WO2024197022A1

WO2024197022A1 - Intravenous dimethyltryptamine (dmt) administration method for treating, preventing, and/or ameliorating depression

Info

Publication number: WO2024197022A1
Application number: PCT/US2024/020704
Authority: WO
Inventors: Deepak Cyril D’Souza
Original assignee: Yale University
Current assignee: Yale University
Priority date: 2023-03-21
Filing date: 2024-03-20
Publication date: 2024-09-26
Anticipated expiration: 2025-09-21

Abstract

The present disclosure relates, in one aspect, to a method of treating, preventing, and/or ameliorating depression in a subject in need thereof, the method comprising intravenous administration (i.e., bolus and continuous infusion) of dimethyltryptamine (DMT) to the subject. The present disclosure further relates to kits useful for performing the methods described herein.

Description

TITLE

Intravenous Dimethyltryptamine (DMT) Administration Method for Treating, Preventing, and/or Ameliorating Depression

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63/453,709, filed March 21. 2023. which application is incorporated herein by reference in its entirety.

BACKGROUND

Depressive disorders strongly affect quality of life and are associated with considerable morbidity and mortality (Cuijpers et al., Lancet Psychiatry, Volume 7, Issue 11, November 2020, Pages 925-927). Depressive disorders affect a considerable percentage of the world population. For example, major depressive disorder (MDD) is estimated to affect about 2% of the world population (Lancet. 2018 Nov 10; 392(10159): 1789-1858). Treatments available to depressive disorders include antidepressants and psychotherapy. However, such treatments have demonstrated limited efficacy, significant side-effects, and take weeks to begin to have therapeutic effects.

There is thus a need in the art for methods of treating, preventing, and/or ameliorating depression and/or depressive disorders in a subject. The present disclosure addresses this need.

BRIEF SUMMARY

In one aspect, the disclosure provides a method of treating, preventing, and/or ameliorating depression in a subject in need thereof. In certain embodiments, the method comprises intravenously administering to the subject a first bolus dose of dimethyltryptamine (DMT), or a salt, solvate, or isotopologue thereof, or any mixtures thereof. In certain embodiments, the method comprises intravenously administering to the subject a second dose of DMT. or a salt, solvate, or isotopologue thereof, or any mixtures thereof, by continuous infusion.

In one aspect, the disclosure provides a kit for treating, preventing, and/or ameliorating depression in a subject. In certain embodiments, the kit comprises dimethyltryptamine (DMT), or a salt, solvate, or isotopically labeled derivative thereof, or any mixture thereof. In certain embodiments, the kit comprises a manual providing instructions. In certain embodiments, the instructions are for intravenous administration of a first bolus administration of DMT, or a salt, solvate, or isotopically labeled derivative thereof to the subject. In certain embodiments, the instructions are for intravenous administration of a second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, by continuous infusion to the subject.

BRIEF DESCRIPTION OF THE FIGURES

The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application.

FIG. 1 depicts the change in depression in the participants, in accordance with some embodiments. This figure shows changes in HamD-17 total scores of individual participants the day after 0.1 mg/kg and 0.3 mg/kg DMT relative to baseline. Each subject is represented by one line. The group mean is also shown. *Note that subject #7 completed the 0. 1 mg/kg dosing session before being withdrawn for administrative reasons.

FIGs. 2A-2B depict exemplary' dosing regimens of the present disclosure corresponding to the doses the subject actually receives (FIG. 2A) and the dose the subject is told they may receive (FIG. 2B).

FIG. 3 depicts completed and ongoing studies comprising intravenous administration (z. e. , bolus and/or continuous infusion) of dimethyltryptamine.

FIG. 4 provides a bar graph depicting individual ratings of overall tolerability' of a 0. 1 mg/kg DMT dose and 0.3 mg/kg DMT dose scored on a scale of 0 = intolerable to 100 = well-tolerated. Overall tolerability of the test day was scored at the end of each test day. Subjects 1-3 are healthy volunteers and subjects 4-10 are individuals with major depressive disorder. The far right group corresponds to the group mean; error bars indicate standard errors of the mean (S.E.M.).

FIG. 5 provides a CONSORT diagram, depicting the enrollment of subjects, their allocation to treatment, disposition status, and how they are analyzed in the trial.

FIGs. 6A-6B describe certain aspects of the clinical trial participants’ demographic and clinical characteristics, in accordance with some embodiments.

FIGs. 7A-7C depict the blood pressure and heart rate changes in means (error bars indicate standard error of mean) over time on the 0.1 mg/kg and 0.3 mg/kg DMT, in accordance with some embodiments. FIG. 7A: systolic blood pressure (mm Hg). FIG. 7B: diastolic blood pressure (mm Hg). FIG. 7C: heart rate (beats/minute). Arrows indicate the time at which DMT was administered. n=10 for 0.1 mg/kg (n=3 healthy, n=7 depressed) and n=9 for 0.3 mg/kg (n=3 healthy, n=6 depressed).

FIGs. 8A-8B describe adverse events experienced by the clinical trial participants, in accordance with some embodiments.

FIGs. 9A-9B depict in session VAS anxiety (FIG. 9A) and depression (FIG. 9B) with intravenous (IV) DMT administration. Values are mean sores of the peak changes in VAS anxiety and depression, at 0. 1 mg/kg and 0.3 mg/kg dosages. Error bars indicate standard errors of the mean for each time point.

FIG. 10 provides a bar graph depicting peak change in VAS psychedelic effects with IV DMT administration. Peak change in VAS psychedelic effects, at 0.1 mg/kg and 0.3 mg/kg dosages. Error bars indicate standard errors of the mean.

FIG. 11 provides a bar graph depicting psychotomimetic effects with IV DMT administration, for the total score (which is a sum of the scores of the six factors). Acute effects are measured via the psychotomimetic states inventory (PSI). Values are the mean scores of the peak changes plus the positive standard errors of the mean for each time point.

FIGs. 12A-12F provide bar graphs depicting psychotomimetic effects with IV DMT administration. Acute effects are measured via the psychotomimetic states inventory (PSI). Values are the mean scores of the peak changes, plus the positive standard errors of the mean for each of the six factors of the PSI, for each time point.

FIG. 13 provides serum DMT levels in healthy control and depression subjects with intravenous administration of DMT. Y-axis: serum DMT levels (ng/dl); X-axis: 60 min before DMT administration; and 30 and 60 min after DMT administration. Each subject’s levels at each dose are displayed separately. Solid line (0.1 mg/kg) and dotted line (0.3 mg/kg). Mean of the group at each dose is also displayed.

DETAILED DESCRIPTION

Orally administrations of serotonergic psychedelics (also referred to as serotonergic hallucinogens) such as psilocybin and lysergic acid diethylamide (LSD) have been applied in the treatment of neuropsychiatnc disorders such as major depressive disorder, and are considered effective.

However, these compounds cause acute psychedelic effects in the patients, which take time to emerge and last for several hours. The psychedelic effects are sometimes experienced as negative and the patients can become anxious with the acute psychedelic effect and have a “bad trip.” As a result, in the existing model two therapists are required to be present for the entire dosing session to attend to participants who have a bad trip and to facilitate psychotherapy.

The study described herein evaluated the intravenous administration of dimethyltryptamine (DMT) to treat depression. This study provided the first indication of therapeutic efficacy. Notably, the present study discovered that, in contrast to the conventional orally administered psilocybin, LSD, and ayahuasca, intravenously administered dimethyltryptamine (DMT) allows for near instantaneous acute psychedelic effects which last for only 20-30 minutes. Due to the quick onset and short duration of the psychedelic effects, even if the patient experiences a “bad trip,” managing the psychedelic effects are much easier. Furthermore, the results show that the intravenous DMT administration was well tolerated by both MDD patients and HC individuals and suggested that intravenous DMT has low abuse potential. Lastly, the reduction in depression symptoms observed the day after administration are in sharp contrast with the onset of traditional antidepressant medications, which may take weeks.

Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter.

Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0. 1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g, 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y. or about Z has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise.

In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined. is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting: information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference.

In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process.

Description

A V-Dimethyltry ptamine (DMT) is a naturally occurring indole alkaloid endogenous to several plants and animals. DMT is one of the active constituents of ayahuasca, a traditional South American brewed tea. It is classified as a psychedelic agent because it can produce a range of brief yet intense psychedelic effects including visual and auditor}' hallucinations, profoundly altered reality, “spiritual insights”, distortion of body perception, alterations in mood, and euphoria or anxiety (depending on the set and setting) similar to those of psilocybin, mescaline, and LSD.

DMT has been studied in double-blind, randomized, placebo-controlled studies in humans, but has not been administered to individuals with major depressive disorder (MDD). Its effects appear to be dose related; the dose at which psychedelic effects emerge has been determined. DMT has also been identified in the pineal gland and brain in animals and humans. Endogenous DMT is synthesized from the essential amino acid tryptophan, which is decarboxylated to tryptamine and transmethylated via enzyme indole ethylamine-N- methyltransferase (INMT) with S-adenosylmethionine (SAM) as a substrate to catalyze the addition of methyl groups to form N, methyl tryptamine and DMT. Although its biological function in animals remains unclear. DMT concentrations can be elevated in certain areas of the brain; for example, DMT levels have been shown to be elevated in rodent brains under stress.

