the dosage or aggregate dosage of
noribogaine, noribogaine derivative, or salt or solvate thereof is between
about 60 mg and
about 100 mg. In one embodiment, the dosage or aggregate dosage of
noribogaine,
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noribogaine derivative, or salt or solvate thereof is between about 60 mg and
about 90 mg.
In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or salt or solvate thereof is between about 60 mg and about 80 mg.
In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt or solvate thereof is between about 60 mg and about 70 mg.
[0453] In some embodiments, the patient is administered periodically, such as
once,
twice, three times, four times or five times daily with noribogaine,
noribogaine derivative,
or a pharmaceutically acceptable salt or solvate thereof. In some embodiments,
the
administration is once daily, or once every second day, once every third day,
three times a
week, twice a week, or once a week. The dosage and frequency of the
administration
depends on the route of administration, content of composition, age and body
weight of
the patient, condition of the patient, without limitation. Determination of
dosage and
frequency suitable for the present technology can be readily made a qualified
clinician.
[0454] Noribogaine, noribogaine derivative, or a pharmaceutically acceptable
salt or
solvate thereof, suitable for administration in accordance with the methods
provide herein,
can be suitable for a variety of delivery modes including, without limitation,

oral,transdermal, sublingual, buccal, intrapulmonary or intranasal delivery.
Compositions
suitable for internal, pulmonary, rectal, nasal, vaginal, lingual,
intravenous, intra-arterial,
intramuscular, intraperitoneal, intracutaneous and subcutaneous routes may
also be used.
Possible dosage forms include tablets, capsules, pills, powders, aerosols,
suppositories,
parenterals, and oral liquids, including suspensions, solutions and emulsions.
Sustained
release dosage forms may also be used. All dosage forms may be prepared using
methods
that are standard in the art (see e.g., Remington's Pharmaceutical Sciences,
16th ed., A.
Oslo editor, Easton Pa. 1980).
[0455] In a preferred embodiment, noribogaine, noribogaine derivative, or a
pharmaceutically acceptable salt or solvate thereof is administered orally,
which may
conveniently be provided in tablet, caplet, sublingual, liquid or capsule
form. In certain
embodiments, the noribogaine is provided as noribogaine HO, with dosages
reported as
the amount of free base noribogaine. In some embodiments, the noribogaine HC1
is
provided in hard gelatin capsules containing only noribogaine HC1 with no
excipients.
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[0456] The patient may suffer from addiction to any opioid or opiate, or
opioid-like
drug. In a preferred embodiment, the opioid or opioid-like drug is selected
from the group
consisting of heroin, cocaine, opiate, methadone, morphine, codeine,
hydrocodone,
oxycodone, and methamphetamine. In one embodiment, the opioid or opioid-like
drug is
heroin. In one embodiment, the opioid or opioid-like drug is methadone. In one

embodiment, the opioid or opioid-like drug is morphine.
Alcohol Dependence
[0457] In one aspect, this invention relates to treatment of acute withdrawal
from alcohol
in an alcohol dependent patient comprising administration of a therapeutically
effective
amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable
salt and/or
solvate thereof.
[0458] In one aspect, this invention relates to a method for treating alcohol
abuse in an
alcohol-dependent patient, comprising administering to the patient a dosage of

noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof that provides an average serum concentration of about 50 ng/mL to
about 850
ng/mL,said concentration being sufficient to inhibit or ameliorate said abuse
while
maintaining a QT interval of less than about 500 ms during said treatment.
[0459] In one aspect, this invention relates to a method for attenuating
withdrawal
symptoms in a human patient susceptible to such symptoms due to alcohol
dependence,
comprising administering to the patient a dosage of noribogaine, noribogaine
derivative,
or pharmaceutically acceptable salt and/or solvate thereof that provides an
average serum
concentration of about 60 ng/mL to about 400 ng/mL, said concentration being
sufficient
to attenuate said symptoms while maintaining a QT interval of less than about
500 ms
during said treatment. In some embodiments, the concentration is sufficient to
attenuate
said symptoms while maintaining a QT interval of less than about 470 ms during
treatment. Preferably, the concentration is sufficient to attenuate said
symptoms while
maintaining a QT interval of less than about 450 ms during treatment. In one
embodiment,
the concentration is sufficient to attenuate said symptoms while maintaining a
QT interval
of less than about 420 ms during treatment. In one embodiment, the withdrawal
symptoms
are symptoms of acute withdrawal.
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[0460] In one aspect, this invention relates to a method for attenuating
withdrawal
symptoms in a human patient susceptible to such symptoms due to alcohol
dependence,
comprising administering to the patient a dosage of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt and/or solvate thereof that provides an
average serum
concentration of about 50 ng/mL to about 400 ng/mL, said concentration being
sufficient
to attenuate said symptoms while maintaining a QT interval of less than about
500 ms
during said treatment. In some embodiments, the concentration is sufficient to
attenuate
said symptoms while maintaining a QT interval of less than about 470 ms during

treatment. Preferably, the concentration is sufficient to attenuate said
symptoms while
maintaining a QT interval of less than about 450 ms during treatment. In one
embodiment,
the concentration is sufficient to attenuate said symptoms while maintaining a
QT interval
of less than about 420 ms during treatment. In one embodiment, the withdrawal
symptoms
are symptoms of acute withdrawal.
[0461] In one embodiment, the average serum concentration of noribogaine is
from
about 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL. In one

embodiment, the average serum concentration of noribogaine is from about 50
ng/mL to
about 700 ng/mL or about 60 ng/mL to about 700 ng/mL. In one embodiment, the
average
serum concentration of noribogaine is from about 50 ng/mL to about 600 ng/mL,
or about
60 ng/mL to about 600 ng/mL. In a preferred embodiment, the average serum
concentration of noribogaine is from about 50 ng/mL to about 500 ng/mL, or
about 60
ng/mL to about 500 ng/mL. In one embodiment, the average serum concentration
of
noribogaine is from about 50 ng/mL to about 400 ng/mL, or about 60 ng/mL to
about 400
ng/mL. In one embodiment, the average serum concentration of noribogaine is
from about
50 ng/mL to about 300 ng/mL, or about 60 ng/mL to about 300 ng/rnL. In one
embodiment, the average serum concentration of noribogaine is from about 50
ng/mL to
about 200 ng/mL, or about 60 ng/mL to about 200 ng/mL. In one embodiment, the
average
serum concentration of noribogaine is from about 50 ng/mL to about 100 ng/mL,
or about
60 ng/mL to about 100 ng/mL. The ranges include both extremes as well as any
subranges
between.
[0462] In one embodiment, the dosage or aggregate dosage of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt ancUor solvate thereof is from
greater than
about 1 mg/kg to about 8 mg/kg body weight per day. The aggregate dosage is
the
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combined dosage, for example the total amount of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt and/or solvate thereof administered over a 24-
hour period
where smaller amounts are administered more than once per day. In one
embodiment, the
dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt
and/or solvate
thereof is from about 1.3 mg/kg to about 7 mg/kg body weight. In one
embodiment, the
dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt
and/or solvate
thereof is from about 1.3 mg/kg to about 6 mg/kg body weight. In one
embodiment, the
dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt
and/or solvate
thereof is from about 1.3 mg/kg to about 5 mg/kg body weight. In a preferred
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt and/or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg body
weight. In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt and/or solvate thereof is from about 1.3 mg/kg to about 3 mg/kg body
weight. In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt and/or solvate thereof is from about 1.3 mg/kg to about 2 mg/kg body
weight. In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt and/or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg body
weight. In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt and/or solvate thereof is from about 1.7 mg/kg to about 3 mg/kg body
weight. In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt and/or solvate thereof is from about 2 mg/kg to about 4 mg/kg body
weight. In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt and/or solvate thereof is from about 2 mg/kg to about 3 mg/kg body
weight. In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt and/or solvate thereof is about 2 mg/kg body weight. The ranges include
both
extremes as well as any subranges there between.
[0463] In one embodiment, the dosage or aggregate dosage of noribogaine,
noribogaine
derivative, or salt and/or solvate thereof is about 8 mg/kg body weight per
day. In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt and/or solvate thereof is about 7 mg/kg body weight per day. In one
embodiment, the
dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt
and/or solvate
thereof is about 6 mg/kg body weight per day. In one embodiment, the dosage or
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aggregate dosage of noribogaine, noribogaine derivative, or salt and/or
solvate thereof is
about 5 mg/kg body weight per day. In one embodiment, the dosage or aggregate
dosage
of noribogaine, noribogaine derivative, or salt and/or solvate thereof is
about 4 mg/kg
body weight per day. In one embodiment, the dosage or aggregate dosage of
noribogaine,
noribogaine derivative, or salt and/or solvate thereof is about 3 mg/kg body
weight per
day. In one embodiment, the dosage or aggregate dosage of noribogaine,
noribogaine
derivative, or salt and/or solvate thereof is about 2 mg/kg body weight per
day. In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt and/or solvate thereof is about 1.7 mg/kg body weight per day. In one
embodiment,
the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt
and/or
solvate thereof is about 1.5 mg/kg body weight per day. In one embodiment, the
dosage or
aggregate dosage of noribogaine, noribogaine derivative, or salt and/or
solvate thereof is
about 1.3 mg/kg body weight per day. In one embodiment, the dosage or
aggregate dosage
of noribogaine, noribogaine derivative, or salt and/or solvate thereof is
about 1 mg/kg
body weight per day.
[0464] In one aspect, this invention relates to treatment or attenuation of
post-acute
withdrawal from alcohol dependence, and/or symptoms of withdrawal, in an
addicted
patient by administering a maintenance amount of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt and/or solvate thereof.
[0465] In some aspects, this invention relates to a method to prevent relapse
of alcohol
abuse and/or use in an addicted patient treated to ameliorate said abuse, said
method
comprising periodically administering to said patient a maintenance dosage of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof.
[0466] In some embodiments, the patient undergoes long-term (e.g., one month,
three
months, six months, one year or longer) treatment with maintenance doses of
noribogaine,
noribogaine derivative, or salt and/or solvate thereof. In some embodiments,
the patient is
treated for acute withdrawal with therapeutic doses of noribogaine as
described above, and
then the amount of noribogaine is reduced to maintenance levels after acute
withdrawal
symptoms would be expected to have subsided. Acute withdrawal symptoms
generally are
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the most pronounced in the first week after cessation of alcohol use, although
acute
withdrawal may last as long as six weeks or more.
[0467] In some embodiments, the patient is administered a high (therapeutic)
dose of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof for a period of time to ameliorate the most significant withdraw
symptoms, and
then is administered a lower (maintenance) dose to prevent relapse to drug
use. In some
embodiments, the patient is administered a therapeutic dose of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof for a
period of time
to ameliorate the most significant withdraw symptoms, and then is administered
a
decreasing (tapered) amount of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof over time until the maintenance dose is
reached.
Drug Addiction
[0468] In one aspect, this invention relates to treatment of acute withdrawal
from an
addictive substance in an addicted patient comprising administration of a
therapeutically
effective amount of noribogaine, noribogaine derivative, or pharmaceutically
acceptable
salt and/or solvate thereof.
[0469] In one aspect, this invention relates to a method for treating
substance abuse in an
addicted patient, comprising administering to the patient a dosage of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt and/or solvate
thereof that
provides an average serum concentration of 50 ng/mL to 180 ng/mL, said
concentration
being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval of less
than about 500 ms during said treatment.
[0470] In one aspect, this invention relates to a method for attenuating
withdrawal
symptoms in a human patient susceptible to such symptoms due to substance
addiction,
comprising administering to the patient a dosage of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt and/or solvate thereof that provides an
average serum
concentration of 80 ng/mL to 180 ng/mL, said concentration being sufficient to
attenuate
said symptoms while maintaining a QT interval of less than about 500 ms during
said
treatment. In some embodiments, the concentration is sufficient to attenuate
said
symptoms while maintaining a QT interval of less than about 470 ms during
treatment.
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Preferably, the concentration is sufficient to attenuate said symptoms while
maintaining a
QT interval of less than about 450 ms during treatment. In one embodiment, the

concentration is sufficient to attenuate said symptoms while maintaining a QT
interval of
less than about 420 ms during treatment. In one embodiment, the withdrawal
symptoms
are symptoms of acute withdrawal.
104711 In one aspect, this invention relates to a method for attenuating
withdrawal
symptoms in a human patient susceptible to such symptoms due to substance
addiction,
comprising administering to the patient a dosage of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt ancUor solvate thereof that provides an
average serum
concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to
attenuate
said symptoms while maintaining a QT interval of less than about 500 ms during
said
treatment. In some embodiments, the concentration is sufficient to attenuate
said
symptoms while maintaining a QT interval of less than about 470 ms during
treatment.
Preferably, the concentration is sufficient to attenuate said symptoms while
maintaining a
QT interval of less than about 450 ms during treatment. In one embodiment, the

concentration is sufficient to attenuate said symptoms while maintaining a QT
interval of
less than about 420 ms during treatment. In one embodiment, the withdrawal
symptoms
are symptoms of acute withdrawal.
104721 In one embodiment, the average serum concentration of noribogaine is
from 50
ng/mL to 180 ng/mL, or 60 ng/mL to 180 ng/mL. In one embodiment, the average
serum
concentration of noribogaine is from 50 ng/mL to 150 ng/mL, or 60 ng/mL to 150
ng/mL.
In one embodiment, the average serum concentration of noribogaine is from 50
ng/mL to
100 ng/mL, or 60 ng/mL to 100 ng/mL. In one embodiment, the average serum
concentration of noribogaine is from 80 ng/mL to 150 ng/mL. In one embodiment,
the
average serum concentration of noribogaine is from 80 ng/mL to 100 ng/mL. The
ranges
include both extremes as well as any subranges between.
104731 The patient may suffer from addiction to any addictive drug or
substance. In a
preferred embodiment, the drug is selected from the group consisting of
benzodiazepines,
cannabinoids and synthetic cannabinoids, stimulants, barbiturates, gamma-
hydroxybutyrate (GHB), ketamine, PCP, dextromethorphan (DXM), lysergic acid
diethylamide (LSD), mescaline, anabolic steroids, and derivatives of each
thereof.
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[0474] In one aspect, this invention relates to treatment or attenuation of
post-acute
withdrawal from an addictive substance, and/or symptoms of withdrawal, in an
addicted
patient with a maintenance amount of noribogaine, noribogaine derivative, or
pharmaceutically acceptable salt and/or solvate thereof.
[0475] In some aspects, this invention relates to a method to prevent relapse
of drug
abuse in an addicted patient treated to ameliorate said abuse, said method
comprising
periodically administering to said patient a maintenance dosage of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt and/or solvate
thereof.
Pain
[0476] As will be apparent to the skilled artisan upon reading this
disclosure, the present
invention provides a method for treating pain in a patient by alleviating
and/or inhibiting
pain in said patient, comprising administering to the patient a dosage of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt and/or solvate
thereof.
[0477] In one aspect, this invention relates to treatment of pain in a patient
suffering
from pain comprising administration of a therapeutically effective amount of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt and/or solvate
thereof.
[0478] In one aspect, this invention relates to a method for treating pain in
a patient
suffering from pain, comprising administering to the patient a dosage of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt and/or solvate
thereof that
provides an average serum concentration of 20 ng/mL to 180 ng/mL, said
concentration
being sufficient to inhibit or ameliorate said pain while maintaining a QT
interval of less
than about 500 ms during said treatment. In one embodiment, the concentration
is
sufficient to inhibit or ameliorate said pain while maintaining a QT interval
prolongation
of less than about 20 ms during said treatment.
[0479] In one aspect, this invention relates to a method for attenuating pain
in a human
patient, comprising administering to the patient a dosage of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof that
provides an
average serum concentration of 20 ng/mL to 180 ng/mL, said concentration being

sufficient to attenuate said symptoms while maintaining a QT interval of less
than about
500 ms during said treatment. In some embodiments, the concentration is
sufficient to
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attenuate said symptoms while maintaining a QT interval of less than about 470
ms during
treatment. Preferably, the concentration is sufficient to attenuate said
symptoms while
maintaining a QT interval of less than about 450 ms during treatment. In one
embodiment,
the concentration is sufficient to attenuate said symptoms while maintaining a
QT interval
of less than about 420 ms during treatment.
[0480] In one aspect, this invention relates to a method for attenuating pain
in a human
patient susceptible to such symptoms, comprising administering to the patient
a dosage of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL,
said
concentration being sufficient to attenuate said symptoms while maintaining a
QT interval
of less than about 500 ms during said treatment. In some embodiments, the
concentration
is sufficient to attenuate said symptoms while maintaining a QT interval of
less than about
470 ms during treatment. Preferably, the concentration is sufficient to
attenuate said
symptoms while maintaining a QT interval of less than about 450 ms during
treatment. In
one embodiment, the concentration is sufficient to attenuate said symptoms
while
maintaining a QT interval of less than about 420 ms during treatment.
[0481] In one aspect, this invention relates to a method for attenuating pain
in a human
patient susceptible to such symptoms, comprising administering to the patient
a dosage of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof that provides an average serum concentration of 80 ng/mL to 100 ng/mL,
said
concentration being sufficient to attenuate said symptoms while maintaining a
QT interval
of less than about 500 ms during said treatment. In some embodiments, the
concentration
is sufficient to attenuate said symptoms while maintaining a QT interval of
less than about
470 ms during treatment. Preferably, the concentration is sufficient to
attenuate said
symptoms while maintaining a QT interval of less than about 450 ms during
treatment. In
one embodiment, the concentration is sufficient to attenuate said symptoms
while
maintaining a QT interval of less than about 420 ms during treatment.
[0482] In one embodiment, the average serum concentration of noribogaine is
from 50
ng/mL to 180 ng/mL, or 20 ng/mL to 180 ng/mL. In one embodiment, the average
serum
concentration of noribogaine is from 50 ng/mL to 150 ng/mL, or 20 ng/mL to 150
ng/mL.
In one embodiment, the average serum concentration of noribogaine is from 50
ng/mL to
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100 ng/mL, or 20 ng,/mL to 100 ng/mL. In one embodiment, the average serum
concentration of noribogaine is from 80 ng/mL to 100 ng/mL.The ranges include
both
extremes as well as any subranges between.
[0483] In one embodiment, the dosage or aggregate dosage of noribogaine,
noribogaine
derivative, or salt andJor solvate thereof is from 0.1 mg/kg to 4 mg/kg body
weight per
day. The aggregate dosage is the combined dosage, for example the total amount
of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof administered over a 24-hour period where smaller amounts are
administered more
than once per day. In another embodiment, the therapeutically effective amount
of the
compound is from 0.1 mg to 3 mg per kg body weight per day. In another
embodiment,
the therapeutically effective amount of the compound is from 0.1 mg to 2 mg
per kg body
weight per day. In another embodiment, the therapeutically effective amount of
the
compound is from 0.1 mg to 1.5 mg per kg body weight per day. In another
embodiment,
the therapeutically effective amount of the compound is from 0.1 mg to 1 mg
per kg body
weight per day. In another embodiment, the therapeutically effective amount of
the
compound is from 0.5 mg to 3 mg per kg body weight per day. In another
embodiment,
the therapeutically effective amount of the compound is from 0.5 mg to 2 mg
per kg body
weight per day. In another embodiment, the therapeutically effective amount of
the
compound is from 0.5 mg to 1.5 mg per kg body weight per day. In another
embodiment,
the therapeutically effective amount of the compound is from 0.5 mg to 1.3 mg
per kg
body weight per day. In another embodiment, the therapeutically effective
amount of the
compound is from 0.5 mg to 1.2 mg per kg body weight per day. In another
embodiment,
the therapeutically effective amount of the compound is from 0.5 mg to 1.1 mg
per kg
body weight per day. In another embodiment, the therapeutically effective
amount of the
compound is from 0.5 mg to 1 mg per kg body weight per day. In another
embodiment,
the therapeutically effective amount of the compound is from 0.7 mg to 1.5 mg
per kg
body weight per day. The ranges include both extremes as well as any subranges
there
between.
[0484] In one embodiment, the therapeutically effective amount of the compound
is
about 3 mg/kg body weight per day. In one embodiment, the therapeutically
effective
amount of the compound is about 2 mg/kg body weight per day. In one
embodiment, the
therapeutically effective amount of the compound is about 1.5 mg/kg body
weight per day.
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In one embodiment, the therapeutically effective amount of the compound is
about 1.4
mg/kg body weight per day. In one embodiment, the therapeutically effective
amount of
the compound is about 1.3 mg/kg body weight per day. In one embodiment, the
therapeutically effective amount of the compound is about 1.2 mg/kg body
weight per day.
In one embodiment, the therapeutically effective amount of the compound is
about 1.1
mg,/kg body weight per day. In one embodiment, the therapeutically effective
amount of
the compound is about 1 mg/kg body weight per day. In one embodiment, the
therapeutically effective amount of the compound is about 0.9 mg/kg body
weight per day.
In one embodiment, the therapeutically effective amount of the compound is
about 0.8
mg/kg body weight per day. In one embodiment, the therapeutically effective
amount of
the compound is about 0.7 mg/kg body weight per day. In one embodiment, the
therapeutically effective amount of the compound is about 0.6 mg/kg body
weight per day.
In one embodiment, the therapeutically effective amount of the compound is
about 0.5
mg/kg body weight per day. In one embodiment, the therapeutically effective
amount of
the compound is about 0.4 mg/kg body weight per day. In one embodiment, the
therapeutically effective amount of the compound is about 0.3 mg/kg body
weight per day.
In one embodiment, the therapeutically effective amount of the compound is
about 0.2
mg/kg body weight per day. In one embodiment, the therapeutically effective
amount of
the compound is about 0.1 mg/kg body weight per day.
[0485] In one embodiment, the dosage or aggregate dosage of noribogaine or
salt or
solvate thereof is between 60 mg and 150 mg. In one embodiment, the dosage or
aggregate
dosage of noribogaine or salt or solvate thereof is between 70 mg and 150 mg.
In one
embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate
thereof is
between 80 mg and 140 mg. In one embodiment, the dosage or aggregate dosage of

noribogaine or salt or solvate thereof is between 90 mg and 140 mg. In one
embodiment,
the dosage or aggregate dosage of noribogaine or salt or solvate thereof is
between 90 mg
and 130 mg. In one embodiment, the dosage or aggregate dosage of noribogaine
or salt or
solvate thereof is between 100 mg and 130 mg. In one embodiment, the dosage or

