Note: Descriptions are shown in the official language in which they were submitted.
WO 2022/235529
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METHOD OF TITRATING DOSE OF PSYCHEDELICS
BACKGROUND OF THE INVENTION
1. TECHNICAL FIELD
[0001]
The present invention relates to compositions and methods for dosing
psychedelics.
2. BACKGROUND ART
[0002]
Psychedelics including lysergic acid diethylamide (LSD) are substances
capable
of inducing unique subjective effects including alterations of consciousness,
positive emotions,
enhanced introspection, changes in the perception of the environment, the
body, and the self
as well as synesthesia, mystical-type experiences, and experiences of ego
dissolution
(Carhart-Harris et al., 2016b; Do!der et al., 2016; Holze et al., 2021;
Liechti, 2017; Passie et
al., 2008; Schmid et al., 2015).
[0003]
All serotonergic psychedelics including LSD, psilocybin, DMT, and
mescaline are
nonspecific serotonin agonists including agonist activity at the serotonin 5-
HT2A receptor
(Rickli et al., 2016) and may therefore produce overall largely similar
effects. Additionally,
psychedelic substances produce their acute effects in humans via activation of
the serotonin 5-
HT2A receptor as specifically shown in clinical studies for LSD (Holze et al.,
2021; PreIler et
al., 2017). LSD and other hallucinogens are partial agonists of the serotonin
5-HT2A receptor
(Lopez-GimOnez, et al. Hallucinogens and Serotonin 5-HT2A Receptor-Mediated
Signaling
Pathways. Curr Top Behav Neurosci. 2018;36:45-73; Canal CE. Serotonergic
Psychedelics:
Experimental Approaches for Assessing Mechanisms of Action. Handb Exp
Pharmacol.
2018;252:227-260).
[0004]
Acute effects of psychedelics that may contribute to their therapeutic
benefits
include enhancing the therapeutic relationship by increased openness, trust,
feelings of
connectedness or emulsion with people, insight in psychological problems and
stimulation of
neuroregenerative processes as described in detail elsewhere (Vollenweider &
PreIler, 2020).
[0005]
Psychedelic administration, especially at doses believed to be
therapeutic, has a
side effect of hallucinations or perceptual disturbances (Unger!eider, J.
THOMAS. The acute
side effects from LSD." The problems and prospects of LSD (1968): 61-68),
(Nichols,
Psychedelics, Pharmacol Rev 68:264-355). These side effects make it unsafe for
subjects to
administer psychedelics except under direct medical supervision and could
present a
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significant risk to patient safety if the side effects occur while the patient
is driving, operating
machinery or not under medical supervision. These side effects that are the
hallmarks of
psychedelic administration are mediated by the drug's activity at the
serotonin 5-HT2A
receptor, as evidenced by the fact that blockade of this activity (by
administration of a 5-HT2A
antagonist, such as ketanserin) can attenuate these psychoactive /
hallucinogenic side effects
(Holze et al., 2020).
[0006]
Repeat administration of psychedelics (e.g., on a daily basis) has
been shown to
qualitatively have clinical benefit while the side effects of
hallucination/perceptual disturbance
may go away after a few days of treatment due to tachyphylaxis (i.e., via down
regulation of 5-
HT2A receptors) as reviewed by Buchborn (2016).
Nonetheless, for the first days of
administration of a psychedelic drug, the subject is likely to experience the
common adverse
events of hallucination, perceptual disturbance and others that may present a
risk to the
patient.
[0007]
The Cleveland Clinic describes that titration is a method that limits
potential side
effects by taking time to see how one's body reacts to a drug, wherein
medication is started at
a low dose and then the dose is raised every couple of weeks until the maximum
effective
dose (target dose) has been achieved or side effects occur. Caffrey, et al.
(Ther Adv Drug Sat.
2021 Jan 19; 11: 2042098620958910) describes that titration is commonly used
for drugs with
a narrow therapeutic index to provide treatment at the lowest dose possible
while minimizing
medication use and side effects. It is a patient-centered approach to provide
individualized
therapy. Titration has been used for antibiotics, anticoagulants,
anticonvulsants,
antidepressants, antidiabetics, antipsychotics, opioids, and stimulants.
[0008]
There remains a need for treatments with psychedelics that avoid or
reduce
unwanted side effects.
SUMMARY OF THE INVENTION
[0009]
The present invention provides for a method of dosing a psychedelic
that avoids
the side effects of hallucinations and perceptual disturbances by
administering the psychedelic
to an individual in a titrating dosing regimen and reducing side effects of
hallucinations and
perceptual disturbances.