Mechanism of Action DMT interacts with a variety of serotonin receptors as well as glutamate, acetylcholine, TAAR, and sigma 1 receptors. DMT binds serotonin receptors 5-HT1A. 5- HT1B, 5-HT1D, 5-HT2A, 5- HT2B, 5-HT2C, 5-HT5A, 5-HT6, and 5-HT7 with affinities ranging from 39 nM to 2. 1 pM. DMT’s affinity for the 5-HT1 A receptor is higher compared to 5-methoxy-dimethyl tryptamine (5-MeO-DMT), 6.5 ± 1.5 nM and 170 ± 35 nM, respectively. DMT binds to the 5-HT2A receptor with relatively high affinity, IC50 75 ± 1 nM, yet other psychedelics that lack visual effects have a higher affinity for the 5-HT2A receptor (5-MeO-DMT; 14 ± 1 nM), therefore how critical 5HT2A receptors are to the MO A of DMT is in question.

The precise mechanism of action of the psychedelic effects of DMT is not known, although research on related compounds would suggest a role for 5-HT2A receptors. Previously it was thought that endogenous DMT concentrations in the body were too low to be clinically relevant. That changed after the discovery of the activity’ of DMT at trace amine- associated receptors (TAAR). DMT binds to these receptors with high affinity⁷ and acts as an agonist. Furthermore, DMT can be sequestered in neurotransmitter vesicles at concentrations high enough to have pharmacological effects. These findings suggest that DMT may have a role in physiological/psychopathological processes.

DMT interactions with the glutamatergic systems are complex and involve the serotonergic system. Studies have demonstrated increased activation of glutamate-dependent pyramidal neurons in the primary frontal cortex (PFC) secondary to activation of postsynaptic 5-HT2A receptors in deep layers of PFC. DMT has no direct activity on dopamine receptors based on animal models of dopamine receptor activity. It does, however, appear that DMT increases central dopamine turnover and enhances striatal dopamine synthesis in rats. DMT significantly decreases concentration of acetylcholine (ACH) in the corpus striatum but does not have any effect on levels of ACH in the cortex. DMT binds avidly to sigma 1 receptors and appears to have agonist-like effects even at low micromolar concentrations. Whether these receptors play a role in the psychedelic effects of DMT remains unclear.

Acute Transient Behavioral Effects ofN.N-Dimethyltryptamine

Several groups have studied the pharmacological effects of DMT. DMT has been extensively used to study altered states of consciousness in healthy individuals. In these studies volunteers were administered DMT intravenously and the subjective, behavioral, neuroendocrine, autonomic, and cardiovascular effects were recorded. DMT produces a range of psychedelic effects similar to psilocybin, including profound dose-related alterations in perceptions, emotion, and thought in humans. DMT is known to have rapid onset (1- 2 minutes) and short duration (20 to 30 minutes) of effects. These effects completely replace subjects’ previously ongoing mental experience and seem more vivid and compelling than dreams or waking awareness.

The effects peak quickly (2 minutes). Total duration of effects is brief and usually fully resolves in 20-30 min. Psychedelic effects are characterized as a powerful ‘"rush” that is marked by a sense of tremendous acceleration and psychic and somatic tension. It is accompanied by a sense of dissociation from bodily awareness and complex visions described as “more real than real.” The time course of DMT blood levels correlated with the intensity of subjective effects. In addition, multiple biological variables including corticotropin and B-endorphin. HR, blood pressure, and pupil diameter increase in a dosedependent relationship. Prolactin and cortisol blood levels lagged 5 to 10 minutes behind these changes, while core temperature and GH effects did not begin until the 15 to 30 minute mark and tend to correspond with the resolution of psychedelic effects. The effects are exquisitely dose-related. The threshold dose at which psychedelic effects occur is approximately 0.2 mg/kg; at 0. 1 mg/kg. psychedelic effects are not observed.

Potential Therapeutic Benefit of N,N -Dimethyl tryptamine and Related Compounds in Psychiatric Disorders

Emerging evidence suggests that DMT and related compounds may produce long lasting effects, some of which may be of therapeutic potential. A number of research groups are exploring and/or have explored the efficacy and safety of psilocybin in various neuropsychiatric disorders, including major depressive disorder (MDD), cluster headache, anxiety disorder, alcohol use disorder, substance use disorders, migraine headache, and obsessive-compulsive disorder (OCD).

While early results suggest that serotonergic hallucinogens may produce benefits in MDD and OCD, the early research w ork has also generated a number of important questions that need to be addressed before this approach can be implemented clinically, including the role of integrative psychotherapy in beneficial effects, the benefit of acute psychedelic effects, optimum dosage, and dosing frequency, inter alia.

As described in greater detail herein (see Example 2), the safety, tolerability, and efficacy of DMT in both healthy and depressed volunteers in a pilot study. HAMD-17 scores decreased significantly (p = 0.017) compared to baseline in MDD participants the day after receiving 0.3 mg/kg DMT (mean difference -4.5 points, 95% CI: -7.80 to -1.20, Hedge’s g = 0.75). Results of the pilot study showed that intravenous DMT may have next day (rapid) antidepressant effect in patients with treatment-resistant MDD in this pilot study. FIG. 1 shows changes in HAMD-17 total scores of individual participants the day after 0. 1 mg/kg and 0.3 mg/kg DMT relative to baseline. Each subject is represented by a line in a different color. The group mean is shown in black.

Definitions

The term “about’’ as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range.

A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

A “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

A disease or disorder is “alleviated” if the severity' of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced.

In one aspect, the terms “co-administered” and “co-administration” as relating to a subject refer to administering to the subject a compound and/or composition of the disclosure along with a compound and/or composition that may also treat or prevent a disease or disorder contemplated herein. In certain embodiments, the co-administered compounds and/or compositions are administered separately, or in any kind of combination as part of a single therapeutic approach. The co-administered compound and/or composition may be formulated in any kind of combinations as mixtures of solids and liquids under a variety of solid, gel, and liquid formulations, and as a solution.

The term “depressive symptoms”, as used herein, refers to symptoms associated with major depressive disorder and include one or more of the following: Feeling sad or having a depressed mood; Loss of interest or pleasure in activities once enjoyed; Changes in appetite - weight loss or gain unrelated to dieting; Trouble sleeping or sleeping too much; Loss of energy or increased fatigue; Increase in purposeless physical activity (e.g., inability’ to sit still, pacing, handwringing); or slowed movements or speech (these actions must be severe enough to be observable by others.

The terms "drug", ‘'active substance”, '‘active ingredient”, “pharmaceutically active ingredient”, “active agent” or “therapeutic agent” are to be understood as meaning a compound in free form or in the form of a pharmaceutically acceptable salt, in particular compounds of the type specified herein.

The term “independently selected from” as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase “X¹, X², and X³ are independently selected from noble gases” would include the scenario where, for example, X¹, X², and X³ are all the same, where X¹. X². and X³ are all different, where X¹ and X² are the same but X³ is different, and other analogous permutations.

The term “intravenous or intravenously” refers to a pharmaceutical composition designed to be administered to a vein.

The term “mg/kg” as used herein refers to the amount of compound or drug, for example. Compound (I), or a pharmaceutically acceptable salt thereof, per kilogram of body weight of a patient or subject.

As used herein, the term “pharmaceutical composition” or “composition” refers to a mixture of at least one compound useful w ithin the disclosure with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient. Multiple techniques of administering a compound exist in the art including, but not limited to, subcutaneous, intravenous, oral, aerosol, inhalational, rectal, vaginal, transdermal. intranasal, buccal, sublingual, parenteral, intrathecal, intragastrical, ophthalmic, pulmonary, and topical administration.

As used herein, the term '‘pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, the term '‘pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function. Each carrier must be “acceptable"’ in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the patient. Some examples of materials that may sen e as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the disclosure, and are physiologically acceptable to the patient. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the disclosure. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the disclosure are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

As used herein, the language “pharmaceutically acceptable salt"’ refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic acids, inorganic bases, organic acids, inorganic bases, solvates, hydrates, and clathrates thereof.

As used herein, a “pharmaceutically effective amount,” “therapeutically effective amount,” or “effective amount” of a compound is that amount of compound that is sufficient to provide a beneficial effect to the subject to which the compound is administered.

As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

The term “psychotherapy” as used herein, refers to the informed and intentional application of clinical methods and interpersonal stances derived from established psychological principles for the purpose of assisting people to modify their behaviors, cognitions, emotions, and/or other personal characteristics in directions that the participants deem desirable.

As used herein, the terms “subject” and “individual” and “patient” can be used interchangeably and may refer to a human or non-human mammal or a bird. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. In certain embodiments, the subject is human. The term “substantially” as used herein refers to a ma ority of, or mostly, as in at least about 50%. 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of’ as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5. 3, 2.5, 2. 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0. 1, 0.01, or about 0.001 wt% or less. The term “substantially free of’ can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4. 3.5, 3, 2.5. 2, 1.5, 1, 0.9. 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.

