THERAPEUTIC USES OF IBOGAINE AND RELATED COMPOUNDS

UTILISATIONS THERAPEUTIQUES DE L'IBOGAINE ET COMPOSES ASSOCIES

English Abstract

This invention relates generally to methods and compositions related to
therapeutic uses
of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt
and/or solvate thereof.

Claims

What is claimed is:
1. A method for treating nicotine addiction in a patient in need thereof,
comprising
administering to the patient a therapeutically effective amount of ibogaine,
ibogaine
derivative, or a pharmaceutically acceptable salt and/or solvate thereof,
wherein said
therapeutically effective amount is from about 50 ng to less than 10 ptg per
kg body weight
per day.
2. The method of claim 1, wherein the therapeutically effective amount is
from about 50
ng to about 1 pig per kg body weight per day.
3. A method for treating alcohol dependence in a human patient suffering
therefrom,
comprising administering to the patient a dosage of ibogaine, ibogaine
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.
4. The method of claim 3, wherein the ibogaine, ibogaine derivative, or
pharmaceutically acceptable salt and/or solvate thereof is administered as a
single dose or
multiple doses.
5. The method of claim 4, wherein the aggregate dosage of ibogaine,
ibogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof is from
about 1.3
mg/kg to about 4 mg/kg per day.
6. 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 ibogaine, ibogaine 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.
7. The method of claim 6, wherein the withdrawal symptoms are due to acute
withdrawal.
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8. The method of claim 6, wherein the ibogaine, ibogaine derivative, or
pharmaceutically acceptable salt and/or solvate thereof is administered as a
single dose or
multiple doses.
9. The method of claim 6, wherein the aggregate dosage of ibogaine,
ibogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof is from
about 1.3
mg/kg to about 4 mg/kg per day.
10. 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 ibogaine, ibogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof, wherein the patient is no longer physically dependent on alcohol.
11. The method of claim 10, wherein 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.
12. A method for treating opioid or opioid-like drug abuse in a human
patient addicted
thereto, comprising administering to the patient a dosage of ibogaine wherein
the dosage
provides an average serum concentration of about 50 ng/mL to about 500 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, wherein the QT interval is less than about 450
ms.
14. 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 ibogaine 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.
15. A method to prevent relapse of opioid or opioid-like drug abuse in a
patient treated to
ameliorate said abuse, said method comprising periodically administering to
said patient a
maintenance dosage of ibogaine wherein the patient is no longer abusing the
opioid or opioid-
like drug.
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16. A method for treating opioid or opioid-like drug abuse in a patient
addicted thereto,
comprising selecting an addicted patient who is prescreened to evaluate
tolerance for
prolongation of QT interval, administering to the patient a dosage of ibogaine
that provides
an average serum concentration of about 50 ng/mL to about 500 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.
17. The method of claim 16, wherein the prescreening step comprises
ascertaining that
treatment with ibogaine, ibogaine derivative, or pharmaceutically acceptable
salt thereof will
not result in a QT interval greater than about 500 ms.
18. The method of claim 17, wherein the prescreening step comprises
ascertaining that
treatment with ibogaine will not result in a QT interval greater than about
470 ms.
19. The method of claim 17, wherein the prescreening step comprises
ascertaining that
treatment with ibogaine will not result in a QT interval greater than about
450 ms.
20. A method for treating substance abuse in a human patient addicted
thereto, comprising
administering to the patient a dosage of ibogaine, wherein the dosage provides
an average
serum concentration of about 50 ng/mL to about 500 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.
21. 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 ibogaine 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.
22. A method to prevent relapse of substance abuse in a patient treated to
ameliorate said
abuse, said method comprising periodically administering to said patient a
maintenance
dosage of ibogaine, wherein the patient is no longer abusing the substance.
23. The method of claim 22, wherein the dosage is less than about 70% of a
therapeutic
dose of ibogaine, and further wherein the prolongation of the QT interval is
no greater than
about 30 ms.
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24. The method of claim 22, 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 20 ms.
25. A method for treating substance abuse in a patient addicted thereto,
comprising
selecting an addicted patient who is prescreened to evaluate tolerance for
prolongation of QT
interval, administering to the patient a dosage of ibogaine that provides an
average serum
concentration of about 50 ng/mL to about 500 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.
26. The method of any one of claims 20-25, wherein the addictive substance
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.
27. A method for treating pain in a patient, comprising administering to
the patient a
dosage of ibogaine that provides an average serum concentration of about 50
ng/mL to about
500 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.
28. A method for alleviating pain symptoms in a human patient susceptible
to such
symptoms, comprising administering to the patient a dosage of ibogaine that
provides an
average serum concentration of about 50 ng/mL to about 400 ng/mL, said
concentration
being sufficient to alleviate said pain symptoms while maintaining a QT
interval of less than
about 500 ms during said treatment.
29. The method of claim 28, wherein the pain symptoms are due to chronic
pain.
30. 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
ibogaine, ibogaine 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 ibogaine or
ibogaine
derivative serum level of between about 50 ng/mL and about 400 ng/mL while
maintaining a
QT interval of less than about 500 ms during said treatment.
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31. 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 ibogaine, ibogaine 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
re-sensitize the patient to the opioid as an analgesic while maintaining a QT
interval of less
than about 500 ms during said treatment.
32. A method for treating an anxiety-related disorder in a patient in need
thereof,
comprising administering to the patient a therapeutically effective amount of
ibogaine,
ibogaine 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 ibogaine 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. The method of claim 32, wherein the anxiety-related disorder is
selected from the
group consisting of generalized anxiety disorder, panic disorder, obsessive-
compulsive
disorder, and social anxiety disorder.
34. A method for treating an impulse control disorder in a patient in need
thereof,
comprising administering to the patient a therapeutically effective amount of
ibogaine,
ibogaine 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 ibogaine 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. The method of claim 34, wherein 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,
kleptomania, sexual compulsion, paraphilia, intern& addiction,
trichotillomania, pathological
skin picking, and compulsive shopping.
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
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ibogaine, ibogaine 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 ibogaine
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
ibogaine,
ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate
thereof, and further
wherein the therapeutically effective amount provides an efficacious average
ibogaine 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.
38. A pharmaceutical composition comprising a therapeutically effective
amount of
ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or
solvate thereof and a
pharmaceutically acceptable excipient, wherein the therapeutically effective
amount of
ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or
solvate thereof is an
amount that delivers an aggregate amount of ibogaine of about 50 ng to less
than 10 jig per
kg body weight per day.
39. The pharmaceutical composition of claim 6, wherein the therapeutically
effective
amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt
thereof is an
amount that delivers an aggregate amount of ibogaine of about 50 ng to about 1
lug per kg
body weight per day.
40. A pharmaceutically acceptable formulation comprising a unit dose of
ibogaine
wherein the amount of ibogaine is sufficient to provide a serum concentration
of about 50
ng/mL to about 500 ng/mL when administered to a patient.
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Description

WO 2015/134405
PCT/US2015/018356
THERAPEUTIC USES OF IBOGAINE AND RELATED COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit from U.S. Provisional Application No.
61/952,724,
filed March 13, 2014, U.S. Provisional Application No. 61/952,725, filed March
13, 2014,
U.S. Provisional Application No. 61/947,397, filed March 3, 2014, U.S.
Provisional
Application No. 61/952,718, filed March 13, 2014, U.S. Provisional Application
No.
61/952,740, filed March 13, 2014, U.S. Provisional Application No. 61/952,736,
filed March
13, 2014, U.S. Provisional Application No. 61/952,743, filed March 13, 2014,
and U.S.
Provisional Application No. 62/049,968, filed September 12, 2014, each of
which is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates generally to the use of each of ibogaine, an
ibogaine
derivative, or a pharmaceutically acceptable salt and/or solvate thereof at a
dosage that
provides a therapeutic serum concentration for treating or preventing a
disease or disorder in
a patient.
STATE OF THE ART
Nicotine Addiction
[0003] 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.
[0004] More than 40 percent of existing smokers attempt to quit smoking
annually. Various
approved therapies (varenicline, bupropion, nicotine patch/gum, nicotine nasal
spray/inhaler,
hypnotherapy, biofeedback) have long been in clinical use to treat nicotine
dependence.
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Current therapies directed toward smoking cessation tend to focus on
counseling, behavioral
treatment such as hypnosis, and/or 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.
[0005] 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.
Alcohol Dependence
[0006] Alcohol dependence (also referred to alcohol abuse, alcohol addiction,
or
alcoholism) is a 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.
[0007] 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 (DTs),
hallucinations, shakes, and heart failure. Post-acute withdrawal can last
significantly longer,
with symptoms such as anxiety, depression, sleep disturbance, fatigue, and
tension being
common.
[0008] 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
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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.
Substance or Drug Addiction
[0009] Substance or drug addiction is a serious public health problem
throughout the world.
Heroin and other opioids, including prescription painkillers, are widely
abused and account
for a large percentage of illicit drug use. Opioid use is also linked to
approximately 50% of
violent crimes in the United States and costs the U.S. economy billions of
dollars per year.
As many as 23.5 million people in the US (almost 10%) have a drug or alcohol
abuse
problem, although only a small fraction of those receive treatment.
100101 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
attacks, strokes,
hallucinations and DTs. Withdrawal 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
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.
[0011] 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 or
methadone) and that the addict attend a clinic daily for an extended amount of
time. 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.
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Depression
[0012] 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.
[0013] Post-traumatic stress disorder (PTSD), as defined by DSM-III-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.
[0014] 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.
[0015] 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
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obesity, heart disease, and stroke. Similarly, 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.
[0016] 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 ibogaine 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.
Tolerance To Opioid Analgesics
[0017] Addictive opioid analgesic agents such as morphine are well-
characterized and
exceptionally potent analgesics. 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.
[0018] 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.
[0019] 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
depression, nausea,
sedation, euphoria or dysphoria, decreased gastrointestinal motility, and
itching.
[0020] It would be beneficial to provide a method for modulating opioid
analgesic tolerance
in a patient taking one or more opioid analgesics for the treatment of pain.
Impulse Control Disorder, Anxiety-Related Disorders, Violence And/Or Anger, Or