aggregate dosage of noribogaine or salt or solvate thereof is between 110 mg
and 130 mg.
[0486] In another embodiment, there is provided a unit dose of noribogaine or
salt or
solvate thereof which is about 120 mg per dose. It being understood that the
term "unit
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dose" means a dose sufficient to provide therapeutic results whether given all
at once or
serially over a period of time.
[0487] In one embodiment, the dosage or aggregate dosage of noribogaine or
salt or
solvate thereof is between 10 mg and 100 mg. In one embodiment, the dosage or
aggregate
dosage of noribogaine or salt or solvate thereof is between 50 mg and 100 mg.
In one
embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate
thereof is
between 60 mg and 100 mg. In one embodiment, the dosage or aggregate dosage of

noribogaine or salt or solvate thereof is between 60 mg and 90 mg. In one
embodiment,
the dosage or aggregate dosage of noribogaine or salt or solvate thereof is
between 60 mg
and 80 mg. In one embodiment, the dosage or aggregate dosage of noribogaine or
salt or
solvate thereof is between 60 mg and 70 mg.
Treating Migraine
[0488] In some embodiments, the invention provides for a method for treating
migraines
and/or symptoms thereof in a subject, comprising administering to the patient
in need
thereof a therapeutically effective amount of noribogaine, a noribogaine
derivative, or a
pharmaceutically acceptable salt of each thereof. In one embodiment, the
method further
comprises administering at least one agent known to treat or prevent migraines
and/or
symptoms thereof. In a preferred embodiment, treatment with noribogaine and/or
the agent
does not result in a QT interval prolongation of more than about 50 ms. Where
noribogaine is discussed throughout the specification, it is to be understood
that such an
agent may optionally be administered in conjunction with (e.g., before, after,
or
concurrently with) noribogaine or derivative.
[0489] The subject or patient may be any patient who exhibits migraine ancUor
symptoms thereof. In a preferred embodiment, the patient is subject to
recurrent migraines.
In one embodiment, the patient has chronic migraine. Chronic migraine is
characterized by
headaches (tension and/or migraine) on more than 15 days per month for at
least 3 months,
with migraine (without aura) on at least 8 days per month (or successful
treatment of
expected symptoms).
[0490] In one aspect, this invention relates to a method for treating migraine
and/or
symptoms thereof in a patient, comprising administering to the patient a
dosage of
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noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate thereof
that provides an average serum concentration of about 50 ng/mL to about 180
ng/mL, said
concentration being sufficient to treat said migraine and/or symptoms while
maintaining a
QT interval of less than about 500 ms during said treatment.
[0491] In some embodiments, the concentration is sufficient to treat the
patient while
maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the
concentration is sufficient to treat the patient while maintaining a QT
interval of less than
about 450 ms during treatment. In one embodiment, the concentration is
sufficient to treat
the patient while maintaining a QT interval of less than about 420 ms during
treatment.
[0492] In one embodiment, the QT interval is not prolonged more than about 50
ms. In
one embodiment, the QT interval is not prolonged more than about 40 ms. In one

embodiment, the QT interval is not prolonged more than about 30 ms. In one
embodiment,
the QT interval is not prolonged more than about 20 ms. In one embodiment, the
QT
interval is not prolonged more than about 10 ms.
[0493] In one embodiment, the dosage of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt or solvate thereof provides a serum
concentration of
between about 1000 ng=hr/mL and about 6000 ng=hr/mL. In one embodiment, the
dosage
of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate
thereof provides a serum concentration of between about 1200 ng=hr/mL and
about 5800
ng-hr/mL. In one embodiment, the dosage of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt or solvate thereof provides a serum
concentration of
between about 1200 ng=hr/mL and about 5500 ng=hr/mL. The ranges include both
extremes as well as any subranges between.
[0494] In one embodiment, the dosage of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt or solvate thereof provides a maximum serum
concentration (Cmax) of less than about 250 ng/mL. In one embodiment, the
dosage of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate thereof
provides a Cmax between about 40 ng/mL and about 250 ng/mL. In a preferred
embodiment, the dosage of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof provides a Cmax between about 60 ng/mL and
about 200
ng/mL. In one embodiment, the dosage of noribogaine, noribogaine derivative,
or
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pharmaceutically acceptable salt or solvate thereof provides a Cmax between
about 100
ng/mL and about 180 ng/mL.
[0495] In one embodiment, the dosage or aggregate dosage of noribogaine,
noribogaine
derivative, or salt or solvate thereof is from about 1 mg/kg to about 4 mg/kg
body weight
per day. The aggregate dosage is the combined dosage, for example the total
amount of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate thereof
administered over a 24-hour period where smaller amounts are administered more
than
once per day. In one embodiment, the dosage or aggregate dosage of
noribogaine,
noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to
about 4 mg/kg
body weight. In one embodiment, the dosage or aggregate dosage of noribogaine,

noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to
about 3 mg/kg
body weight. In one embodiment, the dosage or aggregate dosage of noribogaine,

noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to
about 2 mg/kg
body weight. In one embodiment, the dosage or aggregate dosage of noribogaine,

noribogaine derivative, or salt or solvate thereof is from about 1.5 mg/kg to
about 3 mg/kg
body weight. In one embodiment, the dosage or aggregate dosage of noribogaine,

noribogaine derivative, or salt or solvate thereof is from about 1.7 mg/kg to
about 3 mg/kg
body weight. In one embodiment, the dosage or aggregate dosage of noribogaine,

noribogaine derivative, or salt or solvate thereof is from about 2 mg/kg to
about 4 mg/kg
body weight. In one embodiment, the dosage or aggregate dosage of noribogaine,

noribogaine derivative, or salt or solvate thereof is from about 2 mg/kg to
about 3 mg/kg
body weight. In one embodiment, the dosage or aggregate dosage of noribogaine,

noribogaine derivative, or salt or solvate thereof is about 2 mg/kg body
weight. The ranges
include both extremes as well as any subranges there between.
[0496] In one embodiment, the dosage or aggregate dosage of noribogaine,
noribogaine
derivative, or salt or solvate thereof is between about 70 mg and about 150
mg. In one
embodiment, the dosage or aggregate dosage of noribogaine, noribogaine
derivative, or
salt or solvate thereof is between about 75 mg and about 150 mg. In one
embodiment, the
dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or
solvate
thereof is between about 80 mg and about 140 mg. In one embodiment, the dosage
or
aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate
thereof is
between about 90 mg and about 140 mg. In one embodiment, the dosage or
aggregate
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dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is
between about
90 mg and about 130 mg. In one embodiment, the dosage or aggregate dosage of
noribogaine, noribogaine derivative, or salt or solvate thereof is between
about 100 mg
and about 130 mg. In one embodiment, the dosage or aggregate dosage of
noribogaine,
noribogaine derivative, or salt or solvate thereof is between about 110 mg and
about 130
mg.
[0497] In some embodiments, the therapeutically effective amount of the
compound is
from about 50 ng to about 10 jig per kilogram body weight per day. In another
embodiment, the therapeutically effective amount of the compound is from about
50 ng to
about 5 jig per kilogram body weight per day. In another embodiment, the
therapeutically
effective amount of the compound is from about 50 ng to about 1 g per
kilogram body
weight per day. In another embodiment, the therapeutically effective amount of
the
compound is from about 50 ng to about 1 g per kilogram body weight per day.
In yet
another embodiment, the therapeutically effective amount of the compound is
from about
500 ng to less than 10 jig per kilogram body weight per day. In yet another
embodiment,
the therapeutically effective amount of the compound is from about 1 jig to
less than 10
g per kilogram body weight per day. In yet another embodiment, the
therapeutically
effective amount of the compound is about 50 ng, about 100 ng, about 150 ng,
about 200
ng, about 250 ng, about 300 ng, about 350 ng, about 400 ng, about 450 ng,
about 500 ng,
about 550 ng, about 600 ng, about 650 ng, about 700 ng, about 750 ng, about
800 ng,
about 850 ng, about 900 ng, about 950 ng, about 1 g, about 2 g, about 3 g,
about 3
g, about 4 g, about 5 jug, about 6 jig, about 7 jig, about 8 g, about 9 jig,
or about 10 g
per kilogram body weight per day. The therapeutically effective amount of the
compound
may be any amount within any of these ranges, including endpoints.
[0498] In some embodiments, the therapeutically effective amount of
noribogaine,
derivative, prodrug, or salt thereof is administered once a day. In some
embodiments, the
therapeutically effective amount is administered twice per day. In some
embodiments, the
therapeutically effective amount is administered more than two times per day.
[0499] Where the therapeutically effective amount is administered more than
one time
per day, a portion of the total therapeutically effective amount is
administered at each
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time. For example, an 90 kg patient taking 1 pig noribogaine per kg body
weight per day
would take 90 g once a day, 45 jig twice a day, or 30 jig three times a day,
etc.
[0500] In some embodiments, the therapeutically effective amount of
noribogaine,
derivative, prodrug, or salt thereof is administered when needed, e.g., when
the patient has
a migraine or symptoms thereof or anticipates having a migraine (e.g.,
anticipates or
experiences a trigger, has symptoms or predrome phase, etc).
[0501] In some embodiments, noribogaine, noribogaine derivative, or a
pharmaceutically acceptable salt or solvate thereof is administered to a
patient
periodically, such as once, twice, three times, four times or five times
daily. In some
embodiments, the administration is once daily, or once every second day, once
every third
day, three times a week, twice a week, or once a week. The dosage and
frequency of the
administration depends on the route of administration, content of composition,
age and
body weight of the patient, condition of the patient, without limitation.
Determination of
dosage and frequency suitable for the present technology can be readily made
by a
qualified clinician.
[0502] In some embodiments, the noribogaine or noribogaine derivative is
administered
sublingually, intrapulmonary, buccally, or intranasally. These routes of
administration are
discussed in further detail below in the subsection titled "Dosage and Routes
of
Administration."
Preventing Migraine
[0503] In some embodiments, the invention provides for a method for preventing
or
attenuating migraine and/or symptoms thereof in a subject, comprising
administering to
the patient in need thereof a prophylactically effective amount of
noribogaine, a
noribogaine derivative, or a pharmaceutically acceptable salt of each thereof.
In some
embodiments, the invention provides for a method for preventing or attenuating
migraine
and/or symptoms thereof in a subject, comprising administering to the patient
in need
thereof a prophylactically effective amount of noribogaine, a noribogaine
derivative, or a
pharmaceutically acceptable salt of each thereof in conjunction with an agent
known to
prevent migraines and/or symptoms thereof. Where noribogaine is discussed
throughout
the specification, it is to be understood that such an agent may optionally be
administered
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in conjunction with (e.g., before, after, concurrently or substantially
concurrently with)
noribogaine or derivative.
[0504] In some embodiments, the noribogaine is administered on an as-needed
basis by
the patient. In some embodiments, the noribogaine may be administered before
the
migraine and/or symptoms thereof occurs. For example, the patient may take a
dose of
noribogaine in anticipation of symptoms (e.g., after, concurrent with, or in
anticipation of
a migraine trigger; when one or more predrome symptoms are experienced; etc).
In some
embodiments, the prophylactically effective amount of noribogaine may be
administered
on a regularly scheduled basis (e.g., daily, every other day, weekly, etc.) to
prevent
migraine.
[0505] In one embodiment, the prophylactically effective amount of the
compound is up
to about 90% of the therapeutic amount. In one embodiment, the
prophylactically
effective amount of the compound is up to about 80% of the therapeutic amount.
In one
embodiment, the prophylactically effective amount of the compound is up to
about 70%
of the therapeutic amount. In one embodiment, the prophylactically effective
amount of
the compound is up to about 60% of the therapeutic amount. In one embodiment,
the
prophylactically effective amount of the compound is up to about 50% of the
therapeutic
amount. In one embodiment, the prophylactically effective amount of the
compound is up
to about 40% of the therapeutic amount. In one embodiment, the
prophylactically
effective amount of the compound is up to about 30% of the therapeutic amount.
In one
embodiment, the prophylactically effective amount of the compound is up to
about 20%
of the therapeutic amount. In one embodiment, the prophylactically effective
amount of
the compound is up to about 10% of the therapeutic amount.
[0506] In one embodiment, the prophylactically effective amount of the
compound is
from about 50 ng to less than 10 jig per kilogram body weight per day. In
another
embodiment, the prophylactically effective amount of the compound is from
about 50 ng
to about 5 jig per kilogram body weight per day. In another embodiment, the
prophylactically effective amount of the compound is from about 50 ng to about
1 lag per
kilogram body weight per day. In yet another embodiment, the prophylactically
effective
amount of the compound is from about 500 ng to less than 10 jig per kilogram
body
weight per day. In yet another embodiment, the prophylactically effective
amount of the
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compound is from about 1 jig to less than 10 jig per kilogram body weight per
day. The
prophylactically effective amount of the compound may be any amount within any
of
these ranges, including endpoints.
[0507] In one embodiment, the QT interval is not prolonged more than about 30
ms. In a
preferred embodiment, the QT interval is not prolonged more than about 20 ms.
In one
embodiment, the QT interval is not prolonged more than about 10 ms.
[0508] In some embodiments, the prophylactically effective amount of
noribogaine,
derivative, prodrug, or salt thereof is administered once a day. In some
embodiments, the
prophylactically effective amount is administered twice per day. In some
embodiments,
the prophylactically effective amount is administered more than two times per
day.
[0509] Where the prophylactically effective amount of noribogaine is
administered more
than one time per day, a portion of the total prophylactically effective
amount is
administered at each time. For example, an 90 kg patient taking 1 jig
noribogaine per kg
body weight per day would take 90 jig once a day, 45 jig twice a day, or 30
jig three times
a day, etc.
[0510] In some embodiments, the patient is administered periodically, such as
once,
twice, three times, four times or five times daily with noribogaine,
noribogaine derivative,
or a pharmaceutically acceptable salt or solvate thereof. In some embodiments,
the
administration is once daily, or once every second day, once every third day,
three times a
week, twice a week, or once a week. The dosage and frequency of the
administration
depends on the route of administration, content of composition, age and body
weight of
the patient, condition of the patient, without limitation. Determination of
dosage and
frequency suitable for the present technology can be readily made a qualified
clinician.
[0511] In some embodiments, the noribogaine or noribogaine derivative is
administered
orally, sublingually, intrapulmonary, buccally, or intranasally. These routes
of
administration are discussed in further detail below in the subsection titled
"Dosage and
Routes of Administration."
[0512] In some embodiments, the maintenance average serum level of noribogaine
is
about 10% to about 80% of the therapeutic average serum level of noribogaine.
In some
embodiments, the maintenance average serum level of noribogaine is about 70%
of the
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therapeutic average serum level of noribogaine. In some embodiments, the
maintenance
average serum level of noribogaine is about 60% of the therapeutic average
serum level of
noribogaine. In some embodiments, the maintenance average serum level of
noribogaine is
about 50% of the therapeutic average serum level of noribogaine. In some
embodiments,
the maintenance average serum level of noribogaine is about 40% of the
therapeutic
average serum level of noribogaine. In some embodiments, the maintenance
average
serum level of noribogaine is about 30% of the therapeutic average serum level
of
noribogaine. In some embodiments, the maintenance average serum level of
noribogaine is
about 20% of the therapeutic average serum level of noribogaine. In some
embodiments,
the maintenance average serum level of noribogaine is about 10% of the
therapeutic
average serum level of noribogaine.
Reducing Analgesics Tolerance
[0513] In one aspect of this invention, patient is being treated with an
addictive opioid
analgesic to relieve the patient's pain. The pain may be of any type and from
any source.
In one embodiment, the patient is treated for acute pain. In one embodiment,
the patient is
treated for chronic pain. In one embodiment, the patient is treated for
nociceptive pain. In
one embodiment, the patient is treated for neuropathic pain. In some
embodiments, the
pain is caused by surgery, diabetes, trigeminal neuralgia, fibromyalgia,
cancer, central
pain syndrome, tissue damage, physical injury, and the like. In some
embodiments, the
source of the pain is unknown or unclear.
[0514] In one aspect, this invention relates to a method for modulating
tolerance to an
opioid analgesic in a patient undergoing opioid analgesic therapy, the method
comprising
interrupting or administering concurrently with said opioid analgesic an
amount of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate thereof
that provides an average serum concentration of about 50 ng/mL to about 180
ng/mL, said
concentration being sufficient resensitize the patient to the opioid as an
analgesic while
maintaining a QT interval of less than about 500 ms during said treatment.
[0515] In one embodiment, the average serum concentration of noribogaine is
from 50
ng/mL to 180 ng/mL, or 60 ng/mL to 180 ng/mL. In one embodiment, the average
serum
concentration of noribogaine is from 50 ng/mL to 150 ng/mL, or 60 ng/mL to 150
ng/mL.
In one embodiment, the average serum concentration of noribogaine is from 50
ng/mL to
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100 ng/mL, or 60 ng,/mL to 100 ng/mL. In one embodiment, the average serum
concentration of noribogaine is from 80 ng/mL to 100 ng/mL. The ranges include
both
extremes as well as any subranges between.
[0516] In one embodiment, the dosage or aggregate dosage of noribogaine,
noribogaine
derivative, or salt or solvate thereof is between 10 mg and 100 mg. In one
embodiment,
the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt
or solvate
thereof is between 20 mg and 100 mg. In one embodiment, the dosage or
aggregate dosage
of noribogaine, noribogaine derivative, or salt or solvate thereof is between
30 mg and 100
mg. In one embodiment, the dosage or aggregate dosage of noribogaine,
noribogaine
derivative, or salt or solvate thereof is between 40 mg and 100 mg. In one
embodiment,
the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt
or solvate
thereof is between 50 mg and 100 mg. In one embodiment, the dosage or
aggregate dosage
of noribogaine, noribogaine derivative, or salt or solvate thereof is between
60 mg and 100
mg. In one embodiment, the dosage or aggregate dosage of noribogaine,
noribogaine
derivative, or salt or solvate thereof is between 60 mg and 90 mg. In one
embodiment, the
dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or
solvate
thereof is between 60 mg and 80 mg. In one embodiment, the dosage or aggregate
dosage
of noribogaine, noribogaine derivative, or salt or solvate thereof is between
60 mg and 70
mg.
[0517] The patient may be receiving any addictive opioid analgesic for the
treatment of
pain. In a preferred embodiment, the opioid analgesic is selected from the
group consisting
of fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, buprenorphine,
codeine,
heroin, thebaine, buprenorphine, methadone, meperidine, tramadol, tapentadol,
levorphanol, sufentanil, pentazocine, oxymorphone, and derivatives of each
thereof.
Depression
[0518] As will be apparent to the skilled artisan upon reading this
disclosure, this
invention provides a method for treating depression and/or PTSD in a patient
in need
thereof, comprising administering to the patient a therapeutically effective
amount of
noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt
and/or solvate
thereof. In a preferred embodiment, the patient is not addicted to cocaine or
an opiate.
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Noribogaine derivatives include, but are not limited to, the compounds
described in the
"Compositions of the Invention" section above.
[0519] The following description of depressive disorders and PTSD is provided
for the
purpose of facilitating an understanding of the utility of the compounds and
compositions
of this invention. The definitions of depressive disorders and PTSD given
below are those
listed in American Psychiatric Association, 1994a or American Psychiatric
Association,
1987. Additional information regarding these disorders can be found in this
reference, as
well as other references cited below, all of which are hereby incorporated
herein by
reference.
[0520] In some embodiments, it is contemplated that the compounds of this
invention
will be effective in treating depression in patients who have been diagnosed
as having
depression based upon the administration of any of the following tests:
Hamilton
Depression Rating Scale (HDRS), Hamilton depressed mood item, Clinical Global
Impressions (CGI)-Severity of Illness. It is further contemplated that the
compounds of the
invention will be effective in improving certain of the factors measured in
these tests, such
as the HDRS subfactor scores, including the depressed mood item, sleep
disturbance
factor and anxiety factor, and the CGI-Severity of Illness rating. It is also
contemplated
that the compounds of this invention will be effective in preventing relapse
of major
depressive episodes.
[0521] This invention provides, in certain embodiments, a method of treating a
patient
suffering from major depressive disorder, which comprises administering to the
patient a
therapeutically effective amount of any of the compounds utilized herein
effective to treat
the subject's major depressive disorder.
[0522] The invention also provides a method of treating a patient suffering
from
dysthymic disorder, bipolar I or II disorder, schizoaffective disorder, a
cognitive disorder
with depressed mood, a personality disorder, insomnia, hypersomnia,
narcolepsy,
circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder or
sleepwalking
disorder.
[0523] It is contemplated that the compounds utilized herein can be effective
in treating
PTSD in patients who have been diagnosed as having PTSD based upon the
administration
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of any of the following tests: Clinician-Administered PTSD Scale Part 2
(CAPS), the
patient-rated Impact of Event Scale (IES). It is further contemplated that the
compounds
described herein will be effective in inducing improvements in the scores of
the CAPS,
TES, CGI-Severity of Illness or CGI-Global Improvement tests. It is also
contemplated that
the compounds described herein will be effective in preventing relapse of
PTSD.
[0524] This invention provides a method of treating post-traumatic stress
disorder in a
subject, which comprises administering to the patient a therapeutically
effective amount of
any of the compounds utilized herein to treat the subject's post-traumatic
stress disorder.
[0525] Another aspect of the current invention provides a method for treating
depression
and/or PTSD in a patient in need thereof, which method comprises administering

noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt
and/or solvate
thereof to the patient, wherein the amount of the noribogaine or a noribogaine
derivative is
sufficient to treat depression and/or PTSD in the patient.
[0526] In a preferred embodiment, the invention provides a method for treating