The term “suicidality”, as used herein, refers to thoughts of suicide (suicidal ideation) and suicide, suicide attempts and preparatory⁷ acts (suicidal behavior).

As used herein, the term “treatment” or “treating” is defined as the application or administration of a therapeutic agent, z.e., a compound useful within the disclosure (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a disease or disorder and/or a symptom of a disease or disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disease or disorder and/or the symptoms of the disease or disorder. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

The term “treatment resistant depression (TRD)”, as used herein, refers to a type of major depressive disorder where the patient has not responded to adequate doses of two different antidepressants taken at an adequate dose for a sufficient duration of time, which is usually six weeks.

Methods

In one aspect, the present disclosure provides a method of treating, preventing, and/or ameliorating depression in a subject in need thereof. In certain embodiments, the method comprises (a) intravenously administering to the subject a first bolus dose of dimethyltryptamine (DMT), or a salt, solvate, or isotopologue thereof, or any mixtures thereof. In certain embodiments, the method comprises (b) intravenously administering to the subject a second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, by continuous infusion.

In certain embodiments, the depression is at least partially treatment-resistant. In certain embodiments, the depression is fully treatment resistant.

In certain embodiments, the depression is a major depressive disorder (MDD).

In certain embodiments, the first bolus dose is administered over a period of about 1, 2, 3, 4. 5. 6, 7, 8. 9, or about 10 minutes. In certain embodiments, the first bolus dose is administered over a period of about 5 minutes.

In certain embodiments, the first bolus dose comprises about 5, 6, 7, 8 ,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 mg of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof. In certain embodiments, the first bolus dose comprises about 10 to about 14 mg of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof.

In certain embodiments, the first bolus dose comprises about 10 mg of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof.

In certain embodiments, the second dose of DMT. or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered at a rate of about 0.010 mg/kg/min.

In certain embodiments, the second dose of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered over a period of about 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or about 70 minutes. In certain embodiments, the second dose of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered over a period of about 55 minutes.

In certain embodiments, the first bolus dose comprises about 14 mg of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof.

In certain embodiments, the second dose of DMT. or a salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered at a rate of about 0.015 mg/kg/min.

In certain embodiments, the second dose of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered over a period of about 40, 41, 42, 43, 44, 45, 46, 47. 48. 49. 50. 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or about 70 minutes. In certain embodiments, the second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered over a period of about 55 minutes.

In certain embodiments, the DMT, or the salt, solvate, or isotopically labeled derivative thereof, is substantially pure.

In certain embodiments, the salt of DMT of the first bolus dose and/or the second dose is N, JV-di methyl tryptamine hemifumurate.

In certain embodiments, the subject is administered a total dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, of less than about 100 mg,

In certain embodiments, the subject is administered a total dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, of about 30, 31. 32. 33. 34. 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,

62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86,

87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or about 99 mg. In certain embodiments, the total dose has a range of about 49 mg to about 72 mg.

In certain embodiments, the subject is in a minimally incapacitating psychedelic state. In certain embodiments, the subject can communicate with another human.

In certain embodiments, psychedelic effects experienced by the subject after the administration last for 60 minutes or less.

In certain embodiments, steps (a)-(b) are repeated after about one week. In certain embodiments, steps (a)-(b) are repeated after about two weeks. In certain embodiments, steps (a)-(b) are repeated after about three weeks. In certain embodiments, steps (a)-(b) are repeated after about four weeks. In certain embodiments, steps (a)-(b) are repeated after about five weeks. In certain embodiments, steps (a)-(b) are repeated after about six weeks. In certain embodiments, steps (a)-(b) are repeated after about seven weeks. In certain embodiments, steps (a)-(b) are repeated after about eight weeks. In certain embodiments, steps (a)-(b) are repeated after about nine weeks. In certain embodiments, steps (a)-(b) are repeated after about ten weeks.

In certain embodiments, the subject is not administered a monoamine oxidase inhibitor (MAOI).

In certain embodiments, the subject is further subjected to psychotherapy. In certain embodiments, the subject is not further subjected to psychotherapy.

In certain embodiments, the subject is further administered a medication for psychological distress or a medication for hypertension. In certain embodiments, the subject has a Hamilton Rating Scale for Depression (HAMD-17) of 17. or an equivalent thereof on a comparable scale, or higher prior to the administration of the DMT or the salt, solvate, or isotopically labelled derivative thereof, or any mixture thereof.

In certain embodiments, the HAMD-17 score of the subject is reduced by about 3.0 points or more the day after the administration of the DMT or the salt, solvate, or isotopically labelled derivative thereof, or any mixture thereof.

Kits

In another aspect, the present disclosure provides a kit for treating, preventing, and/or ameliorating depression in a subject. In certain embodiments, the kit comprises (a) dimethyltryptamine (DMT), or a salt, solvate, or isotopically labeled derivative thereof, or any mixture thereof. In certain embodiments, the kit comprises (b) a manual providing instructions for: (i) intravenous administration of a first bolus administration of DMT, or a salt, solvate, or isotopically labeled derivative thereof to the subject; and (ii) intravenous administration of a second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, by continuous infusion to the subject.

In certain embodiments, the depression is a major depressive disorder (MDD).

In certain embodiments, the manual instructs that the first bolus dose is administered over a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or about 10 minutes. In certain embodiments, the manual instructs that the first bolus dose is administered over a period of about 5 minutes.

In certain embodiments, the manual instructs that the first bolus dose comprises about 5, 6, 7, 8 ,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 mg of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof.

In certain embodiments, the manual instructs that the first bolus dose comprises about 10 mg of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof.

In certain embodiments, the manual instructs that the second dose of DMT. or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered at a rate of about 0.010 mg/kg/min.

In certain embodiments, the manual instructs that the second dose of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion, is administered over a period of about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or about 70 minutes. In certain embodiments, the manual instructs that the second dose of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion, is administered over a period of about 55 minutes.

In certain embodiments, the manual instructs that the first bolus dose comprises about 14 mg of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof.

In certain embodiments, the manual instructs that the second dose of DMT. or a salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered at a rate of about 0.015 mg/kg/min.

In certain embodiments, the manual instructs that the second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion, is administered over a period of about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or about 70 minutes. In certain embodiments, the manual instructs that the second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion, is administered over a period of about 55 minutes.

In certain embodiments, the DMT, or the salt, solvate, or isotopically labeled derivative thereof, is substantially pure. In certain embodiments, the salt of DMT of the first bolus dose and/or the second dose is /V.A imethyltryptamine hemifumurate.

In certain embodiments, the manual instructs that the subject is administered a total dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, of less than about 100 mg. In certain embodiments, the manual instructs that the subject is administered a total dose of DMT. or a salt, solvate, or isotopologue thereof, or any mixtures thereof, of about 30. 31. 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45. 46. 47. 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or about 99 mg. In certain embodiments, the total dose has a range of about 49 mg to about 72 mg. In certain embodiments, the total dose has a range of about 49 mg to about 72 mg.

In certain embodiments, the manual instructs that administration of the first bolus dose and the second dose are repeated after about one week. In certain embodiments, the manual instructs that administration of the first bolus dose and the second dose are repeated after about two weeks. In certain embodiments, the manual instructs that administration of the first bolus dose and the second dose are repeated after about three weeks. In certain embodiments, the manual instructs that administration of the first bolus dose and the second dose are repeated after about four weeks. In certain embodiments, the manual instructs that administration of the first bolus dose and the second dose are repeated after about five weeks. In certain embodiments, the manual instructs that administration of the first bolus dose and the second dose are repeated after about six weeks. In certain embodiments, the manual instructs that administration of the first bolus dose and the second dose are repeated after about seven weeks. In certain embodiments, the manual instructs that administration of the first bolus dose and the second dose are repeated after about eight weeks. In certain embodiments, the manual instructs that administration of the first bolus dose and the second dose are repeated after about nine weeks. In certain embodiments, the manual instructs that administration of the first bolus dose and the second dose are repeated after about ten weeks.

In certain embodiments, the manual instructs that the subject is not administered a monoamine oxidase inhibitor (MAOI).

In certain embodiments, the manual instructs that the subject is further subjected to psychotherapy. In certain embodiments, the manual instructs that the subject is not further subjected to psychotherapy.

In certain embodiments, the manual instructs that the subject is further administered a medication for psychological distress or a medication for hypertension.

In certain embodiments, the manual provides instructions for using the Hamilton Rating Scale for Depression.

In certain embodiments, the manual instructs that an initial Hamilton Rating Scale for Depression (HAMD-17) score, or an equivalent thereof, is measured prior to the administration of the DMT or the salt, solvate, or isotopically labelled derivative thereof, or any mixture thereof.

In certain embodiments, the manual instructs that a second Hamilton Rating Scale for Depression (HAMD-17) score, or an equivalent thereof, is measured about 24 or more hours after the administration of the DMT or the salt, solvate, or isotopically labelled derivative thereof, or any mixture thereof.

Combination Therapies

In some embodiments, the method of treating or preventing the depressive disorder or includes administering to the subject the effective amount of at least one compound and/or composition contemplated within the disclosure.