Regulating Food Intake
[0021] Obsessive compulsive disorder (OCD) is characterized by recurrent and
persistent
ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or
repetitive,
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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.
[0022] 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 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.
[0023] 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.
[0024] 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
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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).
[0025] 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.
[0026] 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.
[0027] 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.
[0028] Given the prevalence and impact of anxiety disorders, impulse control
disorder,
anger/violence-related disorders, and overweight/obesity, there is a need for
treatments that
address these issues. Prior to the embodiments described herein, the
therapeutic dosing of
ibogaine and its derivatives for treating anxiety disorders, impulse control
disorder,
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anger/violence-related disorders, or regulation of food intake 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 OF THE INVENTION
[0029] Ibogaine has been used as a botanical preparation from the root bark of
iboga
tabemathe for over 100 years both as a crude preparation and as semisynthetic
ibogaine,
which was marketed in France until about 1970. The therapeutic use of ibogaine
is limited
due to potentially adverse side effects. For example, ibogaine exhibits
undesirable stimulant
and hallucinogenic properties, and in addition, can induce tremors. At
conventional doses,
ibogaine causes adverse side effects in a majority of patients receiving
treatment.
[0030] In the United States, ibogaine is classified as a Schedule I controlled
substance. The
use of ibogaine 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, the ranges
generally
used to treat addiction (e.g., 15 mg/kg to 20 mg/kg) cause hallucinations and
may be fatal.
Lotsof and Wachtel, Manual for Ibogaine Therapy: Screening, Safety, Monitoring
&
Aftercare (2d revision, 2003), accessed at www.ibogaine.desk.nUmanual.html;
Hoelen, et al.
New Engl. J. Med. 360(3), 308 (2009), which is incorporated herein by
reference in its
entirety for all of its methods, compositions and teachings.
[0031] Further, prior to the embodiments described herein, the therapeutic
dosing of
ibogaine and its derivatives for treating opioid or opioid-like drug addiction
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. A prolonged
QT interval is a
marker of potential ventricular tachyarrhythmia which, and can result in
death. Serious
complications, including ventricular tachyarrhythmia and death, can result
from prolongation
of the treated patient's QT interval by ibogaine, rendering high doses of
ibogaine
unacceptable.
[0032] Heretofore, it was unclear whether a therapeutic dose of ibogaine could
be found
that resulted in QT interval prolongation within an acceptable range. It is
expected that other
compounds that share ibogaine's core structure will have a similar
prolongation effect on QT
interval. See, U.S. Provisional Patent Application No. 61/945,746 filed
February 27, 2014
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entitled METHOD FOR ACUTE AND LONG-TERM TREATMENT OF DRUG
ADDICTION.
Nicotine
[0033] This invention is based, in part, on the discovery that at very low
doses, direct blood
stream delivery of ibogaine will reduce the desire to smoke. Such dosing is
well below that
previously described. Direct blood stream delivery of ibogaine is contemplated
to enhance
the amount of ibogaine delivered to the brain, because ibogaine so
administered does not
initially pass through the liver before reaching the brain as it does when
ingested. Direct
blood stream delivery of ibogaine includes sublingual, pulmonary and
intranasal delivery
where the ibogaine is absorbed directly into the blood stream and then into
the brain. The
rapid delivery of ibogaine into the brain causes a significant reduction in
the craving to
smoke on a rapid basis, typically less than 15 minutes after administration.
The very low
doses and direct delivery from the blood stream to the brain is also
contemplated to avoid
significant QT prolongation or to keep the QT prolongation within the
acceptable range.
[0034] Ibogaine is believed to bind to several receptors in the brain,
including nicotinic
acetylcholine receptors (nAChRs) and opiod receptors (e.g., -opiod
receptors). Without
being bound by theory, it is believed that the nAChR has a greater binding
affinity for
ibogaine than other receptors in the brain. This allows treatment of nicotine
addiction ancUor
nicotine cravings using much lower doses of ibogaine than are currently used
for the
treatment of other conditions, such as opioid 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 ibogaine are required to treat or prevent nicotine cravings
in such situations
than would be required in a patient who is currently addicted to nicotine.
[0035] 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
ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or
solvate of each
thereof.
[0036] 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
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therapeutically effective amount of ibogaine, an ibogaine derivative, or a
pharmaceutically
acceptable salt ancUor solvate of each thereof. In one aspect, a
therapeutically effective
amount of ibogaine 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 ibogaine
or ibogaine
derivative is administered once a day, twice a day, or more than twice a day.
[0037] 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
ibogaine or an ibogaine derivative or pharmaceutically acceptable salt and/or
solvate thereof,
wherein the ibogaine or derivative or pharmaceutically acceptable salt and/or
solvate thereof
is administered by sublingual, intranasal, or intrapulmonary delivery.
[0038] In another aspect, relates to methods of preventing relapse of nicotine
use,
comprising administration of a prophylactic amount of ibogaine, an ibogaine
derivative, or a
pharmaceutically acceptable salt and/or solvate of each thereof to inhibit a
behavioral craving
for nicotine.
[0039] 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 ibogaine, an ibogaine derivative, or a
pharmaceutically
acceptable salt and/or solvate of each thereof. In one aspect, a
prophylactically effective
amount of ibogaine or derivative is from about 50 ng to less than 10 tg per kg
of body
weight. In some embodiments, the prophylactically effective amount of ibogaine
or ibogaine
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.
[0040] 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 ibogaine, an ibogaine derivative, or a
pharmaceutically
acceptable salt and/or solvate thereof, wherein the ibogaine, derivative, or
salt and/or solvate
thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
[0041] In one aspect, provided herein is a method for treating nicotine
addiction in a patient
in need thereof, comprising administering to the patient a therapeutically
effective amount of
ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or
solvate thereof,
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wherein said therapeutically effective amount is from about 50 ng to less than
10 jig per kg
body weight per day.
[0042] 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 ibogaine,
ibogaine
derivative, or pharmaceutically acceptable salt ancUor solvate 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.
[0043] In another 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 ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt
ancUor solvate
thereof, wherein said prophylactically effective amount is from about 50 ng to
less than 10 lug
per kg body weight per day.
[0044] 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 ibogaine, ibogaine
derivative, or
pharmaceutically acceptable salt and/or solvate thereof is administered by
sublingual,
intranasal, or intrapulmonary delivery. In another embodiment, the ibogaine,
ibogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof is
administered on an
as-needed basis as determined by the subject. In another embodiment, the
ibogaine, ibogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof is
administered before
the nicotine craving occurs. In another embodiment, the ibogaine, ibogaine
derivative, or
pharmaceutically acceptable salt and/or solvate thereof is administered after
the nicotine
craving occurs.
Alcohol
[0045] One aspect of the current invention is predicated, at least in part, on
the surprising
discovery that treatment of alcohol dependence with ibogaine and derivatives
thereof can be
achieved with an acceptable QT interval prolongation when such compounds are
administered within a narrow dosage range. Specifically, dosing an addicted
patient with
greater than about 1 mg/kg body weight to 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
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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.
[0046] In one aspect of the invention, the narrow therapeutic doses of
ibogaine, ibogaine
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 ibogaine,
ibogaine 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
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,
ibogaine
derivative, or pharmaceutically acceptable salt and/or solvate thereof will
not require further
clinical monitoring.
[0047] Some aspects of the current invention are further predicated on the
discovery that
even lower doses of ibogaine, ibogaine 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 ibogaine can prevent a
patient who is no
longer physically dependent on alcohol from relapsing to use thereof. Without
being bound
by theory, it is believed that a patient who is no longer physically dependent
on alcohol
requires less ibogaine 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 ibogaine results in a QT interval prolongation
that does not
require clinical cardiac monitoring.
[0048] In some embodiments, the therapeutic dose of ibogaine, ibogaine
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 ibogaine,
ibogaine derivative, or pharmaceutically acceptable salt and/or solvate
thereof administered
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to the patient provides an average serum concentration of about 50 ng/mL to
about 400
ng/mL.
[0049] In some embodiments, the patient is administered a high (therapeutic)
dose of
ibogaine, ibogaine 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 ibogaine,
ibogaine 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 ibogaine, ibogaine 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 ibogaine is tapered over time from the high
therapeutic dose
to a lower therapeutic dose.
[0050] In some embodiments, the dose of ibogaine, ibogaine 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 a single
dose. In
some embodiments, the dose of ibogaine, ibogaine 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 ibogaine, ibogaine derivative, or 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 ibogaine, ibogaine 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 ibogaine, ibogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof is from greater than about 1 mg/kg to 3
mg/kg.
[0051] In some embodiments, the serum concentration of ibogaine 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
ibogaine, ibogaine
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 ibogaine,
ibogaine 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
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dose or therapeutic dose of ibogaine, ibogaine 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 ibogaine, ibogaine 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 ibogaine, and if clinician determines that the
QT prolongation
would be unacceptable risk, ibogaine therapy will be contraindicated.
[0052] In one aspect, provided herein is amethod for treating alcohol
dependence in a
human patient suffering therefrom, comprising administering to the patient a
dosage of
ibogaine, ibogaine 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.
[0053] In one embodiment, the ibogaine, ibogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof is administered as a single dose or
multiple doses.
[0054] In another embodiment, the aggregate dosage of ibogaine, ibogaine
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 ibogaine,
ibogaine
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
ibogaine,
ibogaine 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 ibogaine,
ibogaine 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 ibogaine,
ibogaine derivative, or pharmaceutically acceptable salt and/or solvate
thereof is about 2
mg/kg per day. In another embodiment, the dosage of ibogaine, ibogaine
derivative, or
pharmaceutically acceptable salt and/or solvate thereof provides an average
serum
concentration of about 50 ng/mL to about 200 ng/mL.
[0055] In another embodiment, the QT interval is less than about 470 ms. In
another
embodiment, the QT interval is less than about 450 ms.
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[0056] In another embodiment, the method further comprising selecting an
addicted patient
who is prescreened to evaluate tolerance for prolongation of QT interval. In
another
embodiment, the prescreening step comprises ascertaining that ibogaine
treatment will not
result in a QT interval greater than about 500 ms. In another embodiment, the
prescreening
step comprises ascertaining that ibogaine treatment will not result in a QT
interval greater
than about 470 ms. In another embodiment, the prescreening step comprises
ascertaining that
ibogaine treatment will not result in a QT interval greater than about 450 ms.
[0057] 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 ibogaine, ibogaine 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.
[0058] In one embodiment, the withdrawal symptoms are due to acute withdrawal.
In
another embodiment, the ibogaine, ibogaine 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 ibogaine, ibogaine 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 ibogaine, ibogaine 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 ibogaine,
ibogaine
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
ibogaine,
ibogaine 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 ibogaine,
ibogaine 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.
[0059] In another 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 ibogaine, ibogaine derivative, or
phaiinaceutically
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acceptable salt and/or solvate thereof, wherein the patient is no longer
physically dependent
on alcohol.
[0060] 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.
Drug Addiction
[0061] This invention is predicated, at least in part, on the surprising
discovery that
treatment of addiction with ibogaine can be achieved with an acceptable QT
interval
prolongation when such compounds are administered within a narrow dosage
range.
Specifically, dosing an addicted patient with from greater than about 1 mg/kg
body weight to
about 4 mg/kg body weight, ibogaine will provide a therapeutic reduction in
withdrawal
symptoms and/or an increase in time to resumption of substance use in addicted
patients
without unacceptable prolongation of the patient's QT interval.
[0062] In some aspects of the invention, the dose range of ibogaine that
provides both
therapeutic results and an acceptable QT interval prolongation of less than 50
milliseconds in
substance-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.
[0063] In some embodiments, the narrow therapeutic doses of ibogaine
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 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.
[0064] Some aspects of the current invention are further predicated on the
discovery that
even lower doses of ibogaine, 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 drug use. That is, a lower dose of the compound can prevent a
patient who is
no longer physically addicted to a substance from relapsing to use of that
substance. Without
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being bound by theory, it is believed that a patient who is no longer
physically addicted to the
drug requires less compound to prevent relapse because the drug does not
compete with the
compound 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 results in a QT interval prolongation that does not require
clinical cardiac
monitoring.
[00651 In some embodiments, the therapeutic dose of ibogaine administered to
the patient is
sufficient to provide an average serum concentration of the compound 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 thereof administered to the patient provides an average serum
concentration
of about 50 ng/mL to about 400 ng/mL.
[0066] In some embodiments, the patient is administered a high (therapeutic)
dose of
ibogaine 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 ibogaine for a
period of time
to ameliorate the most significant withdraw symptoms, and then is administered
a decreasing
(tapered) amount of ibogaine 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 the compound is
tapered over time
from the high therapeutic dose to a lower therapeutic dose.
[0067] 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 greater than about 1 mg/kg to about 8
mg/kg. In a
preferred embodiment, the aggregate dose of ibogaine is from greater than
about 1 mg/kg to
about 4 mg/kg. In another preferred embodiment, the aggregate dose of ibogaine
is from
greater than about 1 mg/kg to 3 mg/kg.
[0068] 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 ibogaine provides
prolongation of
the QT interval of less than 80 ms. In a preferred embodiment, the maintenance
dose of
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ibogaine provides prolongation of the QT interval of less than 50 ms. In some
embodiments,
the maintenance dose or therapeutic dose of ibogaine provides prolongation of
the QT
interval of less than 30 ms. In a preferred embodiment, the maintenance dose
of ibogaine
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 the compound, and if clinician determines that the QT
prolongation would be
unacceptable risk, therapy will be contraindicated.
Substance Abuse
[0069] In one aspect, provided herein is a method for treating substance abuse
in a human
patient addicted thereto, comprising administering to the patient a dosage of
ibogaine, an
ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate
thereof, preferably
ibogaine, wherein the dosage provides an average serum concentration of about
50 ng/mL to
about 500 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.
[0070] In one embodiment, the method of claim 1 or 2, wherein the ibogaine is
administered as a single dose or multiple doses. In another embodiment, the
aggregate
dosage of ibogaine is from about 1.3 mg,/kg to about 4 mg/kg per day. In
another
embodiment, the aggregate dosage of ibogaine is from about 1.5 mg/kg to about
3 mg/kg per
day. In another embodiment, the aggregate dosage of ibogaine is from about 2
mg/kg to
about 4 mg/kg per day. In another embodiment, the aggregate dosage ibogaine is
from about
2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage
of ibogaine
is about 2 mg/kg per day. In another embodiment, the dosage of ibogaine
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.
[0071] In one aspect, provided herein is 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 ibogaine that provides an average
serum
concentration of about 50 ng/mL to about 400 ng/mL, said concentration being
sufficient to
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attenuate said symptoms while maintaining a QT interval of less than about 500
ms during
said treatment.
[0072] In one embodiment, the the withdrawal symptoms are due to acute
withdrawal.
[0073] In another embodiment, the ibogaine is administered as a single dose or
multiple
doses. In another embodiment, the aggregate dosage of ibogaine is from about
1.3 mg/kg to
about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine
is from
about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate
dosage
ibogaine is from about 2 mg/kg to about 4 mg/kg per day. In another
embodiment, the
aggregate dosage of ibogaine is from about 2 mg/kg to about 3 mg/kg per day.
In another
embodiment, the aggregate dosage of ibogaine 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.
[0074] In another aspect, provided herein is a method to prevent relapse of
substance abuse
in a patient treated to ameliorate said abuse, said method comprising
periodically
administering to said patient a maintenance dosage of ibogaine, wherein the
patient is no
longer abusing the substance.
[0075] In one embodiment, the dosage is less than about 70% of a therapeutic
dose of
ibogaine, 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.
[0076] In one embodiment, the unit dose of ibogaine is administered in one or
more
dosings.
[0077] In another aspect, provided herein is a method for treating substance
abuse in a
patient addicted thereto, comprising selecting an addicted patient who is
prescreened to
evaluate tolerance for prolongation of QT interval, administering to the
patient a dosage of
ibogaine that provides an average serum concentration of about 50 ng/mL to
about 500
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.
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[0078] In one embodiment, the prescreening step comprises ascertaining that
treatment with
ibogaine will not result in a QT interval greater than about 500 ms. In
another embodiment,
the prescreening step comprises ascertaining that treatment with ibogaine will
not result in a
QT interval greater than about 470 ms. In another embodiment, the prescreening
step
comprises ascertaining that treatment with ibogaine will not result in a QT
interval greater
than about 450 ms.
[0079] In another embodiment, the addictive substance 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.
Opioid Or Opioid¨Like Drug Abuse
[0080] 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 dosage
of ibogaine wherein the dosage provides an average serum concentration of
about 50 ng/mL
to about 500 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.
[0081] In another embodiment, the ibogaine is administered as a single dose or
multiple
doses. In another embodiment, the aggregate dosage of ibogaine is from about
1.3 mg/kg to
about 4 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine
is from
about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate
dosage of