depression and/or posttraumatic stress disorder in a patient in need thereof,
comprising
administering to the patient a therapeutically effective amount of
noribogaine, noribogaine
derivative, or a pharmaceutically acceptable salt and/or solvate thereof,
wherein the patient
is not addicted to cocaine or an opiate, and further wherein the
therapeutically effective
amount provides average noribogaine serum levels of between 50 to 800 ng/ml.
In some
embodiments, the average noribogaine serum level provided by the dosage is
less than
about 50 ng/mL. In one embodiment, the therapeutically effective amount is
between 0.5
mg to 4 mg per kg of body weight. In one embodiment, the therapeutically
effective
amount is between 50 ng to less than 100 jig per kg of body weight. In one
embodiment,
depression is treated. In one embodiment, posttraumatic stress disorder is
treated. In one
embodiment, the noribogaine, noribogaine derivative, or pharmaceutically
acceptable salt
and/or solvate thereof is administered by sublingual, intranasal, or
intrapulmonary
delivery.
[0527] In some embodiments, the composition is administered via sublingual,
intranasal,
or intrapulmonary delivery. In one aspect, the invention provides
administering a
pharmaceutical composition comprising a pharmaceutically effective amount of
noribogaine and a pharmaceutically acceptable excipient, wherein the
therapeutically
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effective amount of noribogaine is an amount that delivers an aggregate amount
of
noribogaine of 50 ng to less than 100 pig per kg body weight per day. In some
aspects, the
therapeutically effective amount of noribogaine is an amount that delivers an
aggregate
amount of noribogaine of 50 ng to 50 pig per kg body weight per day. In some
aspects, the
therapeutically effective amount of noribogaine is an amount that delivers an
aggregate
amount of noribogaine of 50 ng to 10 pig per kg body weight per day. In some
aspects, the
therapeutically effective amount of noribogaine is an amount that delivers an
aggregate
amount of noribogaine of 50 ng to 1 pig per kg body weight per day. In some
aspects, the
composition is administered once per day. In some aspects, the composition is
administered two or more times per day. In some embodiments, the composition
is
administered less than once a day, for example once every two days, once every
three
days, once every four days, once a week, etc.
[0528] In some embodiments, the composition is administered via oral,
transdermal,
internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous,
intraarterial,
intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery. In
one
embodiment, the dosage or aggregate dosage of compound is from 0.5 mg to 4 mg
per kg
body weight per day. The aggregate dosage is the combined dosage, for example
the total
amount of noribogaine or pharmaceutically acceptable salt and/or solvate
thereof
administered over a 24-hour period where smaller amounts are administered more
than
once per day. In one embodiment, the dosage or aggregate dosage of compound is
from 1
mg to 4 mg per kg body weight per day. In one embodiment, the dosage or
aggregate
dosage of compound is about 1 mg to 3 mg per kg body weight per day. In one
embodiment, the dosage or aggregate dosage of compound is from 1 mg to 2 mg
per kg
body weight per day. In one embodiment, the dosage or aggregate dosage of
compound is
from 1.5 mg to 3 mg per kg body weight per day. In one embodiment, the dosage
or
aggregate dosage of compound is from 1.7 mg to 3 mg per kg body weight per
day. In one
embodiment, the dosage or aggregate dosage of compound is from 2 mg to 4 mg
per kg
body weight per day. In one embodiment, the dosage or aggregate dosage of
compound is
from 2 mg to 3 mg per kg body weight per day. In one embodiment, the dosage or

aggregate dosage of compound is about 2 mg per kg body weight per day.
[0529] In one embodiment, the dosage or aggregate dosage of compound is about
4
mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage
of
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compound is about 3 mg/kg body weight per day. In one embodiment, the dosage
or
aggregate dosage of compound is about 2 mg/kg body weight per day. In one
embodiment,
the dosage or aggregate dosage of compound is about 1.7 mg/kg body weight per
day. In
one embodiment, the dosage or aggregate dosage of compound is about 1.5 mg/kg
body
weight per day. In one embodiment, the dosage or aggregate dosage of compound
is about
1.3 mg/kg body weight per day. In one embodiment, the dosage or aggregate
dosage of
compound is about 1 mg/kg body weight per day. In one embodiment, the dosage
or
aggregate dosage of compound is less than about 1 mg/kg body weight per day.
[0530] In certain preferred embodiments of this invention, noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof is
administered in an
amount that provides an average serum concentration of noribogaine from 50
ng/mL to
180 ng/mL, or 60 ng/mL to 180 ng/mL. In one embodiment, the average serum
concentration of noribogaine is from 50 ng/mL to 150 ng/mL, or 60 ng/mL to 150
ng/mL.
In one embodiment, the average serum concentration of noribogaine is from 50
ng/mL to
100 ng/mL, or 60 ng/mL to 100 ng/mL. In one embodiment, the average serum
concentration of noribogaine is from 80 ng/mL to 100 ng/mL. The ranges include
both
extremes as well as any subranges between.
[0531] In some embodiments, the patient is administered periodically, such as
once,
twice, three times, four times or five times daily with noribogaine,
noribogaine derivative,
or salt and/or solvate thereof. In some embodiments, the administration is
once daily, or
once every second day, once every third day, three times a week, twice a week,
or once a
week. The dosage and frequency of the administration depends on the route of
administration, content of composition, age and body weight of the patient,
condition of
the patient, without limitation. Determination of dosage and frequency
suitable for the
present technology can be readily made by a qualified clinician.
[0532] In one aspect, this invention relates to a method for attenuating
symptoms of
depression and/or PTSD in a human patient, comprising administering to the
patient a
dosage of noribogaine or pharmaceutically acceptable salt and/or solvate
thereof that
provides an average serum concentration of 50 ng/mL to 180 ng/mL, said
concentration
being sufficient to attenuate said symptoms while maintaining a QT interval of
less than
about 500 ms during said treatment. In some embodiments, the concentration is
sufficient
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to attenuate said symptoms while maintaining a QT interval of less than about
470 ms
during treatment. Preferably, the concentration is sufficient to attenuate
said symptoms
while maintaining a QT interval of less than about 450 ms during treatment. In
one
embodiment, the concentration is sufficient to attenuate said symptoms while
maintaining
a QT interval of less than about 420 ms during treatment.
[0533] In one embodiment, the QT interval is not prolonged more than about 50
ms. In
one embodiment, the QT interval is not prolonged more than about 40 ms. In one

embodiment, the QT interval is not prolonged more than about 30 ms. In a
preferred
embodiment, the QT interval is not prolonged more than about 20 ms. In one
embodiment,
the QT interval is not prolonged more than about 10 ms.
[0534] Noribogaine, a noribogaine derivative, or a pharmaceutically acceptable
salt
and/or solvate thereof can also be used in conjunction with any of the
vehicles and
excipients commonly employed in pharmaceutical preparations, e.g., talc, gum
Arabic,
lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous
solvents, oils,
paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be
added to
preparations, particularly to those for oral administration. Solutions can be
prepared using
water or physiologically compatible organic solvents such as ethanol, 1,2-
propylene
glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial
esters of
glycerine and the like. Parenteral compositions containing noribogaine may be
prepared
using conventional techniques that may include sterile isotonic saline, water,
1,3-
butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water,
Ringer's
solution, etc.
Anxiety etc.
[0535] As will be apparent to the skilled artisan upon reading this
disclosure, this
invention provides a method for treating anxiety disorder, impulse control
disorder,
anger/violence-related disorders, or regulating food intake in a patient in
need thereof,
comprising administering to the patient a therapeutically effective amount of
noribogaine,
a noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate
thereof. In a
preferred embodiment, the patient is not addicted to cocaine or an opiate.
Noribogaine
derivatives include, but are not limited to, the compounds described in the
"Compositions
of the Invention" section above.
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[0536] The following description of anxiety disorders and impulse control
disorders is
provided for the purpose of facilitating an understanding of the utility of
the compounds
and compositions of this invention. Disorders associated with violence ancUor
anger are
included in these descriptions.The definitions of anxiety disorders and
impulse control
disorders given below are those listed in American Psychiatric Association,
2013,
American Psychiatric Association, 1994a, or American Psychiatric Association,
1987.
Additional information regarding these disorders can be found in this
reference, as well as
other references cited below, all of which are hereby incorporated herein by
reference.
[0537] Anxiety disorders include panic disorder, agoraphobia with or without
history of
panic disorder, specific phobia, social phobia, obsessive-compulsive disorder,
post-
traumatic stress disorder, acute stress disorder and generalized anxiety
disorder. It is
contemplated that the compounds of this invention will be effective in
treating these
disorders in patients who have been diagnosed as having such disorders.
[0538] This invention provides for a method of treating a patient suffering
from anxiety
which comprises administering to the patient an amount of any of the compounds

described herein effective to treat the subject's anxiety.
[0539] It is contemplated that the compounds described herein will be
effective in
treating obsessions and compulsions in patients who have been diagnosed as
having
obsessive compulsive disorder based upon administration of appropriate tests,
which may
include, but are not limited to any of the following: Yale Brown Obsessive
Compulsive
Scale (YBOCS) (for adults), National Institute of Mental Health Global OCD
Scale
(NIMH GOCS), CGI-Severity of Illness scale. It is further contemplated that
the
compounds described herein will be effective in inducing improvements in
certain of the
factors measured in these tests, such as a reduction of several points in the
YBOCS total
score. It is also contemplated that the compounds described herein will be
effective in
preventing relapse of obsessive compulsive disorder.
[0540] This invention provides a method of treating obsessions and compulsions
in a
patient with obsessive compulsive disorder, which comprises administering to
the patient a
therapeutically effective amount of any of the compounds utilized herein
effective to treat
the subject's obsessions and compulsions.
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[0541] It is contemplated that the compounds described herein will be
effective in
treating panic disorder in patients who have been diagnosed with panic
disorder on the
basis of frequency of occurrence of panic attacks, or by means of the CGI-
Severity of
Illness scale. It is further contemplated that the compounds described herein
will be
effective in inducing improvements in certain of the factors measured in these
evaluations,
such as a reduction in frequency or elimination of panic attacks, an
improvement in the
CGI-Severity of Illness scale or a CGI-Global Improvement score of 1 (very
much
improved), 2 (much improved) or 3 (minimally improved). It is also
contemplated that the
compounds described herein will be effective in preventing relapse of panic
disorder.
[0542] This invention provides a method of treating panic disorder, with or
without
agoraphobia, in a subject, which comprises administering to the patient a
therapeutically
effective amount of any of the compounds utilized herein to treat the
subject's panic
disorder.
[0543] It is contemplated that the compounds described herein can be effective
in
treating social anxiety disorder in patients who have been diagnosed as having
social
anxiety disorder based upon the administration of any of the following tests:
the Liebowitz
Social Anxiety Scale (LSAS), the CGI-Severity of Illness scale, the Hamilton
Rating Scale
for Anxiety (HAM-A), the Hamilton Rating Scale for Depression (HAM-D), the
axis V
Social and Occupational Functioning Assessment Scale of DSM-IV, the axis II
(ICD-10)
World Health Organization Disability Assessment, Schedule 2 (DAS-2), the
Sheehan
Disability Scales, the Schneier Disability Profile, the World Health
Organization Quality
of Life-100 (WHOQOL-100), or other tests as described in Bobes, 1998, which is

incorporated herein by reference. It is further contemplated that the
compounds described
herein will be effective in inducing improvements as measured by these tests,
such as the a
change from baseline in the Liebowitz Social Anxiety Scale (LSAS), or a CGI-
Global
Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally

improved). It is also contemplated that the compounds described herein will be
effective in
preventing relapse of social anxiety disorder.
[0544] This invention provides a method of treating social anxiety disorder in
a patient
which comprises administering to the patient a therapeutically effective
amount of any of
the compounds utilized herein to treat the subject's social anxiety disorder.
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[0545] It is contemplated that the compounds utilized herein can be effective
in treating
generalized anxiety disorder in patients who have been diagnosed as having
this disorder
based upon the diagnostic criteria described in DSM-IV or DSM-5. It is further

contemplated that the compounds utilized herein will be effective in reducing
symptoms
of this disorder, such as the following: excessive worry and anxiety,
difficulty controlling
worry, restlessness or feeling keyed up or on edge, being easily fatigued,
difficulty
concentrating or mind going blank, irritability, muscle tension, or sleep
disturbance. It is
also contemplated that the compounds described herein will be effective in
preventing
relapse of general anxiety disorder.
[0546] The invention provides a method of treating generalized anxiety
disorder in a
subject, which comprises administering to the patient an amount of any of the
compounds
described herein effective to treat the subject's generalized anxiety
disorder.
105471 Impulse control disorders include pathological gambling (PG),
kleptomania,
trichotillomania (TTM), intermittent explosive disorder (TED), and pyromania.
Impulse
control disorders may also include pathological skin picking (PSP), compulsive
sexual
behavior (CSB), compulsive buying (CB), conduct disorder, antisocial
personality
disorder, oppositional defiant disorder, borderline personality disorder,
attention
deficit/hyperactivity disorder (ADHD, which includes attention deficit
disorder, ADD),
schizophrenia, mood disorders, paraphilia, and interne addiction. Symptoms of
impulse
control disorders include: repetitive participation in behavior despite
adverse
consequences, diminished control over the behavior, an urge/impulse to engage
in the
behavior, and feelings of pleasure while participating in the behavior.
[0548] It is contemplated that the compounds utilized herein can be effective
in treating
impulse control disorders in patients who have at least one impulse control
disorder based
upon the diagnostic criteria described in DSM-IV or DSM-5. It is further
contemplated
that the compounds utilized herein will be effective in reducing symptoms of
this disorder,
including impulsivity or lack of self-control. It is also contemplated that
the compounds
described herein will be effective in preventing relapse of the impulse
control disorder.
[0549] It is contemplated that the compounds utilized herein can be effective
in treating
ADHD or ADD in patients who have the disorder, based upon the diagnostic
criteria
described in DSM-IV or DSM-5. It is further contemplated that the compounds
utilized
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herein will be effective in reducing symptoms of this disorder, including
impulsivity or
lack of self-control. It is also contemplated that the compounds described
herein will be
effective in preventing relapse of ADD or ADHD.
[0550] It is contemplated that the compounds utilized herein can be effective
in treating
schizophrenia in patients who have the disorder, based upon the diagnostic
criteria
described in DSM-IV or DSM-5. Schizophrenia is characterized by delusions,
hallucinations, disorganized speech and behavior, and other symptoms that
cause social or
occupational dysfunction. It is further contemplated that the compounds
utilized herein
will be effective in reducing symptoms of this disorder. It is also
contemplated that the
compounds described herein will be effective in preventing relapse of
schizophrenia.
[0551] It is contemplated that the compounds described herein will be
effective in
treating non-suicidal self injury disorder in patients who have been diagnosed
with this
disorder based on the patient's exhibition of symptoms including deliberate
tissue injury
without suicidal intent (e.g., cutting, burning, self-poisoning, or self-
mutilation). It is
further contemplated that the compounds described herein will be effective in
inducing
improvements in certain of these factors, such as a reduction in frequency or
elimination
of self injury. It is also contemplated that the compounds described herein
will be effective
in preventing relapse of non-suicidal self injury disorder.
[0552] This invention provides a method of treating non-suicidal self injury
disorder in a
subject, which comprises administering to the patient a therapeutically
effective amount of
any of the compounds utilized herein to treat the subject's non-suicidal self
injury
disorder.
[0553] It is contemplated that the compounds described herein will be
effective in
treating Miinchausen syndrome in patients who have been diagnosed with this
disorder
based on the patient's propensity for feigning disease, illness, or
psychological trauma to
draw attention, sympathy, or reassurance to themselves. Symptoms may include
frequent
hospitalizations, knowledge of several illnesses, frequent requests for
medication (e.g.,
pain killers), willingness to undergo extensive surgery, few to no visitors
during
hospitalizations, and exaggerated or fabricated stories about multiple medical
problems. It
is further contemplated that the compounds described herein will be effective
in inducing
improvements in certain of these factors, such as a reduction in frequency or
elimination
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of one or more symptoms. It is also contemplated that the compounds described
herein
will be effective in preventing relapse of Miinchausen syndrome. Miinchausen
syndrome
also includes Miinchausen syndrome by proxy, in which a caregiver exaggerates,

fabricates, or induces illness in someone in his/her care.
[0554] This invention provides a method of treating Miinchausen syndrome in a
subject,
which comprises administering to the patient a therapeutically effective
amount of any of
the compounds utilized herein to treat the subject's Miinchausen syndrome.
[0555] It is contemplated that the compounds described herein will be
effective in
treating disruptive mood dysregulation disorder in patients who have been
diagnosed with
this disorder on the basis of severe and recurrent temper outbursts, grossly
out of
proportion to the stimulus or situation, as well as a persistent
irritable/angry mood most of
the time. It is further contemplated that the compounds described herein will
be effective
in inducing improvements in certain of these factors, such as a reduction in
frequency or
elimination of tember outbursts and/or an improvement in mood. It is also
contemplated
that the compounds described herein will be effective in preventing relapse of
disruptive
mood dysregulation disorder disorder.
[0556] This invention provides a method of treating disruptive mood
dysregulation
disorder in a subject, which comprises administering to the patient a
therapeutically
effective amount of any of the compounds utilized herein to treat the
subject's disruptive
mood dysregulation disorder.
[0557] It is contemplated that the compounds utilized herein can be effective
in reducing
the frequency, intensity, and duration of anger and/or violence in individuals
prone to one
or both. Although anger and violence disorders other than those associated
with other
disorders (e.g., as described above) are not outlined in DSM IV or DSM 5, many
health
professionals recognize that such disorders are associated with significant
dysfunction.
Anger management training and other psychosocial treatments are often used in
an effort
to treat these individuals.
[0558] It is contemplated that the compounds utilized herein can be effective
in
regulating food intake and/or reducing food cravings in patients in need
thereof. In some
embodiments, the patient is overweight. In some embodiments, the patient is
obese. In
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some embodiments, the patient exhibits comorbidities associated with
overweight/obesity,
for example coronary heart disease, high blood pressure, stroke, type 2
diabetes, abnormal
levels of blood fats, metabolic syndrome, cancer, osteoarthritis, sleep apnea,
reproductive
issues, and/or gallstones.
[0559] In a preferred embodiment, the invention provides a method for treating
anxiety
disorders, impulse control disorders, OCD, and/or anger/violence-related
disorders, or
regulating food intake and/or food cravings, in a patient in need thereof,
comprising
administering to the patient a therapeutically effective amount of
noribogaine, noribogaine
derivative, or a pharmaceutically acceptable salt and/or solvate thereof,
wherein the patient
is not addicted to cocaine or an opiate, and further wherein the
therapeutically effective
amount provides average noribogaine serum levels of between about 50 to about
180
ng/ml. In some embodiments, the average noribogaine serum level provided by
the dosage
is less than about 50 ng/mL. In one embodiment, the therapeutically effective
amount is
between about 1 mg to about 4 mg per kg of body weight. In one embodiment, the

therapeutically effective amount is between about 50 ng to about 100 p.g per
kg of body
weight. In one embodiment, an anxiety disorder is treated. In one embodiment,
OCD is
treated. In one embodiment, an impulse control disorder is treated. On one
embodiment,
an anger-related disorder is treated. in one embodiment, a violence-related
disorder is
treated. In one embodiment, symptoms of anger are reduced or eliminated. In
one
embodiment, violent outbursts are reduced or eliminated. In one embodiment,
food intake
is regulated. In one embodiment, food cravings are attenuated. In one
embodiment, the
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
Dosage and Routes of Administration
[0560] In some embodiments, the composition is administered via sublingual,
intranasal,
or intrapulmonary delivery. In one aspect, the invention provides
administering a
pharmaceutical composition comprising a pharmaceutically effective amount of
noribogaine and a pharmaceutically acceptable excipient, wherein the
therapeutically
effective amount of noribogaine is an amount that delivers an aggregate amount
of
noribogaine of about 50 ng to about 100 ps per kg body weight per day. In some
aspects,
the therapeutically effective amount of noribogaine is an amount that delivers
an aggregate
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amount of noribogaine of about 50 ng to about 50 jig per kg body weight per
day. In some
aspects, the therapeutically effective amount of noribogaine is an amount that
delivers an
aggregate amount of noribogaine of about 50 ng to about 10 jig per kg body
weight per
day. In some aspects, the therapeutically effective amount of noribogaine is
an amount that
delivers an aggregate amount of noribogaine of about 50 ng to about 1 Jig per
kg body
weight per day. In some aspects, the composition is administered once per day.
In some
aspects, the composition is administered two or more times per day. In some
embodiments, the composition is administered less than once a day, for example
once
every two days, once every three days, once every four days, once a week, etc.
[0561] In some embodiments, the composition is administered via oral, buccal,
transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual,
intravenous, intraarterial,
intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery.
[0562] In one embodiment, the dosage or aggregate dosage of compound is from
about 1
mg to about 4 mg per kg body weight per day. The aggregate dosage is the
combined
dosage, for example the total amount of noribogaine, noribogaine derivative,
or
pharmaceutically acceptable salt and/or solvate thereof administered over a 24-
hour period
where smaller amounts are administered more than once per day.
[0563] In some embodiments, the patient is administered periodically, such as
once,
twice, three times, four times or five times daily with noribogaine,
noribogaine derivative,
or salt and/or solvate thereof. In some embodiments, the administration is
once daily, or
once every second day, once every third day, three times a week, twice a week,
or once a
week. The dosage and frequency of the administration depends on the route of
administration, content of composition, age and body weight of the patient,
condition of
the patient, without limitation. Determination of dosage and frequency
suitable for the
present technology can be readily made by a qualified clinician.
[0564] In another embodiment, there is provided a unit dose of noribogaine,
noribogaine derivative, or salt or solvate thereof which is about 50 mg to
about 200 mg per
dose. In one embodiment, the unit dose is about 50 to about 120 mg per dose.
In one
embodiment, the unit dose is about 120 mg per dose. It being understood that
the term
"unit dose" means a dose sufficient to provide therapeutic results whether
given all at once
or serially over a period of time.
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[0565] In one aspect, this invention relates to a method for attenuating
symptoms of
anxiety disorder, impulse control disorder, or an anger and/or violence-
related disorder in
a human patient, comprising administering to the patient a dosage of
noribogaine or
pharmaceutically acceptable salt and/or solvate thereof that provides an
average serum
concentration of about 50 ng/mL to about 180 ng/mL, said concentration being
sufficient
to attenuate said symptoms while maintaining a QT interval of less than about
500 ms
during said treatment. In some embodiments, the concentration is sufficient to
attenuate
said symptoms while maintaining a QT interval of less than about 470 ms during

treatment. Preferably, the concentration is sufficient to attenuate said
symptoms while
maintaining a QT interval of less than about 450 ms during treatment. In one
embodiment,
the concentration is sufficient to attenuate said symptoms while maintaining a
QT interval
of less than about 420 ms during treatment.
[0566] In one aspect, this invention relates to a method for attenuating food
cravings in a
human patient, comprising administering to the patient a dosage of noribogaine
or
pharmaceutically acceptable salt ancUor solvate thereof that provides an
average serum
concentration of about 50 ng/mL to about 400 ng/mL, said concentration being
sufficient
to attenuate said cravings while maintaining a QT interval of less than about
500 ms
during said treatment. In some embodiments, the concentration is sufficient to
attenuate
said cravings while maintaining a QT interval of less than about 470 ms during
treatment.
Preferably, the concentration is sufficient to attenuate said cravings while
maintaining a
QT interval of less than about 450 ms during treatment. In one embodiment, the

concentration is sufficient to attenuate said cravings while maintaining a QT
interval of
less than about 420 ms during treatment.
[0567] In one embodiment, the QT interval is not prolonged more than about 50
ms. In
one embodiment, the QT interval is not prolonged more than about 40 ms. In one