In some embodiments, the composition for treating depressive disorder includes at least one compound and/or composition contemplated within the disclosure. In some embodiments, the subject is further administered at least one additional agent that treats or prevents a depressive disorder. In other embodiments, the compound and the at least one additional agent are co-administered to the subject. In yet other embodiments, the compound and the at least one additional agent are co-formulated.

The compounds contemplated within the disclosure are intended to be useful in combination with one or more additional compounds. These additional compounds may comprise compounds of the present disclosure and/or at least one additional agent for treating depressive disorders, and/or at least one additional agent that treats one or more diseases or disorders contemplated herein.

A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

Administration/Dosage/Formulations

The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations contemplated within the disclosure may be administered to the subject either prior to or after the onset of a disease and/or disorder contemplated herein. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection, or a combination of a bolus and constant infusion. Further, the dosages of the therapeutic formulations contemplated within the disclosure may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. In certain embodiments, the duration of drug administration contemplated within the disclosure may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

Administration of the compositions contemplated within the disclosure to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease and/or disorder contemplated herein in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound contemplated within the disclosure to treat a disease and/or disorder contemplated herein in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A nonlimiting example of an effective dose range for a therapeutic compound contemplated within the disclosure is from about 0.01 and 10 mg/kg of body weight/per day. In certain embodiments, an effective bolus and constant infusion dose range is 10-14 mg bolus over 5 minutes followed by 0.01-0.015 mg/kg/min over 55 to 110 minutes.

Actual dosage levels of the active ingredients in the pharmaceutical compositions contemplated within the disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.

A medical doctor, e.g., physician, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician could start doses of the compounds contemplated within the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms contemplated within the disclosure are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound for the treatment of a disease and/or disorder contemplated herein.

In certain embodiments, the compositions of the disclosure are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions of the disclosure comprise a therapeutically effective amount of a compound of the disclosure and a pharmaceutically acceptable carrier.

The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity⁷ may 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. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or poly alcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.

In certain embodiments, the present disclosure is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the disclosure, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of depressive disorder in a patient.

Formulations may be employed in admixtures with conventional excipients, z.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g, other analgesic agents.

Although the present study discovered certain advantageous of parenteral administration of the compounds contemplated herein, the present specification is not limited thereto. Routes of administration of any of the compositions of the disclosure include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the disclosure may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g, sublingual, lingual, (trans)buccal. (trans )urethral, vaginal (e.g, trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry' powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present disclosure are not limited to the particular formulations and compositions that are described herein.

Parenteral Administration

For parenteral administration, the compounds of the disclosure may be formulated for injection or infusion, for example, intravenous injection or infusion, or for administration in a bolus dose and/or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used.

Additional Administration Forms

Additional dosage forms of this disclosure include dosage forms as described in U.S. Patents Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms of this disclosure also include dosage forms as described in U.S. Patent Applications Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms of this disclosure also include dosage forms as described in PCT Applications Nos. WO 03/35041; WO 03/35040; WO 03/35029; WO 03/35177; WO 03/35039; WO 02/96404; WO 02/32416; WO 01/97783; WO 01/56544; WO 01/32217; WO 98/55107; WO 98/11879; WO 97/47285; WO 93/18755; and WO 90/11757.

It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

EXAMPLES

Various embodiments of the present application can be better understood by reference to the following Examples which are offered by way of illustration. The scope of the present application is not limited to the Examples given herein.

Example 1: Phase I Study of the Safety, Tolerability, Electrophysiological Effects, and Efficacy of Dimethyltryptamine (DMT) in Humans

In one aspect, the present study aims to determine the safety, tolerability, electrophysiological effects, and efficacy of dimethyltryptamine (DMT) in humans. In certain embodiments, administration of DMT may result in decreases in depression, associated symptoms, and neuroplastic changes in depressed subjects. In certain embodiments, the changes in neuroplasticity are indexed using electroencephalographic (EEG) measures and tasks. These neuronal changes may in parallel cause changes in mood measured both in healthy and depressed subjects, which are captured using appropriate psychometric measures of mood.

FIGs. 2A-2B illustrate the formulation that certain participants in the present study actually receive and the formulation certain participants in the present study are told they may receive.

In certain embodiments, the study involves a hybrid between subject and within subject design to maximize the collection of safety, tolerability, electrophysiological (EEG) and efficacy data. Thus, in certain embodiments, the present study comprises a double-blind, randomized (1 :1:1), placebo-controlled, parallel study, wherein participants receive placebo, low dose DMT, or medium dose DMT at the first dosing session. Six weeks later participants complete a second dosing session in which all participants receive medium dose DMT under double-blind conditions. Age- and gender-matched healthy controls are studied to benchmark the EEG data.

Specific Aims

In one aspect, it is hypothesized herein that bolus and continuous infusion DMT dosing regimens are safe and well-tolerated both acutely, subacutely (4 weeks) and long-term (24 weeks) in individuals with Major Depressive Disorder (MDD) and health controls.

In certain embodiments, the study described herein will determine the acute (day of), subacute (4 weeks), and longer-term safety and tolerability of DMT. Acute cardiovascular changes (z.e., heart rate, blood pressure, oxygen saturation), subjective (psychedelic [MEQ- 30], psychotomimetic [PSI], anxiety [VAS]) and tolerability (VAS), and clinical assessments by the study psychiatrist will be assessed on each test day. Adverse events, dropout rates will be measured throughout the trial.

In certain embodiments, study of healthy controls is essential to understand the “normal’' dose-related response to DMT across the subjective, behavioral, and electrophysiological (EEG) measures. In certain embodiments, the study of healthy controls is also critical to understand whether individuals with psychiatric disorders such as depression, respond differently to DMT.

In another aspect, it is hypothesized herein that DMT will produce rapid and sustained reductions in depression in individuals with Major Depressive Disorder (MDD).

In certain embodiments, the study described herein will determine whether DMT, in a dose-related manner, reduces depression measured by the HAM-D. the day after and 1, 2 and 4 eeks in individuals with current Major Depressive Disorder. This will be determined in a double-blind, randomized, placebo-controlled, parallel group design testing variable dosing (z.e., low and medium) intravenous DMT. In addition, other relevant symptoms will be measured including self-reported depression (QIDS) and anxiety (HAM-A).

Complementing the results from the analysis of the parallel group design, further information on dose-related effects will be realized by within subjects’ comparisons between HAM-D scores of participants who received low- dose, medium dose, or placebo, at the first dosing session with the second dose of medium dose DMT.

In another aspect, it is hypothesized herein that DMT will result in dose-related increases in short and longer-term electrophysiological biomarkers of neuroplasticity in individuals diagnosed with Major Depressive Disorder.

In certain embodiments, healthy controls are included to benchmark the EEG indices of plasticity and to explore group differences in pharmacokinetic/pharmacodynamic relationships._The study of healthy controls is essential to understand the “normal” dose- related response to DMT across the subjective, behavioral, and psychophysiological measures. The study of healthy controls is also critical to understand whether individuals with MDD, respond differently to DMT. In certain embodiments, the present study will determine whether DMT, in a dose-related manner, increases resting state and task related electrophysiological indices of neural plasticity the day after and 4 weeks after administration.

In another aspect, it is hypothesized herein that administration of DMT (low or medium and medium) will be tolerated acutely (day of), subacutely (4 weeks) and at long term follow up (24 weeks). In certain embodiments, the present study will determine the acute, subacute, and longer-term safety and tolerability of repeated administration of DMT in depressed humans. Safety and tolerability will be assessed in the 2 groups of subjects who receive DMT twice: 1) low dose followed by medium, and 2) medium dose followed by medium.

In another aspect, it is hypothesized herein that, relative to single dose, repeated dosing of DMT will result in increased change on measures of depression and anxiety with respect to magnitude and duration of change. In certain embodiments, the present study will determine the cumulative effect of repeated administration of DMT on depression and anxiety in depressed individuals.

Effects on anxiety and depression will be assessed in the 2 groups of subjects who receive DMT twice: 1) low dose followed by medium dose, and 2) medium dose followed by medium dose, measured about 20 weeks after subjects receive a second dose of DMT. Endpoints will be measured using the HAM-D and HAM-A scales.

In another respect, relative to single dose, repeated dosing of DMT will result in increased change in electrophysiological biomarkers of neuroplasticity. In certain embodiments, the present study will determine the cumulative effect of repeated administration of DMT on electrophysiological markers of neuroplasticity in depressed individuals and healthy controls. Effects on electrophysiological markers of neuro plasticity will be assessed in the 2 groups of subjects who receive DMT twice: 1) low dose followed by medium dose, and 2) medium dose followed by medium dose, measured 10 weeks after subjects receive a second dose of DMT.

Design

The dose-related safety, tolerability, electrophysiology and efficacy of DMT will be studied in individuals with major depression and healthy controls in a double-blind, placebo- controlled, randomized, hybrid (within subject, between subject design) study within 5 years. Healthy individuals and individuals with current major depression will participate in 2 DMT sessions separated by 4 weeks, during which they will receive placebo, low, and medium dose DMT. Subjects will be prepared for the DMT session and also debriefed after each DMT session.