ibogaine is from about 2 mg/kg to about 4 mg/kg per day. In another
embodiment, the
aggregate dosage ibogaine is from about 2 mg/kg to about 3 mg/kg per day. In
another
embodiment, the aggregate dosage of ibogaine is about 2 mg/kg per day. In
another
embodiment, the dosage of ibogaine 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.
[0082] 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 ibogaine that provides an
average serum
concentration of about 50 ng/mL to about 400 ng/mL, said concentration being
sufficient to
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attenuate said symptoms while maintaining a QT interval of less than about 500
ms during
said treatment.
[0083] In another embodiment, the withdrawal symptoms are due to acute
withdrawal. In
another embodiment, the ibogaine is administered as a single dose or multiple
doses. In
another embodiment, the aggregate dosage of ibogaine is from about 1.3 mg/kg
to about 4
mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from
about 1.5
mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage
ibogaine is
from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the
aggregate dosage
of ibogaine is from about 2 mg/kg to about 3 mg/kg per day. In another
embodiment, the
aggregate dosage of ibogaine 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.
[0084] In another aspect, provided herein is a method to prevent relapse of
opioid or
opioid-like drug abuse in a patient treated to ameliorate said abuse, said
method comprising
periodically administering to said patient a maintenance dosage of ibogaine
wherein the
patient is no longer abusing the opioid or opioid-like drug.
[0085] In one embodiment, the dosage is less than about 70% of a therapeutic
dose of
ibogaine 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.
[0086] In one embodiment, the unit dose of ibogaine is administered in one or
more
dosings.
[0087] In one aspect, provided herein is a method for treating opioid or
opioid-like drug
abuse in a patient addicted thereto, comprising selecting an addicted patient
who is
prescreened to evaluate tolerance for prolongation of QT interval,
administering to the patient
a dosage of ibogaine that provides an average serum concentration of about 50
ng/mL to
about 500 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.
[0088] In one embodiment, the prescreening step comprises ascertaining that
treatment with
ibogaine, ibogaine derivative, or pharmaceutically acceptable salt thereof
will not result in a
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QT interval greater than about 500 ms. In another embodiment, the prescreening
step
comprises ascertaining that treatment with ibogaine will not result in a QT
interval greater
than about 470 ms. In another embodiment, the prescreening step comprises
ascertaining that
treatment with ibogaine will not result in a QT interval greater than about
450 ms.
Pain
[0089] 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.
[0090] 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 centralized in one
area before
becoming somewhat spread out. Acute pain generally responds well to
medications (e.g.,
morphine).
[0091] 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.
[0092] Debilitating chronic pain affects tens of millions of people annually.
Accordingly,
this costs hundreds of millions of dollars in terms of medication, physical
therapy, and lost
production. The current methods for treating chronic pain have a limited
success rate and in
some cases may result in chemical dependency.
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[0093] Numerous treatments have been developed in attempts to ameliorate pain
in its
various categories. However, in many cases, treatment requires the use of
addictive or habit-
forming substances (e.g., morphine or methadone). Accordingly, there is a
significant need
for an effective, non-addictive treatment for pain, such as chronic,
debilitating, nociceptive
pain, that reduces the need for habit-forming pain relieving drugs.
[0094] Furthermore, human clinical studies demonstrate that the lower dosing
of ibogaine
has minimal impact on the alleviation of pain in patients. Thus, the
previously disclosed
broad range has now been found to be insufficient for at least some human
therapies at the
lower end of this range.
[0095] In some embodiments, the current invention is predicated on the
surprising
discovery that treatment with a narrow dosage range of ibogaine, an ibogaine
derivative, or a
pharmaceutically acceptable salt and/or solvate thereof, preferably 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.
[0096] 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.
[0097] 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.
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[0098] 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.
[0099] In one aspect, provided herein is a method for treating pain in a
patient, comprising
administering to the patient a dosage of ibogaine that provides an average
serum
concentration of about 50 ng/mL to about 500 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.
[0100] In one embodiment, the ibogaine is administered as a single dose or
multiple doses.
In another embodiment, the aggregate dosage of ibogaine is from about 1.3
mg/kg to about 4
mg/kg per day. In another embodiment, the aggregate dosage of ibogaine is from
about 1.5
mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of
ibogaine is
from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the
aggregate dosage
ibogaine is from about 2 mg/kg to about 3 mg/kg per day. In another
embodiment, the
aggregate dosage of ibogaine thereof is about 2 mg/kg per day. In another
embodiment, the
dosage of ibogaine provides an average serum concentration of about 50 ng/mL
to about 200
ng/mL.
[0101] In one 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
ibogaine that provides an average serum concentration of about 50 ng/mL to
about 400
ng/mL, said concentration being sufficient to alleviate said pain symptoms
while maintaining
a QT interval of less than about 500 ms during said treatment.
[0102] In one embodiment, the pain symptoms are due to chronic pain. In
another
embodiment, the ibogaine is administered as a single dose or multiple doses.
In another
embodiment, the aggregate dosage of ibogaine is from about 1.3 mg/kg to about
4 mg/kg per
day. In another embodiment, the aggregate dosage of ibogaine is from about 1.5
mg/kg to
about 3 mg/kg per day. In another embodiment, the aggregate dosage of ibogaine
is from
about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate
dosage of
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ibogaine is from about 2 mg/kg to about 3 mg/kg per day. In another
embodiment, the
aggregate dosage of ibogaine is about 2 mg/kg per day.
[0103] In one embodiment, the unit dose of ibogaine is administered in one or
more dosings.
Depression
[0104] The current invention is predicated on the surprising discovery that
treatment with a
narrow dosage range of ibogaine, ibogaine 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 symptoms of depression and/or
PTSD in
affected patients. Preferably, the dose range that provide both therapeutic
results and an
acceptable QT interval prolongation of less than 50 milliseconds 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.
[0105] 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
ibogaine, ibogaine derivative, or pharmaceutically acceptable salt ancUor
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.
[0106] In some embodiments, the therapeutic dose of ibogaine 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 ibogaine 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. In one embodiment, the
dose of
ibogaine or pharmaceutically acceptable salt and/or solvate thereof
administered to the
patient provides an average serum concentration of about 50 ng/mL to about 200
ng/mL.
[0107] In a preferred embodiment, the narrow therapeutic doses of ibogaine,
ibogaine
derivative, or pharmaceutically acceptable salt and/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
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interval, e.g., to determine whether the patient has any pre-existing cardiac
conditions which
would disqualify him/her from treatment with ibogaine or ibogaine derivative.
[0108] 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.
[0109] 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
ibogaine, ibogaine
derivative, or salt and/or solvate thereof in a sustained release manner such
that the serum
concentration of ibogaine or ibogaine derivative is maintained at a
therapeutically effective
amount for a 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.
[0110] In one 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 ibogaine, ibogaine 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 ibogaine or ibogaine derivative serum level of between
about 50 ng/mL
and about 400 ng/mL while maintaining a QT interval of less than about 500 ms
during said
treatment.
[0111] In one embodiment, the therapeutically effective amount is between
about 1 mg to
about 4 mg per kg of body weight. In another embodiment, the therapeutically
effective
amount is between about 50 ng to less than 100 jig per kg of body weight. In
another
embodiment, the dosage of ibogaine, ibogaine derivative, or a 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
QT interval is less than about 420 ms. In another embodiment, the method
further
comprising selecting a patient who is prescreened to evaluate tolerance for
prolongation of
QT interval.
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[0112] In another embodiment, depression is treated. In another embodiment,
posttraumatic
stress disorder is treated.
[0113] In another embodiment, the ibogaine, ibogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof is administered by sublingual,
intranasal, or
intrapulmonary delivery. In another embodiment, ibogaine or ibogaine
derivative or a
pharmaceutically acceptable salt and/or solvate thereof is administered.
Reducing Tolerance To Opioid Analgesics
[0114] This invention is directed, in part, to the use of ibogaine, an
ibogaine derivative, or a
pharmaceutically acceptable salt and/or solvate thereof, preferably ibogaine,
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.
[0115] The use of ibogaine for the modulation of tolerance to opioid analgesic
agents is
limited due to potentially adverse side effects. The use of ibogaine to
modulate opioid
tolerance is generally not favored due to the adverse side effects that can
result from
receiving a therapeutic dose according to conventional known methods.
[0116] In one embodiment, ibogaine, ibogaine derivative, or pharmaceutically
acceptable
salt and/or solvate thereof is administered concurrently with the opioid
analgesic. In one
embodiment, ibogaine, ibogaine 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 ibogaine, ibogaine derivative, or pharmaceutically
acceptable salt
and/or solvate thereof is administered. In one embodiment, two or more doses
of ibogaine,
ibogaine derivative, or pharmaceutically acceptable salt and/or solvate
thereof are
administered. In one embodiment, the opioid analgesic is interrupted for a
period of time
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while ibogaine, ibogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof is administered. In one embodiment, a non-opioid analgesic is
administered while the
opioid analgesic is interrupted. In one embodiment, ibogaine, ibogaine
derivative, or
pharmaceutically acceptable salt and/or solvate thereof acts as an analgesic.
In one
embodiment, the opioid analgesic is not interrupted during ibogaine treatment.
[0117] 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
ibogaine, ibogaine derivative or phamiaceutically 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 re-sensitize the patient to the opioid as an
analgesic while
maintaining a QT interval of less than about 500 ms during said treatment.
[0118] In one embodiment, the ibogaine, ibogaine 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 ibogaine,
ibogaine
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.
[0119] In another embodiment, the dose or aggregate dosage of ibogaine,
ibogaine
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
ibogaine,
ibogaine 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
ibogaine, ibogaine 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 ibogaine, ibogaine 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 ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or
solvate thereof is
about 2 mg/kg per day.
[0120] In another embodiment, the dosage of ibogaine, ibogaine derivative, or
pharmaceutically acceptable salt ancUor solvate thereof provides an average
serum
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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.
[0121] In another embodiment, the method further comprises selecting a patient
who is
prescreened to evaluate tolerance for prolongation of QT interval. In another
embodiment,
the prescreening step comprises ascertaining that ibogaine treatment will not
result in a QT
interval greater than about 500 ms. In another embodiment, the prescreening
step comprises
ascertaining that ibogaine treatment will not result in a QT interval greater
than about 470 ms.
In another embodiment, the prescreening step comprises ascertaining that
ibogaine treatment
will not result in a QT interval greater than about 450 ms.
[0122] In another embodiment, 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, oxymorphone. In another embodiment, the opioid
analgesic is
morphine.
Impulse Control
[0123] The current invention is also predicated on the surprising discovery
that treatment
with a narrow dosage range of ibogaine or pharmaceutically acceptable salt
and/or solvate
thereof, between greater than about 1 mg/kg body weight and about 4 mg/kg body
weight,
provides a therapeutic reduction in symptoms of anxiety disorders, impulse
control disorder,
anger/violence-related disorders in affected patients, or provides a
therapeutic reduction in
food consumption. Preferably, the dose range that provides both therapeutic
results and an
acceptable QT interval prolongation of less than about 50 milliseconds 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 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.
[0124] In some embodiments, the dose that provides both therapeutic results
and an
acceptable QT interval prolongation of less than about 50 milliseconds is
between about 60
mg and about 150 mg. In some embodiments, the dose that provides both
therapeutic results
and an acceptable QT interval prolongation of less than about 50 milliseconds
is about 100
mg. In some embodiments, the dose that provides both therapeutic results and
an acceptable
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QT interval prolongation of less than about 50 milliseconds is about 120 mg.
In some
embodiments, the dose that provides both therapeutic results and an acceptable
QT interval
prolongation of less than about 50 milliseconds is about 1.5 mg/kg body
weight. In some
embodiments, the dose that provides both therapeutic results and an acceptable
QT interval
prolongation of less than about 50 milliseconds is about 2 mg/kg body weight.
[0125] In some embodiments, the patient is administered an initial dose of
ibogaine,
ibogaine derivative, or pharmaceutically acceptable salt 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 about 5 mg to about
50 mg. In
one embodiment, such a dosing regimen provides an average serum concentration
of ibogaine
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.
[0126] Furthermore, at very low doses, direct blood stream delivery of
ibogaine 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 ibogaine enhances the amount of ibogaine
delivered to the
brain, because ibogaine does not pass through the liver as it does when
ingested. Direct blood
stream delivery of ibogaine includes sublingual, pulmonary and intranasal
delivery where the
ibogaine is absorbed directly into the blood stream and then into the brain.
The rapid
delivery of ibogaine 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.
[0127] 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
ibogaine, ibogaine 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
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WO 2015/134405 PCT/US2015/018356
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 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.
[0128] In some embodiments, the therapeutic dose of ibogaine or
pharmaceutically
acceptable salt and/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 ibogaine, ibogaine 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.
[0129] In some embodiments, the therapeutic dose of ibogaine, ibogaine
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
ibogaine 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 ibogaine 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 ibogaine or pharmaceutically acceptable
salt and/or
solvate thereof administered to the patient provides an average serum
concentration of less
than about 50 ng/mL.
[0130] 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 ibogaine, ibogaine 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 ibogainc
serum level of
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WO 2015/134405 PCT/US2015/018356
between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval of
less than
about 500 ms during said treatment.
[0131] 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.
[0132] In another 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 ibogaine, ibogaine 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
ibogaine 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.
[0133] 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,
kleptomania, sexual compulsion, paraphilia, interne addiction,
trichotillomania, pathological
skin picking, and compulsive shopping.
[0134] In another 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 ibogaine, ibogaine 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 ibogaine 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.
[0135] In another 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 ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt
and/or solvate
thereof, and further wherein the therapeutically effective amount provides an
efficacious
average ibogaine 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.
32
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WO 2015/134405 PCT/US2015/018356
[0136] In one embodiment, the method comprises:
a) administering an initial dose of ibogaine, ibogaine 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 ibogaine, ibogaine
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.
[0137] In one 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.
[0138] In another embodiment, the QT interval is less than about 450 ms. In
another
embodiment, the method further comprises selecting a patient who is
prescreened to evaluate
tolerance for prolongation of QT interval.
[0139] In another embodiment, the ibogaine, ibogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof is administered by sublingual, buccal,
intranasal, or
intrapulmonary delivery.
[0140] In another embodiment, ibogaine or a pharmaceutically acceptable salt
and/or solvate
thereof is administered.
[0141] In some embodiments, the maintenance dose of ibogaine is 5 mg to 100
mg. In some
embodiments, the maintenance dose of ibogaine is about 1.5 mg/kg body weight.
In some
embodiments, the maintenance dose of ibogaine is about 1 mg/kg body weight. In
some
embodiments, the maintenance dose of ibogaine is about 0.9 mg/kg body weight.
In some
embodiments, the maintenance dose of ibogaine is about 0.8 mg/kg body weight.
In some
embodiments, the maintenance dose of ibogaine is about 0.7 mg/kg body weight.
In some
embodiments, the maintenance dose of ibogaine is about 0.6 mg/kg body weight.
In some
embodiments, the maintenance dose of ibogaine is about 0.5 mg/kg body weight.
In some
embodiments, the maintenance dose of ibogaine is about 0.4 mg/kg body weight.
In some
33
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WO 2015/134405 PCT/US2015/018356
embodiments, the maintenance dose of ibogaine is about 0.3 mg/kg body weight.
In some
embodiments, the maintenance dose of ibogaine is about 0.2 mg/kg body weight.
In some
embodiments, the maintenance dose of ibogaine is about 0.1 mg/kg body weight.
Compounds Administered
[0142] In the various method, formulation and kit aspects and embodiments, in
one
embodiment a compound utilized herein is represented by, or ibogaine as used
herein is
replaced by, a compound Formula I:
R1
X
wherein
R is hydrogen or Ci-C3-alkoxy,
RI is hydrogen, Ci-C3-alkyl, C1-C3 alkoxy, or CH2-Y-CH3 where Y is 0 or NH,
and
X is H, COOH, or COOR2, where R2 is C1-C6 alkyl or (CH2CH20)nCH3, where n = 1
to 3.
[0143] In another embodiment, ibogaine or a pharmaceutically acceptable salt
and/or
solvate thereof is utilized. In another embodiment, ibogaine or a
pharmaceutically acceptable
salt and/or solvate thereof is utilized. In another embodiment, the ibogaine,
ibogaine
derivative, is chosen from the group consisting of ibogaine, coronaridine,
ibogamine,
voacangine, 18-methoxycoronaridine, 2-methoxyethy1-18-methoxycoronaridinate,
18-
methylaminocoronaridine or a pharmaceutically acceptable salt and/or solvate
thereof.
[0144] In another embodiment, the compound utilized herein is chosen from the
group
consisting of ibogaine, coronaridine, ibogamine, voacangine, 18-
methoxycoronaridine, 2-
methoxyethy1-18-methoxycoronaridinate, 18-methylaminocoronaridine and a
pharmaceutically acceptable salt and/or solvate.
[0145] In another embodiment, the compound utilized herein is selected from
the group
consisting of 16-hydroxymethy1-18-hydroxyibogaline, 16-hydroxymethy1-18-
methoxyibogaline, 16-ethoxycarbony1-18-hydroxyibogaline laurate, and 16-
ethoxycarbonyl-
18-hydroxyibogaline methoxyethoxymethyl ether and a pharmaceutically
acceptable salt
and/or solvate thereof.
34
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PCT/US2015/018356
[0146] In one embodiment, the ibogaine derivative is represented by Formula
II:
R1
II
H R2
or a pharmaceutically acceptable salt and/or solvate thereof,
wherein
R is hydrogen or C1-C3 alkoxy;
RI is hydrogen, Ci-C3 alkyl, Ci-C3 alkoxy, (CH2)õ,0C(0)alkyl, (CH2).0H,
(CH2),n0alkyl, (CH2)õ,0(CH2)p0(CH2)q0(CH2)rCH3 or CH2-Y-CH3 where each of m,
p and q is 1, 2 or 3; and r is 0, 1 or 2,Y is 0 or NH; and
R2 is H, (CH2)n0H, COOH, or COOR4, where R4 is CI-C6 alkyl or (CH2CH20)11CH3,
where n is 1, 2, or 3.
[0147] In one embodiment, the ibogaine derivative is selected from the group
consisting of
coronaridine, ibogamine, voacangine, 18-methoxycoronaridine, 2-Methoxyethy1-18-