embodiment, the QT interval is not prolonged more than about 30 ms. In a
preferred
embodiment, the QT interval is not prolonged more than about 20 ms. In one
embodiment,
the QT interval is not prolonged more than about 10 ms.
[0568] Noribogaine, a noribogaine derivative, or a pharmaceutically acceptable
salt
and/or solvate thereof can also be used in conjunction with any of the
vehicles and
excipients commonly employed in pharmaceutical preparations, e.g., talc, gum
Arabic,
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lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous
solvents, oils,
paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be
added to
preparations, particularly to those for oral administration. Solutions can be
prepared using
water or physiologically compatible organic solvents such as ethanol, 1,2-
propylene
glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial
esters of
glycerine and the like. Parenteral compositions containing noribogaine may be
prepared
using conventional techniques that may include sterile isotonic saline, water,
1,3-
butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water,
Ringer's
solution, etc.
Sustained Treatment
[0569] As will be apparent to the skilled artisan upon reading this
disclosure, one aspect
of the present invention provides a method for treating a condition in a
patient, such
condition being treatable by noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof, the method comprising administering to the
patient an
initial unit dose of noribogaine, noribogaine derivative, or pharmaceutically
acceptable
salt or solvate thereof, followed by at least one additional dose of
noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, such that
an average
therapeutic serum concentration is achieved by the initial unit dose and
maintained by the
at least one additional dose.
[0570] In one aspect, this invention relates to a method for treating a
condition in a
patient which is treatable with noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof while maintaining an acceptable QT interval
prolongation in said patient, the method comprising:
a) administering to the patient an initial unit dose of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof, wherein
said unit dose
provides a therapeutic average serum concentration of 50 ng/mL to 180 ng,/mL
which
serum concentration imparts minimal QT interval prolongation; and
b) maintaining said serum concentration by periodically administering at
least
one additional dose of noribogaine, noribogaine derivative, or
pharmaceutically acceptable
salt or solvate thereof, such that the at least one additional dose maintains
the average
serum concentration of 50 ng/mL to 180 ng/mL during treatment
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wherein said additional dose or doses are continued as necessary to treat said

condition.
[0571] In one aspect, the serum concentration provides a maximum QT interval
of less
than about 500 ms during said treatment. In some embodiments, the serum
concentration
provides a maximum QT interval of less than about 470 ms during treatment.
Preferably,
the serum concentration provides a maximum QT interval of less than about 450
ms
during treatment. In one embodiment, the serum concentration provides a
maximum QT
interval of less than about 420 ms during treatment.
[0572] In one embodiment, the QT interval is not prolonged more than about 50
ms. In
one embodiment, the QT interval is not prolonged more than about 40 ms. In one

embodiment, the QT interval is not prolonged more than about 30 ms. In one
embodiment,
the QT interval is not prolonged more than about 20 ms. In one embodiment, the
QT
interval is not prolonged more than about 10 ms.
[0573] In one embodiment, the average serum concentration of noribogaine is
from 50
ng/mL to 180 ng/mL, or 60 ng/mL to 180 ng/mL. In one embodiment, the average
serum
concentration of noribogaine is from 50 ng/mL to 150 ng/mL, or 60 ng/mL to 150
ng/mL.
In one embodiment, the average serum concentration of noribogaine is from 50
ng/mL to
100 ng/mL, or 60 ng/mL to 100 ng/mL. In one embodiment, the average serum
concentration of noribogaine is from 80 ng/mL to 150 ng/mL. In one embodiment,
the
average serum concentration of noribogaine is from 80 ng/mL to 100 ng/mL. In
some
aspects of the invention, a lower serum concentration may be therapeutic for a
given
condition. In one embodiment, the therapeutic serum concentration is between 1
ng/mL
and 10 ng/mL. By way of non-limiting example, the therapeutic serum
concentration for
treatment of nicotine addiction is believed to be lower than that for
addiction to opioids.
The ranges above include both extremes as well as any subranges between.
[0574] In
some embodiments, the initial unit dose of noribogaine, noribogaine
derivative, or salt or
solvate thereof is from 50 mg to 120 mg. In one embodiment, the initial dose
is about 50
mg. In one embodiment, the initial dose is about 55 mg. In one embodiment, the
initial
dose is about 60 mg. In one embodiment, the initial dose is about 65 mg. In
one
embodiment, the initial dose is about 70 mg. In one embodiment, the initial
dose is about
75 mg. In one embodiment, the initial dose is about 80 mg. In one embodiment,
the initial
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dose is about 85 mg. In one embodiment, the initial dose is about 90 mg. In
one
embodiment, the initial dose is about 95 mg. In one embodiment, the initial
dose is about
100 mg. In one embodiment, the initial dose is about 105 mg. In one
embodiment, the
initial dose is about 110 mg. In one embodiment, the initial dose is about 115
mg. In one
embodiment, the initial dose is about 120 mg.
[0575] In some embodiments, the initial unit dose of noribogaine, noribogaine
derivative, or salt or solvate thereof is administered as subdoses, such that
the aggregate
dose achieves the unit dose. In some embodiments, the initial unit dose is
administered as
subunit doses, which subunit doses are administered serially until the unit
dose level is
achieved, wherein the aggregate of subunit doses provides the initial unit
dose and further
provides the therapeutic average serum concentration. In some embodiments, the

aggregate dose provides a therapeutic serum concentration of 80 ng/mL to 150
ng/mL. In
some embodiments, the subdoses are administered every 15 minutes to 6 hours
until the
unit dose is achieved. In some embodiments, the subdoses are administered
every 15
minutes, every 30 minutes, every 1 hour, every 2 hours, every 3 hours, every 4
hours,
every 5 hours, or every 6 hours until the unit dose is achieved. The ranges
above include
both extremes as well as any subranges between.
[0576] In some embodiments, the one or more additional doses are lower than
the initial
dose. In one embodiment, the one or more additional doses are from 5 mg to 75
mg. In one
embodiment, the one or more additional doses may or may not comprise the same
amount
of noribogaine, noribogaine derivative, or salt or solvate thereof. In one
embodiment, at
least one additional dose is about 5 mg. In one embodiment, at least one
additional dose is
about 10 mg. In one embodiment, at least one additional dose is about 15 mg.
In one
embodiment, at least one additional dose is about 20 mg. In one embodiment, at
least one
additional dose is about 25 mg. In one embodiment, at least one additional
dose is about
30 mg. In one embodiment, at least one additional dose is about 35 mg. In one
embodiment, at least one additional dose is about 40 mg. In one embodiment, at
least one
additional dose is about 45 mg. In one embodiment, at least one additional
dose is about
50 mg. In one embodiment, at least one additional dose is about 55 mg. In one
embodiment, at least one additional dose is about 60 mg. In one embodiment, at
least one
additional dose is about 65 mg. In one embodiment, at least one additional
dose is about
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70 mg. In one embodiment, at least one additional dose is about 75 mg. The
ranges above
include both extremes as well as any subranges between.
[0577] In one embodiment, the one or more additional doses are administered
periodically. In one embodiment, the one or more additional doses are
administered every
4 hours to every 48 hours. In a preferred embodiment, the one or more
additional doses are
administered every 6 hours to every 24 hours. In one embodiment, the one or
more
additional doses are administered every 4 hours. In one embodiment, the one or
more
additional doses are administered every 6 hours. In one embodiment, the one or
more
additional doses are administered every 8 hours. In one embodiment, the one or
more
additional doses are administered every 10 hours. In one embodiment, the one
or more
additional doses are administered every 12 hours. In one embodiment, the one
or more
additional doses are administered every 18 hours. In one embodiment, the one
or more
additional doses are administered every 24 hours. In one embodiment, the one
or more
additional doses are administered every 36 hours. In one embodiment, the one
or more
additional doses are administered every 48 hours. The ranges above include
both extremes
as well as any subranges between.[0578] In some embodiments, the therapeutic
dose of
noribogaine, noribogaine derivative, or salt or solvate thereof is a tapered
dosing over a
period of time, during which the patient is detoxified, for example, without
suffering
significant acute withdrawal symptoms. Without being bound by theory, it is
believed that
tapering will allow the full therapeutic effect of noribogaine with less
prolongation of the
QT interval. Tapering involves administration of one or more subsequently
lower doses of
noribogaine over time. For example, in some embodiments, the first tapered
dose is 50%
to 95% of the initial or at least one additional dose. In some embodiments,
the second
tapered dose is 40% to 90% of the initial or at least one additional dose. In
some
embodiments, the third tapered dose is 30% to 85% of the initial or at least
one additional
dose. In some embodiments, the fourth tapered dose is 20% to 80% of the
initial or at least
one additional dose. In some embodiments, the fifth tapered dose is 10% to 75%
of the
initial or at least one additional dose.
[0579] In some embodiments, the first tapered dose is given after the first
dose of
noribogaine. In some embodiments, the first tapered dose is given after the
second, third,
or a subsequent dose of noribogaine. The first tapered dose may be
administered at any
time after the previous dose of noribogaine. The first tapered dose can be
given once, for
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example, followed by subsequent further tapered doses, or it can be given
multiple times
with or without subsequent, further tapered doses (e.g., second, third,
fourth, etc. tapered
doses), which likewise can be given once or over multiple administrations, for
example. In
some embodiments, the first tapered dose is administered one hour, 6 hours, 12
hours, 18
hours, 24 hours, 36 hours, 48 hours, or more after the previous dose of
noribogaine.
Similarly, second, third, fourth, etc. tapered doses, if given, can be given
one hour, 6
hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after the
previous dose of
noribogaine.
[0580] In some embodiments, the dose is tapered starting 12 to 96 hours after
the initial
dose. In some embodiments, the dose is tapered starting 12 hours after the
initial dose. In
some embodiments, the dose is tapered starting 18 hours after the initial
dose. In some
embodiments, the dose is tapered starting 24 hours after the initial dose. In
some
embodiments, the dose is tapered starting 30 hours after the initial dose. In
some
embodiments, the dose is tapered starting 36 hours after the initial dose. In
some
embodiments, the dose is tapered starting 42 hours after the initial dose. In
some
embodiments, the dose is tapered starting 48 hours after the initial dose. In
some
embodiments, the dose is tapered starting 54 hours after the initial dose. In
some
embodiments, the dose is tapered starting 60 hours after the initial dose. In
some
embodiments, the dose is tapered starting 66 hours after the initial dose. In
some
embodiments, the dose is tapered starting 72 hours after the initial dose. In
some
embodiments, the dose is tapered starting 78 hours after the initial dose. In
some
embodiments, the dose is tapered starting 84 hours after the initial dose. In
some
embodiments, the dose is tapered starting 90 hours after the initial dose. In
some
embodiments, the dose is tapered starting 96 hours after the initial dose.
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[0581] In some embodiments, at least one additional dose is administered 4
hours to 24
hours after the initial unit dose. In some embodiments, the additional doses
are
administered 4 hours to 24 hours after the previous dose. In some embodiments,
the doses
are administered every 4 hours to 24 hours. In some embodiments, the doses are

administered as needed. The dosage and frequency of the administration depends
on the
route of administration, dosage, age and body weight of the patient, condition
of the
patient, without limitation. Determination of dosage and frequency suitable
for the present
technology can be readily made a qualified clinician.
[0582] In some embodiments, the doses are administered at varying time points.
That is,
each dose need not be administered at the same interval as the previous dose.
In some
embodiments, the additional doses are administered more frequently at the
beginning of
treatment, and less frequently after a certain period of time. For example and
without
limitation, withdrawal symptoms are the most severe in the first 72 hours
after the last
dose of the drug of addiction. Noribogaine, noribogaine derivative, or a
pharmaceutically
acceptable solvate or salt thereof may be administered, for example, every 4
hours to 12
hours for the first 72 hours, and less frequently (e.g., 12 hours to 24 hours)
thereafter.
[0583] In some embodiments, the noribogaine, noribogaine derivative, or a
pharmaceutically acceptable salt or solvate thereof is administered for an
indefinite period
of time (e.g., for several months or several years, up to the lifetime of the
patient).
[0584] In some embodiments, the patient undergoes long-term (e.g., one year or
longer)
treatment with maintenance doses of noribogaine, noribogaine derivative, or
salt or solvate
thereof. In some embodiments, the patient is first treated for acute symptoms
of the
condition with therapeutic doses of noribogaine as described above, and then
the amount
of noribogaine is reduced to maintenance levels, for example after acute
symptoms would
be expected to have subsided. This is particularly relevant to treating drug
addiction, as
acute withdrawal symptoms generally are the most pronounced in the first 48 to
72 hours
after cessation of the drug of addiction, although acute withdrawal may last
as long as a
week or more.
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Patient Pre-screening and Monitoring
[0585] Pre-screening of patients before treatment with noribogaine and/or
monitoring of
patients during noribogaine, noribogaine derivative, or pharmaceutically
acceptable said
and/or solvate thereof treatment may be required to ensure that QT interval is
not
prolonged beyond a certain value. For example, QT interval greater than about
500 ms can
be considered dangerous for individual patients. Pre-screening and/or
monitoring may be
necessary at high levels of noribogaine treatment.
[0586] In a preferred embodiment, a patient receiving a therapeutic dose of
noribogaine
is monitored in a clinical setting. Monitoring may be necessary to ensure the
QT interval is
not prolonged to an unacceptable degree. A "clinical setting" refers to an
inpatient setting
(e.g., inpatient clinic, hospital, rehabilitation facility) or an outpatient
setting with
frequent, regular monitoring (e.g., outpatient clinic that is visited daily to
receive dose and
monitoring). Monitoring includes monitoring of QT interval. Methods for
monitoring of
QT interval are well-known in the art, for example by ECG.
[0587] In one embodiment, a patient receiving a maintenance dose of
noribogaine is not
monitored in a clinical setting. In one embodiment, a patient receiving a
maintenance dose
of noribogaine is monitored periodically, for example daily, weekly, monthly,
or
occasionally.
[0588] In one aspect, this invention relates to a method for treating,
preventing, or
attenuating a disease or disorder or symptoms of a disease or disorder
described herein
who is prescreened to evaluate the patient's expected tolerance for
prolongation of QT
interval, administering to the patient a dosage of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt or solvate thereof that provides an average
serum
concentration of about 50 ng/mL to about 180 ng/mL, said concentration being
sufficient
to inhibit or ameliorate said abuse or symptoms while maintaining a QT
interval of less
than about 500 ms during said treatment. In some embodiments, the
concentration is
sufficient to attenuate said abuse or symptoms while maintaining a QT interval
of less than
about 470 ms during treatment. Preferably, the concentration is sufficient to
attenuate said
abuse or symptoms while maintaining a QT interval of less than about 450 ms
during
treatment. In one embodiment, the concentration is sufficient to attenuate
said abuse or
symptoms while maintaining a QT interval of less than about 420 ms during
treatment.
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[0589] In one embodiment, prescreening of the patient comprises ascertaining
that
noribogaine treatment will not result in a maximum QT interval over about 500
ms. In one
embodiment, prescreening of the patient comprises ascertaining that
noribogaine treatment
will not result in a maximum QT interval over about 470 ms. In one embodiment,

prescreening comprises ascertaining that noribogaine treatment will not result
in a
maximum QT interval over about 450 ms. In one embodiment, prescreening
comprises
ascertaining that noribogaine treatment will not result in a maximum QT
interval over
about 420 ms. In one embodiment, prescreening comprises determining the
patient's pre-
treatment QT interval.
[0590] As it relates to pre-screening or pre-selection of patients, patients
may be selected
based on any criteria as determined by the skilled clinician. Such criteria
may include, by
way of non-limiting example, pre-treatment QT interval, pre-existing cardiac
conditions,
risk of cardiac conditions, age, sex, general health, and the like. The
following are
examples of selection criteria for disallowing noribogaine treatment or
restricting dose of
noribogaine administered to the patient: high QT interval before treatment
(e.g., such that
there is a risk of the patient's QT interval exceeding about 500 ms during
treatment);
congenital long QT syndrome; bradycardia; hypokalemia or hypomagnesemia;
recent
acute myocardial infarction; uncompensated heart failure; and taking other
drugs that
increase QT interval. In some embodiments, the methods can include selecting
and/or
administering/providing noribogaine to a patient that lacks one more of such
criteria.
[0591] In one embodiment, this invention relates to pre-screening a patient to
determine
if the patient is at risk for prolongation of the QT interval beyond a safe
level. In one
embodiment, a patient at risk for prolongation of the QT interval beyond a
safe level is not
administered noribogaine. In one embodiment, a patient at risk for
prolongation of the QT
interval beyond a safe level is administered noribogaine at a limited dosage.
[0592] In one embodiment, this invention relates to monitoring a patient who
is
administered a therapeutic dose of noribogaine. In one embodiment, the dose of

noribogaine is reduced if the patient has serious adverse side effects. In one
embodiment,
the noribogaine treatment is discontinued if the patient has serious adverse
side effects. In
one embodiment, the adverse side effect is a QT interval that is prolonged
beyond a safe
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level. The determination of a safe level of prolongation is within the skill
of a qualified
clinician.
[0593] In one aspect, this invention relates to a method for treating an
anxiety disorder,
an impulse control disorder, or an anger/violence-related disorder, and/or
treating or
attenuating the symptoms thereof in a patient, comprising selecting a patient
exhibiting
symptoms of an anxiety disorder, impulse control disorder, or anger/violence-
related
disorder who is prescreened to evaluate the patient's expected tolerance for
prolongation
of QT interval, administering to the patient a dosage of noribogaine,
noribogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof that
provides an
average serum concentration of about 50 ng/mL to about 850 ng/mL, said
concentration
being sufficient to inhibit or ameliorate said disorder or symptoms while
maintaining a QT
interval of less than about 500 ms during said treatment. In some embodiments,
the
concentration is sufficient to attenuate said symptoms while maintaining a QT
interval of
less than about 470 ms during treatment. Preferably, the concentration is
sufficient to
attenuate said symptoms while maintaining a QT interval of less than about 450
ms during
treatment. In one embodiment, the concentration is sufficient to attenuate
said symptoms
while maintaining a QT interval of less than about 420 ms during treatment.
[0594] In one aspect, this invention relates to a method for regulating food
intake,
and/or treating or attenuating food cravings, in a patient, comprising
selecting an
overweight or obese patient who is prescreened to evaluate the patient's
expected
tolerance for prolongation of QT interval, administering to the patient a
dosage of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof that provides an average serum concentration of about 50 ng/mL to
about 180
ng/mL, said concentration being sufficient to inhibit or ameliorate said
disorder or
symptoms while maintaining a QT interval of less than about 500 ms during said

treatment.
Kit of Parts
[0595] One aspect of this invention is directed to a kit of parts for the
treatment a
condition in a patient which is treatable with noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt or solvate thereof, wherein the kit comprises
a
composition comprising noribogaine, noribogaine derivative, or salt or solvate
thereof and
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a means for administering the composition to a patient in need thereof. The
means for
administration to a patient can include, for example, any one or combination
of a
pharmaceutically acceptable formulation comprising noribogaine, or a
noribogaine
derivative, or a pharmaceutically acceptable salt or solvate thereof (e.g., a
pill, transdermal
patch, injectable, and the like, without limitation) and optionally a means
for dispensing
and/or administering the formulation (e.g., a syringe, a needle, an IV bag
comprising the
composition, a vial comprising the composition, an inhaler comprising the
composition,
etc, without limitation). In one embodiment, the kit of parts further
comprises instructions
for dosing and/or administration of the composition.
[0596] In some aspects, the invention is directed to a kit of parts for
administration of
noribogaine, the kit comprising multiple delivery vehicles, wherein each
delivery vehicle
contains a discrete amount of noribogaine and further wherein each delivery
vehicle is
identified by the amount of noribogaine provided therein; and optionally
further
comprising a dosing treatment schedule in a readable medium. In some
embodiments, the
dosing treatment schedule includes the amount of noribogaine required to
achieve each
average serum level is provided. In some embodiments, the kit of parts
includes a dosing
treatment schedule that provides an attending clinician the ability to select
a dosing
regimen of noribogaine based on the sex of the patient, mass of the patient,
and the serum
level that the clinician desires to achieve. In some embodiments, the dosing
treatment
schedule further provides information corresponding to the volume of blood in
a patient
based upon weight (or mass) and sex of the patient. In an embodiment, the
storage
medium can include an accompanying pamphlet or similar written information
that
accompanies the unit dose form in the kit. In an embodiment, the storage
medium can
include electronic, optical, or other data storage, such as a non-volatile
memory, for
example, to store a digitally-encoded machine-readable representation of such
information.
[0597] The term "delivery vehicle" as used herein refers to any formulation
that can be
used for administration of noribogaine to a patient. Non-limiting, exemplary
delivery
vehicles include caplets, pills, capsules, tablets, powder, liquid, or any
other form by
which the drug can be administered. Delivery vehicles may be intended for
administration
by oral, inhaled, injected, or any other means.
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[0598] The term "readable medium" as used herein refers to a representation of
data that
can be read, for example, by a human or by a machine. Non-limiting examples of
human-
readable formats include pamphlets, inserts, or other written forms. Non-
limiting examples
of machine-readable formats include any mechanism that provides (i.e., stores
and/or
transmits) information in a form readable by a machine (e.g., a computer,
tablet, and/or
smartphone). For example, a machine-readable medium includes read-only memory
(ROM); random access memory (RAM); magnetic disk storage media; optical
storage
media; and flash memory devices. In one embodiment, the machine-readable
medium is a
CD-ROM. In one embodiment, the machine-readable medium is a USB drive. In one
embodiment, the machine-readable medium is a Quick Response Code (QR Code) or
other
matrix barcode.
[0599] In some aspects, the machine-readable medium comprises software that
contains
information regarding dosing schedules for the unit dose form of noribogaine
and
optionally other drug information. In some embodiments, the software may be
interactive,
such that the attending clinician or other medical professional can enter
patient
information. In a non-limiting example, the medical professional may enter the
weight and
sex of the patient to be treated, and the software program provides a
recommended dosing
regimen based on the information entered. The amount and timing of noribogaine