Subjects

Individuals with Major Depressive Disorder and/or Major Depression and healthy controls are included in the present study. Participants between the ages of 21-65 years old may be eligible if healthy or experiencing depression that is sub-optimally responding to treatment. Alcohol and street drug use that does not meet criteria for use disorder will be evaluated by researchers on a case-by-case basis. Further, while recreational DMT use is rare in comparison with other mind-altering substances, psychedelic drugs, such as DMT, may induce expectancy effects in experienced users. Thus, the study described herein circumvents this potential variability by limiting participation of subjects who have considerable experience with DMT or related psychedelics.

Common Inclusion Criteria

1. Males and females

2. Age 21 to 75 years;

3. Body mass index between 18-35 kg/m²;

4. Able to provide written informed consent;

5. Willing to refrain from taking any medications not approved by the study physician;

6. Willing to refrain from using street drugs or alcohol the day before, the day of, and the day after each test session;

7. Negative urine drug screen on the morning of each test session (the following drugs will be tested for: cocaine, opioids, benzodiazepines, cannabinoids, stimulants);

8. Willing and able to abstain from smoking throughout each test session;

9. Women who are of child-bearing potential (WOCBP) and sexually active must be willing to practice an effective means of birth control;

10. Willing not to drive to and from the testing session.

Inclusion Criteria for Subjects withMDD

1. Diagnosed with Major Depressive Disorder (MDD), single or recurrent episode, and currently experiencing a Major Depressive Episode (MDE),moderate to severe degree (Score >17 on the 21 -item clinician-rated HAMD); 2. Unsatisfactory response to at least one adequate antidepressant trial (at least 6 weeks on a therapeutic dose) during the current depressive episode and/or unable to tolerate existing antidepressants, assessed with the Antidepressant Treatment History Form - Short Form (ATHF-SF);

3. Engaged in treatment for depression with a clinician and willing to continue treatment for the duration of the study:

4. Consent to allow the research team to engage the treating clinician.

Common Exclusion Criteria

1. Clinically significant risk for imminent suicidal or homicidal behavior during the course of the participation in the study;

2. Psychosis: a. Current or past history of any psychotic disorder including Schizophrenia, Bipolar I Disorder, Delusional Disorder, Paranoid Personality Disorder, or Schizoaffective Disorder (clinical judgement will be exercised); b. History of psychotic symptoms in the current or previous depressive episodes;

3. Currently⁷ taking an antidepressant medication (including SSRIs, SNRIs, TCAs, and MAOIs) or other medications (e.g., efavirenz, locanserin) that may alter the effects of 5HT2A agonists. Exceptions are medications used at low doses for sleep. If a subject meets all other study criteria, he/she may consider discontinuation of antidepressant under clinical supervision contingent upon the approval of the patient’s clinician. Subjects will need to be off prohibited medications for at least five half-lives of the medication’s major metabolites prior to the first test session;

4. Currently taking over the counter products such as 5-hydroxytryptophan and St. John’s wort, due to potential interactions with DMT;

5. Cognitive dysfunction that could interfere with study participation;

6. Recent history⁷ of meeting criteria for alcohol or substance use disorder (excluding caffeine and nicotine);

7. Alcohol use of >7 in females and 14 in males drinks per week (NIAAA guidelines);

8. Lifetime history of hallucinogen use disorder;

9. Regular (>once per month) use or misuse of serotonergic hallucinogens including DMT, psilocybin, LSD, and related compounds;

10. History of intolerance to drugs known to significantly alter perception, e.g.. DMT ketamine, psilocybin, LSD, Salvinorin A, mescaline, etc.; 11. Hypotension, as defined as a baseline blood pressure < 90/60 mmHg or orthostatic hypotension as defined as a sustained reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of 10 mm Hg within 3 min of standing or head- up tilt;

12. Pregnancy or currently breast feeding (lactation);

13. Medical conditions deemed by the PI, or his designee, to be unstable including but not limited to uncontrolled hypertension (e.g.. >140/90 averaged across four assessments, uncontrolled insulin-dependent diabetes, renal or hepatic failure, seizure disorder, etc.;

14. Participation in any clinical trial with an investigational drug or device within the past month or concurrent to study participation;

15. Any current or past history of any physical condition or abnormal screening laboratory test that, in the investigator’s opinion, might put the subject at risk or interfere with study results interpretation.

16. IQ < 80 measured by the Weschler Test of Adult Reading (WTAR).

Exclusion criteria for depressed subjects

1. Current primary psychiatric disorder other than MDD;

2. Medically significant condition rendering unsuitability for the study;

3. History of mania; and

4. History of psychosis.

Exclusion criteria for healthy controls

1. No cunent DSM-V psychiatric disorder, excluding nicotine and caffeine use disorder;

2. No lifetime use of psychiatric medication >3 months (proxy for psychiatric disorders).

3. No family history of serious mental illness (e.g., schizophrenia, bipolar disorder)

Inclusion criteria for healthy controls

1. No current DSM-5 psychiatric disorder, excluding nicotine and caffeine use disorder;

Screening

Individuals who pass a brief telephone screening will be invited for a full evaluation and will undergo a secondary screen to confirm that they meet all inclusion and exclusion criteria. Subjects will be asked about a family history of psychiatric disorders, specifically psychotic disorders or drug abuse. Subjects will undergo a structured psychiatric evaluation, personality screen (e.g., NEO Personality Inventory), as well as auditory and visual testing to ensure they can complete the EEG assessments. The Wechsler Test of Adult Reading will be administered to estimate IQ. The screening process will take 4-6 hours.

Subjects will undergo a medical and psychiatric evaluation including medical/psychiatric history, physical examination, laboratory tests (e.g., hematology, serum chemistry profile, liver and thyroid studies, urinalysis, urine toxicology, and urine pregnancy), and EKG. Subjects with MDD will be assessed using the Antidepressant Treatment History Form - Short Form (ATHF-SF).

To enhance the reliability of the information collected during this process, an outside informant provided by the candidate, such as a family member or friend, will also be interviewed.

MDD Participant Follow-Up

For depressed subjects, their outpatient mental health clinician will be contacted to verify the candidate’s diagnosis of major depressive disorder that has failed one adequate antidepressant trial and to ensure appropriate follow up.

The prospective participant’s clinician is contacted to confirm the diagnosis, history, medication treatment, etc., and the clinician is asked to provide an opinion on the safety and feasibility of tapering antidepressant medications in a planned way.

The frequency of contact between the study participant and their clinician is determined by a number of factors including the severity' of illness, the need for a medication taper, information on how the participant fared with previous medication free periods, etc. For example in this 16 week study, the research team will have at least 18 visits of which 3 visits will last 4-6 hours, 4 visits will last 4 hours, and the rest of the visits 30 minutes each. Collectively this level of contact far exceeds what most individuals with depression have in the community. It allows the study staff to detect any changes in the patient’s clinical status which can then be relayed to the outpatient mental health clinician for clinical follow up. which may necessitate more frequent follow up.

Both the patient and their clinician will be made aware at the very' outset that participation is contingent on an inadequate response to antidepressant treatments and continued follow up. Preparation

One psychoeducation session will be held before the first test session to provide detailed information about the expected effects of DMT and THC and to discuss strategies to cope with negotiating a ‘’bad trip.’’ The first session will be conducted at the end of screening once the subject is deemed eligible. Then, either the day before or on the morning of each drug session, this information will be briefly reviewed. During the preparatory session. MDD subjects will be invited to discuss their mood symptoms and their history relevant to depression, e.g, trauma, interpersonal challenges, etc. Healthy controls and MDD subjects will be provided information about what psychedelic effects to expect. Furthermore, to address expectancy, they were told that while they may not benefit from study participation, their participation may lead to knowledge that may help others. Expectancy will be measured by scales such as the Stanford Expectations of Treatment Scale, and Credibility and Expectancy Questionnaire. Quality of Life will be measured using the SF-36 form.

Dosing session

The drug dosing sessions will last up to approximately 4-6 hours in total. Subjects will undergo a brief medical assessment (e.g, vital signs, urine drug screen, pregnancy test, breath alcohol determination, and determination of any medication changes or study prohibitions) on the morning of each test day. A light standard breakfast will be served. Intravenous line will be placed. See Tables 1 A-1B for a brief description of the procedures to be performed.

Table 1A. Schedule (days 0 to 35)

* Resting and task-related

Table IB. Schedule (days 42 to 98)

*Resting and task-related

Debriefing

For the approximately 2 hours between the waning of DMT and the time of discharge. participants will be debriefed by a psychiatrist. Additionally, the day after, 1, 2. and 4 weeks after each session, participants will be contacted to check on their well-being, to monitor for any adverse events, and, in MDD participants, to administer the HAMD-17 and to help them process and integrate the experience Outcome Measures

Safety

Defined by the US FDA as “the risk to the subject or patient from a drug or biologic assessed by tests", safety was assessed by monitoring vital signs and recording adverse events, including physiological indices (z. e. , blood pressure and heart rate will be measured before, during, and after the dose of DMT on each test day; pulse oximetry will be measured continuously); psychedelic effects (z.e., the 30-item revised Mystical Experience Questionnaire (MEQ30) will be used to measure mystical/psychedelic experiences associated with drugs like psilocybin); psychotomimetic effects (z.e., to capture the effects of DMT on perception, thought, and sensory processing, participants will be measured using the Psychotomimetic States Inventory); anxiety (z.e., assessed using a visual analog scale that subjects will be asked to score from 0 (not at all) to 100 (worst ever) to capture anxiety); depression (z.e., ONLY depressed subjects will be asked to score from 0 (not at all) to 100 (worst ever) to capture the depression);

Additionally, intensity of experience will be determined, utilizing the Challenging Experience Questionnaire (CEQ) (z.e.. a 26 item likert-scale style survey will be used to provide a phenomenological profile specifically of challenging aspects of experiences with psilocybin). Drug reinforcing effects will be assessed with questions such as '‘How- likely are you to use this drug recreationally? 0 (not at all) -A 100 (most of all)” and “How much are you willing to pay for the acute effects that you experienced during the dosing session? $0

$100?”.