methoxycoronaridinate, and 18-Methylaminocoronaridine.
[0148] In one embodiment, the ibogaine derivative is selected from the group
consisting of
16-hydroxymethy1-18-hydroxyibogaline, 16-hydroxymethy1-18-methoxyibogaline, 16-

ethoxycarbony1-18-hydroxyibogaline laurate, and 16-ethoxycarbony1-18-
hydroxyibogaline
methoxyethoxymethyl ether.
[0149] In one embodiment, the compound is of Formula IA:
R1
X
IA
wherein
R is hydrogen or Ci-C3-alkoxy,
RI is hydrogen, Ci-C3-alkyl, Ci-C3 alkoxy, or CH2-Y-CH3 where Y is 0 or NH,
and
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WO 2015/134405 PCT/US2015/018356
X is H, COOH, or COOR2, where R2 is C1-C6 alkyl or (CH2CH20),ICH3, where n = 1

to 3.
[0150] In another embodiment, the ibogaine derivative is represented by
Formula II:
R1
II
H R2
or a pharmaceutically acceptable salt and/or solvate thereof,
wherein
R is OCH3;
RI is CH2CH3; and
R2 is COOR4, where R4 is (CH2CH20).CH3, where n is 1.
[0151] When replacing ibogaine, the compounds of formula I, II, and
subformulas thereof
as utilized herein exclude ibogaine.
[0152] In a preferred embodiment, the compound utilized herein is:
0
a pharmaceutically acceptable salt thereof, or a solvate of each thereof.
DETAILED DESCRIPTION
[0153] 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.
[0154] 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 in
another section. Unless defined otherwise, all technical and scientific terms
used herein have
36
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WO 2015/134405 PCT/US2015/018356
the same meaning as commonly understood by one of ordinary skill in the art to
which this
invention belongs.
[0155] 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.
Definitions
[0156] 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.
[0157] 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 ( -) 10 %, 5 % or 1 % or any subrange or subvalue there
between.
[0158] "Administration" refers to introducing an agent, such as ibogaine, 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 may be
administered by direct blood stream delivery, e.g. sublingual, intranasal, or
intrapulmonary
administration.
[0159] 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 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 ancUor provides a patient with a
prescription for a
drug is administering the drug to the patient.
[0160] "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 ibogaine or salt and/or solvate thereof one, two,
three, or more
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WO 2015/134405 PCT/US2015/018356
times per day. Administration may be via transdermal patch, gum, lozenge,
sublingual tablet,
intranasal, intrapulmonary, oral administration, or other administration.
[0161] "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.
[0162] As used herein, is a single bond or a double bond.
[0163] As used herein, the term "alkyl" refers to monovalent saturated
aliphatic
hydrocarbyl groups having from 1 to 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 "Cx 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.
[0164] "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,
R20_c(0)_, _
NR2 C(0)R2 ,
R20-C(0)O-, _NR2 OR205
C(0)NR20R205
C(S)NR20R20, _N¨K 20¨
l,(0)NR2 R205 20 ¨
K L(S)NR2 R2
, -0-C(0)NR20R20

,
S(0)2NR20R20

,
0-S(0)2NR20R20, _N-.K 20_
S(0)2NR2 R2o, _c"R20)NR20-K 205
aryl, aryloxy,
arylthio, azido, carboxyl, -C(0)0-R21, -NR20-C(0)0-R21, -0-C(0)0-R21, cyano,
cycloalkyl,
cycloalkyloxy, cycloalkylthio, -NR20C(=NR20)N(R20)2, halo, hydroxy,
hydroxyamino,
_NR2oNR2oR2o,
alkoxyamino, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic,
heterocyclyloxy, heterocyclylthio, nitro, spirocycloalkyl,
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SO3H, -0S(0)2-R21, _s(0)2-R21, -C(S)-R21,
thiocyanate, thiol, and alkylthio; each R2 is
independently selected from the group consisting of hydrogen, alkyl,
cycloalkyl, aryl,
heteroaryl, and heterocycle, or two R2 groups attached to a common atom are
optionally
joined together with the atom bound thereto to form a heterocycle; and each
R21 is
independently selected from the group consisting of alkyl, cycloalkyl, aryl,
heteroaryl, and
heterocycle.
[0165] "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.
[0166] "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.
[0167] "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, alkoxy, -C(0)-R20, _NR20c(o)R20,
R20-C(0)0-, -NR2 K20, _ K C(0)NR20¨ , _ 20 C(S)NR20R20, _met (0)NR2oR2o,
_N¨K 20
(S)NR2 R2
0
, -0-C(0)NR20R20,
S(0)2NR20¨K 20, _ 0-S(0)2NR 20R20, _N¨K 20_ S(0)2NR2OR20, .c(=NR20)NR20¨K 20,
aryl, aryloxy,
arylthio, azido, carboxyl, -C(0)0-R21, _N¨K 20_
C(0)0-R21, -0-C(0)0-R21, cyano, cycloalkyl,
cycloalkyloxy, cycloalkylthio, -NR20c (_NR2o)N(R2o)2,
halo, hydroxy, hydroxyamino,
_NR2oN R20¨ 20,
alkoxyamino, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic,

heterocyclyloxy, heterocyclylthio, nitro, spirocycloalkyl,
SO3H, -0S(0)2-R21, _s(0)2_,R21, -C(S)-R21,
thiocyanate, thiol, and alkylthio; each R2 is
independently selected from the group consisting of hydrogen, alkyl,
cycloalkyl, aryl,
heteroaryl, and heterocycle, or two R2 groups attached to a common atom are
optionally
joined together with the atom bound thereto to form a heterocycle; and each
R21 is
independently selected from the group consisting of alkyl, cycloalkyl, aryl,
heteroaryl, and
heterocycle.
[0168] "Cyano" refers to the group -CN.
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[0169] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 or 3 to 8
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.
[0170] "Substituted cycloalkyl" refers to a cycloalkyl group having from 1 to
5 or
preferably 1 to 3 substituents selected from the group consisting of oxo,
thione, alkyl,
substituted alkyl, alkoxy, -C(0)-R20, -NR20C(0)R20

,
R20_C(0)¨_, _
NR2 R2o,
C(0)NR20R20

,
C(S)NR20R20, _N¨K 20 (0)NR2 R2o, _N¨K 20 -
(S)NR2 R2
o, -0-C(0)NR20R20, -
S(0)2NR2 R
20, -O-S(0)2NR20R20, _N¨K 20_
S(0)2NR2 R 20, _c(=NR20)NR20R20, aryl, aryloxy,
arylthio, azido, carboxyl, -C(0)0-R21, -NR20-C(0)0-R21, -0-C(0)0-R21, cyano,
cycloalkyl,
cycloalkyloxy, cycloalkylthio, -NR20C(=NR20)N(R20)2, halo, hydroxy,
hydroxyamino,
,
_NR2oNR2oR2o
alkoxyamino, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclic,

heterocyclyloxy, heterocyclylthio, nitro, spirocycloalkyl,
SO3H, -0S(0)2-R21, -S(0)2-R21, -C(S)-R21, thiocyanate, thiol, and alkylthio;
each R2 is
independently selected from the group consisting of hydrogen, alkyl,
cycloalkyl, aryl,
heteroaryl, and heterocycle, or two R2 groups attached to a common atom are
optionally
joined together with the atom bound thereto to form a heterocycle; and each
R21 is
independently selected from the group consisting of alkyl, cycloalkyl, aryl,
heteroaryl, and
heterocycle.
[0171] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and
preferably is
fluoro or chloro.
[0172] "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.
[0173] "Heteroaryl" refers to an aromatic group of from 5 to 14 ring atoms,
including from
1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting
of oxygen,
nitrogen and sulfur. In some embodiments, heteroaryl comprises 5, 6, or 7 ring
atoms,
including 1 to 4 heteroatoms. 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
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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.
[0174] "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.
[0175] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocycly1"
refers to a
saturated or partially saturated, but not aromatic, group having from 3 to 14
ring atoms,
including from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms
selected from the
group consisting of nitrogen, sulfur, or oxygen. In some embodiments,
heteroaryl comprises
3, 4, 5, 6 or 7 ring atoms, including 1 to 4 heteroatoms. 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.
[0176] "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.
[0177] "Ibogaine" refers to the compound:
0
ccK
It should be understood that where "ibogaine" is mentioned herein, one more
polymorphs of
ibogaine can be utilized and are contemplated. Ibogaine is isolated from
Tabernanth iboga, a
shrub of West Africa. Ibogaine can also be synthesized using known methods.
See, e.g.,
Biichi, et al. (1966), J. Am. Chem Society, 88(13), 3099-3109 Unless specified
otherwise,
"ibogaine" as used herein refers to ibogaine, ibogaine derivative, or a
pharmaceutically
acceptable salt and/or solvate thereof.
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WO 2015/134405 PCT/US2015/018356
[0178] In some embodiments, the ibogaine or ibogaine derivative is represented
by Formula
R1
R13
I R2
R12
or a pharmaceutically acceptable salt and/or solvate thereof,
wherein
R is H, halo, C1-C3 alkyl, substituted Ci-C3 alkyl, 012.1 , NH2, NHR10,
NR10R11,
NHC(0)R1 , or NR1 C(0)R11;
R1 is H, C1-C3 alkyl, substituted Ci-C3 alkyl, Ci-C3 alkoxy, CH2-X-CH3, or
(CH2)õ,R3;
R2 is H, COOH, COOR4, (CH2)õOH, CH(OH)R5, CH2OR5, C(0)NH2, C(0)NHR5,
C(0)NR5R6, C(0)NHNH2, C(0)NHNHR5, C(0)NHNR5R6, C(0)NR5NH2,
C(0)NR5NHR6, C(0)NR5NR6R7, C(0)NHNH(C(0)R5),
C(0)NHNR5(C(0)R6), C(0)NR5NH(C(0)R6), C(0)NR5NR6(C(0)R7), CN, or
C(0)R5;
R3 is C1-C3 alkyl, benzyl, substituted Ci-C3 alkyl, YH, YR8, YC(0)R8, C(0)YR8,