[00010]
The present invention provides for a kit for administering a titrating
dosing
regimen of a psychedelic, including a pharmaceutically effective amount of the
psychedelic in
dosage forms separated in packaging according to dose and time of
administration in a
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titrating dosing regimen, and instructions for use.
[00011] The present invention also provides for a method of treating
an individual with
psychedelics, by administering the psychedelic to the individual having a
condition or disease
in a titrating dosing regimen and reducing side effects of hallucinations and
perceptual
disturbances during treatment.
DESCRIPTION OF THE DRAWINGS
[00012] Other advantages of the present invention are readily
appreciated as the same
becomes better understood by reference to the following detailed description
when considered
in connection with the accompanying drawings wherein:
[00013] FIGURE 1 is a graph of dose versus time.
DETAILED DESCRIPTION OF THE INVENTION
[00014] The present invention provides for a method of dosing a
psychedelic that avoids
the side effects of hallucinations and perceptual disturbances by
administering the psychedelic
to an individual in a titrating dosing regimen and reducing side effects of
hallucinations,
perceptual disturbances, and other immediately detectable effects of the
psychedelic while
preserving desired therapeutic benefits.
[00015] More specifically, the titrating dosing regimen can include
administering a starting
dose to the individual, and at a set amount of time, increasing the dose a set
amount and
administering the increased dose to the individual, and repeating these steps
over a period of
time that the individual is being treated and until a maximum desired dose is
reached. The
dosing regimen can generally be described by the following equation: Dose = X
(starting dose)
+ Y (dose increase) * Z (period of time)
[00016] As opposed to the prior uses of repeat daily administration
(of for example 100
pg LSD every day), the starting dose can be a sub-perceptual dose (e.g., 10
pg) and taper up
over time in a regimen that would never have the hallucinatory side effect but
would achieve
an effective dose that would be perceptual/hallucinogenic if administered in
the absence of the
titration regimen (e.g., 30, 50, 100 or 200 pg as the target therapeutic
dose). For example, the
starting dose can be 10 pg, which is increased by 10 pg every (2, 3, 4, 5, 6
or 7 days). Other
starting doses can be within the ranges described below. Other examples of
dosing can be
found in Buchborn (2016).
[00017] The time period can be hours, days, weeks, months, or years,
or intervals of
dose titration with intervals of non-dosing, where each dose titration period
can lead to the
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ability to avoid hallucinations, perceptual, and other detectable effects of
the psychedelic, while
preserving or enhancing desired therapeutic effects.
[00018] The starting dose and increased dose levels can be
administered once per day,
twice per day or three times per day, and can be administered by a care giver,
healthcare
provider, or self administered by the patient with or without supervision.
[00019] The dose increase can be any small amount such as 10, 20, 30
or 50 pg, and
can be effected and determined by drug and formulation variation, and patient
specific factors
such as weight, height, body surface area, biochemical assays, metabolic
assays, or genomic
assays.
[00020] The dosage form used can be any suitable dosage form such as
tablets,
capsules, lozenges, transdermal patches, implanted devices, solutions, gels,
emulsions, or any
solid or liquid form, or some combination of forms, as well as those further
described below.
[00021] The starting dose can also be a larger loading dose
administered under medical
supervision followed by repeat sub-perceptual doses to maintain the treatment
benefit while
limiting side effects to only the first dose.
[00022] The psychedelics in the present invention can be, but are
not limited to, lysergic
acid diethylamide (LSD), psilocybin, mescaline, 5-methoxy-N,N-
dimethyltryptamine (5-Me0-
DMT), dimethyltryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-
dimethoxy-4-
bromoamphetamie (DOB), salts thereof, tartrates thereof, analogs thereof, or
homologues
thereof. Preferably, the dose of the psychedelic is one that provides a
meaningful effect. A
dose of 0.01-1 mg (10-1000 14) can be used of LSD. Psilocybin can be dosed at
5-50 mg,
mescaline can be dosed at 50-800 mg, 5-Me0-DMT can be dosed at 1-20 mg, DMT
can be
dosed at 20-100 mg, DOI can be dosed at 0.1-5 mg, and DOB can be dosed at 0.1-
5 mg.
Effects of the psychedelic drug can last 1-12 hours after administration, and
the individual can
be supervised by medical personnel such as a psychiatrist during this time. If
lower doses are
given, medical supervision can be unnecessary.