recommended to be delivered will be within the dosages that result in the
serum
concentrations as provided herein.
[0600] In some embodiments, the kit of parts comprises multiple delivery
vehicles in a
variety of dosing options. For example, the kit of parts may comprise pills or
tablets in
multiple dosages, such as 120 mg, 90 mg, 60 mg, 30 mg, 20 mg, 10 mg, and/or 5
mg of
noribogaine per pill. Each pill is labeled such that the medical professional
and/or patient
can easily distinguish different dosages. Labeling may be based on printing or
embossing
on the pill, shape of the pill, color of pill, the location of the pill in a
separate, labeled
compartment within the kit, and/or any other distinguishing features of the
pill. In some
embodiments, all of the delivery vehicles within a kit are intended for one
patient. In some
embodiments, the delivery vehicles within a kit are intended for multiple
patients.
[0601] One aspect of this invention is directed to a kit of parts for the
treatment,
prevention, or attenuation of a disease or disorder or symptoms of a disease
or disorder
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described herein, wherein the kit comprises a unit dose form of noribogaine,
noribogaine
derivative, or salt or solvate thereof. The unit dose form provides a patient
with an average
serum level of noribogaine of from about 50 ng/mL to about 180 ng/mL or about
60
ng/mL to about 180 ng/mL. The unit dose form provides a patient with an
average serum
level of noribogaine of from about 50 ng/mL to about 800 ng/mL or about 60
ng/mL to
about 800 ng/mL. In one embodiment, the unit dose form provides a patient with
an
average serum level of noribogaine of from about 50 ng/mL to about 400 ng/mL
or about
60 ng/mL to about 400 ng/mL. In one embodiment, the unit dose form provides a
patient
with an average serum level of noribogaine of from 80 ng/mL to 100 ng/mL.
[0602] In some embodiments, the unit dose of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt or solvate thereof is from 20 mg to 120 mg.
In one
embodiment, the unit dose is 20 mg. In one embodiment, the unit dose is 30 mg.
In one
embodiment, the unit dose is 40 mg. In one embodiment, the unit dose is 50 mg.
In one
embodiment, the unit dose is 60 mg. In one embodiment, the unit dose is 70 mg.
In one
embodiment, the unit dose is 80 mg. In one embodiment, the unit dose is 90 mg.
In one
embodiment, the unit dose is 100 mg. In one embodiment, the unit dose is 110
mg. In one
embodiment, the unit dose is 120 mg.
[0603] In some embodiments, the unit dose form comprises one or multiple
dosages to
be administered periodically, such as once, twice, three times, four times or
five times
daily with noribogaine or its prodrug. In some embodiments, the administration
is once
daily, or once every second day, once every third day, three times a week,
twice a week, or
once a week. The dosage and frequency of the administration depends on
criteria
including the route of administration, content of composition, age and body
weight of the
patient, condition of the patient, sex of the patient, without limitation, as
well as by the
severity of the addiction. Determination of the unit dose form providing a
dosage and
frequency suitable for a given patient can readily be made by a qualified
clinician.
[0604] In some embodiments, the initial unit dose and one or more additional
doses of
noribogaine, noribogaine derivative, or salt or solvate thereof are provided
as one or
multiple dosages to be administered periodically, such as once, twice, three
times, four
times or five times daily with noribogaine or its prodrug. In some
embodiments, the
administration is once daily, or once every second day, once every third day,
three times a
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week, twice a week, or once a week. The dosage and frequency of the
administration
depends on criteria including the route of administration, content of
composition, age and
body weight of the patient, condition of the patient, sex of the patient,
without limitation,
as well as by the severity of the addiction. Determination of the unit dose
form providing a
dosage and frequency suitable for a given patient can readily be made by a
qualified
clinician.
106051 In one aspect, provided herein is a kit of parts comprising two or more
doses of
noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or
solvate thereof,
wherein the two or more doses comprise an amount of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof that is
sufficient to
maintain a serum concentration of 50 ng/mL to 180 ng/mL when administered to a
patient.
106061 In one embodiment, one dose comprises an initial dose of noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt or solvate
thereof, said initial
dose being sufficient to achieve a therapeutic serum concentration when
administered to a
patient; and
at least one additional dose, said additional dose sufficient to maintain a
therapeutic serum
concentration when administered to a patient, wherein the therapeutic serum
concentration
is between 50 ng/mL and 180 ng/mL In another embodiment, the initial dose is
from 75
mg to 120 mg. In another embodiment, the at least one additional dose is from
5 mg to 25
mg.
106071 These dose ranges may be achieved by transdermal, oral, or parenteral
administration of noribogaine, noribogaine derivative, or a pharmaceutically
acceptable
salt or solvate thereof in unit dose form. Such unit dose form may
conveniently be
provided in transdermal patch, tablet, caplet, liquid or capsule form. In
certain
embodiments, the noribogaine is provided as noribogaine HO, with dosages
reported as
the amount of free base noribogaine. In some embodiments, the noribogaine HCl
is
provided in hard gelatin capsules containing only noribogaine HC1 with no
excipients. In
some embodiments, noribogaine is provided in saline for intravenous
administration.
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Formulations
[0608] This invention further relates to pharmaceutically acceptable
formulations
comprising a unit dose of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt or solvate thereof, wherein the amount of noribogaine is
sufficient to
provide an average serum concentration of about 50 ng/mL to about 180 ng/mL
when
administered to a patient. In a preferred embodiment, the amount of
noribogaine is
sufficient to provide an average serum concentration of about 80 ng/mL to
about 100
ng/mL when administered to a patient. In one embodiment, the amount of
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt thereof is an
amount that
delivers an aggregate amount of noribogaine of about 50 ng to about 10 n per
kg body
weight per day.
[0609] In some embodiments, the unit dose of noribogaine is administered in
one or
more dosings.[0610] This invention further relates to pharmaceutically
acceptable
formulations comprising a unit dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof, wherein the amount of
noribogaine is
sufficient to provide andJor maintain an average serum concentration of about
50 ng/mL to
about 180 ng/mL when administered to a patient. In a preferred embodiment, the
amount
of noribogaine is sufficient to provide andJor maintain an average serum
concentration of
80 ng/mL to 100 ng/mLwhen administered to a patient.
[0611] In some embodiments, the unit dose of noribogaine is administered in
one or
more dosings.
[0612] In one embodiment, the amount of noribogaine is sufficient to provide
an average
serum concentration of noribogaine from 50 ng/mL to 180 ng/mL, or 60 ng/mL to
180
ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide
an average
serum concentration of noribogaine from 50 ng/mL to 150 ng/mL, or 60 ng/mL to
150
ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide
an average
serum concentration of noribogaine from about 50 ng/mL to about 120 ng/mL, or
about 60
ng/mL to about 120 ng/mL. In one embodiment, the amount of noribogaine is
sufficient to
provide an average serum concentration of noribogaine from about 50 ng/mL to
about 100
ng/mL, or about 60 ng/mL to about 100 ng/mL. In one embodiment, the amount of
noribogaine is sufficient to provide an average serum concentration of
noribogaine from
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about 50 ng/mL to about 120 ng/mL, or about 60 ng/mL to about 120 ng/mL. In
one
embodiment, the amount of noribogaine is sufficient to provide an average
serum
concentration of noribogaine from about 50 ng/mL to about 100 ng/mL, or about
60
ng/mL to about 100 ng/mL. In one embodiment, the amount of noribogaine is
sufficient to
provide an average serum concentration of noribogaine from about 80 ng/mL to
about 100
ng/mL.The ranges include both extremes as well as any subranges between.
[0613] In some embodiments, the initial unit dose of noribogaine, noribogaine
derivative, or pharmaceutically acceptable salt or solvate thereof is from
about 50 mg to
about 120 mg. In one embodiment, the unit dose is about 50 mg. In one
embodiment, the
unit dose is about 55 mg. In one embodiment, the unit dose is 60 mg. In one
embodiment,
the unit dose is about 65 mg. In one embodiment, the unit dose is about 70 mg.
In one
embodiment, the unit dose is about 75 mg. In one embodiment, the unit dose is
about 80
mg. In one embodiment, the unit dose is about 85 mg. In one embodiment, the
unit dose is
about 90 mg. In one embodiment, the unit dose is about 95 mg. In one
embodiment, the
unit dose is about 100 mg. In one embodiment, the unit dose is 105 mg. In one
embodiment, the unit dose is about 110 mg. In one embodiment, the unit dose is
about 115
mg. In one embodiment, the unit dose is about 120 mg.
[0614] In some embodiments, the at least one additional dose of noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof
is from 5 mg
to 75 mg. In one embodiment, the unit dose is 5 mg. In one embodiment, the
unit dose is
mg. In one embodiment, the unit dose is 15 mg. In one embodiment, the unit
dose is 20
mg. In one embodiment, the unit dose is 25 mg. In one embodiment, the unit
dose is 30
mg. In one embodiment, the unit dose is 35 mg. In one embodiment, the unit
dose is 40
mg. In one embodiment, the unit dose is 45 mg. In one embodiment, the unit
dose is 50
mg. In one embodiment, the unit dose is 55 mg. In one embodiment, the unit
dose is 60
mg. In one embodiment, the unit dose is 65 mg. In one embodiment, the unit
dose is 70
mg. In one embodiment, the unit dose is 75 mg.
[0615] In some embodiments, the formulation comprises a delivery vehicle, as
described
above. In one embodiment, the delivery vehicle comprises 5 mg to 120 mg
noribogaine,
noribogaine derivative, or pharmaceutically acceptable salt or solvate
thereof.
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[0616] In some embodiments, the formulation is a controlled release
formulation. The
term "controlled release formulation" includes sustained release and time-
release
formulations. Controlled release formulations are well-known in the art. These
include
excipients that allow for sustained, periodic, pulse, or delayed release of
the drug.
Controlled release formulations include, without limitation, embedding of the
drug into a
matrix; enteric coatings; micro-encapsulation; gels and hydrogels; implants;
transdermal
patches; and any other formulation that allows for controlled release of a
drug.
[0617] In one embodiment, the amount of noribogaine is sufficient to provide
an average
serum concentration of noribogaine from about 50 ng/mL to about 180 ng/mL, or
about 60
ng/mL to about 180 ng/mL. In one embodiment, the amount of noribogaine is
sufficient to
provide an average serum concentration of noribogaine from about 50 ng/mL to
about 150
ng/mL, or about 60 ng/mL to about 150 ng/mL. In one embodiment, the amount of
noribogaine is sufficient to provide an average serum concentration of
noribogaine from
about 50 ng/mL to about 120 ng/mL, or about 60 ng/mL to about 120 ng/mL. In
one
embodiment, the amount of noribogaine is sufficient to provide an average
serum
concentration of noribogaine from about 50 ng/mL to about 100 ng/mL, or about
60
ng/mL to about 100 ng/mL. In one embodiment, the amount of noribogaine is
sufficient to
provide an average serum concentration of noribogaine from about 80 ng/mL to
about 100
ng/mL. The ranges include both extremes as well as any subranges between.
[0618] In some embodiments, the unit dose of noribogaine, noribogaine
derivative, or
pharmaceutically acceptable salt or solvate thereof is from about 20 mg to
about 120 mg.
In one embodiment, the unit dose is about 20 mg. In one embodiment, the unit
dose is
about 30 mg. In one embodiment, the unit dose is about 40 mg. In one
embodiment, the
unit dose is about 50 mg. In one embodiment, the unit dose is about 60 mg. In
one
embodiment, the unit dose is about 70 mg. In one embodiment, the unit dose is
about 80
mg. In one embodiment, the unit dose is about 90 mg. In one embodiment, the
unit dose is
about 100 mg. In one embodiment, the unit dose is about 110 mg. In one
embodiment, the
unit dose is about 120 mg.
[0619] This invention further relates to pharmaceutically acceptable
formulations
comprising a unit dose of noribogaine, noribogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof, wherein the amount of noribogaine is
sufficient to
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provide an average serum concentration of about 50 ng/mL to about 850 ng/mL
when
administered to a patient. In a preferred embodiment, the amount of
noribogaine is
sufficient to provide an average serum concentration of about 50 ng/mL to
about 400
ng/mLwhen administered to a patient.
[0620] In one embodiment, the amount of noribogaine is sufficient to provide
an average
serum concentration of noribogaine from about 50 ng/mL to about 800 ng/mL or
about 60
ng/mL to about 800 ng/mL. In one embodiment, the amount of noribogaine is
sufficient to
provide an average serum concentration of noribogaine from about 50 ng/mL to
about 700
ng/mL or about 60 ng/mL to about 700 ng/mL. In one embodiment, the amount of
noribogaine is sufficient to provide an average serum concentration of
noribogaine from
about 50 ng/mL to about 600 ng/mL, or about 60 ng/mL to about 600 ng/mL. In a
preferred embodiment, the amount of noribogaine is sufficient to provide an
average
serum concentration of noribogaine from about 50 ng/mL to about 500 ng/mL, or
about 60
ng/mL to about 500 ng/mL. In one embodiment, the amount of noribogaine is
sufficient to
provide an average serum concentration of noribogaine from about 50 ng/mL to
about 400
ng/mL, or about 60 ng/mL to about 400 ng/mL. In one embodiment, the amount of
noribogaine is sufficient to provide an average serum concentration of
noribogaine from
about 50 ng/mL to about 300 ng/mL, or about 60 ng/mL to about 300 ng/mL. In
one
embodiment, the amount of noribogaine is sufficient to provide an average
serum
concentration of noribogaine from about 50 ng/mL to about 200 ng/mL, or about
60
ng/mL to about 200 ng/mL. In one embodiment, the amount of noribogaine is
sufficient to
provide an average serum concentration of noribogaine from about 50 ng/mL to
about 100
ng/mL, or about 60 ng/mL to about 100 ng/mL. The ranges include both extremes
as well
as any subranges between.
[0621] In some embodiments, the formulation is designed for periodic
administration,
such as once, twice, three times, four times or five times daily with
noribogaine,
noribogaine derivative, or a pharmaceutically acceptable salt or solvate
thereof. In some
embodiments, the administration is once daily, or once every second day, once
every third
day, three times a week, twice a week, or once a week. The dosage and
frequency of the
administration depends on the route of administration, content of composition,
age and
body weight of the patient, condition of the patient, without limitation.
Determination of
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dosage and frequency suitable for the present technology can be readily made a
qualified
clinician.
[0622] In some embodiments, the formulation designed for administration in
accordance
with the methods provide herein can be suitable for a variety of delivery
modes including,
without limitation, oral,transdermal, sublingual, buccal, intrapulmonary or
intranasal
delivery. Formulations suitable for internal, pulmonary, rectal, nasal,
vaginal, lingual,
intravenous, intra-arterial, intramuscular, intraperitoneal, intracutaneous
and subcutaneous
routes may also be used. Possible formulations include tablets, capsules,
pills, powders,
aerosols, suppositories, parenterals, and oral liquids, including suspensions,
solutions and
emulsions. Sustained release dosage forms may also be used. All formulations
may be
prepared using methods that are standard in the art (see e.g., Remington's
Pharmaceutical
Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).
[0623] In a preferred embodiment, the formulation is designed for oral
administration,
which may conveniently be provided in tablet, caplet, sublingual, liquid or
capsule form.
In certain embodiments, the noribogaine is provided as noribogaine HC1, with
dosages
reported as the amount of free base noribogaine. In some embodiments, the
noribogaine
HC1 is provided in hard gelatin capsules containing only noribogaine HC1 with
no
excipients.
[0624] Noribogaine or a noribogaine derivative can also be used in conjunction
with any
of the vehicles and excipients commonly employed in pharmaceutical
preparations, e.g.,
talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous
or non-
aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and
flavoring agents
may also be added to preparations, particularly to those for oral
administration. Solutions
can be prepared using water or physiologically compatible organic solvents
such as
ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols,
triglycerides,
partial esters of glycerine and the like. Parenteral compositions containing
noribogaine
may be prepared using conventional techniques that may include sterile
isotonic saline,
water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with
water,
Ringer's solution, etc.
[0625] The compositions utilized herein may be formulated for aerosol
administration,
particularly to the respiratory tract and including intrapulmonary or
intranasal
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administration. The compound will generally have a small particle size, for
example of
the order of 5 microns or less. Such a particle size may be obtained by means
known in
the art, for example by micronization. The active ingredient may be provided
in a
pressurized pack with a suitable propellant such as a chlorofluorocarbon
(CFC), (for
example, dichlorodifluoromethane, trichlorofluoromethane, or
dichlorotetrafluoroethane),
carbon dioxide or other suitable gases. The aerosol may conveniently also
contain a
surfactant such as lecithin. The dose of drug may be controlled by a metered
valve.
Alternatively, the active ingredients may be provided in the form of a dry
powder, for
example a powder mix of the compound in a suitable powder base such as
lactose, starch,
starch derivatives such as hydroxypropylmethyl cellulose and
polyvinylpyrrolidine. In
some embodiments, the powder carrier will form a gel in the nasal cavity. The
powder
composition may be presented in unit dose form, for example in capsules or
cartridges,
gelatin or blister packs, from which the powder may be administered by means
of an
inhaler.
[0626] The compositions utilized herein may be formulated for sublingual
administration, for example as sublingual tablets. Sublingual tablets are
designed to
dissolve very rapidly. The formulations of these tablets contain, in addition
to the drug, a
limited number of soluble excipients, usually lactose and powdered sucrose,
but
sometimes dextrose and mannitol.
[0627] It has been discovered that noribogaine has a bitter taste to at least
some patients.
Accordingly, compositions for oral use (including sublingual, inhaled, and
other oral
formulations) may be formulated to utilize taste-masking technologies. A
number of ways
to mask the taste of bitter drugs are known in the art, including addition of
sugars, flavors,
sweeteners, or coatings; use of lipoproteins, vesicles, and/or liposomes;
granulation;
microencapsulation; numbing of taste buds; multiple emulsion; modification of
viscosity;
prodrug or salt formation; inclusion or molecular complexes; ion exchange
resins; and
solid dispersion. Any method of masking the bitterness of the compound of the
invention
may be used.
EXAMPLES
[0628] The following Examples are intended to further illustrate certain
embodiments of
the disclosure and are not intended to limit its scope.
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Example 1. Pharmacokinetics and pharmaco dynamics of noribogaine in humans
[0629] Thirty-six healthy, drug-free male volunteers, aged between 18-55
years, were
enrolled in and completed the study. This was an ascending single-dose,
placebo-
controlled, randomized double blind, parallel group study. Mean (SD) age was
22.0 (3.3)
years, mean (SD) height was 1.82 (0.08) m, and mean (SD) weight was 78.0 (9.2)
kg.
Twenty-six subjects were Caucasian, 3 were Asian, 1 Maori, 1 Pacific Islander,
and 5
Other. The protocol for this study was approved by the Lower South Regional
Ethics
Committee (LRS/12/06/015), and the study was registered with the Australian
New
Zealand Clinical Trial Registry (ACTRN12612000821897). All subjects provided
signed
informed consent prior to enrolment, and were assessed as suitable to
participate based on
review of medical history, physical examination, safety laboratory tests,
vital signs and
ECG.
[0630] Within each dose level, 6 participants were randomized to receive
noribogaine
and 3 to receive placebo, based on a computer-generated random code. Dosing
began with
the lowest noribogaine dose, and subsequent cohorts received the next highest
dose after
the safety, tolerability, and blinded pharmacokinetics of the completed cohort
were
reviewed and dose-escalation approved by an independent Data Safety Monitoring
Board.
Blinded study drug was administered as a capsule with 240 ml of water after an
overnight
fast of at least 10 hours. Participants did not receive any food until at
least 5 hours post-
dose. Participants were confined to the study site from 12 hours prior to drug

administration, until 72 hours post-dose, and there were subsequent outpatient
assessments
until 216 hours post-dose.
[0631] Blood was obtained for pharmacokinetic assessments pre-dose and then at
0.25,
0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12,
14, 18, 24, 30, 36, 48,
60, 72, 96, 120, 168 and 216 hours post-dose. Samples were centrifuged and
plasma stored
at -70 C until analyzed. Block 24 hour urine collections were obtained
following study
drug administration for the 30 and 60 mg cohorts. Aliquots were frozen at -20
C until
analyzed.
[0632] Pulse oximetry and capnography data were collected continuously using a
GE
Carescape B650 monitoring system from 2 hours prior to dosing and until six
hours after
dosing, and thereafter at 12, 24, 48 and 72 hours post-dosing. Additional
oximetry data
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were collected at 120, 168 and 216 hours. Pupillary miosis was assessed by
pupillometry.
Dark-adapted pupil diameter was measured in triplicate using a Neuroptics PLR-
200
pupillometer under standardized light intensity (<5 lux) pre-dose, and at 2,
4, 6, 12, 24, 48,
72, 96, 120, 168 and 216 hours post-dosing.
[0633] Plasma noribogaine concentrations were determined in the 3 mg and 10 mg
dose
groups using a validated, sensitive LCMSMS method. Sample preparation involved

double extraction of basified plasma samples with tert-butyl methyl ether,
drying the
samples under a stream of nitrogen and reconstitution of sample with
acetonitrile:B.P.
water (5:95, v/v) containing 0.1% (v/v) formic acid. The compounds were
separated by a
150 x 2.0 mm Luna 5[1m C18 column and detected with a triple ¨ quadruple API
4000 or
5000 mass spectrometer using electrospray ionization in positive mode and
multiple
reaction monitoring. Noribogaine-d4 was used as the internal standard. The
precursor-
production transition values for noribogaine were m/z 297.6 -> 122.3, and for
the internal
standard noribogaine-d4 m/z 301.1 -> 122.2. Analyst software was used for
data
acquisition and processing. The ratio of the peak area of noribogaine to the
internal
standard noribogaine-d4 was used for calibration and measurement of the
unknown
concentration of noribogaine. The lower limit of quantification (LLOQ) was
0.025 ng/ml
noribogaine. The calibration curve was between 0.025 and 25.600 ng/ml
noribogaine.
Mobile phase A was acetonitrile:B.P. water (5:95, v/v) containing 0.1% (v/v)
formic acid,
and mobile phase B was acetonitrile:B.P. water (95:5, v/v) containing 0.1%
(v/v) formic
acid. Total run time was 6 minutes. Binary flow: Initial concentration was 8%
mobile
phase B; hold at 8% mobile phase B for 0.5 minutes and linear rise to 90%
mobile phase B
over 1.5 minutes; hold at 90% mobile phase B for 1 minute and then drop back
to 8%
mobile phase B over 0.01 minute. Equilibrate system for 3 minutes. Total run
time was 6
minutes. Within- and between-day assay precision was <9%, and within- and
between-
day assay accuracy was < 9%.
[0634] Plasma noribogaine concentrations were determined in the 30 mg and 60
mg
dose groups using a validated, sensitive LCMSMS method. Sample preparation
involved
deproteinization of plasma samples with acetonitrile and dilution of sample
with 0.1%
(v/v) formic acid. The compounds were separated by a 150 x 2.0 mm Luna 5[tm
C18
column and detected with a triple ¨ quadruple API 4000 or 5000 mass
spectrometer using
electrospray ionization in positive mode and multiple reaction monitoring.
Noribogaine-d4
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was used as the internal standard. The precursor-product ion transition values
for
noribogaine were m/z 297.6 -> 122.3, and for the internal standard noribogaine-
d4 m/z
301.1 -> 122.2. Analyst software was used for data acquisition and
processing. The ratio
of the peak area of noribogaine to the internal standard noribogaine-d4 was
used for
calibration and measurement of the unknown concentration of noribogaine. The
LLOQ
was 0.50 ng/ml noribogaine. The calibration curve was between 0.50 and 256.00
ng/ml
noribogaine. Mobile phase was the same as method A, and binary flow was also
the same
as method A. The within- and between-day assay precision was <9%, and the
within- and
between-day assay accuracy was < 9%.
[0635] Plasma noribogaine glucuronide concentrations were determined in the 30
mg
and 60 mg dose groups using a validated sensitive LCMSMS method. Sample
preparation
involved deproteinization of plasma samples with acetonitrile, drying the
samples under a
stream of nitrogen and reconstitution of sample with acetonitrile: B.P. water
(5:95, v/v)
containing 0.1% (v/v) formic acid. The compounds were separated by a 150 x 2.0
mm
Luna 5mm C18 column and detected with a triple ¨ quadruple API 4000 or 5000
mass
spectrometer using electrospray ionization in positive mode and multiple
reaction
monitoring. Noribogaine-d4 was used as the internal standard. The precursor-
product ion
transition values for noribogaine glucuronide were m/z 472.8 -> 297.3, and for
the internal
standard noribogaine-d4 m/z 301.1 -> 122.2. Analyse software was used for data