C(0)NH2, C(0)NHR8, C(0)NR8R9, NH2, NHR8, NR8R9, NHC(0)R8,
0(CH2)p0(CH2)q0(CH2),CH3 or NR8C(0)R9;
R4 is Ci-C6 alkyl or (CH2CH20)nal3;
R5, R6, R7, R8, R9, R1 , and R11 are independently alkyl or substituted alkyl;
R12 is H, alkyl, or substituted alkyl;
R13 is H, OR10, alkyl, or substituted alkyl;
Xis 0 or NH;
YisOorS;
m is an integer selected from 0-8;
each of n, p and q is 1, 2 or 3; and
r is 0, 1 or 2.
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[0179] In some embodiments, the ibogaine or ibogaine derivative is represented
by Formula
R1
H R2
or a pharmaceutically acceptable salt and/or solvate thereof,
wherein
R is hydrogen or C1-C3 alkoxy,
RI is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, (CH2).0C(0)alkyl, (CH2)m0H,
(CH2)mOalkyl, (CH2).0(CH2)p0(CH2)q0(CH2)1CH3 or CH2-Y-CH3 where each of m,
p and q is 1,2 or 3; and r is 0, 1 or 2,Y is 0 or NH, and
R2 is H, (CH2)n0H, COOH, or COOR4, where R4 is C1-C6 alkyl or (CH2CH20),ICH3,
where n is 1,2, or 3.
[0180] In one embodiment, R is methoxy. In one embodiment, RI is ethyl. In one

embodiment, RI is methoxy. In one embodiment, RI is CH2-Y-CH3 where Y is 0. In
one
embodiment, RI is CH2-Y-CH3 where Y is NH. In one embodiment, R2 is hydrogen.
In one
embodiment, In one embodiment, R2 is COOR4 and R4 is methyl. In one
embodiment, n = 1.
In a preferred embodiment, R, RI and R2 are all not hydrogen. In one
embodiment, when R is
methoxy and RI is hydrogen, then R2 is COOH or COOR4. In another embodiment,
when R
is methoxy and RI is hydrogen, then X is COOR4 where R4 is (CH2CH20)CH3.
[0181] In one embodiment, R12 is hydrogen.
[0182] In one embodiment, RI is H. In one embodiment, RI is C1-C3 alkyl, such
as ethyl.
In one embodiment, RI is CH2CH2OH. In one embodiment, Rl is CH2CH2OCH3. In one

embodiment, RI is CH2CH20CH2Ph. In one embodiment, RI is CH2CH20C(0)alkyl. In
one
embodiment, RI is CH2CH20(CH2)p0(CH2)q0(CH2)1CH3.
[0183] In one embodiment, R2 is CH2OH and CH(OH)R5. In one embodiment, R2 is
CH2OR5. In one embodiment, R2 is CO2R5. In one embodiment, R2 is C(0)NH2,
C(0)NHR5, or C(0)NR5R6. In one embodiment, R2 is C(0)NHNH2, C(0)NHNHR5,
C(0)NR5NH2, C(0)NHNR5R6, C(0)NH5NHR6, or C(0)NR5NR6R7. In one embodiment, R2
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is C(0)NHNH(C(0)R5), C(0)NHNOC(0)R6), C(0)NR5NH(C(0)R6), or
C(0)NR5NR6(C(0)R7). In one embodiment, R2 is C(0)R5.
[0184] In some embodiments, the ibogaine or ibogaine derivative is selected
from:
Name Structure
coronaridine
H 02CH3
18-hydroxycoronaridine OH
H 0- 2CH3
18-methoxycoronaridine OCH3
H 02CH3
18-benzyloxycoronaridine
0
H 02CH3
18-hydroxycoronaridine laurate 0 (CH2)10CH3
-1)
H 0- 2CH3
18-hydroxycoronaridine
methoxyethoxymethyl ether
H 02CH3
18-hydroxycoronaridine acetate
H 0- 2CH3
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WO 2015/134405 PCT/US2015/018356
voacangine
0
H 02cH3
18-hydroxyvoacangineN OH
0
H 0- 2CH3
18-methoxyvoacangineN OCH3
0
H 0- 2CH3
18-benzyloxyvoacangine
0
0
H 0- 2CH3
18-hydroxyvoacangine laurate o_t(CH2)10CH3
0
H 0- 2CH3
18-hydroxyvoacangine acetate
0
H 02CH3
18-hydroxyvoacangine
methoxyethoxymethyl ether 0
H 0- 2CH3
conopharyngine
0
H 0- 2CH3
18-hydroxyconopharyngineN OH
0
H 0- 2CH3
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18-methoxyconopharyngine OCH3
0
H 02c3
18-benzy1oxyconopharyngine
0
0
H co2c3
18-hydroxyconopharyngine laurate (CH2)1oCH3
0
H 02CH3
18-hydroxyconopharyngine acetate
0
H 02CH3
18-hydroxyconopharyngine
methoxyethoxymethyl ether 0
H c52c3
ibogamine
16-ethoxycarbony1-18-N OH
hydroxyibogamine
= 02CH2CH3
16-hydroxymethy1-18- OH
hydroxyibogamine
= H2OH
16-ethoxycarbony1-18- OCH3
methoxyibogamine
= 02CH2CH3
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16-hydroxymethy1-18- OCH3
methoxyibogamine
= H2OH
16-ethoxycarbony1-18-
benzyloxyibogamine 0
= 02CH2CH3
16-ethoxycarbony1-18- 0 (CH2)10CH3
hydroxyibogamine laurate
= 02CH2CH3
16-ethoxycarbony1-18- 0.õ(
hydroxyibogamine acetate
= 02CH2CH3
16-ethoxycarbony1-18-
0oo
,/
hydroxyibogamine
methoxyethoxymethyl ether
H 602CH2CH3
ibogaine
0
16-ethoxycarbony1-18- OH
0
hydroxyibogaine
Hc5O2CH2CH3
16-hydroxymethy1-18- OH
0
hydroxyibogaine
H2OH
16-ethoxycarbony1-18- 0,
0
methoxyibogaine
H 02CH2CH3
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WO 2015/134405 PCT/US2015/018356
16-hydroxymethy1-18-N OCH3
0
methoxyibogaine
H2OH
16-ethoxycarbony1-18-
benzyloxyibogaine 0
0
H 0- 2CH2CH3
16-ethoxycarbony1-18- 0_1(CH2)10CH3
0
hydroxyibogainelaurate
H 02CH2CH3
16-ethoxycarbony1-18-
0
,==
hydroxyibogaine acetate
H 0- 2CH2CH3
16-ethoxycarbony1-18-
hydroxyibogaine 0
methoxyethoxymethyl ether
H 0- 2CH2CH3
ibogaline
0
16-ethoxycarbonyl- 18-
N OH
hydroxyibogaline
H 0- 2CH2CH3
1 OH
0
hydroxyibogaline

H2OH
16-ethoxycarbony1-18-N OCH3
0
methoxyibogaline
'0
H 0- 2CH2CH3
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WO 2015/134405 PCT/US2015/018356
16-hydroxymethy1-18-N OCH3
0
methoxyibogaline
H H2OH
1
16-ethoxycarbony1-18-
11
benzyloxyibogaline 0
0
H 02CH2CH3
16-ethoxycarbony1-18- 0,1(CH2)10CH3
hydroxyibogaline laurate 0
iiIiIII
02CH2CH3
16-ethoxycarbony1-18-
0
hydroxyibogaline acetate
H 02CH2CH3
16-ethoxycarbony1-18-
hydroxyibogaline 0
methoxyethoxymethyl ether 1101 \
'0
02CH2CH3
and pharmaceutically acceptable salts and/or solvates thereof.
[0185] This invention is not limited to any particular chemical form of the
compounds, 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.
[0186] In one embodiment, the ibogaine derivative is:
H0 0
(coronaridine),
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(ibogamine),
0
H 0 0
(voacangine),
0,
H 0 0
(18-methoxycoronaridine, 18-MC),
0,
H 0 0
(2-Methoxyethy1-18-methoxycoronaridinate, ME-18-MC), or
N,
0
(18-Methylaminocoronaridine, 18-MAC).
[0187] "Pharmaceutically acceptable composition" refers to a composition that
is suitable
for administration to a mammal, particularly, a human. Such compositions
include various
excipients, diluents, carriers, and such other inactive agents well known to
the skilled artisan.
[0188] "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 molecule
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WO 2015/134405 PCT/US2015/018356
contains an acidic functionality, include, by way of example only, sodium,
potassium,
calcium, magnesium, ammonium, tetraalkylammonium, and the like.
[0189] 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.
[0190] 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,
isopropanol, butanol, Cl-
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.
[0191] "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
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WO 2015/134405 PCT/US2015/018356
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
ibogaine, in the context of treating nicotine dependency, refers to an amount
of the ibogaine
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
ibogaine, in the context of treating alcohol dependency, refers to an amount
of ibogaine 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 ibogaine
in the context of treating opioid or opioid-like drug dependency, refers to an
amount of
compound 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 ibogaine in the context of treating drug dependency, refers to an
amount of
compound 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 ibogaine, in the context of treating pain, refers to an amount of
ibogaine that
provides immediate and/or sustained pain relief 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 an
agent, in the context
of treating anxiety disorders, impulse control disorder, and/or anger/violence-
related
disorders, refers to an amount of the agent that attenuates the anxiety
disorder, impulse
control disorder, or anger/violence-related disorders, and/or symptoms
thereof, in the patient.
A therapeutically effective amount of an agent, in the context of regulating
food intake and/or
controlling food cravings, refers to an amount of the agent that reduces the
patient's food
intake and/or reduces food cravings in the patient.
[0192] A "therapeutic level" of a drug is an amount of ibogaine 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
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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
ibogaine is mentioned, it is to be understood that the term "ibogaine"
encompasses any form
of ibogaine, including derivatives thereof.
[0193] 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
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 is 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 ibogaine 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.
[0194] As defined herein, a "maintenance 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. 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
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. 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 ibogaine to attenuate cravings
for a period of
time when nicotine use is not feasible., or any subvalue or subrange there
between.
[0195] "Treatment", "treating", and "treat" are defined as acting upon a
disease, disorder,
or condition with ibogaine 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
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WO 2015/134405 PCT/US2015/018356
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 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,
ancUor 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 ancUor neuropathic pain; and preventing the recurrence of
long-term pain.
[0196] "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 ibogaine, ibogaine derivative, or pharmaceutically
acceptable salt
and/or solvate thereof 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.
[0197] As used herein, the terms "addiction", "abuse", and "dependence" are
used
interchangeably to refer to the patient's inability to stop using nicotine,
alcohol, a drug, or the
like, even when it would be in his/her best interest to stop. A patient may be
physically and/or
behaviorally addicted to a substance. The DSM1V-TR criteria for dependency
include:
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
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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
[0198] 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.
[0199] As used herein, the term "patient" refers to mammals and includes
humans and
non-human mammals.
[0200] 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
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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."
[0201] 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.
[0202] 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, lofentanil, loperamide, laudanum,
meperidine,
meptazinol, metazocine, methadone, 3-methylfentanyl, 3-methylthiofentanyl,
metopon,
morphine, morpheridine, MPPP (1-methyl-4-phenyl-4-propionoxypiperidine),
myrophine,
narceine, nicomorphine, noracymethadol, norlevorphanol, normethadone,
nalorphine,
nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,
papaveretum,
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para-fluorofentanyl, paregoric, PEPAP (14-2-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.
[0203] 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.
[0204] 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.
[0205] 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 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
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disorder may or may not be associated with agoraphobia, or an irrational and
often disabling
fear of being out in public.
[0206] 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) interferes 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.
[0207] 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).
[0208] 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 ancUor 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, internet addiction, trichotillomania,
pathological skin picking,
and compulsive shopping. Impulse control disorder may be related to anxiety
disorder and/or
OCD.
[0209] 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
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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.
[0210] 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.
[0211] 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.
[0212] 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. This
phenomena¨
also known as deafferentation pain¨is almost universally reported by amputees
and
quadriplegics.
[0213] 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.
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[0214] 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).
[0215] 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.
[0216] 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 is administered. In one aspect, a therapeutically effective
amount of ibogaine
or derivative is from about 50 ng to less than 100 ps per kg of body weight.
Where other
routes of administration are used, a higher dose of the compound is
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.
[0217] 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.
[0218] "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
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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. 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.
[0219] "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.
[0220] "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.
[0221] "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.
[0222] 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
such that a higher
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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).
[0223] 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, buccal, or intranasal delivery)
is used, a lower
dose of the compound is administered. In one aspect, a therapeutically
effective amount of
ibogaine or derivative is from about 50 ng to less than about 100 jig per kg
of body weight.
Where other routes of administration are used, a higher dose of the compound
is
administered. In one embodiment, the therapeutically effective amount of the
compound is
from about 1 mg to about 4 mg per kg of body weight per day.
[0224] The term "dose" refers to a range of ibogaine, ibogaine derivative, or
pharmaceutical salt or solvate thereof that provides a therapeutic serum level
of ibogaine
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.
[0225] 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
[0226] As will be apparent to the skilled artisan upon reading this
disclosure, in one aspect
this invention provides compositions for treating a disease or disorder as
described herein in a
subject, comprising ibogaine. In another aspect this invention further
provides compositions
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for treating, attenuating, or preventing a disease or disorder or symptoms of
a disease or
disorder as described herein in a subject, comprising ibogaine.
[0227] This invention is not limited to any particular chemical form of the
compounds, 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.
[0228] In one aspect, the invention provides a pharmaceutical composition
comprising a
therapeutically or prophylactically effective amount of ibogaine and a
pharmaceutically
acceptable excipient, wherein the therapeutically or prophylactically
effective amount of
ibogaine is an amount that delivers an aggregate amount of ibogaine of about
50 ng to less
than 10 jig per kg body weight per day. In some aspects, the therapeutically
or
prophylactically effective amount of ibogaine is an amount that delivers an
aggregate amount
of ibogaine of about 50 ng to about 10 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. Dosing schemes are
discussed in
further detail below in the subsection titled "Dosing and Routes of
Administration."
[0229] In some embodiments, the composition is formulated for sublingual,
intranasal, or
intrapulmonary delivery. These routes of administration are discussed in
further detail below
in the subsection titled "Dosing and Routes of Administration."
[0230] In one aspect, the invention provides a pharmaceutical composition
comprising a
pharmaceutically effective amount of ibogaine, derivative, or salt and/or
solvate thereof and a
pharmaceutically acceptable excipient, wherein the therapeutically effective
amount of
ibogaine is an amount that delivers an aggregate amount of ibogaine of about
50 ng to less
than 100 l.tg per kg body weight per day. In some aspects, the therapeutically
effective
amount of ibogaine is an amount that delivers an aggregate amount of ibogaine
of about 50
ng to about 50 lug per kg body weight per day. In some aspects, the
therapeutically effective
amount of ibogaine is an amount that delivers an aggregate amount of ibogaine
of about 50
ng to about 10 lug per kg body weight per day. In some aspects, the
therapeutically effective
amount of ibogaine is an amount that delivers an aggregate amount of ibogaine
of about 50
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ng to about 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.
[0231] In some embodiments, the composition is foi ______ ululated for oral,
transdei mai, 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 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 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 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. In
another embodiment, the therapeutically effective amount of the compound is
about 2 mg per
kg body weight per day. The ranges include both extremes as well as any
subranges there
between.
[0232] 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
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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.
[0233] In another aspect, provided herein is a pharmaceutical composition
comprising a
therapeutically effective amount of ibogaine, ibogaine derivative, or
pharmaceutically
acceptable salt ancUor solvate thereof and a pharmaceutically acceptable
excipient, wherein
the therapeutically effective amount of ibogaine, ibogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof is an amount that delivers an aggregate
amount of
ibogaine of about 50 ng to less than 10 lig per kg body weight per day.
[0234] In one embodiment, the therapeutically effective amount of ibogaine,
ibogaine
derivative, or pharmaceutically acceptable salt thereof is an amount that
delivers an aggregate
amount of ibogaine of about 50 ng to about 1 lug per kg body weight per day.
[0235] 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 1 mg to about 2 mg per kg body weight per day. In
another
embodiment, the therapeutically effective amount of the compound is from about
1.3 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 1.7
mg to about 3 mg per kg body weight per day. In another embodiment, the
therapeutically
effective amount of the compound is from about 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. In another
embodiment, the
therapeutically effective amount of the compound is about about 2 mg per kg
body weight
per day. The ranges include both extremes as well as any subrange or subvalue
there
between.
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[0236] 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.
[0237] In another aspect, provided herein is a pharmaceutically acceptable
formulation
comprising a unit dose of ibogaine, wherein the amount of ibogaine is
sufficient to provide a
serum concentration of about 50 ng/mL to about 500 ng/mL when administered to
a patient.
Methods of the Invention
[0238] As will be apparent to the skilled artisan upon reading this
disclosure, this invention
provides a method for treating nicotine addiction, alcohol dependence, drug
addiction,pain,
depression, impulse control, anxiety, violence/anger, food intake, or
tolerance to opioids in a
subject, comprising administering to the patient in need thereof a
therapeutically effective
amount of ibogaine, an ibogaine derivative, or a pharmaceutically acceptable
salt and/or
solvate of each thereof. This invention further provides a method for
treating, attenuating, or
preventing a disease or disorder or symptoms of a disease or disorder in a
subject amenable to
treatment with the compounds utilized herein, comprising administering to the
patient in need
thereof a therapeutically or prophylactically effective amount of ibogaine, an
ibogaine
derivative, or a pharmaceutically acceptable salt and/or solvate of each
thereof.
a. Treating Nicotine Addiction
[0239] In some embodiments, the invention provides, in certain aspect, a
method for
treating nicotine addiction in a subject, comprising administering to the
patient in need
thereof a therapeutically effective amount of ibogaine, an ibogaine
derivative, or a
pharmaceutically acceptable salt and/or solvate of each thereof.
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[0240] 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.
[0241] In some embodiments, the therapeutically effective amount of the
compound is from
about 50 ng to less than 10 l.tg 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 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 jig to less than 10 pig 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 jig, about 2 jig, about 3 jig, about 3 jig, about 4 jig, about 5 jig, about
6 jig, about 7 jig,
about 8 jig, about 9 ng, about 10 lug per kilogram body weight per day. The
therapeutically
effective amount of the compound may be any amount within any of these ranges,
including
endpoints.
[0242] In some embodiments, the patient is administered periodically, such as
once, twice,
three times, four times or five times daily with ibogaine, ibogaine
derivative, or a
pharmaceutically acceptable 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, 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.
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[0243] 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 lag ibogaine per kg body weight per day
would take 90 lig
once a day, 45 jig twice a day, or 30 tig three times a day, etc.
[0244] In some embodiments, the therapeutically effective amount of ibogaine,
derivative,
or salt and/or solvate 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.
[0245] An ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt
and/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 and
transdermal 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, lEaston Pa. 1980). In some
embodiments,
the ibogaine or ibogaine 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."
[0246] In a preferred embodiment, ibogaine, ibogaine derivative, or a
pharmaceutically
acceptable salt and/or solvate thereof is administered orally, which may
conveniently be
provided in tablet, caplet, sublingual, liquid or capsule form. In certain
embodiments, the
compound is provided as a pharmaceutically acceptable salt, for example
ibogaine HCl, with
dosages reported as the amount of free base compound. In some embodiments, the