[00023] The present invention can carry out its clinical effect by
down-regulating (or
reducing the expression of) the serotonin 5-HT2A receptor or by another
mechanism of action
that reduces the hallucinogenic effects of a psychedelic drug over time.
[00024] The compounds of the present invention are administered and
dosed in
accordance with good medical practice, considering the clinical condition of
the individual
patient, the site and method of administration, scheduling of administration,
patient age, sex,
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body weight and other factors known to medical practitioners. The
pharmaceutically "effective
amount" for purposes herein is thus determined by such considerations as are
known in the
art. The amount must be effective to achieve improvement including but not
limited to
improved survival rate or more rapid recovery, or improvement or elimination
of symptoms and
other indicators as are selected as appropriate measures by those skilled in
the art.
[00025] In the method of the present invention, the compounds of
the present invention
can be administered in various ways. It should be noted that they can be
administered as the
compound and can be administered alone or as an active ingredient in
combination with
pharmaceutically acceptable carriers, diluents, adjuvants, and vehicles. The
compounds can
be administered orally, transcutaneously, subcutaneously or parenterally
including
intravenous, intramuscular, and intranasal administration. The patient being
treated is a warm-
blooded animal and, in particular, mammals including man. The pharmaceutically
acceptable
carriers, diluents, adjuvants, and vehicles as well as implant carriers
generally refer to inert,
non-toxic solid or liquid fillers, diluents or encapsulating material not
reacting with the active
ingredients of the invention.
[00026] The doses can be single doses or multiple doses or a
continuous dose over a
period of several hours, days, weeks, or months.
[00027] When administering the compound of the present invention
parenterally, it will
generally be formulated in a sublingual or buccal dissolving tablet,
dissolving film, intranasal
powder, intranasal solution, inhaled powder, inhaled solution, transdermal
patch, transdermal
patch (with microneedles or other permeation enhancers) or as a unit dosage
injectable form
(solution, suspension, emulsion). The pharmaceutical formulations suitable for
injection
include sterile aqueous solutions or dispersions and sterile powders for
reconstitution into
sterile injectable solutions or dispersions. The carrier can be a solvent or
dispersing medium
containing, for example, water, ethanol, polyol (for example, glycerol,
propylene glycol, liquid
polyethylene glycol, and the like), suitable mixtures thereof, and vegetable
oils.
[00028] Proper fluidity can be maintained, for example, by the use
of a coating such as
lecithin, by the maintenance of the required particle size in the case of
dispersion and by the
use of surfactants. Nonaqueous vehicles such a cottonseed oil, sesame oil,
olive oil, soybean
oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl
myristate, may also be
used as solvent systems for compound compositions. Additionally, various
additives which
enhance the stability, sterility, and isotonicity of the compositions,
including antimicrobial
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preservatives, antioxidants, chelating agents, and buffers, can be added.
Prevention of the
action of microorganisms can be ensured by various antibacterial and
antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, and the like. In many
cases, it will be
desirable to include isotonic agents, for example, sugars, sodium chloride,
and the like.
Prolonged absorption of the injectable pharmaceutical form can be brought
about by the use of
agents delaying absorption, for example, aluminum monostearate and gelatin.
According to
the present invention, however, any vehicle, diluent, or additive used would
have to be
compatible with the compounds.
[00029] Sterile injectable solutions can be prepared by
incorporating the compounds
utilized in practicing the present invention in the required amount of the
appropriate solvent
with various of the other ingredients, as desired.
[00030] A pharmacological formulation of the present invention can
be administered to
the patient in an injectable formulation containing any compatible carrier,
such as various
vehicle, adjuvants, additives, and diluents; or the compounds utilized in the
present invention
can be administered parenterally to the patient in the form of slow-release
subcutaneous
implants or targeted delivery systems such as monoclonal antibodies, vectored
delivery,
iontophoretic, polymer matrices, liposomes, and microspheres. Examples of
delivery systems
useful in the present invention include: 5,225,182; 5,169,383; 5,167,616;
4,959,217;
4,925,678; 4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and
4,475,196. Many
other such implants, delivery systems, and modules are well known to those
skilled in the art.
[00031] The present invention provides for a kit for administering a
titrating dosing
regimen of a psychedelic, including a pharmaceutically effective amount of the
psychedelic in
dosage forms separated in packaging according to dose and time of
administration in a
titrating dosing regimen, and instructions for use. The starting dose and each
additional
increased dose can be in different colors and/or sizes for an individual to
easily distinguish
them. The increased dose can be a single dosage form or multiple separate
dosage forms
(i.e., one dosage form (i.e., tablet, patch, etc.) for each dose increase).