acquisition and processing. The ratio of the peak area of noribogaine
glucuronide to the
internal standard noribogaine-d4 was used for calibration and measurement of
the
unknown concentration of noribogaine glucuronide. The LLOQ was 0.050 ng/ml
noribogaine glucuronide. The calibration curve was between 0.050 and 6.400
ng/ml
noribogaine glucuronide. Mobile phases was the same as method A. Binary flow:
Initial
concentration was 6% mobile phase B; hold at 6% mobile phase B for 0.5 minutes
and
linear rise to 90% mobile phase B over 2 minutes; hold at 90% mobile phase B
for 1
minute and then drop back to 6% mobile phase B over 0.01 minute. Equilibrate
system for
3.5 minutes. Total run time was 7 minutes. The within- and between-day assay
precision
was < 11%, and the within- and between-day assay accuracy was < 10%.
[0636] Urine noribogaine and noribogaine glucuronide concentrations were
determined
in the 30 mg and 60 mg dose groups using a validated sensitive LCMSMS method.
Sample preparation involved deproteinization of urine samples with
acetonitrile and
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dilution of the sample with 0.1% (v/v) formic acid. The compounds were
separated by a
150 x 2.0 mm Luna 5[tm C18 column and detected with a triple ¨ quadruple API
4000 or
5000 mass spectrometer using electrospray ionization in positive mode and
multiple
reaction monitoring. Noribogaine-d4 was used as the internal standard. The
precursor-
production transition values for noribogaine were m/z 297.6 -> 122.3,
noribogaine
glucuronide m/z 472.8 -> 297.3, and for the internal standard noribogaine-d4
m/z 301.1 ->
122.2. Analyst software was used for data acquisition and processing. The
ratios of the
peak area of noribogaine and noribogaine glucuronide to the internal standard
noribogaine-d4 were used for calibration and measurement of the unknown
concentration
of noribogaine and its glucuronide. Assay LLOQ was 20.0 ng/ml for noribogaine
and 2.0
ng/ml for noribogaine glucuronide. The calibration curve was between 20.0 and
5120.0
ng/ml noribogaine, and 2.0 and 512.0 ng/ml noribogaine glucuronide. Mobile
phases were
as described in method A, and binary flow as in method C. The within- and
between-day
assay precision was < 13%, and within- and between-day assay accuracy was <
12%.
[0637] Noribogaine and noribogaine glucuronide concentrations above the limit
of
quantification were used to calculate pharmacokinetic parameters using model-
independent methods. The maximum plasma concentration (Cmax) and time to
maximum
plasma concentration (Tmax) were the observed values. Plasma concentration
data in the
post-distribution phase of the plasma concentration-time plot were fitted
using linear
regression to the formula ln C = in Co ¨ t.Kel, where Co was the zero-time
intercept of the
extrapolated terminal phase and Kel was the terminal elimination rate
constant. The half-
life (t1/2) was determined using the formula t112= 0.693/Kel. The area under
the
concentration-time curve (AUC) from time zero to the last determined
concentration-time
point (tf) in the post distribution phase was calculated using the trapezoidal
rule. The area
under the curve from the last concentration-time point in the post
distribution phase (Ctf)
to time infinity was calculated from AUCt,õ= Ctf/Kel. The concentration used
for Ctf was
the last determined value above the LLOQ at the time point. The total AUC0_,,
was
obtained by adding AUCtf and AUCt_.. Noribogaine apparent clearance (CL/F) was

determined using the formula CL/F = Dose/AUC0_00 x 1000, and apparent volume
of
distribution (Vd/F) was determined using the formula Vd/F = (CL/F)/Kel. Total
urine
noribogaine was the sum of both analytes.
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WO 2015/126836 PCT/US2015/016186
[0638] Summary statistics (means, standard deviations, and coefficients of
variation)
were determined for each dose group for safety laboratory test data, ECG and
pharmacokinetic parameters, and pharmacodynamic variables. Categorical
variables were
analysed using counts and percentages. Dose-proportionality of AUC and Cmax
was
assessed using linear regression. The effect of dose on pharmacodynamic
parameter values
over time was assessed using two-factor analysis of variance (ANOVA). Pairwise

comparisons (with Tukey-Kramer adjustment) between each dose group to the
placebo
were conducted at each time point using the least squares estimates obtained
from the
ANOVA, using SAS Proc Mixed (SAS ver 6.0).
Results
106391 Pharrnacokinetics: Mean plasma concentration-time plots of noribogaine
are
shown in Figure 1, and mean pharmacokinetic parameters are shown in Table 1.
Table 1
' '' mg ___________________
0,509111-1
,r &atm,
(mean (mean (mean (mean (SD)
;
74.2 (13.1) 254.5 (78.9) 700.4 (223.3) 1962.2
(726.5)
(ng.hr/m1)
AUC0_216== ID 72.2 (13.2) 251.4 (78.5) 677.6 (221.1) 1935.4
(725.4)
Cmax ,g====
(n,g/m1)
52(14) 145(21) 559(148) 1160(225)
;;;;;;,,,!;;
Tmax (hr) 1.9 (0.6) 2.9 (1.8) 1.8 (0.6) 2.4 (0.6)
tii2(hr) 40.9 (8.7) 49.2 (11.5) 27.6 (7.0)) 29.1 (9.3)
.Vd/F. 2485.1 (801.5) 3085.8 (1197.0) 1850.8 (707.9) 1416.8
(670.1)
CL/F :(L/h) 41.4 (7.0) 42.3 (12.0) 46.9 (16.4) 34.0 (11.4)
Nbribbgaine glucuronide
AUC0,., .....
25.8 (9.3) 67.1 (21.9)
(ng.hr/r.p1) .
AU CO-2 I 6 25.7 (9.1) 65.0 (21.5)
(ng.ht/M1):
(.'.rnax ..... . ;41i1
1.8 (0.6) 4.1 (1.2)
(*ml,)
TmaX (hr) ..... - 3.0 (0.6)
3.8 (1.2)
(hr): - 20.6 (4.9) 23.1 (3.0)
[0640] Noribogaine was rapidly absorbed, with peak concentrations occurring 2-
3 hours
after oral dosing. Fluctuations in individual distribution-phase concentration-
time profiles
may suggest the possibility of enterohepatic recirculation (see highlighted
individual 4-8
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hour profiles in Figure 1, insert). Both Cmax and AUC increased linearly with
dose
(Table 1, upper panel). Mean half-life estimates of 28-50 hours were observed
across dose
groups for noribogaine. Volume of distribution was extensive (1417-3086 L
across dose
groups).
[0641] Mean plasma noribogaine glucuronide concentration-time plots for the 30
mg
and 60 mg dose group are shown in Figure 2, and mean pharmacokinetic
parameters are
shown in Table 1, lower panel. Noribogaine glucuronide was detected in all
subjects by
0.75 hours, with peak concentrations occurring 3-4 hours after noribogaine
dosing. Mean
half-life of 21-23 hours was estimated for plasma noribogaine glucuronide. The
proportion
of noribogaine glucuronide Cmax and AUC relative to noribogaine was 3-4% for
both
dose groups. Total urine noribogaine elimination was 1.16 mg and 0.82 mg for
the 30 mg
and 60 mg dose groups respectively, representing 3.9% and 1.4% of the doses
administered.
[0642] The subject mean serum levels over time of noribogaine free base from a
single
dose of 3 mg noribogaine free base under fasting conditions were plotted. The
mean Cmax
of 5.2 ng/ml was observed 1.9 hours after administration, while the mean
AUC/24 hr of
3.1 ng/ml was obtained.
[0643] The subject mean serum levels over time of noribogaine free base from a
single
dose of 10 mg noribogaine free base under fasting conditions were plotted. The
mean
C. of 14.5 ng/ml was observed 2.9 hours after administration, while the mean
AUC/24
hr of 10.6 ng/ml was obtained.
[0644] The subject mean serum levels over time of noribogaine free base from a
single
dose of 30 mg noribogaine free base under fasting conditions were plotted. The
mean
C. of 55.9 ng/ml was observed between 1.75 hours after administration, while
the mean
AUC/24 of 29.2 ng/ml was obtained.
[0645] The subject mean serum levels over time of noribogaine free base from a
single
dose of 60 mg noribogaine free base under fasting conditions were plotted. The
mean
C. of 116 ng/ml was observed between 1.75 hours after administration, while
the mean
AUC/24 ng/ml of 61 was obtained.
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[0646] The subject mean serum levels over time of noribogaine free base for
all 4
cohorts were plotted. The extrapolated dosage of noribogaine free base
required to
provide a C. ranging from about 5.2 ng/ml to about 1980 ng/ml and an AUC/24 hr
of
about 3.1 ng/ml to about 1100 ng/ml was determined.
[0647] Pharmacodynamics: There was no evidence of pupillary constriction in
subjects
dosed with noribogaine. No between-dose group differences in pupil diameter
were
detected over time. After adjusting for baseline differences, comparison of
each dose
group with placebo by ANOVA showed no statistically significant differences
(p>0.9).
[0648] Noribogaine treatment showed no analgesic effect in the cold pressor
test.
Analgesic effect was assessed based on duration of hand immersion in ice water
and on
visual analog scale (VAS) pain scores upon hand removal from the water bath.
For
duration of hand immersion, after adjusting for baseline differences,
comparison of each
dose group with placebo by ANOVA showed no statistically significant
differences
(p>0.9). Similarly, for VAS pain scores, after adjusting for baseline
differences,
comparison of each dose group with placebo by ANOVA showed no statistically
significant differences (p=0.17).
Example 2. Safety and tolerability of noribogaine in healthy humans
[0649] Safety and tolerability of noribogaine were tested in the group of
volunteers from
Example 1. Cold pressor testing was conducted in 1 C water according to the
method of
Mitchell et al. (J Pain 5:233-237, 2004) pre-dose, 6, 24, 48, 72 and 216 hours
post-dosing.
Safety evaluations included clinical monitoring, recording of adverse events
(AEs), safety
laboratory tests, vital signs, ECG telemetry from -2h to 6h after dosing, and
12-lead
electrocardiograms (ECGs) up to 216 hours post-dosing.
Results
[0650] A total of thirteen adverse events were reported by seven participants
(Table 2).
Six adverse events were reported by three participants in the placebo group,
five adverse
events were reported by two subjects in the 3 mg dose group, and one adverse
event was
reported by single subjects in the 10 mg and 30 mg dose groups, respectively.
The most
common adverse events were headache (four reports) and epistaxis (two
reports). All
adverse events were of mild-moderate intensity, and all resolved prior to
study
completion. There were no changes in vital signs or safety laboratory tests of
note. In
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particular, there were no changes in oximetry or capnography, or changes in
respiratory
rate. There were no QTcF values >500 msec at any time. One subject dosed with
10 mg
noribogaine had a single increase in QTcF of >60 msec at 24 hours post-dosing.
Table 2
Dose Mild Moderate 'c
(ng) HO m
Placebo Blepharitis Epistaxis
Bruising
:
HO I Dry Skin
111 1111 111 Eye pain, nonspecific
: Infection at cannula site
. Back pain Headache
Dizziness
. .
Epistaxis
=
Headache
Headache
30 Headache
09 ..
Example 3. Safety,
tolerability, and efficacy of noribogaine in opioid-addicted humans
[0651] This example is to illustrate that noribogaine can be administered at a
therapeutic
dosing while maintaining an acceptable QT interval. While the therapy employed
is
directed to opioid-dependent participants in a randomized, placebo-controlled,
double-
blind trial, the results show that a therapeutic window can be established for
noribogaine.
[0652] The efficacy of noribogaine in humans was evaluated in opioid-dependent

participants in a randomized, placebo-controlled, double-blind trial. Patients
had been
receiving methadone treatment as the opioid substitution therapy, but were
transferred to
morphine treatment prior to noribogaine administration. This was done to avoid
negative
noribogaine-methadone interactions that are not observed between noribogaine
and
morphine. See U.S. Application Serial Nos. 14/214,157, filed March 14, 2014
and
14/346,655, filed March 21, 2014, which are incorporated herein by reference
in their
entireties.
[0653] Three cohorts of nine (9) subjects (6 administered noribogaine and 3
administered placebo in each cohort) were evaluated for tolerability,
pharmacokinetics,
and efficacy. Cohort 1 received a single dose of 60 mg noribogaine or placebo.
Cohort 2
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WO 2015/126836 PCT/US2015/016186
received a single dose of 120 mg noribogaine or placebo. Cohort 3 received a
single dose
of 180 mg noribogainc or placebo. Treatment was administered 2 hours after
last
morphine dose and the time to resumption of morphine (opioid substitution
treatment,
OST) was determined. Few adverse effects of noribogaine were observed in any
of the
participants, including no hallucinatory effects. Table 3 shows the reported
adverse events
for each treatment that were not attributable to withdrawal from opioids.
Headaches were
frequent in the placebo and 60 mg noribogaine treatment groups, but were
attenuated in
the 120 mg and 180 mg dose groups.
Table 3: Treatment Emergent Adverse Events Summary
+-
Sym00t 0,g0n Cos* Pinet10 00 nx: ;20 mg 168:, rpg
Pre001:0.1 Teem (64)
lYssmbre of SaJjouts Stopvetimj, nni AEsi MI 177,6%; : 16.6 (323%)
20:0 t100.016) : 2:4 ((6.7%)
Ear sod ktabyrktif; Disonfixl 0 0 2.2 (33.3%) 0
'7056060 0 0 (.2(3%) 0
Er, thscolsrs 2:(222%1 3:3 .,50Ø%) . 6:0 (M%)
1/4,1)s.;a) tolmfmerli 2ZaZ214) 21(33.3%) 60(8.3.S%)
5:4(042%)
ray 610 0 1:1 06.7%) 0 0
(1.*2(0320.4402,13124,0140t 3.2Z2%) 2:2 (13 2%) 72(33..%J
42(333%
. Naom1 14412414) 0 3;2 (2.13%)
Orli PAck.at 0 0 IA (10,1%) '11 -
4:10,1%6
Vo.11:10%i 0 0 21 f16.7V 1:1600.:7%)

1::66r0p:00 ti (11.14) 0 1:i (1V.P.,4) 0
C..42;40,441 :LI MAIO 2:2(333%) 0 0
6µ,1,4),* 0;4010f0:0 a+,1I Adrnoiamdeo $go Covtison6 02 (33.3%) 0 2:2
(22324) 1:1 (16.7%)
Cathole, S:so Re4thei Reac.tices 0 0 0 1=1 {10 2%)
1:::sfttce 3606010 22 (222%) 0 2.2 (322%) ... 0
, 61660041 1:1 (11.11,c) 0 0 0
fokaio.s ono infwelomns 11 (11.1%) 0 1.-1 ((61%) . .. .
22 i33.3).)
C06,0:66 0 0 1:0 (6.r%) 1:1-
(111:2%)
tjtimary 7:00 031066.,) 0 0 0 I!) 0 0.7M
Cattwer 360 000.2ion 1:1 (11.414) 0 0 -- 0
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[0654] Figure 3 indicates the average serum noribogaine concentration over
time after
administration of noribogaine for each cohort (60 mg, diamonds; 120 mg,
squares; or 180
mg, triangles). Further results are detailed in U.S. Provisional Patent
Application No.
62/023,100 , filed July 10, 2014, and titled "METHODS FOR ACUTE AND LONG-
TERM TREATMENT OF DRUG ADDICTION," which is incorporated herein by
reference in its entirety.
Results
[0655] Pharrnacokinetic results for each cohort are given in Table 4. Maximum
serum
concentration of noribogaine (Cmax) increased in a dose-dependent manner. Time
to
Cmax (Tmax) was similar in all three cohorts. Mean half-life of serum
noribogaine was
similar to that observed in healthy patients.
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Table 4: Pharmacokinetic results from the Patients in Phase I B Study
Cohort 1 ...................................... Cohort
.... ...... ............ . . .
Data (mean SD) Data (mean SD) Data
PK parameter ..... ................ ......... . .
.........
troil . [range] ....
81.64 23.77 172.79 30.73 267.88 46.92
Cmax (ng/ml)
[41.29¨ 113.21] [138.84 ¨ 229.55] [204.85 ¨338.21]
359 092 299 1.23
...... ......................................... 44I*180: HHHHHHHHHHHH:
-----------------------
[3 -.00 8.00]
- - , --------- . . - .
-----
AUC(0.4) 2018.01 613.91 3226.38 1544.26 6523.28 2909.80
(ng.hr/m1) [1094.46¨ 2533.44] [1559.37 ¨5638.98] [3716.69 ¨ 10353.12]
AUC0 2060 31 60939 328050 1581 43 688767 348891
::tniolirimo,:,,:,,:,,i,m,,:::-:[1:1-22:a9-..---:4..2.4$:tkilINIltt$9,-$A4;--
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29.32 7.28 30.45 9.14 23.94 5.54
Half-life (hrs)
[18.26 ¨ 37.33] [21.85 ¨48.33] [19.32 ¨ 34.90]
14407 8540 210643 164454 103219 36530
.................. . . . . . . . . . .
CUF 32 ...... 14 12.38 44.68 21.40 31.47 13.12
[23.51 ¨ 53.46] [20.80 ¨75.20] [14.66 ¨48.20]
[0656] Figure 4 indicates the time to resumption of morphine (OST) for
patients treated
with placebo (circles), 60 mg noribogaine (squares), 120 mg noribogaine
(triangles), and
180 mg noribogaine (inverted triangles). Patients receiving a single 120 mg
dose of
noribogaine exhibited an average time to resumption of opioids of greater than
20 hours.
Patients receiving a single 180 mg dose of noribogaine exhibited an average
time to
resumption of opioids similar to that of placebo. This demonstrates that
increasing the
dose of noribogaine to 180 mg results in a shorter time to resumption of OST
than
observed in patients receiving 120 mg noribogaine. Time to resumption of OST
after
treatment with 180 mg was still longer than untreated patients (7 hours, not
shown) or
those administered 60 mg noribogaine.
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[0657] Patients were evaluated based on the Clinical Opiate Withdrawal Scale
(COWS),
Subjective Opiate Withdrawal Scale (SOWS), and Objective Opiate Withdrawal
Scale
(00WS) scoring systems over the period of time between administration of
noribogaine
(or placebo) until resumption of OST. These scales are outlined in Guidelines
for the
Psychosocially Assisted Pharmacological Treatment of Opioid Dependence, World
Health
Organization, Geneva (2009), Annex 10, which is incorporated herein by
reference in its
entirety. The scales measure the intensity of withdrawal symptoms, based on
clinical,
subjective, and objective indicia.
[0658] Figure 5 shows the COWS scores at time of resumption of OST for each
cohort.
Box includes values representing 25% - 75% quartiles. Diamond = median;
crossbar in
box = mean; whiskers = values within standard deviation of mid-quartiles. No
outliers
present. The highly variable COWS scores across and within each cohort
indicates that
patients were resuming opiates without relation to the intensity of
withdrawal. This was
also reflected in SOWS and 0OWS scores at the time of resumption of OST.
[0659] Figure 6A shows the mean change in total COWS scores over the first six
hours
following dosing and prior to resumption of OST. Figure 6B shows the mean
AUC(0-6
hours) of the COWS total score change from baseline. Figure 7A shows the mean
change
in total 0OWS scores over the first six hours following dosing and prior to
resumption of
OST. Figure 7B shows the mean AUC(0-6 hours) of the 0OWS total score change
from
baseline. Figure 8A shows the mean change in total SOWS scores over the first
six hours
following dosing and prior to resumption of OST. Figure 8B shows the mean
AUC(0-6
hours) of the SOWS total score change from baseline. These data indicate that
withdrawal
symptoms get worse over time after cessation of OST, and that patients
administered
placebo experience generally worse withdrawal symptoms over that period.
Patients who
received 120 mg noribogaine generally experienced fewer withdrawal symptoms
than the
other patients, regardless of the scale used. Patients administered placebo
generally
experienced more withdrawal symptoms than patients who were administered
noribogaine.
[0660] Patients' QT intervals were evaluated at regular time points throughout
the study.
Figure 9A shows the average change in QT interval (AQTcl, i.e., QT interval
prolongation) over the first 24 hours post noribogaine (or placebo)
administration. Figure
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9B shows the estimated correlation between noribogaine concentration and
change in QT
interval. There is a dose-dependent increase in QT interval prolongation that
is correlated
with the serum concentration of noribogaine.
[0661] Based on above data, it is believed that the therapeutic window for a
single bolus
dose of noribogaine is bound at the lower end by 50 mg and at the upper end by
less than
180 mg. In particular, the therapeutic serum concentration in vivo appears to
be between
about 50 ng/mL and about 180 ng/mL.
**1 think this can be removed now bc updated results and are covered in the
"other"
example 3 above.Example 4. Multiple dosing of noribogaine in humans
[0662] The efficacy of multiple dosing of noribogaine in humans is evaluated
in opioid-
dependent participants in a randomized, placebo-controlled, double-blind
trial. Patients are
receiving methadone treatment as the opioid substitution therapy, but are
transferred to
morphine treatment prior to noribogaine administration.
[0663] Patients are treated with an initial unit dose of noribogaine of 80 mg,
followed by
15 mg to 20 mg of noribogaine every 6 hours to 12 hours, as indicated in Table
5.
Table 5
Flour 0 6 12 18 24 30 36 42 48 54 60 66 72 84 96 108 120 132 144 156
Dose
80 20 25 20 20 15 20 15 20 15 20 15 20 20 20 20 20 20 20 20
(mg)
[0664] Patients are treated with an initial unit dose of noribogaine of 80 mg,
which is
administered as subdoses of 40 mg followed by 20 mg at 2 hours and 4 hours
after the first
dose. The initial unit dose is followed by 15 mg to 20 mg of noribogaine every
6 hours to
12 hours, as indicated in Table 6.
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Table 6
Hour 0 2 4 6 12 18 24 30 36 42 48 54 60 66 72 84 96 108 120 132
Dose
40 20 20 20 25 20 20 15 20 15 20 15 20 15 20 20 20 20 20 20
(mg)
Example 5. Efficacy of noribogaine to modulate opioid tolerance in humans
[0665] A female patient, age 59, undergoing opioid analgesic therapy for
chronic back
pain, is treated with noribogaine hydrochloride at a dose of about 2 mg/kg
concurrently
with the opioid. The amount of opioid required to treat her back pain to the
same level as
before noribogaine treatment is determined after noribogaine treatment.
Example 6. Effect of noribogaine on nicotine dependence in Sprague-Dawley rats