pharmaceutically acceptable salt is provided in hard gelatin capsules
containing only the salt
with no excipients.
b. Preventing Relapse Of Nicotine Use
[0247] 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 ibogaine, an ibogaine
derivative, or a
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pharmaceutically acceptable salt and/or solvate 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
ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or
solvate of each
thereof.
[0248] 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 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 ibogaine, ibogaine
derivative,
or pharmaceutically acceptable salt and/or solvate thereof is administered
before and/or
during a period of time when the patient expects to be unable to use nicotine,
wherein the
ibogaine, derivative, or salt and/or solvate 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.
[0249] In some embodiments, the ibogaine, derivative, or salt and/or solvate
is administered
on an as-needed basis by the patient. In some embodiments, the ibogaine,
derivative, or salt
and/or solvate may be administered before the nicotine craving occurs. For
example, the
patient may take a dose of ibogaine, derivative, or salt and/or solvate 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 ibogaine,
derivative, or salt and/or solvate after the nicotine craving occurs, for
example during the
craving, in order to reduce or eliminate the craving. In some embodiments, the
dose of
ibogaine, derivative, or salt and/or solvate 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.
[0250] 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
1 jig per
kilogram body weight per day. In another embodiment, the prophylactically
effective amount
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of the compound is from about 50 ng to about 500 ng per kilogram body weight
per day. In
yet another embodiment, the prophylactically effective amount of the compound
is from
about 50 ng to about 100 lag per kilogram body weight per day. The
prophylactically
effective amount of the compound may be any amount within any of these ranges,
including
endpoints.
[0251] In some embodiments, the prophylactically effective amount of ibogaine,
derivative,
or salt ancUor solvate 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.
[0252] Where the prophylactically effective amount of ibogaine, derivative, or
salt and/or
solvate thereof 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 lig ibogaine derivative, or salt and/or solvate per kg body weight
per day would take
90 n once a day, 45 tg twice a day, or 30 jig three times a day, etc.
[0253] In some embodiments, the ibogaine or ibogaine 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."
c. Alcohol Dependence
[0254] 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 ibogaine.
[0255] 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
ibogaine,
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.
[0256] 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 ibogaine that provides an
average serum
concentration of about 60 ng/mL to about 400 ng/mL, said concentration being
sufficient to
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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.
102571 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 ibogaine 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.
102581 In one embodiment, the average serum concentration of ibogaine 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 ibogaine 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
ibogaine 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 ibogaine
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 ibogaine 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 ibogaine is from about 50 ng/mL to about 300 ng/mL, or about
60 ng/mL to
about 300 ng/mL. In one embodiment, the average serum concentration of
ibogaine is from
about 50 ng/mL to about 200 ng/mL, or about 60 ng/mL to about 200 ng/mL. In
one
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embodiment, the average serum concentration of ibogaine 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.
[0259] In some embodiments, the patient is administered periodically, such as
once, twice,
three times, four times or five times daily with ibogaine, ibogaine
derivative, or a
pharmaceutically acceptable 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, 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.
[0260] In some embodiments, the ibogaine or ibogaine 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."
[0261] In some embodiments, the therapeutically effective amount of ibogaine
is
administered orally, which may conveniently be provided in tablet, caplet,
sublingual, liquid
or capsule form. In certain embodiments, the ibogaine is provided as ibogaine
HC1, with
dosages reported as the amount of free base ibogaine. In some embodiments, the
ibogaine
HC1 is provided in hard gelatin capsules containing only ibogaine HC1 with no
excipients.
[0262] 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 ibogaine. 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 ibogaine.
[0263] These dosing amounts, including administration of a maintenance amount
of
ibogaine, are discussed in further detail below in the subsection titled
"Dosage and Routes of
Administration."
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d. Drug Addiction
[0264] In some aspects, the present invention provides a method for treating
substance
abuse or addiction, including acute and post-acute withdrawal symptoms, in an
addicted
patient, comprising administering to the patient a dosage ibogaine.
[0265] 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 ibogaine.
[0266] 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 ibogaine
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.
[0267] 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 ibogaine 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.
[0268] 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 ibogaine 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.
[0269] In some embodiments, the therapeutic dose of ibogaine 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 the compound with less
prolongation of the
QT interval. Tapering involves administration of one or more subsequently
lower doses of the
compound over time.
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[0270] In one aspect, this invention relates to treatment or attenuation of
post-acute
withdrawal from an addictive substance in an addicted patient with a
maintenance amount of
ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or
solvate thereof.
[0271] In some aspects, this invention relates to a method to prevent relapse
of substance
abuse in an addicted patient treated to ameliorate said abuse, said method
comprising
periodically administering to said patient a maintenance dosage of ibogaine.
[0272] In some embodiments, the patient undergoes long-term (e.g., one year or
longer)
treatment with maintenance doses of ibogaine. In some embodiments, the patient
is treated
for acute withdrawal with therapeutic doses of ibogaine and then the amount of
compound 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.
e. Pain
[0273] In one aspect, this invention relates to treatment of pain in a patient
suffering from
pain comprising administration of a therapeutically effective amount of
ibogaine.
[0274] 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
ibogaine 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 pain. In one
embodiment, the
dosage of ibogaine results in prolongation of the QT interval of less than
about 50 ms. In one
embodiment, the dosage of ibogaine results in a QT interval of less than about
500 ms
[0275] In one embodiment, the average serum concentration of ibogaine is from
about 50
ng/mL to about 800 ng/mL or about 20 ng/mL to about 800 ng/mL. In one
embodiment, the
average serum concentration of ibogaine is from about 50 ng/mL to about 700
ng/mL or
about 20 ng/mL to about 700 ng/mL. In one embodiment, the average serum
concentration of
ibogaine is from about 50 ng/mL to about 600 ng/mL, or about 20ng/mL to about
600 ng/mL.
In a preferred embodiment, the average serum concentration of is from about 50
ng/mL to
about 500 ng/mL, or about 20ng/mL to about 500 ng/mL. In one embodiment, the
average
serum concentration of ibogaine is from about 50 ng/mL to about 400 ng/mL, or
about
20ng/mL to about 400 ng/mL. In one embodiment, the average serum concentration
of
ibogaine is from about 50 ng/mL to about 300 ng/mL, or about 20ng/mL to about
300 ng/mL.
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In one embodiment, the average serum concentration of ibogaine is from about
50 ng/mL to
about 200 ng/mL, or about 2Ong/mL to about 200 ng/mL. In one embodiment, the
average
serum concentration of ibogaine is from about 50 ng/mL to about 100 ng/mL, or
about
2Ong/mL to about 100 ng/mL. The ranges include both extremes as well as any
subranges
between.
[0276] In one embodiment, the dosage or aggregate dosage of ibogaine is from
greater than
about 1 mg/kg to about 8 mg/kg body weight per day.
f. Depression
[0277] 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.
[0278] 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.
[0279] 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.
[0280] 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.
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[0281] 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 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,
IES, 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.
[0282] 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.
[0283] 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
ibogaine,
an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate
thereof to the
patient, wherein the amount of the ibogaine or ibogaine derivative is
sufficient to treat
depression and/or PTSD in the patient.
[0284] 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 ibogaine, ibogaine
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 ibogaine or ibogaine derivative serum levels of between about 50 to
about 800 ng/ml
In some embodiments, the average ibogaine or ibogaine derivative 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 8 mg per kg of body weight. In one
embodiment, the
therapeutically effective amount is between about 50 ng to less than 100 lug
per kg of body
weight. In one embodiment, depression is treated. In one embodiment,
posttraumatic stress
disorder is treated. In one embodiment, the ibogaine, ibogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof is administered by sublingual,
intranasal, or
intrapulmonary delivery.
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g. Reduced Tolerance To Opioid Analgesics
[0285] As will be apparent to the skilled artisan upon reading this
disclosure, the present
invention provides a method for modulating tolerance to opioids in a patient
undergoing
opioid analgesic therapy, comprising administering to the patient a dosage of
ibogaine,
ibogaine derivative, or pharmaceutically acceptable salt and/or solvate
thereof.
[0286] 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.
[0287] 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 ibogaine,
ibogaine 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 resensitize the patient to the opioid as an analgesic while
maintaining a QT
interval of less than about 500 ms during said treatment.
[0288] 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 ibogaine,
ibogaine 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 resensitize the patient to the opioid as an analgesic
while maintaining a
QT interval of less than about 500 ms during said treatment. In some
embodiments, the
concentration is sufficient to resensitize the patient to the opioid as an
analgesic while
maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the
concentration is sufficient to resensitize the patient to the opioid as an
analgesic while
maintaining a QT interval of less than about 450 ms during treatment. In one
embodiment,
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the concentration is sufficient to resensitize the patient to the opioid as an
analgesic while
maintaining a QT interval of less than about 420 ms during treatment.
[0289] In some embodiments, the patient is administered periodically, such as
once, twice,
three times, four times or five times daily with ibogaine, ibogaine
derivative, or a
pharmaceutically acceptable 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, dosage, age and body weight of the patient,
condition of the
patient, opioid analgesic to which tolerance is being modulated, length of
time of analgesic
treatment, and the like, without limitation. Determination of dosage and
frequency suitable
for the present technology can be readily made a qualified clinician.
[0290] 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.
h. Impulse
Control Disorder, Anxiety-Related Disorders, Violence And/Or Anger,
Or Regulating Food Intake
[0291] 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 ibogaine,
an ibogaine
derivative, or a pharmaceutically acceptable salt and/or solvate thereof. In a
preferred
embodiment, the patient is not addicted to cocaine or an opiate.
[0292] 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 and/or
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 these references, as well as other
references cited
below, all of which are hereby incorporated herein by reference.
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[0293] 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.
[0294] 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.
[0295] 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 and/or symptoms thereof.
[0296] This invention provides a method of treating obsessions and/or
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/or compulsions.
[0297] 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.
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[0298] 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.
[0299] 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.
[0300] 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.
[0301] 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.
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[0302] 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.
[0303] 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 internet 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.
[0304] 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.
[0305] 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
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.
[0306] 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
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reducing symptoms of this disorder. It is also contemplated that the compounds
described
herein will be effective in preventing relapse of schizophrenia.
[0307] 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.
[0308] 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.
[0309] It is contemplated that the compounds described herein will be
effective in treating
Munchausen 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 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.
[0310] This invention provides a method of treating Milnchausen 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.
[0311] 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
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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.
[0312] 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.
[0313] 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.
[0314] This invention provides a method of treating anger- and/or violence-
related 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 anger- and/or
violence-related
disorder.
[0315] 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 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.
[0316] This invention provides a method of regulating food intake and/or
reducing food
cravings in a subject, which comprises administering to the patient a
therapeutically effective
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amount of any of the compounds utilized herein to regulate/reduce the
subject's food intake
and/or food cravings.
[0317] 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 ibogaine,
ibogaine
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 ibogaine serum levels of between about 50 to about 180 ng/ml.
In some
embodiments, the average ibogaine 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 ps 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 ibogaine, ibogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof is administered by sublingual, buccal,
intranasal, or
intrapulmonary delivery.
[0318] 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 ibogaine 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.
[0319] 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 ibogaine or