Shortly after resolution of effects, participants were instructed to retroactively rate the highest effects experienced since the last time they were prompted to provide a rating.

Tolerability

Tolerability, as defined by the US FDA as “the degree to which overt adverse effects can be tolerated” by a subject, was assessed. At the end of the test day, after all drug effects had worn off, participants were asked to score 1) the overall experience on a visual analog scale [VAS] (0 = intolerable to 100 = well-tolerated).

Electrophysiological

EEG is an inexpensive, noninvasive and easily replicable means of assessing neural activity before and after DMT administration. EEG will be recorded at a sampling rate of 1000 Hz using 64 channels with a nose reference, with additional electrodes to record the vertical and horizontal electrooculogram (EOG; Neuroscan SynAmps RT, Compumedics Neuroscan, Charlotte, NC, USA). Electrode impedances were maintained below 10 kQ. EEG data will be bandpass filtered from 0. 1 - 100 Hz (24 dB/oct) and notch filtered at 60 Hz. The EEG will be then segmented into epochs consisting of a 300 ms baseline and ending 500 ms after stimulus onset. Ocular movement correction will be applied using Gratton’s algorithm. After baseline correction (-300 ms before stimulus onset), any trial with a voltage greater than ± 150 pV will be excluded from analysis. All EEG preprocessing and analysis will be performed using Brain Vision Analyzer 2.0 (Brain Products GmbH, Germany). EEG will be used 1) to determine that DMT has engaged the target of interest (target engagement) and 2) to measure an antidepressant-relevant response to DMT (outcome). Resting state EEG will be collected the day after each dosing session.

Task Related (Long Term Potentiation)

For DMT to produce improvements in depression that last well after its acute pharmacological effects, it is suggested herein that it may alter neuroplasticity (the target). Furthermore, it will be important to determine whether DMT alters neuroplasticity differentially in healthy subjects and individuals with depression.

Target engagement: One form of synaptic plasticity is the ability of synapses to strengthen over time in response to increases or decreases in their activity. Long-term potentiation (LTP) is a persistent increase in synaptic strength following high-frequency stimulation and is believed to be a neural substrate of learning and memory. In order to examine the hypothesis that DMT increases neuroplasticity, LTP will be measured. While traditionally studied in slice preparations, it is now possible to index LTP using event related potentials. DMT' s effects on plasticity will be identified as indexed by LTP using auditory and visual LTP tasks.

It is further proposed herein to include a measure of the lasting potentiation of the amplitude of the auditory and visual N 100 event-related potential (ERP) following high- frequency auditory and visual stimulation, respectively. This paradigm has been shown to have the properties of long-term potentiation (LTP), including 1) frequency dependency. 2) temporal stability, 3) input specificity, and 4) de-potentiation by low frequency stimulation. The outcome measure will be increased N 100 amplitude after tetanic stimulation.

The primary outcome measure will be evoked theta power before the auditory tetanus (block 1) versus after the tetanus (block 2). Evoked theta power is the temporal-spectral equivalent of the N100-P200 event-related potential (ERP) complex as assessed in previous LTP studies. Evoked power, which is a method of examining event-related oscillations (EVOs), yields more information than traditional ERPs (i.e., ERPs only provide amplitude (voltage) and temporal information, while EVOs provide amplitude (power), temporal, and spectral information). Evoked theta power will be determined via automated algorithms as described in the literature. Briefly, time-locked, evoked power will be determined via time- frequency analysis and will be performed using a complex Morlet wavelet transform. After preprocessing, and individual trial averaging, a continuous wavelet transform will be carried out using 1 Hz frequency steps from 1-80 Hz. A wavelet parameter of 8 will be utilized, and a 300 ms baseline correction will be applied. A temporal-spectral region of interest (ROI) approach will be used, as the time window and frequency band of interest will be between 80-250 ms and 4-8 Hz. respectively (corresponding to the traditional N100-P200 ERP complex).

Efficacy

In one aspect, efficacy will be assessed by reductions in depression, including HAM- D and/or QID-SR16 assessments.

HAM-D is a 21 -item clinician-rated questionnaire used to measure depression symptoms and response to treatment in clinical trials of depression. The sum of scores on the first 17 items is used to assess change in the severity of depression. The HAMD-17 was chosen as the primary efficacy measure due to its high reliability and validity.

QIDS-SR16: The QIDS-SR16 is a 16-item self-report screening instrument for depression. Suboptimal response is defined by a score of > 16 (severe depression) after at least 6 w eeks of treatment, or a score of > 11 (moderately severe depression) after at least 8 w eeks of treatment.

In another aspect, efficacy will be assessed by reductions in suicidality, including use of the Columbia suicide severity rating scale (C-SSRS) to assess changes in suicidal ideation and/or behavior. The baseline version will be collected at baseline and the ‘Since the Last Visit' version will be used the day before and after each test session.

In another aspect, efficacy will be assessed by reductions in anxiety, including the use of HAM- A measurement. The scale consists of 14 items, each defined by a series of symptoms, and measures both psychic anxiety and somatic anxiety.

In another aspect, efficacy will be assessed by improvements in quality of life, including the use of SF-36 measurement and/or assessment. The health-related quality of life (SF-36) assesses 8 subscales of the health-related quality of life, or subjective health, which are conceptually subsumed in the areas of “physical” and “mental” health.

In another aspect, efficacy will be assessed by duration of antidepressant effects. It is hypothesized herein that, in depressed individuals, DMT will have a sustained effect lasting several days. The duration of antidepressant effects will be measured by comparing HAM-D scores before and weeks after each dosing session. Secondary Measures

In certain embodiments, subjects will be tested for expectancy effects at screening, and before each dosing session. In certain embodiments, subjects will be asked to guess their treatment assignment, the degree of certainty of their guess and the reason for their guess both immediately after the psychedelic dosing session(s) and at the end of the study. Either the James’ blinding index (BI) or Bang’s BI, will be used to measure the adequacy of the blind.

On each dosing session, blood for DMT-relevant molecules (such as corticotropin, B- endorphin, prolactin, GH, cortisol, melatonin, and cytokines panel levels) will be sampled approximately 30 and 2 minutes before drug administration, then repeated approximately 0, 20, 30, and 60 minutes after drug administration. Changes in personality domains will be further evaluated (e.g., NEO personality inventory ). Further, psychological flexibility will be assessed using the Acceptance and Action Questionnaire (AAQ), which is a one-factor, likert scale assessment of psychological inflexibility.

Dosing Regimen

DMT can be snorted, smoked, vaporized, or injected. However, the oral bioavailability of DMT is very poor unless it is combined with a drug that inhibits its metabolism (e.g., a monoamine oxidase inhibitor (MAOI), such as harmaline). Smoking would not be feasible, as it would result in pyrolysis of drugs as well as introduce unknown oxidation products of undetermined safety into subjects, in addition to lung damage. Administration by vaporization is not uniform between subjects and within subjects, since it depends on a number of variables including dead space, lung vital capacity, depth of inhalation, how long an individual holds his/her breath, etc. The latter may result in pharmacokinetic variability.

The intravenous route has the best bioavailability. Thus, for this study, in order to exercise maximum control of the experiment, the intravenous route has been chosen. As demonstrated in the pilot study described herein, DMT can be administered intravenously.

As indicated elsewhere herein, the goal of the present study is to determine a dosing regimen of DMT that:

(a) allows for psychedelic effects to be reached quickly (i.e., quicker than oral dosing which takes hours and is highly variable); (b) produces psychedelic effects that are not overwhelmingly intense so that participants can be engaged in conversation;

(c) maintains effects longer than the typical 20-30 minutes with the traditional bolus dosing, such that participants may be able to engage in psychotherapy which will be instituted in a subsequent study; and

(d) allows the drug effects to be decreased or stopped in real-time with the IV infusion method. Thus, if a subject is experiencing psychedelic effects that are too intense, the infusion can be lowered, or if the subject has experienced psychedelic effects for a sufficient amount of time, the infusion can be decreased or stopped from reaching the desired effect quickly. The dosing regimen would need to have an acceptable safety profile and should be well-tolerated.