Animals
[0666] Fourteen young adult, male Sprague-Dawley rats (300-325 g) from Harlan
were
used in this study. The rats underwent catheter surgery and training of
nicotine self-
administration.
[0667] Upon arrival, the rats were assigned a unique identification numbers
(tail marks).
Animals were housed 2-3 per cage in suspended polycarbonate rat cages with
filter paper
covering mesh shelf and were acclimated for up to 7 days. All rats were
examined,
handled, and weighed prior to initiation of the study to assure adequate
health and
suitability. During the course of the study, 12/12 light/dark cycles were
maintained. The
room temperature was 20-23 C with a relative humidity maintained 30-70%. Water
was
provided ad libitum for the duration of the study. Following surgery (in 14
nicotine
training rats), all rats were single housed and remained single housed
throughout the
duration of the study.
Test compounds
[0668] Noribogaine (12.5, 25 and 50 mg/kg, converted to free base doses with a

correction factor 1.12) was dissolved in 35% of the total required volume of
0.5% Tween
80 in 5% Dextrose. Suspension was stirred for at least 30 minutes. 1.5%
methylcellulose
was added to make up 65% of the total volume and the suspension was stirred
again for at
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least 30 minutes. As a result, 12.5mg/kg and 25mg/kg doses were clear
solutions and
50mg/kg was a slightly cloudy suspension.
[0669] The mix of 0.5% Tween 80 in 5% Dextrose (35% of total volume) and 1.5%
methylcellulose solution (65% of total volume) was used as compound vehicle
treatment.
[0670] Vehicle and noribogaine were administered orally 2 hours prior to test
at a dose
volume of 5 ml/kg.
[0671] Varenicline (1.7 mg/kg) was dissolved in saline (0.9% NaC1) and
administered
intraperitoneal 30 minutes prior to test. Dose volume of varenicline was 1
ml/kg. The
formulation of varenicline (1.7 mg/kg) was a clear solution.
Nicotine self-administration test
[0672] Apparatus: Intravenous drug self-administration and tests took place in

experimental chambers within sound-attenuating cubicles equipped with an
exhaust fan
(Med Associates, VT). Each chamber contained two response levers situated on
one wall
of the chamber. A stimulus light was located above each lever and a house
light is located
at the top of opposite wall. An infusion pump mounted above each chamber
delivered drug
solution via Tygon tubing connected to a single channel fluid swivel, which
was mounted
on a balance arm above the operant chamber. The output of the liquid swivel
was attached
to the external terminus of the intravenous catheter.
[0673] Food Training and Surgery: Prior to intravenous catheterization,
animals were
trained to lever press for food. After acquiring the lever-press response rats
were prepared
with intravenous catheters. One week later, rats were allowed to self-
administer nicotine
solution (0.03 mg in 0.1m1 over a 0.8 second period under a fix-ratio 3 (FR3))
by pressing
the previously food-paired lever in return for delivery of the drug solution.
In present
study, 4 weeks of operant training was needed to obtain stable nicotine
infusion (defined
as no less than 6 infusions and less than 20% variation in the mean number of
reinforcers
earned in 1-hour training over 3 consecutive days).
[0674] Self-administration Procedures: Animals were first trained to respond
for nicotine
(0.03 mg/kg/infusion) under a FR3, time-out 20 seconds schedule of
reinforcement. After
the completion of training and the establishment of stable baselines, the
effects of
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noribogaine were assessed. Noribogaine or the reference compound varenicline
(a
nicotinic acetylcholine receptor partial agonist) were only administered when
the animals
exhibited responding at baseline levels (i.e. no less than 6 infusions and
less than 20%
variation in the mean number of reinforcers earned in 1-hour training over
last three
consecutive non-drug test days). Compound testing was performed on Wednesdays
and
Fridays, assuming baseline levels of self-administration behavior on Tuesdays
and
Thursdays.
Study Design and Data Analysis
[0675] A within-subject design in which each rat received all treatments was
applied
with a Latin square test schedule. The six treatments which were blind to the
experimenter were:
1. Saline
2. Varenicline 1.7mg/kg
3. Vehicle (35% of 0.5% Tween-80 in 5% Dextrose and 65% of 1.5%
methylcellulose)
4. Noribogaine 12.5 mg/kg
5. Noribogaine 25 mg/kg
6. Noribogaine 50 mg/kg
[0676] The data of nicotine infusions obtained during test sessions were
analyzed via
repeated measure ANOVA followed by Fisher LSD post hoc comparisons where
appropriate. Percentage of inactive lever presses were also analyzed with
repeated
measure ANOVA for non-specific behavioral effects. An effect is considered
significant
if P<0.05. Data are represented as the mean and standard error to the mean
(s.e.m.).
Statistical outliers falling beyond mean +/- (2 x standard deviation) are
removed from the
analysis. With this criterion, 0-2 outliers were eliminated in different
measures.
Results
[0677] The effects of noribogaine and varenicline on nicotine infusion are
shown in
Figure 10A. Repeated measure ANOVA found a significant main effect of
treatment
[F(5,58)= 29.708, P<0.001]. Post hoc comparisons indicated that varenicline
and
noribogaine at both 25 and 50 mg/kg significantly depressed nicotine infusion
(Ps<0.001).
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A trend of depression of nicotine infusions was also found at 12.5 mg/kg dose
(P<0.10).
Data represent mean + s.e.m.
[0678] The effects of noribogaine and varenicline on inactive lever press
during nicotine
self-administration are shown in Figure 10B. Repeated measure ANOVA found no
significant main effect of treatment. [F(5,54)=0.356, P>0.05]. These results
suggest that
the effects of the test compounds on lever-pressing for nicotine infusion was
not
compromised by nonspecific inactive lever pressing.
Example 7: Effect of low dose of noribogaine on smoking cessation in humans
106791 A female habitual smoker intranasally absorbed a nanogram amount of
noribogaine hydrochloride. During a period of several hours, any craving to
smoke
stopped and only resumed afterwards. The patient was unaware during that
period of any
nicotine or smoking cravings.
Example 8: Effect of noribogaine on withdrawal from alcohol in humans
[0680] Six patients are orally administered a single dose of 2 mg/kg
noribogaine, and
three patients receive placebo in a randomized, placebo-controlled, double-
blind trial. All
patients are dependent on alcohol. Treatment is administered at least 2 hours
after last
alcohol use. Patients receiving noribogaine exhibit fewer and/or less severe
symptoms of
alcohol withdrawal compared to those receiving placebo, as determined by self-
evaluation
(e.g., questionnaires) and clinical observation.
Example 9: Efficacy of Noribogaine in Treating Substance Dependency
[0681] The efficacy of noribogaine is evaluated in substance-dependent
participants in a
randomized, placebo-controlled, double-blind trial. Patients are administered
60 mg or
120 mg of the compound and QT interval is measured.
Example 10: Effect of noribogaine on treatment of pain in humans
[0682] A female patient, age 57, with chronic back pain, is treated with
noribogaine
hydrochloride at a dose of about 2 mg/kg. Her pain is attenuated, as
determined by self-
evaluation and clinical evaluation.
Example 11: Effect of noribogaine on chronic migraine in humans
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[0683] A female patient, age 25, with recurrent migraine headaches not
attributable to
withdrawal from opioids, is treated with noribogaine hydrochloride at a dose
of about 1.5
mg/kg. During a period of several hours, her migraine symptoms are attenuated,
as
determined by self-evaluation and clinical evaluation.
Example 12. Forced Swim Test (FST) With Rats
[0684] Animals: Male Sprague-Dawley rats (Taconic Farms, N.Y.) are used in all

experiments. Rats are housed 5 per cage and maintained on a 12:12-h light-dark
cycle.
Rats are handled for 1 minute each day for 4 days prior to behavioral testing.
[0685] Drug Administration: Animals are randomly assigned to receive a single
intraperitoneal administration of vehicle (2.5% Et0H/2.5% Tween-80),
imipramine
(positive control; 60 mg/kg), or Test Compound 60 minutes before the start of
the 5
minute test period. All injections are given using 1 cc tuberculin syringe
with 26 3/8 gauge
needles (Becton-Dickinson, VWR Scientific, Bridgeport, N.J.). The volume of
injection is
1 ml/kg.
[0686] Experimental Design: The procedure used in this study employs a water
depth of
31 cm. The greater depth in this test prevents the rats from supporting
themselves by
touching the bottom of the cylinder with their feet. Swim sessions are
conducted by
placing rats in individual plexiglass cylinders (46 cm tall and 20 cm
diameter) containing
23-25 C water. Swim tests are conducted always between 9:00 and 17:00 hours
and
included an initial 15-minute conditioning test followed 24 hours later by a 5-
minute test.
Drug treatments are administered 60 minutes before the 5-minute test period.
Following
all swim sessions, rats are removed from the cylinders, dried with paper
towels and placed
in a heated cage for 15 minutes and returned to their home cages. All test
sessions are
videotaped using a color video camera and recorded for scoring later.
[0687] Behavioral Scoring: The rat's behavior is rated at 5 second intervals
during the 5
minute test by a single individual, who is blind to the treatment condition.
Scored
behaviors are: 1. Immobility--rat remains floating in the water without
struggling and is
only making those movements necessary to keep its head above water; 2.
Climbing--rat is
making active movements with its forepaws in and out of the water, usually
directed
against the walls; 3. Swimming--rat is making active swimming motions, more
than
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necessary to merely maintain its head above water, e.g. moving around in the
cylinder; and
4. Diving--entire body of the rat is submerged.
[0688] Data Analysis: The forced swim test data (immobility, swimming,
climbing,
diving) are subjected to a randomized, one-way AND VA and post hoc tests
conducted
using the Newman-Keuls test. The data are analyzed using the GraphPad Prism
(v2.01)
(GraphPad Software, Inc., San Diego, Calif.).
Example 13. Forced Swim Test (FST) With Mice
[0689] Animals: DBA/2 mice (Taconic Farms, N.Y.) are used in all experiments.
Animals are housed 5 per cage in a controlled environment under a 12:12 hour
light:dark
cycle. Animals are handled 1 min each day for 4 days prior to the experiment.
This
procedure includes a mock gavage with a 1.5 inch feeding tube.
[0690] Drug Administration: Animals are randomly assigned to receive a single
administration of vehicle (5% Et0H/5% Tween-80), Test Compound, or imipramine
(60
mg/kg) by oral gavage 1 hour before the swim test.
[0691] Experimental Design: The procedure for the forced swim test in the
mouse is
similar to that described above for the rat, with the following modifications.
The cylinder
used for the test is a 1 liter beaker (10.5 cm diameter and 15 cm height)
filled to 800 ml
(10 cm depth) with 23 25 C. water. Only one 5-minute swim test is conducted
for each
mouse, between 13:00 and 17:00 hours. Drug treatments are administered 30-60
minutes
before the 5-minute test period. Following all swim sessions, mice are removed
from the
cylinders, dried with paper towels and placed in a heated cage for 15 minutes.
All test
sessions are videotaped using a Sony color video camera and recorder for
scoring later.
[0692] Behavioral Scoring: The behavior during minutes 2-5 of the test is
played back
on a TV monitor and scored by the investigator. The total time spent immobile
(animal
floating with only minimal movements to remain afloat) and mobile (swimming
and
movements beyond those required to remain afloat) are recorded.
[0693] Data Analysis: The forced swim test data (time exhibiting immobility,
mobility;
seconds) are subjected to a randomized, one-way AND VA and post hoc tests
conducted
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using the Newman-Keuls test. The data are analyzed using the GraphPad Prism
(v2.01)
(GraphPad Software, Inc., San Diego, Calif.).
Example 14: Single dose toxicity in rats
[0694] The objective of this study was to determine the toxicity and
toxicokinetic profile
of noribogaine HC1 following a single oral (gavage) administration in the
Sprague-Dawley
rat. A single dose of 100, 300 and 800 mg/kg (achieved with doses of 400 mg/kg
3 h +/-
30 min apart because of the limitations of maximum dose formulation
concentration). Five
male rats/group were used. Mortality occurred in all male rats in the 800
mg/kg group,
approximately 2-3 h after administration of the second dose of 400 mg/kg.
Hypoactivity,
vocalization, chewing movements, changes in respiration/posture, salivation,
stimuli
sensitivity, tremors, twitches and penile erection occurred prior to death.
Hypoactivity,
vocalization, salivation, stimuli sensitivity, loss of limb function and lying
on the cage
floor occurred on the day of treatment and persisted until Day 2 in 3/5 rats
given 300
mg/kg. The low dose rats treated at 100 mg/kg did not show any treatment
related signs.
The no observed adverse effect level (NOAEL) was determined to be 100 mg/kg.
Example 15: Single dose toxicity in dogs
[0695] In an acute oral toxicity/TK study in dogs, no mortality occurred at
doses of 5
(n=2) or 10 (n=2) mg/kg. Convulsions and other CNS-related clinical signs,
including
twitches, salivation, vocalization, incoordination and hypoactivity, occurred
at a dose of
mg/kg, beginning 20 minutes after dosing and persisting until 3h 40m post-
dose. The 5
mg/kg dose was considered the NOAEL, as only transient reduction in food
consumption
in one dog occurred at that dose.
Example 16: Single dose toxicity in Cynomolgus Monkeys
[0696] The objective of the study was to determine the toxicity and
toxicokinetic profile
of noribogaine following oral (gavage) administration to the cynomolgus
monkey. Each
dose was followed by a 7 day washout period. Dosing was staggered by 45
minutes. On
study day 15, one animal was administered 80 mg/kg and the other animal was
administered 160 mg/kg. The test article was administered as follows in Table
7:
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Table7. Toxicity and Toxicokinetic Study in Cynomolgus monkeys
Treatment on Study Day Dose Level (mg/kg) Number of Animals
1 20 2 males
8 40 2 males
15 80 and 160 2 males
[0697] Parameters monitored on the study included: mortality, clinical signs
and body
weights. Blood samples were collected for TK evaluation. No mortality or
treatment
related clinical signs were noted for doses up to and including 160 mg/kg, The
single dose
maximum tolerated dose (MTD) was determined to be greater than 160 mg/kg based
on
the parameters monitored during the study.
Example 17: Fourteen day repeat dose toxicity and toxicokinetics in rats
[0698] This study was conducted to evaluate the toxicity profile of
noribogaine-HCl
following oral (gavage) administration to the rat for 14 days following Table
8 below:
Table 8. Toxicity and Toxicokinetic Study in Rats
Group Dose Level = Dose: m Toxicology
Animali'''Toxiciikineticisl
(mg/kg/day Concentration Main Recovery Animals = :11
(Mg/mL) Mal
Femal Mal Femal Male Female
;,=0 .
= =
e e eii]]i]]: ;.]:0
===== = =]=]=]= :
I
Control 0 0 10 10 5 5 3 3
Low 25 5 10 10 6 6
Dose
Mid Dose 50 10 10 10 6 6
High 100 20 10 10 5 5 6 6
Dose
[0699] Male and female Sprague-Dawley rats, 10/sex/group, were administered 0,
25, 50
or 100 mg/kg notibogaine HC1 daily by single oral gavage for 14 days. An
additional 5
rats/sex/group in the 0 (control) and 100 mg/kg groups were retained for a 28
day recovery
period during which no drug was administered. Six rats/sex/group (3 rats/sex
controls)
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were similarly dosed and sampled on study days 1 and 14 for analysis of
noribogaine-HCl
concentrations in the blood. Rats were observed for mortality, clinical signs,
body weight,
food consumption, ophthalmology (pre-dose, during week 2, and at the end of
recovery),
hematology, coagulation, clinical chemistry, urinalysis, gross necropsy, organ
weights and
histopathology (full tissue panel, plus immunocytochemistry of 5 sections of
the brain and
spinal cord by staining for GFAP and Calbindin). There were no test article-
related effects
on mortality (none occurred), clinical signs, ophthalmoscopy, hematology,
coagulation
parameters, clinical chemistry, urinalysis, gross necropsy or histopathology.
Food
consumption and body weight were slightly reduced (food consumption: -4.7% in
males
and females; body weight: -5.5% in males and -2.6% in females) in the high
dose (100
mg/kg) groups. Minor increases in liver weight in the mid- and high dose
groups were not
correlated with histopathologic changes and are considered incidental. No
treatment-
related differences in the brain were seen in sections stained for GFAP or
Calbindin.
[0700] The NOAEL dose in this study was interpreted to be 100 mg/kg, the
highest dose
tested in the study.
Example 18: Fourteen day repeat dose toxicity and toxicokinetics in dogs
[0701] The objective of this study was to determine the toxicity profile of
noribogaine
HCl given following oral (gavage) administration to dogs for 14 days according
to the
following Table 9 below:
Table 19. Toxicity and Toxicokinetic Study in Dogs
Group Dose Level r = :::;::1777377
Dose I oxicology Animals :
Concentration Main Recovery
Designation (mg/kg/day)
(mg/mL) Male Female
Male Female
Control 0 0 4 4 4 4
Low Dose 0.5 0.1 4 4
Mid Dose 1.0 0.2 4 4
High Dose 5.0 1.0 4 4 4 4
[0702] Noribogaine HC1 was administered to groups of 4 male and 4 female dogs
by
single oral gavage daily for 14 days at doses of 0, 0.5, 1.0 and 5.0
mg/kg/day. An
additional group of 4 male and 4 female dogs received either the vehicle
control or 5.0
mg/kg/day for 14 days and were held for an additional 28 days after cessation
of dosing to
assess recovery from any potential drug-induced changes. The study was
conducted under
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GLP guidelines and included comprehensive examinations of clinical signs, body
weight,
clinical pathology parameters, ophthalmologic examinations, ECG recordings and

analyses of plasma for bioanalytical measurement of drug levels at appropriate
intervals
during the study. At the termination of the dosing phase and at the
termination of the
recovery phase, all dogs were subjected to a complete post-mortem examination
including
gross examination of major organs and histologic examination of an extensive
list of
tissues. Additional sections of brain were obtained from cerebrum, cerebellus,
brain stem
and spinal cord and examined histologically to evaluate potential effects on
brain
histopathology. In addition, these sections were examined with
immunohistochemical
stains for GFAP for evidence of gliosis and Calbindin for a more comprehensive

examination of cerebellar Purkinje cells. No evidence of adverse effect was
observed in
any dog from any treatment group during the dosing or recovery phase in
clinical
observations, body weights, clinical pathological parameters, ophthalmologic
examinations, ECG recordings, or gross lesions at necropsy. The results of the
plasma
drug level measurements at Day 1 and Day 14 of the study are shown in the
Table below.
Noribogaine-HC1 maximum plasma concentrations (C.) were reached between 0.5
and
0.9 hours post-dosing, following which plasma concentrations gradually
decreased over a
period of up to 24 hours, except in the male dogs and female dogs of Group 4,
for which
significant levels of noribogaine were still detected at 24 h post-dosing on
both Days 1 and
14.
[0703] The only target tissue identified in this study was the lacrimal gland
of dogs
receiving 5 mg/kg/day. The lacrimal gland changes were characterized by slight
to
moderate atrophy and degeneration of the acinar cells accompanied by slight to
moderate
accumulation of brown/yellow pigment and infiltration of mononuclear cells.
There was
an associated mononuclear infiltration in the draining mandibular lymph nodes
of affected
dogs in this dose group. Despite the appearance of isolated ocular
abnormalities in several
dogs in this high dose group on ophthalmologic examination, there was no clear

association between these ocular signs and the appearance of the lacrimal
gland changes
suggesting that these morphologic changes did not result in sufficient
functional
abnormality of the gland to produce physical changes in exterior structures of
the eye.
There was no clear evidence of local irritation associated with drug treatment
in these high
dose dogs. No evidence of drug-induced effect was observed in any other tissue
including
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the extensive sections of brain evaluated with conventional histopathology or
with
immunohistochemistry. Examination of the animals in the recovery group showed
clear
evidence of regeneration of this lacrimal gland change. While slight atrophy
was still
evident in the acinar cells of the gland after 28 days off drug, no evidence
of continuing
and ongoing degeneration or cellular infiltration was observed. The NOAEL in
this study
was 1 mg/kg/day based on the lacrimal gland changes at 5 mg/kg/day. The
results are
summarized in Tables 10 and 11.
Table 10. Mean plasma toxicokinetic parameters for noribogaine in male dogs on