The packaging can
indicate which time period each dose should be taken in, such as in hours,
days, weeks,
months, or years. The packaging can be in a bubble/blister pack form, which
allows the
individual to pop out the exact dose needed for each administration.
[00032] The present invention also provides for a method of treating
an individual with
psychedelics, by administering the psychedelic to the individual having a
condition or disease
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in a titrating dosing regimen and reducing side effects of hallucinations and
perceptual
disturbances during treatment.
[00033] The condition or disease being treated with the methods of
the present invention
can include, but is not limited to, anxiety disorders (including anxiety in
advanced stage illness
e.g. cancer, as well as generalized anxiety disorder), depression (including
post partum
depression, major depressive disorder and treatment-resistant depression),
headache disorder
(including cluster headaches and migraine headache), obsessive compulsive
disorder (OCD),
personality disorders (including conduct disorder), stress disorders
(Including adjustment
disorders and post-traumatic stress disorder), drug disorders (including
alcohol dependence,
nicotine dependence, opioid dependence, cocaine dependence, methamphetamine
dependence), other addictions (including gambling disorder, eating disorder,
and body
dysmorphic disorder), pain, neurodegenerative disorders (such as dementia,
Alzheimer's
Disease, Parkinson's Disease), movement disorders (such as essential tremor,
tardive
dyskinesia), autism spectrum disorder, eating disorders, or neurological
disorders (such as
stroke or traumatic brain injury).
[00034] The invention is further described in detail by reference to
the following
experimental examples. These examples are provided for the purpose of
illustration only, and
are not intended to be limiting unless otherwise specified. Thus, the
invention should in no
way be construed as being limited to the following examples, but rather,
should be construed
to encompass any and all variations which become evident as a result of the
teaching provided
herein.
[00035] EXAMPLE 1
[00036] The following is an example of dosing to achieve uptitration
of LSD. This is also
applicable to other psychedelics. TABLE 1 shows oral administration over
different days and
for different times of daily administration. The dose levels can translate
into 1) a PK threshold
and 2) a 5-HT2A expression threshold that can be tailored via other dosing
regiments and
formulations so that the dosing is done in a way that patients never get PK
levels that match
the (increasing) threshold for perceptual effects.
TABLE 1
Scenario Day 1 2 3 4 5 6 7-14 14-28 29-56
57-84+
1 (daily adm in) 10 10 30 30 50 50 100 200
200 200
2 (2x/daily ad m in) 10 20 40 80 100 200 200 200 200
200
3 20 50 100 100 200 200 200 200 200 200
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[00037] FIGURE 1 shows how the dose increases over time to a
threshold for perceptual
effects. Similar effects would be present for PK levels. TABLE 2 shows dosing
with an
extended release formulation.
TABLE 2
Scenario Day 1 2 3 4 5 6 7 14-28 29-56
57-84+
1 Patch #1 Patch #2 Patch #3 (high dose) Patch
#3 (high dose)
(small dose) (mid dose) weekly or
monthly
2 Patch #1 Patch #2 (mid dose)
Patch #3 (high dose)
(small dose) weekly or
monthly
3 Patch #2 Patch #2 Patch #2 (mid dose)
Patch #2 (mid dose)
(mid dose) (mid dose) weekly or
monthly
[00038] Precise packaging configurations can be used, such as a
dosing kit of multiple
patches that can be applied at regular intervals either at home or in a
clinic. The kit design
(i.e., specific way the patches are sized, any differences in their
properties, and the actual
packaging design) can ensure adherence and so that patients do not
inadvertently expose
themselves to a hallucinogenic dose.
[00039] Throughout this application, various publications,
including United States patents,
are referenced by author and year and patents by number. Full citations for
the publications
are listed below. The disclosures of these publications and patents in their
entireties are
hereby incorporated by reference into this application in order to more fully
describe the state
of the art to which this invention pertains.
[00040] The invention has been described in an illustrative manner,
and it is to be
understood that the terminology, which has been used is intended to be in the
nature of words
of description rather than of limitation.
[00041] Obviously, many modifications and variations of the present
invention are
possible in light of the above teachings. It is, therefore, to be understood
that within the scope
of the appended claims, the invention can be practiced otherwise than as
specifically
described.
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