Thus, in one aspect, the present disclosure relates to each of 2 dosing regimens which enable demonstrations that the safety, tolerability, and efficacy of DMT is dose-related; showing dose-related effects will give greater confidence in interpreting the side-effects and potential beneficial effects of DMT. Furthermore, if, for example, the lower dosing regimen, has a more favorable side-effect profile and also produces beneficial effects in MDD, it will have much greater acceptance from both patients and clinicians. Furthermore, testing 3 doses that will also help with blinding of the study; this point cannot be overemphasized in studies that involve drugs that have high expectancy effects and in conditions such as MDD. where there is a high placebo response.

It is proposed herein to test two different dosing regimens of DMT and placebo that are expected to produce less intense but longer effects than the dosing used in previous studies. In studies by Strassman et al., DMT was administered intravenously as a bolus at doses ranging from 0.05 mg/kg up to 0.4 mg/kg. DMT produced near instantaneous clear psychedelic effects between 0.2 mg/kg and 0.4 mg/kg (i.e., the 0. 1 mg/kg dose did not produce psychedelic effects and at a lower dose (0.05 mg/kg) subjects could not distinguishing it from placebo). At doses of 0.3 mg/kg administered over 30-60 seconds, the effects are rapid, intense and may be overwhelming to participants, a state that would not be compatible with conducting any psychotherapy.

The completed and ongoing DMT studies that included a bolus and continuous infusion are tabulated above (FIG. 3; Table 3). Note however, that other the completed open labeled study described herein, there are no studies in MDD. In brief the typical bolus given over 1-5 minutes ranged from DMT LDso = 21 mg. Following this, continuous infusions were administered anywhere from 20-90 minutes. The dose of continuous infusions ranged from 0.01125 mg/kg/min up to 0.02 mg/kg/min. Strassman & Gallimore modeled the PK/PD of DMT to develop a longer duration of effects. However, their suggested infusion protocol "would likely result in the standard “firing out of a canon ” experience, which could well be overwhelming for many subjects"'.

Lastly the total dose adjusted by time is presented in the last column and ranges from 0.6-1.83 mg/min. Of note, in the study by Daumann et al., all 14 subjects completed the study without adverse event (“All subjects who entered the study completed both experimental days without any complications ”) in contrast to the studies by Gouzoulis-Mayfrank et al., in which 6 of 15 subjects did not complete all test conditions. Strassman and Gallimore surmised that in the Gouzoulis-Mayfrank study where subjects were administered 0.3 mg/kg bolus, followed by an infusion beginning at 1.5 min, at a rate of 0.02 mg/kg/min over 84 minutes, the “very high concentration and is certain to produce extremely intense effects in almost all individuals .”

In one aspect, the dosing regimen of the present disclosure allows for psychedelic effects to be reached quickly (i.e.. more quickly than oral psilocybin dosing). The intravenous route allows for the psychedelic effects to be reached quickly and also stopped quickly, neither of w hich is possible w ith oral administration. Therefore, DMT will be administered intravenously. Furthermore, the bolus dose will be chosen so as not to overwhelm participants. Therefore, a bolus of 10 (low) and 14 (medium) is proposed. These two doses fall between the 10 and 21 mg bolus doses used (FIG. 3; Table 3).

In another aspect, the dosing regimen of the present disclosure produces psychedelic effects that are not overwhelmingly intense such that the subject can be engaged in conversation. Instead of the bolus being administered over 30-60 seconds as described in Strassman etai. Timmerman et al., and D’Souza et al., the bolus is administered over 5 minutes. This will make the bolus much more tolerable.

In another aspect, the dosing regimen of the present disclosure maintains effects longer than the typical 20-30 minutes with traditional bolus infusion, such that the subject may be able to engage with the research team and potentially psychotherapy. In certain embodiments, the dosing regimen comprises 0.01 mg/kg/min (low) and 0.015 mg/kg/min (medium) infused intravenously for up to 55 mins.

In one aspect, the present disclosure provides a low dose regimen comprising a fixed dose of about 10 mg bolus over 5 minutes, followed by 0.01 mg/kg/min over about 55 minutes (i.e., total dose of about 49 mg in a 70 kg individual). In another aspect, the present disclosure provides a medium dose regimen comprising a fixed dose of about 14 mg bolus over 5 minutes, followed by 0.015 mg/kg/min over about 55 minutes (i.e., total dose of about 71.75 mg in a 70 kg individual).

In certain embodiments, if these doses are either not tolerated, unsafe or don’t produce the desired effects after studying the first 10 subjects, the dosing regimen will be adjusted accordingly. Currently, the maximum dose of DMT (z.e., bolus and/or continuous infusion) that participants will receive is 100 mg.

Clinical trials comprising significantly higher doses are reported and/or proposed, for example, Liechti et al. proposed administering: placebo; 0.6 mg/min, for a total 54 mg in a 70 kg individual; 1.2 mg/min, for a total 108 mg in a 70 kg individual; 1.8 mg/min, for a total 162 mg in a 70 kg individual; and 2.4 mg/min, for a total 216 mg in a 70 kg individual.

Placebo will be administered to mimic the bolus and continuous infusion used for administering DMT as described herein. Therefore, participants will receive an equivalent volume of normal saline administered over 5 minutes to mimic the bolus administration of 10 or 14 mg. Following this, participants will receive an equivalent volume of normal saline administered over 55 minutes to mimic the continuous infusion.

Sample Size Estimation

It is hypothesized herein that DMT will be safe and well-tolerated both acutely, subacute (4 weeks) and long-term (24 weeks) follow-up in individuals with Major Depressive Disorder and healthy controls. Further, since a dropout rate of 30% is expected, in order to obtain complete data in 60 healthy subjects and depressed subjects, 78 subjects will be recruited. It is likely that the sample size may be revised after some preliminary' data have been observed.

It is hypothesized herein that DMT will produce rapid and sustained reductions in depression in individuals with Major Depressive Disorder. Palhano-Fontes reported significant (large effect size) antidepressant effects of ayahuasca in a parallel-arm, doubleblind, randomized, placebo-controlled trial with ayahuasca in patients (n=29) with treatmentresistant depression. The proposed DMT study, which 1) has both a within-subjects design and between-subjects design, unlike the Palhano-Fontes study and 2) uses IV DMT instead of oral ayahuasca (which has variable/poor bioavailability), will have greater power to detect differences than the Palhano-Fontes study, and therefore, the sample size of 20 per group should be sufficient. For within-subjects analyses, assuming a two-tailed a=0.05, 20 subjects per group will provide 80% statistical power to detect large group effects (f=0.41). It is hypothesized herein that DMT will result in dose-related increases in short and longer-term electrophysiological biomarkers of neuroplasticity in individuals diagnosed with Major Depressive Disorder.

It is hypothesized herein that repeated administration of 0.3 mg/kg DMT will be tolerated acutely, subacutely (4 weeks) and at long term follow up (24 weeks).

It is hypothesized herein that, relative to single dose, repeated dose of DMT will result in increased change on measures of depression and anxiety with respect to magnitude and duration of change. We will have >80% power to detect medium/large within-subject changes (d’=0.66) from originally assigned doses. It is hypothesized herein that, relative to single dose, repeated dose of DMT will result in increased change to electrophysiological biomarkers of neuroplasticity.

Enhanced blinding

It is critical to preserve the blind in studies with psychedelic drugs to reduce the effects of expectancy, which are substantial. Subjects will be told that across the 2 test days they may receive any 2 of the following 5 substances: 1) placebo (normal saline), 2) low dose DMT, 3) medium dose DMT, 4) low dose THC, and 5) medium dose THC.

In actuality, subjects will never receive either dose of THC. Once study enrollment has been completed, subjects will be contacted to disclose the conditions that they were assigned to (FIGs. 2A-2B).

Statistical Analysis

All outcomes will be summarized descriptively and assessed for normality⁷ prior to analysis using normal probability plots and Kolmogorov test statistics. Transformations or nonparametric analyses will be performed as necessary. Prior to undertaking the outcome analyses, analyses of variance or chi-square comparisons will be performed to identify baseline differences across medication conditions. If baseline differences exist across study conditions, covariance adjustments will be made as appropriate across planned analyses. In the linear mixed models (LMM) described below, the best-fitting variance-covariance structure will be based on information criteria. Least-square means will be plotted and compared post-hoc to help interpret the nature of significant effects. All primary tests will be two-sided and considered statistically significant at a=0.05. Post-hoc comparisons will be performed as appropriate and significance levels for secondary outcomes will be adjusted using the Bonferroni correction basing the adjustment on the number of conceptually related statistical tests within each hypothesis. All analyses will be performed using SAS, version 9.4 (SAS Institute Inc., Cary, NC).

DMT will be safe and well-tolerated both acutely, subacute and long-term follow-up in individuals with Major Depressive Disorder and healthy controls. Safety will be assessed by utilizing linear mixed models (LMM) with dose as a between subjects factor and time (day after, 1, and 4 weeks) as a within subjects factor and diagnosis (healthy vs. depressed) as between subjects factor. Parameters include: adverse events, and dropout rates, cardiovascular changes (heart rate, blood pressure, oxygen saturation), subjective changes (psychedelic [MEQ-30], psychotomimetic [PSI], anxiety [VAS]) and tolerability (VAS) will all be measured throughout the trial. We will also model the dose by time interaction.

Complementing the results from the analysis of the parallel group design, long term follow up (24 weeks) will be similarly assessed with sequence as a between subjects factor.