days 1 and 14
Gr 2 - 0.5 mg/kg ' Gr 1.0 mg/kg Cr 4 - 5.0 mg/kg1
'Parameters
DI 014 D1 014 DI 014
T112(h) 1.3 r 1.3 1.2 1.8 4.7 6.5
Tina, (h) 0.7 0.7 0.9 0.8 0.6 0.9
Cmax (ng/ml) 28.8 29.4 58.6 67.6 693 716
AITCI)-iust (heng/m1) 46.6 53.2 102.5 172.3 3515.0
6403.3
A LTC4}-24h (hr*ng/m1) 59.7 64.5 119.8 210.4 3515.0
6403.3
õ õ
AUCO
(heng/m1) 67.8 68.2 120.8 195.7 3630.5 6961.4
Table 11. Mean plasma toxicokinetic parameters for noribogaine in female dogs
on
days 1 and 14
.; .
Cr - 0.5 mg/kg Gr 3 - 1.0 mg/kg Cr 4 - 5.0 mg/kg
Parameters
D1 D14 D1 014 DI D14
Tit(hr) 1.0 1.1 1.4 1.6 4.3 5.7
Tmax(hr) 0.5 1.0 0.8 0.5 0.6 0.6
CillaN (ng/m11) 25.3 29.8 68.5 74.1 691 683
AUCti-inst (heng/m1) 31.5 35.4 148.9 169.0 3367.9
5951.2
AUC4)-241, (hr*ng/m1) 40.4 55.0 176.2 203.7 3367.9
5951.2
(hr*ng/m1) 44.9 45.7 165.3 197.0 3425.7 6283.2
Example 19. Effect of noribogaine on depression in humans
[0704] A male patient, age 55, suffering from depression unrelated to the use
of any
illicit substance, is treated with noribogaine hydrochloride at a dose of
about 1 mg/kg/day
for a period of four weeks. During the treatment period, his depression change
in
symptoms and/or changes in one or more of the following tests: HDRS, Hamilton
depressed mood item, and CGI-Severity of Illness are determined.
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Example 20. Social Interaction Test (SIT)
[0705] Animals: Male albino Sprague-Dawley rats (Taconic Farms, N.Y.) are
housed in
pairs under a 12 hr light dark cycle (lights on at 0700 hrs.) with free access
to food and
water.
[0706] Rats are allowed to acclimate to the animal care facility for 5 days
and are housed
singly for 5 days prior to testing. Animals are handled for 5 minutes per day.
On the test
day, weight matched pairs of rats ( 5%), unfamiliar to each other, are given
identical
treatments and returned to their home cages. Animals are randomly divided into
5
treatment groups, with 5 pairs per group, and are given one of the following
i.p.
treatments: Test Compound (1, 2 or 4 mg/kg), vehicle (1 ml/kg) or
chlordiazepoxide (5
mg/kg). Dosing is done 1 hour prior to testing. Rats are subsequently placed
in a white
perspex test box or arena (54x37x26 cm), whose floor is divided up into 24
equal squares,
for 15 minutes. An air conditioner is used to generate background noise and to
keep the
room at approximately 74 F. All sessions are videotaped using a JVC camcorder
(model
GR-SZ1, Elmwood Park, N.J.) with either TDK (HG ultimate brand) or Sony 30
minute
videocassettes. All sessions are conducted between 13:00 and 16:30 hours.
Active social
interaction, defined as grooming, sniffing, biting, boxing, wrestling,
following and
crawling over or under, is scored using a stopwatch (Sportsline model no. 226,
1/100 sec.
discriminability). The number of episodes of rearing (animal completely raises
up its body
on its hind limbs), grooming (licking, biting, scratching of body), and face
ishing (i.e.
hands are moved repeatedly over face), and number of squares crossed are
scored. Passive
social interaction (animals are lying beside or on top of each other) is not
scored. All
behaviors are assessed later by an observer who is blind as to the treatment
of each pair.
At the end of each test, the box is thoroughly wiped with moistened paper
towels.
[0707] Data Analysis: The social interaction data (time interacting, rearing
and squares
crossed) are subjected to a randomized, one-way ANOVA and post hoc tests
conducted
using the Student-Newman-Keuls test. The data are subjected to a test of
normality
(Shapiro-Wilk test). The data are analyzed using the GBSTAT program, version
6.5
(Dynamics Microsystems, Inc., Silver Spring, Md., 1997).
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Example 21: Effect of noribogaine on food consumption
[0708] The effects of noribogaine and varenicline on food consumption in food
maintained responding rats are shown in Figure 10A. Repeated measure ANOVA
found a
significant main effect of treatment [F(5,33)=16.905, P<0.001]. Post hoc
comparisons
indicated that compared to vehicle treatment, noribogaine (25 and 50 mg/kg)
significantly
decreased food consumption (P<0.05 and P<0.001, respectively). Noribogaine
(12.5
mg/kg) and varenicline (1.7 mg/kg) had no significant effect on this measure.
[0709] The effects of noribogaine and varenicline on inactive lever response
in food
maintained responding rats are shown in Figure 10B. Repeated measure ANOVA
found a
significant main effect of treatment [F(5,31)¨ 7.583, P<0.001]. This main
effect is solely
contributed by high dose noribogaine (50 mg/kg), as shown in post hoc
comparisons
(P<0.001 compared to vehicle treatment.) This result suggests that for high
frequency
lever-pressing in food test the high dose of noribogaine (50 mg/kg) may cause
some
behavioral disturbance.
[0710] At 12.5 mg/kg, noribogaine showed no effect on food consumption. At 25
mg/kg, noribogaine decreased food intake by 10% (P<0.05). At 50 mg/kg,
noribogaine
decreased food intake by 25% (P<0.001). In general, the inactive lever
responding
percentage was very low during food consumption test under all treatments.
Example 22: Single dose toxicity in rats
[0711] The objective of this study was to determine the toxicity and
toxicokinetic profile
of noribogaine HC1 following a single oral (gavage) administration in the
Sprague-Dawley
rat. A single dose of 100, 300 and 800 mg/kg (achieved with doses of 400 mg/kg
3 h +/-
30 min apart because of the limitations of maximum dose formulation
concentration). Five
male rats/group were used. Mortality occurred in all male rats in the 800
mg/kg group,
approximately 2-3 h after administration of the second dose of 400 mg/kg.
Hypoactivity,
vocalization, chewing movements, changes in respiration/posture, salivation,
stimuli
sensitivity, tremors, twitches and penile erection occurred prior to death.
Hypoactivity,
vocalization, salivation, stimuli sensitivity, loss of limb function and lying
on the cage
floor occurred on the day of treatment and persisted until Day 2 in 3/5 rats
given 300
mg/kg. The low dose rats treated at 100 mg/kg did not show any treatment
related signs.
The NOAEL was determined to be 100 mg/kg.
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Example 23. Effect of noribogaine on anxiety disorder in humans
[0712] A male patient, age 45, suffering from generalized anxiety disorder
unrelated to
the use of any illicit substance, is treated with noribogaine hydrochloride at
a dose of
about 1 mg/kg/day for a period of four weeks. His generalized anxiety level is
determined
by the patient's self-reporting of attenuation of at least one of the
following symptoms:
restlessness or feeling keyed up or on edge, being easily fatigued, difficulty
concentrating
or mind going blank, irritability, muscle tension, and sleep disturbance.
Example 24. Effect of noribogaine on nicotine withdrawal in zebrafish
expressed by
anxiety-related endpoints
Animals
[0713] A total of 60 adult wild type short-fin zebrafish (-50:50 male:female
ratio)
were used in this study. Fish were housed in groups of 20-30 fish per 40-L
tank.
Tanks were filled with filtered water and maintained at 25 C. Illumination
(1000-
1100 lx) was provided by ceiling-mounted fluorescent lights on a 12-h cycle
(on: 6.00
h, off: 18.00 h) according to the standards of zebrafish care. All fish used
in this study
were experimentally naive and fed Tetramin Tropical Flakes (Tetra USA,
Blacksburg,
VA) twice a day. Following behavioral testing, the animals were euthanized in
500 mg/L Tricaine (Sigma¨Aldrich, St. Louis, MO) buffered to pH = 7Ø Animal
experimentation in this study fully adhered to national and institutional
guidelines and
regulations.
Test compounds
[0714] A 1 mg/L dose of noribogaine (DMX1) was chosen based on pilot
experiments and literature reports on effective doses other similar compounds.
A pilot
experiment revealed sub-maximal efficacy of noribogaine at 1 mg/L, a dose that
did not
promote any locomotors effects susceptible to be confounded with efficacy
endpoints
of interest in other protocols. A standard 20-mM pre-treatment time was chosen

based on experience with a wide range of other neuroactive compounds and the
results of pilot studies. This exposure time was also sufficient for provoking

physiological (e.g., cortisol and c-fos) responses of zebrafish to multiple
drugs. Drug
exposure in this study was performed by submerging individual zebrafish in a 1-
L
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plastic beaker for 20 mm prior to the testing. The solution was regularly
changed after
each exposure, to ensure that each fish is exposed to a consistent
concentration of
noribogaine. Control fish were exposed to noribogaine-free water for the same
treatment time, as described above.
Tests and Procedures
[0715] Apparatus: Behavioral testing was performed between 11:00 and 15:00 h
using tanks with water adjusted to the holding room temperature (25 C). The
study
used the novel tank test (NTT) protocol. NTT represents one of the most
commonly
used neurophenotyping tests for adult zebrafish. To avoid the test battery or
handling
effects, each assay was performed once, on a separate individual naïve fish
each time.
Prior to testing, fish were pre-exposed individually in a 1-L plastic beaker
for 20 mm to
either drug- treated or drug-free water. During testing, zebrafish behavior
was
recorded by two trained observers blind to the treatments, who manually scored

different behavioral endpoints (inter- and intra-rater reliability in all
experiments
>0.85) with subsequent automated analysis of generated traces by Ethovision
XT8.5
software (Noldus IT, Wageningen, Netherlands). The NTT, used to assess
zebrafish
anxiety and locomotion, was a 1.5-L trapezoidal tank (15 cm height x 28 cm top
x
23 cm bottom x 7 cm width; Aquatic Habitats, Apopka, FL) maximally filled with

water and divided into two equal virtual horizontal portions by a line marking
the
outside walls. Fish were individually pre-exposed to water (water control),
chronic
nicotine (1 mg/L), repeated withdrawal from chronic nicotine (WD), and
repeated
withdrawal plus noribogaine (1 mg/L) for 20 min and tested in the standard 5-
mM NTT.
[0716] Behavioral analyses: Zebrafish behavior was recorded by trained
observers,
scoring the latency to reach the top half of the tank(s), time spent in
top(s), number of
transitions to top, as well as the number and duration(s) of freezing bouts.
Freezing
was defined as a total absence of movement, except for the gills and eyes, for
>2 s.
Trials were also recorded to a computer using a USB webcam (2.0-megapixel,
Gigaware, UK) and subsequently analyzed by Ethovision XT8.5, assessing
distance
traveled (m), velocity (m/s), and meandering endpoints. During manual
observation,
videos were recorded in MPEG1 format with the maximum sample rate 30 fps for
each trial by auto-focusing 2.0 MP USB webcams, placed 25 cm in front of the
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tanks, and attached to laptop computers. Recorded videos were analyzed with
Ethovision XT8.5 software. All environments were calibrated for each arena and
the
calibration axes were placed to designate the origin (0,0) at the center of
each tank. The
exported traces were independently evaluated on a consensus basis by two
trained
observers blinded to the treatments, to illustrate the spatial pattern of
zebrafish
swimming.
[0717] Study Design and Data Analysis: The study exposed adult zebrafish
individually (15 animals per group) to water control, chronic nicotine,
repeated
nicotine withdrawal, and nicotine withdrawal + 1 mg/L noribogaine acutely (for
20
min) by water immersion, following testing in NTT for 5 min, prior to
euthanizing the
fish. Raw data from manual and automatic endpoints were analyzed using
GraphPad
Prism to generate graphics and descriptive statistics, for manual and computer-
generated
endpoints. D'Agostino & Pearson omnibus normality K2 test was performed on
data
groups. When control group passed normality test, data groups were analyzed by
the
Bennett's test or Boniferroni all paired-wise comparisons test (ANOVA). When
data
were not following Gaussian distribution or were non-suitable for previously
described
statistical approach, sub-grouping and/or ranking was performed, data were
treated in a
differential manner to allow sub-groups and/or categorical comparison. The
accepted
value for significance was P<0.05 and higher significance was indicated where
it
applied. For illustration purposes, data analyzed by parametric statistics
were
represented as mean SEM, while non-parametric data were represented as
scattered
points or categorical sub-grouping.
Results
[0718] The effects of noribogaine on zebrafish behavior are shown in Figure
11, panels
A-G, and Figure 12, panels A-G. Zebrafish in the chronic nicotine (Chr Nic)
and nicotine
withdrawal (Nic WD) groups showed increased latency to top(s), while zebrafish
in the
withdrawal + 1 mg/L noribogaine (Nic WD-DMX1) group showed a statistically
significant decrease. Figure 11, panel A. Zebrafish in the chronic nicotine
(Chr Nic) and
nicotine withdrawal (Nic WD) groups also showed decreased transitions to top,
while
zebrafish in the withdrawal + 1 mg/L noribogaine (Nic WD-DMX1) group showed a
statistically significant increase. Figure 11, panel B. In addition, zebrafish
in the chronic
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nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups exhibited normal
habituation
patterns, while zebrafish in the withdrawal + 1 mg/L noribogaine (Nic WD-DMX1)
group
reached values equivalent to the control group at 5 minutes. Figure 11, panel
C.
Statistically significant increases in the duration of time spent in the
top(s) portion of the
tank was exhibited by zebrafish in the withdrawal + 1 mg/L noribogaine (Nic WD-
DMX1)
group as compared to the control, chronic nicotine (Chr Nic) and nicotine
withdrawal (Nic
WD) groups. Figure 11, panel D. Furthermore, zebrafish in the withdrawal + 1
mg/L
noribogaine (Nic WD-DMX1) group exhibited statistically significant increases
in the
duration of time spent in and average entry duration in the top(s) portion of
the tank as
compared to the control, chronic nicotine (Chr Nic) and nicotine withdrawal
(Nic WD)
groups. Figure 11, panels E and F. Fish treated with noribogaine spent an
average of more
time in each of their travels to the top, suggesting a likely anxiolytic-like
effect of
noribogaine. Fish treated with noribogaine also exhibited an increased average
entry
duration as compared to the control, chronic nicotine (Chr Nic) and nicotine
withdrawal
(Nic WD) groups. Figure 11, panel G.
[0719] Total distance traveled in the tank was measured and zebrafish in the
nictotine
withdrawal group exhibited an increased anxiety-like response which was
corrected by
treatment with noribogaine (Figure 12, panel A). Average velocity of zebrafish
was also
corrected by noribogaine treatment (Figure 12, panel B). There was no
difference
observed in the absolute change in direction of zebrafish in any of the test
group (Figure
12, panel C). In addition, zebrafish receiving noribogaine treatment exhibited
a slight
increase in turning rotation rate over both chronic nicotine and nicotine
withdrawal groups
(Figure 12, panel D). On the other hand, no change was seen in the relative
change in
direction between any of the groups or absolute change in direction of
movement per
distance moved (Figure 12, panels E and F). Reduced absolute change in
direction of
movement per distance moved observed in the nicotine withdrawal group was
corrected by
treatment with noribogaine. (Figure 12, panel G). These results suggest
anxiolytic-like
anti-withdrawal effects of noribogaine treatment.
[0720] Anxiety/fear responses were also tested by recording freezing bout
frequency and
freezing duration. Figure 13. More freezing bouts and longer freezing duration
indicate
elevated anxiety and/or fear. Noribogaine treatment (Nic WD + Cpd 1 mg/L) re-
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established the high bouts due to nicotine withdrawal toward control levels
(panel A) and
duration of freezing (panels B and C).
[0721] Effect of noribogaine treatment on movement mobility was also detected.
Figure
14. The labele "immobile" was used to express the frequency of episodes with
dress of
movement independent of spatial displacement (duration of immobility). The
label
"mobile" reflects overall locomotor activity. The label "Hi-mobile" reflects
bouts of
accelerated swimming (>60 % of individual average). A strong decrease in
immobile,
mobile, and high mobile events was observed in nicotine withdrawal zebrafish,
while
noribogaine-treated zebrafish exhibited an increase in high-mobility number of
events.
(Figure 14, panel A). In addition, nicotine withdrawal specifically decreased
mobility of
fish and increased immobility. Chronic nicotine treated fish showed a moderate
increase of
mobility and moderate decrease in immobility durations, while noribogaine-
treated fish
showed control-equivalent values for mobility and immobilitiy endpoints and
displayed a
slight increase of high-mobile activity. (Figure 14, panel B).
Discussion
[0722] Analyses of manual NTT endpoints indicate statistically significant
anxiolytic-like effects of noribogaine at 1 mg/L, as assessed by shorter
latency to
enter the top from control and longer time spent by noribogaine-treated fish
in the
more aversive top (vs. more 'protective' bottom) compartment of the test
(Figure 11,
panels A and D). The number of transitions from top to bottom (top entries)
also
differed at 1 mg/L noribogaine in nicotine withdrawal fish, suggesting general

activation of exploration as this dose. (Figure 11, panel B). Freezing bouts'
frequency
and duration were increased in chronic nicotine and especially nicotine
withdrawal
fish. Noribogaine at 1 mg/L reversed that effect in nicotine withdrawal fish
and re-
established levels to that of the control fish group. (Figure 13) All fish
showed normal
habituation responses, as assessed by the per-minute distribution of swimming
activity in all manual parameters, generally confirming the lack of behavioral

anomalies in the applied testing conditions, which were standard and
consistent with
other published NTT studies. Analyses of computer-generated NTT endpoints
reveal
a consistent pattern of unaltered motor activity (assessed by distance
traveled and
velocity measures) at 1 mg/L noribogaine, but reduced activity in WD group.
(Figure
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12, panels A and B). Heading (movement directionality index) and mean
meandering
(straightness index) were similar in all groups. (Figure 12, panels E and F).
[0723] Erratic movements in this study were automatically measured using the
frequency of high-mobility episodes. These endpoints are generally
characteristic of
higher anxiety states, but may be seen when reaching characteristic states of
altered
perception (e.g., hallucinogenic drugs). In this experiment there was no
changes seen
for chronic nicotine and nicotine withdrawal treatment. (Figure 14). An
increase of hi-
mobility duration and frequency (by a factor of ¨2) was observed in the
noribogaine-
treated fish in the nicotine withdrawal state. Noriobgaine did not evoke
circling
behavior (note unaltered turn angle as well), which would have been common for
anti-
glutaminergic drugs given acutely. Movement mobility (mobility frequency) and
mobility duration, whose endpoints were reflecting general locomotor activity
and
anxiogenic treatments, showed significant effects of chronic nicotine,
nicotine
withdrawal and noribogaine treatment. (Figure 14). Hypo-locomotive effects of
nicotine withdrawal were observed (as seen in both in duration and frequency
of
mobility endpoints, as well as in distance moved and velocity endpoints).
(Figure
14). Moderate hyper-locomotive effects of chronic nicotine (as in literature)
was
observed. (Figure 14). Noribogaine at 1 mg/L reestablished mobility (mobile
and
immobile) durations and frequency in nicotine treated fish to control values
suggesting noribogaine is able to rescue locomotor effects of nicotine
withdrawal state.
(Figure 14).
Conclusion
[0724] Noribogaine treatment can reverse the effects of nicotine withdrawal,
particularly both anxiogenia and hypolocomotion induced by nicotine
withdrawal. The 1
mg/L dose of acute noribogaine evoked a robust anxiolytic-like behavior
without any
overt hyperactivity/hypoactivity in comparison to control in the repeated
nicotine
withdrawal zebrafish model. Chronic nicotine, and especially repeated WD,
evoke
anxiogenic-like and locomotor effects in zebrafish, consistent with zebrafish
and
rodent literature. Anxiogenic-like and locomotor effects of repeated nicotine
withdrawal were fully reversed by noribogaine at dose 1 mg/L. Based on these
results,
beneficial activity of noribogaine in other behavioral paradigms is relevant
to nicotine
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abuse, as well as other drugs' abuse-related models, can be expected at a
potential
dose of 1 mg/L.
Example 25. Effect of noribogaine in zebrafish expressed by anxiety-related
endpoints
Animals
[0725] A total of 60 adult wild type short-fin zebrafish (-50:50 male:female
ratio)
were used in this study. Fish were housed in groups of 20-30 fish per 40-L
tank.
Tanks were filled with filtered water and maintained at 25 C. Illumination
(1000-
1100 lx) was provided by ceiling-mounted fluorescent lights on a 12-h cycle
(on: 6.00
h, off: 18.00 h) according to the standards of zebrafish care. All fish used
in this study
were experimentally naïve and fed Tetramin Tropical Flakes (Tetra USA,
Blacksburg,
VA) twice a day. Following behavioral testing, the animals were euthanized in
500 mg/L Tricaine (Sigma¨Aldrich, St. Louis, MO) buffered to pH = 7Ø Animal
experimentation in this study fully adhered to national and institutional
guidelines and
regulations.
Test compounds
[0726] Pilot experiments performed at 1-, 5- and 10-mg/mL revealed sub-maximal

efficacy of noribogaine at 1 mg/L, a dose that did not promote any locomotors
effects
susceptible to be confounded with efficacy endpoints of interest in other
protocols,
while the 5- and 10-mg/L doses caused reduction in selected swimming motor
activity
levels. As such, a 1 mg/L dose of noribogaine (DMX1 or Cpd) was chosen. A
standard
20-min pre-treatment time was chosen based on experience with a wide range of
other neuroactive compounds and the results of pilot studies. This exposure
time was
also sufficient for provoking physiological (e.g., cortisol and c-fos)
responses of
zebrafish to multiple drugs. Noribogaine exposure in this study was performed
by
submerging individual zebrafish in a 1-L plastic beaker for 20 min prior to
the testing.
The solution was regularly changed after each exposure, to ensure that each
fish is
exposed to a consistent concentration of noribogaine. Control fish were
exposed to
noribogaine-free water for the same treatment time, as described above.
Tests and Procedures
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[0727] Apparatus: Behavioral testing was performed between 11:00 and 15:00 h
using tanks with water adjusted to the holding room temperature (25 C). The
study
used the novel tank test (NTT) protocol. NTT represents one of the most
commonly
used neurophenotyping tests for adult zebrafish. To avoid the test battery or
handling
effects, each assay was performed once, on a separate individual naïve fish
each time.
Prior to testing, fish were pre-exposed individually in a 1-L plastic beaker
for 20 min to
either noribogaine-treated or noribogaine-free water. During testing,
zebrafish behavior
was recorded by two trained observers blind to the treatments, who manually
scored
different behavioral endpoints (inter- and intra-rater reliability in all
experiments
>0.85) with subsequent automated analysis of generated traces by Ethovision
XT8.5
software (Noldus IT, Wageningen, Netherlands). The NTT, used to assess
zebrafish
anxiety and locomotion, was a 1.5-L trapezoidal tank (15 cm height x 28 cm top
x
23 cm bottom x 7 cm width; Aquatic Habitats, Apopka, FL) maximally filled with

water and divided into two equal virtual horizontal portions by a line marking
the
outside walls. Fish were individually pre-exposed to water (water control) or
noribogaine (1, 5 and 10 mg/L) for 20 min and tested in the standard 5-min
NTT.
[0728] Behavioral analyses: Zebrafish behavior was recorded by trained
observers,
scoring the latency to reach the top half of the tank(s), time spent in
top(s), number of
transitions to top, as well as the number and duration(s) of freezing bouts.
Freezing
was defined as a total absence of movement, except for the gills and eyes, for
>2 s.
Trials were also recorded to a computer using a USB webcam (2.0-megapixel,
Gigaware, UK) and subsequently analyzed by Ethovision XT8.5, assessing
distance
traveled (m), velocity (m/s), and meandering endpoints. During manual
observation,
videos were recorded in MPEG1 format with the maximum sample rate 30 fps for
each trial by auto-focusing 2.0 MP USB webcams, placed 25 cm in front of the
tanks, and attached to laptop computers. Recorded videos were analyzed with
Ethovision XT8.5 software. All environments were calibrated for each arena and
the
calibration axes were placed to designate the origin (0,0) at the center of
each tank. The
track data for each fish was exported as raw data into separate
spreadsheets. The exported traces were independently evaluated on a consensus
basis
by two trained observers blinded to the treatments, to illustrate the spatial
pattern of
zebrafish swimming.
204
Date Recue/Date Received 2023-11-27

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