pharmaceutically acceptable salt and/or solvate thereof that provides an
average serum
concentration of about 50 ng/mL to about 250 ng/mL, said concentration being
sufficient to
attenuate said cravings while maintaining a QT interval of less than about 500
ms during said
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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.
[0320] 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.
[0321] 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 ibogaine, ibogaine 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 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.
[0322] 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 ibogaine, ibogaine
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
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inhibit or ameliorate said disorder or symptoms while maintaining a QT
interval of less than
about 500 ms during said treatment.
IV. Dosage and Routes of Administration
Therapeutic Dose
[0323] In one embodiment, the average serum concentration of ibogaine 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 ibogaine 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
ibogaine 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 ibogaine
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 ibogaine 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 ibogaine is from about 50 ng/mL to about 300 ng/mL, or about
60 ng/mL to
about 300 ng/mL. In one embodiment, the average serum concentration of
ibogaine 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 ibogaine 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.
[0324] In one embodiment, the average serum concentration of ibogaine 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 ibogaine 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
ibogaine is from about 50 ng/mL to about 100 ng/mL, or about 60 ng/mL to about
100
ng/mL. In one embodiment, the average serum concentration of ibogaine is from
about 80
ng/mL to about 150 ng/mL. In one embodiment, the average serum concentration
of ibogaine
is from about 80 ng/mL to about 100 ng/mL. The ranges include both extremes as
well as any
subrange or subvalue there between.
[0325] In one embodiment, the dosage of ibogaine, ibogaine 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
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ibogaine, ibogaine 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 ibogaine, ibogaine 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 subrange or
subvalue there
between.
[0326] In one embodiment, the dosage of ibogaine, ibogaine 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
ibogaine, ibogaine
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
ibogaine,
ibogaine 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
ibogaine,
ibogaine derivative, or pharmaceutically acceptable salt or solvate thereof
provides a Cmax
between about 100 ng/mL and about 180 ng/mL. The ranges include both extremes
as well as
any subrange or subvalue there between.
[0327] In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine

derivative, or pharmaceutically acceptable salt and/or solvate thereof is from
greater than
about 1 mg/kg to about 8 mg/kg body weight per day. The aggregate dosage is
the combined
dosage, for example the total amount of ibogaine, ibogaine 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 ibogaine, ibogaine 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 ibogaine, ibogaine 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 ibogaine,
ibogaine 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
ibogaine,
ibogaine 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 ibogaine,
ibogaine
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 ibogaine,
ibogaine derivative,
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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 ibogaine, ibogaine 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 ibogaine, ibogaine 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 ibogaine, ibogaine 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 ibogaine, ibogaine 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
ibogaine,
ibogaine 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.
[0328] In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine
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 ibogaine, ibogaine 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 ibogaine, ibogaine derivative, or salt and/or solvate
thereof is about 6
mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage
of ibogaine,
ibogaine 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 ibogaine, ibogaine
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 ibogaine, ibogaine 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 ibogaine,
ibogaine 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 ibogaine, ibogaine
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 ibogaine, ibogaine 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
ibogaine, ibogaine 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 ibogaine,
ibogaine derivative,
or salt and/or solvate thereof is about 1 mg/kg body weight per day.
[0329] In one aspect, the invention provides administering a pharmaceutical
composition
comprising a pharmaceutically effective amount of ibogaine and a
pharmaceutically
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acceptable excipient, wherein the therapeutically effective amount of ibogaine
is an amount
that delivers an aggregate amount of ibogaine of about 50 ng to about 100 jig
per kg body
weight per day. In some aspects, the therapeutically effective amount of
ibogaine is an
amount that delivers an aggregate amount of ibogaine of about 50 ng to about
50 jig per kg
body weight per day. In some aspects, the therapeutically effective amount of
ibogaine is an
amount that delivers an aggregate amount of ibogaine of about 50 ng to about
1011g per kg
body weight per day. In some aspects, the therapeutically effective amount of
ibogaine is an
amount that delivers an aggregate amount of ibogaine 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.
[0330] 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 ibogaine, ibogaine 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.
[0331] In one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine

derivative, or salt or solvate thereof is between about 70 mg and about 150
mg. In one
embodiment, the dosage or aggregate dosage of ibogaine, ibogaine derivative,
or salt or
solvate thereof is between about 75 mg and about 150 mg. In one embodiment,
the dosage or
aggregate dosage of ibogaine, ibogaine derivative, or salt or solvate thereof
is between about
80 mg and about 140 mg. In one embodiment, the dosage or aggregate dosage of
ibogaine,
ibogaine derivative, or salt or solvate thereof is between about 90 mg and
about 140 mg. In
one embodiment, the dosage or aggregate dosage of ibogaine, ibogaine
derivative, or salt or
solvate thereof is between about 90 mg and about 130 mg. In one embodiment,
the dosage or
aggregate dosage of ibogaine, ibogaine derivative, or salt or solvate thereof
is between about
100 mg and about 130 mg. In one embodiment, the dosage or aggregate dosage of
ibogaine,
ibogaine derivative, or salt or solvate thereof is between about 110 mg and
about 130 mg.
The ranges include both extremes as well as any subrange or subvalue there
between.
[0332] In another embodiment, there is provided a unit dose of ibogainc,
ibogaine
derivative, or salt or solvate thereof which is about 50 mg to about 200 mg
per dose. In one
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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.
[0333] In some embodiments, the patient is administered an initial dose of
ibogaine,
ibogaine 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 ibogaine 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.
[0334] In some embodiments, the initial dose of ibogaine, ibogaine derivative,
or salt or
solvate thereof is from about 75 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.
[0335] 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 about 5 mg
to about 50
mg. In one embodiment, the one or more additional doses may or may not
comprise the same
amount of ibogaine, ibogaine 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.
[0336] In one embodiment, the one or more additional doses are administered
periodically.
In one embodiment, the one or more additional doses are administered
approximately every 4
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WO 2015/134405 PCT/US2015/018356
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
approximately every 8
hours. In one embodiment, the one or more additional doses are administered
approximately
every 10 hours. In one embodiment, the one or more additional doses are
administered
approximately every 12 hours. In one embodiment, the one or more additional
doses are
administered approximately every 18 hours. In one embodiment, the one or more
additional
doses are administered approximately every 24 hours. In one embodiment, the
one or more
additional doses are administered approximately every 36 hours. In one
embodiment, the one
or more additional doses are administered approximately every 48 hours.
[0337] In some embodiments, the patient is administered a high
(therapeutic) dose of
ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or
solvate thereof for a
period of time to ameliorate the most significant symptoms of a disease or
disorder, and then
is administered a lower (maintenance) dose to prevent relapse. In some
embodiments, the
patient is administered a therapeutic dose of ibogaine, ibogaine derivative,
or
pharmaceutically acceptable salt and/or solvate thereof for a period of time
to ameliorate the
most significant symptoms, and then is administered a decreasing (tapered)
amount of
ibogaine, ibogaine derivative, or pharmaceutically acceptable salt and/or
solvate thereof over
time until the maintenance dose is reached.
[0338] For treating pain the following dosages are contemplated as useful.
[0339] In one embodiment, the therapeutically effective amount of the compound
is from
about 0.1 mg to about 5 mg per kg body weight per day. In another embodiment,
the
therapeutically effective amount of the compound is from about 0.1 mg to about
3 mg per kg
body weight per day. In another embodiment, the therapeutically effective
amount of the
compound is from about 0.1 mg to about 2 mg per kg body weight per day. In
another
embodiment, the therapeutically effective amount of the compound is from about
0.1 mg to
about 1.5 mg per kg body weight per day. In another embodiment, the
therapeutically
effective amount of the compound is from about 0.1 mg to about 1 mg per kg
body weight
per day. In another embodiment, the therapeutically effective amount of the
compound is
from about 0.5 mg to about 3 mg per kg body weight per day. In another
embodiment, the
therapeutically effective amount of the compound is from about 0.5 mg to about
2 mg per kg
body weight per day. In another embodiment, the therapeutically effective
amount of the
compound is from about 0.5 mg to about 1.5 mg per kg body weight per day. In
another
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embodiment, the therapeutically effective amount of the compound is from about
0.5 mg to
about 1.3 mg per kg body weight per day. In another embodiment, the
therapeutically
effective amount of the compound is from about 0.5 mg to about 1.2 mg per kg
body weight
per day. In another embodiment, the therapeutically effective amount of the
compound is
from about 0.5 mg to about 1.1 mg per kg body weight per day. In another
embodiment, the
therapeutically effective amount of the compound is from about 0.5 mg to about
1 mg per kg
body weight per day. In another embodiment, the therapeutically effective
amount of the
compound is from about 0.7 mg to about 1.5 mg per kg body weight per day. The
ranges
include both extremes as well as any subranges there between.
[0340] 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. 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.
[0341] In one embodiment, Ibogaine is administered at an amount by weight that
is twice
that administered for noribogaine for treating a same or similar condition.
For example, and
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without limitation, an administration of a dose 80 mg ibogaine approximates a
dose of 40 mg
noribogaine.
Maintenance Dose
[0342] In some embodiments, the maintenance dose of ibogaine, ibogaine
derivative, or
pharmaceutically acceptable salt and/or solvate thereof is about 10% to about
80% of the
therapeutic dose. In some embodiments, the maintenance dose of ibogaine or
pharmaceutically acceptable salt ancUor solvate thereof is about 70% of the
therapeutic dose.
In some embodiments, the maintenance dose is about 60% of the therapeutic
dose. In some
embodiments, the maintenance dose is about 50% of the therapeutic dose. In
some
embodiments, the maintenance dose is about 40% of the therapeutic dose. In
some
embodiments, the maintenance dose is about 30% of the therapeutic dose. In
some
embodiments, the maintenance dose is about 20% of the therapeutic dose. In
some
embodiments, the maintenance dose is about 10% of the therapeutic dose.
[0343] In some embodiments, the maintenance average serum level of ibogaine is
about
10% to about 80% of the therapeutic average serum level of ibogaine. In some
embodiments,
the maintenance average serum level of ibogaine is about 70% of the
therapeutic average
serum level of ibogaine. In some embodiments, the maintenance average serum
level of
ibogaine is about 60% of the therapeutic average serum level of ibogaine. In
some
embodiments, the maintenance average serum level of ibogaine is about 50% of
the
therapeutic average serum level of ibogaine. In some embodiments, the
maintenance average
serum level of ibogaine is about 40% of the therapeutic average serum level of
ibogaine. In
some embodiments, the maintenance average serum level of ibogaine is about 30%
of the
therapeutic average serum level of ibogaine. In some embodiments, the
maintenance average
serum level of ibogaine is about 20% of the therapeutic average serum level of
ibogaine. In
some embodiments, the maintenance average serum level of ibogaine is about 10%
of the
therapeutic average serum level of ibogaine.
Tapered Dosing
[0344] In some embodiments, the therapeutic dose of ibogaine, ibogaine
derivative, or salt
ancUor 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
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ibogaine with less prolongation of the QT interval. Tapering involves
administration of one
or more subsequently lower doses of ibogaine over time. For example, in some
embodiments,
the first tapered dose is about 50% to about 95% of the first or original
dose. In some
embodiments, the second tapered dose is about 40% to about 90% of the first or
original
dose. In some embodiments, the third tapered dose is about 30% to about 85% of
the first or
original dose. In some embodiments, the fourth tapered dose is about 20% to
about 80% of
the first or original dose. In some embodiments, the fifth tapered dose is
about 10% to about
75% of the first or original dose.
[0345] In some embodiments, the first tapered dose is given after the first
dose of ibogaine,
ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate
thereof. In some
embodiments, the first tapered dose is given after the second, third, or a
subsequent dose of
compound. The first tapered dose may be administered at any time after the
previous dose of
compound.
[0346] In one embodiment, the therapeutic dose of ibogaine, ibogaine
derivative, or
pharmaceutically acceptable salt and/or solvate is tapered over time until the
desired
maintenance dose is reached. For example, in some embodiments, the first
tapered dose is
about 50% to about 95% of the therapeutic dose. In some embodiments, the
second tapered
dose is about 40% to about 90% of the therapeutic dose. In some embodiments,
the third
tapered dose is about 30% to about 85% of the therapeutic dose. In some
embodiments, the
fourth tapered dose is about 20% to about 80% of the therapeutic dose. In some

embodiments, the fifth tapered dose is about 10% to about 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.
[0347] The first tapered dose may be administered at any time after the
previous dose of
ibogaine. 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 given after the first dose of ibogaine. In some embodiments, the first
tapered dose is
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given after the second, third, or a subsequent dose of ibogaine. 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 ibogaine. 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 ibogaine.
[0348] 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.
[0349] 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
ibogaine,
ibogaine derivative, or salt and/or solvate thereof In some embodiments, the
patient is treated
for acute withdrawal with therapeutic doses of ibogaine as described above,
and then the
amount of ibogaine 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 week after cessation of alcohol use, although acute
withdrawal may
last as long as six weeks or more.
[0350] 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
ibogaine or
ibogaine derivative and a pharmaceutically acceptable excipient, wherein the
therapeutically
effective amount of ibogaine or ibogaine derivative is an amount that delivers
an aggregate
amount of ibogaine or ibogaine derivative of about 50 ng to less than 100 jig
per kg body
weight per day. In some aspects, the therapeutically effective amount of
ibogaine or ibogaine
derivative is an amount that delivers an aggregate amount of ibogaine or
ibogaine derivative
of about 50 ng to about 50 jag per kg body weight per day. In some aspects,
the
therapeutically effective amount of ibogaine or ibogaine derivative is an
amount that delivers
an aggregate amount of ibogaine or ibogaine derivative of about 50 ng to about
10 jig per kg
body weight per day. In some aspects, the therapeutically effective amount of
ibogaine or
ibogaine derivative is an amount that delivers an aggregate amount of ibogaine
or ibogaine
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WO 2015/134405 PCT/US2015/018356
derivative 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.
[0351] In some embodiments, the composition is administered via oral,
transdermal,
internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous,
intraarterial, intramuscular,
intraperitoneal, intracutaneous or subcutaneous delivery.
[0352] A particularly suitable composition comprises a composition suitable
for a
transdermal route of delivery in which the ibogaine or ibogaine derivative is
applied as part
of a cream, gel or, preferably, patch (for examples of transdermal
formulations, see U.S. Pat.
Nos. 4,806,341; 5,149,538; and 4,626,539, each of which are incorporated
herein by
reference).
[0353] 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.
Formulations
[0354] This invention further relates to pharmaceutically acceptable
formulations
comprising a unit dose of ibogaine, ibogaine derivative, or pharmaceutically
acceptable salt
and/or solvate thereof. In some embodiments, the amount of ibogaine is
sufficient to provide
an average serum concentration of about 50 ng/mL to about 850 ng/mL when
administered to
a patient. In other embodiments, the amount of ibogaine is sufficient to
provide an average
serum concentration of about 50 ng/mL to about 400 ng/mL when administered to
a patient.
[0355] In some embodiments, the unit dose of ibogaine is administered in one
or more
dosings.
[0356] In one embodiment, the amount of ibogaine is sufficient to provide an
average
serum concentration of ibogaine 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 ibogaine is
sufficient to
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WO 2015/134405 PCT/US2015/018356
provide an average serum concentration of ibogaine 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
ibogaine is
sufficient to provide an average serum concentration of ibogaine 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 ibogaine is sufficient to provide an average serum concentration of
ibogaine 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 ibogaine is sufficient to provide an average serum
concentration
of ibogaine 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 ibogaine is sufficient to provide an
average serum
concentration of ibogaine 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 ibogaine is sufficient to
provide an
average serum concentration of ibogaine 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 ibogaine is
sufficient to
provide an average serum concentration of ibogaine 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.
[0357] In some embodiments, the formulation is designed for periodic
administration, such
as once, twice, three time, four times or five time daily with ibogaine or a
pharmaceutically
acceptable 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 a qualified clinician.
Delivery method
[0358] The compositions, provided herein or known, suitable for administration
in
accordance with the methods provided herein, can be suitable for a variety of
delivery modes
including, without limitation, sublingual, intrapulmonary, or intranasal
delivery.
Compositions suitable for internal, pulmonary, rectal, nasal, vaginal,
lingual, intravenous,
intra-arterial, intramuscular, intra-peritoneal, intra-cutaneous and
subcutaneous routes may
also be used. Other dosage forms include tablets, capsules, pills, powders,
aerosols,
suppositories, parenterals, and oral liquids, including suspensions, solutions
and emulsions.
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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).
[0359] The compositions provided herein 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 ibogaine 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.
[0360] The compositions utilized herein may be formulated for aerosol
administration,
particularly to the respiratory tract and including intrapulmonary or
intranasal 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.
[0361] In some embodiments, ibogaine is administered orally, which may
conveniently be
provided in tablet, caplet, sublingual, liquid or capsule form. In certain
embodiments, the
ibogaine is provided as ibogaine HC1, with dosages reported as the amount of
free base
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ibogaine. In some embodiments, the ibogaine HC1 is provided in hard gelatin
capsules
containing only ibogaine HC1 with no excipients.
[0362] 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.
[0363] It has been discovered that ibogaine 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; 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.
Patient Pre-screening and Monitoring
[0364] Pre-screening of patients before treatment with ibogaine and/or
monitoring of
patients during ibogaine treatment may be required to ensure that QT interval
is not
prolonged beyond a certain value. For example, QT interval greater than 500 ms
can be
considered dangerous for individual patients. Pre-screening ancUor monitoring
may be
necessary at high levels of ibogaine treatment.
[0365] In some embodiments, a patient receiving ibogaine 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.
[0366] In one embodiment, a patient receiving ibogaine is not monitored in a
clinical
setting. In one embodiment, a patient receiving ibogaine is monitored
periodically, for
example daily, weekly, monthly, or occasionally.
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[0367] In one aspect, this invention relates to a method for treating a
disease or disorder or
symptoms of a disease or disorder, comprising selecting addicted dependent
patient who is
prescreened to evaluate the patient's expected tolerance for prolongation of
QT interval,
administering to the patient a dosage of ibogaine 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 or symptoms while maintaining a QT interval
of less than
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.
[0368] In one embodiment, prescreening of the patient comprises ascertaining
that ibogaine
treatment will not result in a QT interval over about 500 ms. In one
embodiment,
prescreening of the patient comprises ascertaining that ibogaine treatment
will not result in a
QT interval over about 470 ms. In one embodiment, prescreening comprises
ascertaining that
ibogaine treatment will not result in a QT interval over about 450 ms. In one
embodiment,
prescreening comprises ascertaining that ibogaine treatment will not result in
a QT interval
over about 420 ms. In one embodiment, prescreening comprises determining the
patient's
pre-treatment QT interval.
[0369] 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 ibogaine treatment or restricting dose of
ibogaine
administered to the patient: high QT interval before treatment (e.g., such
that there is a risk of
the patient's QT interval exceeding 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
ibogaine to a
patient that lacks one more of such criteria.
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[0370] 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 ibogaine. In one embodiment, a patient at risk for prolongation
of the QT
interval beyond a safe level is administered ibogaine at a limited dosage.
[0371] In one embodiment, this invention relates to monitoring a patient who
is
administered a therapeutic dose of ibogaine, ibogaine derivative, or
pharmaceutically
acceptable salt and/or solvate thereof. In one embodiment, the dose of
ibogaine is reduced if
the patient has one or more adverse side effects. In one embodiment, the
ibogaine treatment is
discontinued if the patient has one or more adverse side effects. In one
embodiment, the
adverse side effect is a QT interval that is prolonged beyond a safe level.
The determination
of a safe level of prolongation is within the skill of a qualified clinician.
Kit of Parts
[0372] One aspect of this invention is directed to a kit of parts for the
treatment of a disease
or disorder and/or symptoms of a disease or disorder as described herein in a
patient, wherein
the kit comprises a composition comprising ibogaine, ibogaine derivative, or
salt and/or
solvate thereof and 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 ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and/or
solvate thereof;
a transdermal patch, a syringe, a needle, an IV bag comprising the
composition, a vial
comprising the composition, an inhaler comprising the composition, etc. In one
embodiment,
the kit of parts further comprises instructions for dosing and/or
administration of the
composition.
[0373] In some aspects, the invention is directed to a kit of parts for
administration of
ibogaine, the kit comprising multiple delivery vehicles, wherein each delivery
vehicle
contains a discrete amount of ibogaine, ibogaine derivative, or
pharmaceutically acceptable
salt and/or solvate thereof; and further wherein each delivery vehicle is
identified by the
amount of ibogaine, ibogaine derivative, or pharmaceutically acceptable salt
and/or solvate
thereof 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 ibogaine 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
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ability to select a dosing regimen of ibogaine 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.
[0374] The term "delivery vehicle" as used herein refers to any formulation
that can be
used for administration of ibogaine 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.
[0375] 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.
[0376] In some aspects, the machine-readable medium comprises software that
contains
information regarding dosing schedules for the unit dose form of ibogaine 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 ibogaine recommended to be
delivered will
be within the dosages that result in the serum concentrations as provided
herein.
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[0377] 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 240 mg, 120 mg, 90 mg, 60 mg, 30 mg, 20 mg, and/or
10 mg of
ibogaine 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.
[0378] One aspect of this invention is directed to a kit of parts for the
treatment of a disease
or disorder described herein, wherein the kit comprises a unit dose form of
ibogaine, ibogaine
derivative, or salt and/or solvate thereof. The unit dose form provides a
patient with an
average serum level of ibogaine 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 ibogaine of from about 50 ng/mL to about 400 ng/mL or
about 60
ng/mL to about 400 ng/mL.
[0379] In some embodiments, the unit dose form comprises one or multiple
dosages to be
administered periodically, such as once, twice, three time, four times or five
time daily with
ibogaine, ibogaine derivative, or pharmaceutically acceptable 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 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.
[0380] These dose ranges may be achieved by transdermal, oral, or parenteral
administration of ibogaine or a pharmaceutically acceptable salt and/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 ibogaine is
provided as ibogaine
HC1, with dosages reported as the amount of free base ibogaine. In some
embodiments, the
ibogaine HC1 is provided in hard gelatin capsules containing only ibogaine HC1
with no
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excipients. In some embodiments, ibogaine is provided in saline for
intravenous
administration.
103811 In another aspect, provided herein is a kit of parts for administration
of ibogaine, the
kit comprising multiple delivery vehicles, wherein each delivery vehicle
contains a discrete
amount of ibogaine and further wherein each delivery vehicle is identified by
the amount of
ibogaine provided therein; and optionally further comprising a dosing
treatment schedule in a
readable medium.
[0382] In one embodiment, the amount of ibogaine required to achieve each
maximum
serum level is provided in the readable medium. In another embodiment, the
readable
medium is a computer-readable medium. In another embodiment, the multiple
delivery
vehicles contain different amounts of ibogaine. In another embodiment, the
dosing treatment
schedule provides an attending clinician the ability to select a dosing
regimen of ibogaine
based on the sex of the patient, mass of the patient, and the serum level that
the clinician
desires to achieve. In another embodiment, the dosing treatment schedule
further provides
information corresponding to the volume of blood in a patient based upon
weight and sex of
the patient.
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EXAMPLES
[0383] Additional embodiments are disclosed in further detail in the following
examples,
which are not in any way intended to limit the scope of the claims.
Example 1: Effect Of Low Dose Of Ibogaine On Smoking Cessation
[0384] A female habitual smoker intranasally absorbs a milligram amount of
ibogaine
hydrochloride. During a period of several hours, any craving to smoke is
measured
periodically.
Example 2. Efficacy Of Ibogaine, Ibogaine Derivative, Or A Pharmaceutically
Acceptable Salt Thereof In Humans
[0385] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically
acceptable salt
thereof is evaluated in alcohol-dependent participants in a randomized,
placebo-controlled,
double-blind trial. Patients are administered placebo or 60 mg or 120 mg of
the compound
and QT interval is measured.
Example 3. Efficacy Of Ibogaine In Treating Substance Dependency
[0386] The efficacy of ibogaine 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 4. Use Of Ibogaine To Treat Chronic Pain In Humans
[0387] Six patients experiencing chronic pain are screened and selected to
receive
administration of ibogaine. Four patients intranasally absorb a milligram
amount of ibogaine
hydrochloride and the remaining two patients receiv a placebo. The level of
pain and pain
relief of the patients are measured.
Example 5. Forced Swim Test (FST) With Rats
[0388] 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.
[0389] Drug Administration: Animals are randomly assigned to receive a single
intraperitoneal administration of vehicle (2.5% Et0H/2.5% Tween-80),
imipramine (positive
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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.
[0390] 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.
[0391] 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 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.
[0392] 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 6. Forced Swim Test (FST) With Mice
[0393] 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.
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[0394] 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.
[0395] 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.
[0396] 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.
[0397] Data Analysis: The forced swim test data (time exhibiting immobility,
mobility;
seconds) are subjected to a randomized, one-way ANOVA 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 7. Effect of ibogaine on QT interval in humans
[0398] The safety of ibogaine, ibogaine derivative, or a pharmaceutically
acceptable salt
and/or solvate thereof is evaluated in patients 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 8. Effect of ibogaine on depression in humans
[0399] A male patient, age 55, suffering from depression unrelated to the use
of any illicit
substance, is treated with ibogaine hydrochloride at a dose of about 1
mg/kg/day for a period
of four weeks. During the treatment period, his depression is determined by
the patient's self-
reporting of a decrease in symptoms and/or changes in one or more of the
following tests:
HDRS, Hamilton depressed mood item, and CGI-Severity of Illness.
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Example 9. Efficacy of ibogaine to modulate opioid tolerance in humans
[0400] A female patient, age 59, undergoing opioid analgesic therapy for
chronic back pain,
is treated with ibogaine hydrochloride at a dose of about 2 mg/kg concurrently
with the
opioid. The amount of opioid required to treat her back pain after ibogaine
treatment is
measured.
Example 10. Social Interaction Test (SIT)
[0401] 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.
[0402] 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
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.
[0403] 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
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test). The data are analyzed using the GBSTAT program, version 6.5 (Dynamics
Microsystems, Inc., Silver Spring, Md., 1997).
Example 11. Efficacy of ibogaine, ibogaine derivative, or a pharmaceutically
acceptable salt thereof on anxiety-related disorders in humans
[0404] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically
acceptable salt
thereof is evaluated in participants undergoing treatment for an anxiety-
related disorder in a
randomized, placebo-controlled, double-blind trial. Patients are not taking
any other
medications to treat anxiety. Patients are administered placebo or 60 mg or
120 mg of the
compound and QT interval is measured.
Example 12. Efficacy of ibogaine, ibogaine derivative, or a pharmaceutically
acceptable salt thereof on impulse control disorders in humans
[0405] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically
acceptable salt
thereof is evaluated in participants undergoing treatment for an impulse
control disorder in a
randomized, placebo-controlled, double-blind trial. Patients are not taking
any other
medications to treat anxiety. Patients are administered placebo or 60 mg or
120 mg of the
compound and QT interval is measured.
Example 13. Efficacy of ibogaine, ibogaine derivative, or a pharmaceutically
acceptable salt thereof on violence-related disorders in humans
[0406] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically
acceptable salt
thereof is evaluated in participants undergoing treatment for a violence-
related disorder in a
randomized, placebo-controlled, double-blind trial. Patients are not taking
any other
medications to treat anxiety. Patients are administered placebo or 60 mg or
120 mg of the
compound and QT interval is measured. Mean prolongation of the QT interval
and/or the
severity of violent outbursts, are determined by self-evaluation and clinical
evaluation.
Example 14. Efficacy of ibogaine, ibogaine derivative, or a pharmaceutically
acceptable salt thereof on food intake in humans
[0407] The efficacy of ibogaine, ibogaine derivative, or a pharmaceutically
acceptable salt
thereof is evaluated in participants undergoing treatment for obesity related
to over-eating in
a randomized, placebo-controlled, double-blind trial. Patients are not taking
any other
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medications to treat anxiety. Patients are administered placebo or 60 mg or
120 mg of the
compound and QT interval is measured. Mean prolongation of the QT interval,
weight loss
and food intake and/or cravings, are determined by self-evaluation and
clinical evaluation.
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