In one aspect, the present study will determine whether DMT, in a dose-related manner, reduces depression scores in individuals with current Major Depressive Disorder.

The primary outcome measure is change in depression scores in the MDD patients measured by a validated depression scale, e.g., HAM-D, the day after and at 1, 2, 4, 5 weeks after each DMT test day. In addition, other depression-relevant symptoms will be measured including self-reported depression (QIDS) and anxiety (HAM- A).

Complementing the results from the analysis of the parallel group design, further information on dose-related effects will be realized by within subjects’ comparisons between HAM-D scores of participants who received placebo or low dose at the first dosing session with the second dose of medium dose.

It is hypothesized herein that DMT will result in dose-related increases in short and longer-term electrophysiological biomarkers of neuroplasticity in individuals diagnosed with Major Depressive Disorder.

The primary outcome of interest is change in neuroplasticity the day after and 4 weeks after each DMT session. The data will be analyzed using linear mixed models that include dose and diagnosis (healthy vs. depressed) as a between subjects' factor and time (1 day. 4 weeks after DMT test day) as a within subjects factor. The best-fitting variance-covariance structure will be determined by information criteria.

It is hypothesized herein that repeated administration of medium dose DMT will be tolerated acutely, sub acutely, and at long term follow up.

Safety in those receiving two doses of DMT will be assessed by utilizing linear mixed models (LMM) with ORDER (first dose vs. second dose) and time (day after and 1, 2, 4, 5, 24 weeks) as a within subjects factor and sequence (low followed by medium, medium followed by medium) and diagnosis (healthy vs. depressed) as between subjects factors. Parameters include: cardiovascular changes (heart rate, blood pressure, oxygen saturation), subjective changes (psychedelic [MEQ-30], psychotomimetic [PSI], anxiety [VAS]) and tolerability (VAS), adverse events, and dropout rates will all be measured throughout the trial.

It is hypothesized herein that, relative to single dose, repeated dose of DMT will result in increased change on measures of depression and anxiety with respect to magnitude and duration of change.

The primary outcome measure is change in depression scores in the MDD patients measured by a validated depression scale, e.g., HAM-D, the day after and at 1, 2, 4, 5 weeks after the second DMT test day (in subjects that receive two doses). Sequence (low followed by medium, medium followed by medium) will be included as a between subjects factor. In addition, other relevant symptoms will be measured including self-reported depression (QIDS) and anxiety (HAM-A).

It is hypothesized herein that relative to single dose, repeated dose of DMT will result in increased change to electrophysiological biomarkers of neuroplasticity. The primary outcome of interest is change in neuroplast icily the day after and 4 weeks after subjects receive a 2^nd dose of DMT. For measures of neuroplasticity LMM will be used with ORDER (1^st dose vs. 2^nd dose) included as a within-subjects factor and sequence (low followed by medium, medium followed by medium) as well as diagnosis (heathy vs. depressed) will be included as a between subjects factor.

Risks

The risks associated include those associated with the psychological and physical effects of DMT (e.g., blood pressure alteration, GI distress of DMT phlebotomy and IV placement, abuse potential, and loss of confidentiality).

Safety and Tolerability in patients with MDD

In the pilot study of safety, tolerability, and efficacy of DMT, as described herein, in both healthy and depressed volunteers, DMT was tolerated by both healthy (n=3) and MDD participants (n=7) studied; there were no dropouts. Intravenous DMT at doses of 0.1 and 0.3 mg/kg was mostly safe and tolerated and may have next day (rapid) antidepressant effect in patients with treatment-resistant MDD in this pilot study. Participants reported overall tolerability (0 = intolerable to 100 = well-tolerated) as 89.80 (SD 12.95) for the 0.1 mg/kg dose session and 71.11 (SD 24.52) for the 0.3 mg/kg dose session (difference -17.78 [95% CI -32.81 to -2.75] t = -2.72, p = 0.026). After completion of the 0.1 mg/kg dose session, all participants reported willingness to return for the second dose session (0.3 mg/kg). FIG. 4 shows individual ratings of overall tolerability⁷ on the 0.1 mg/kg and 0.3 mg/kg

DMT scored on a scale of 0 = intolerable to 100 = well-tolerated. Overall tolerability of the test day was scored at the end of each test day when there were no lingering effects. Subjects 1-3 are healthy volunteers and subjects 4-10 are individuals with major depressive disorder. The far right indicated the group mean of each. Error bars indicate standard errors of the mean (S.E.M.).

The open label trial described herein was overall concordant with the known effects as described in the literature. The most common adverse events (AEs) were transient anxiety⁷ prior to administration and immediately after drug administration (n = 6), transient headache (n = 2) during onset and after resolution of drug effects, and transient hypertension (n = 2) before dose and during onset of effects (Table 2). Some of the AEs were deemed definitely related to DMT effects while others were deemed unrelated.

Table 2. Schedule of dosing sessions

However, there was one unexpected serious adverse event featuring one participant who developed transient asymptomatic hypotension and bradycardia shortly after administration of 0.3 mg/kg DMT. The participant was awake and responsive throughout the event. The participant was placed in Trendelenburg position and given intravenous fluids. There were no adverse short or long-term consequences. The participant later revealed a history of postural hypotension/syncope which she failed to share at the screening evaluation. There are no known published reports of such events; DMT is typically reported to increase heart rate and blood pressure.

None of the participants experienced any clinically relevant psychotic symptoms. All participants passed a standard field sobriety test and pre-dose baseline-matched Mini-Mental Status Exam prior to discharge. No rescue medications were used during any dosing session to address psychological or physiologic adverse events reported. Tolerance does not develop to the psychological effects of DMT, but some evidence suggests that tolerance may develop to the physiological effects of DMT.

Psychological effects

DMT can produce hallucinations, illusions, altered time perception, altered reality, synesthesia, thought alteration, affect enhancement, and depersonalization. How an individual tolerates these effects varies considerably and is influenced by set and setting. Some individuals may experience the effects as a ’‘bad trip” - with effects that include anxiety, agitation, or fear. In a survey about the main risks of DMT identified by people who use DMT (z.e., smoking), the most common responses were “bad trip” (51%), the potential for “psychospiritual” problems (39%). and physiological problems (26%), including respiratory irritation and bums {, 2014 #6}. When administered intravenously to healthy volunteers at doses ranging from 0. 1 mg/ kg to 0.4 mg/kg, there were no unexpected or serious adverse events reported in previous studies {Strassman, 1995 #14;Strassman, 1994 #31}. Tolerance does not develop to the psychological effects of DMT. but some evidence suggests that tolerance may develop to the physiological effects of DMT. If a subject experiences clinically significant psychological distress or significant physiological changes (high blood pressure - see below) after the administration of DMT, abortion of the infusion will be considered.

Stopping rules for psychological distress

The current view of psychedelic treatment is that the long-term beneficial effects (e.g.. antidepressant effects) of psychedelic treatment are directly correlated to their acute psychedelic effects z.e., the acute psychedelic effects may be necessary for their longer-term antidepressant effects. Therefore, some degree of discomfort during the acute psychedelic experience is considered unavoidable. Subjects will be prepared for this beforehand. While these effects can be experienced as being intense, in session psychological reassurance is typically sufficient to manage acute psychological distress. For example, the use rescue medications to treat psychological distress were not used in the open-label study (n=10 x 2 DMT doses). If, however, the psychological distress warrants the use of rescue medications, the infusion will be stopped. Additionally, if a subject at any point makes it clear that infusion should be stopped it will be stopped.

Physiological effects

Little is known about the lethality of DMT in humans, but extrapolating from animal data, the human LDso is estimated to be 560 mg, which gives a safety margin of >5 to the highest dose proposed in this study (100 mg).

Intravenous DMT is known to increase heart rate rapidly, as well as systolic and diastolic blood pressure. It has been reported that a dose of 0.4 mg/kg DMT (/.e., higher than the highest dose proposed in the cunent study) raised heart rate 26 beats per minute (bpm), systolic pressure by 35 mmHg, and diastolic pressure by 30 mmHg 2 minutes post-injection. There is obvious variability in the response to DMT; for example, the heart rate of some of the participants in the Strassman intravenous DMT study peaked at 150 bpm, while in other participants, the maximum heart rate was no higher than 95 bpm.

These increases in heart rate and blood pressure are well within the range of what has been previously observed in carefully monitored laboratory studies that were conducted over the past 25 years with IV ketamine, IV amphetamine, IV delta-9-tetrahydrocannabinol, IV nicotine, etc. in humans. An approach to manage tachycardia and increased blood pressure, without serious adverse events, is described herein. Hypertension

The frequency of monitoring will be increased to less than every five minutes apart (e.g., every two minutes) until the BP is stable and within appropriate range. In the event that a patient’s systolic pressure remains >180 or diastolic pressure remains > 110 for a significant period of time (~ 10 minutes), the subject may be administered a rapid acting antihypertensive (labetalol 10 mg IV) or a rapid acting oral antihypertensive such as captopril 12.5 mg. and the rapid response team will be called. In the event of increases in systolic pressure >180 or diastolic pressure >110 associated with that a significant period of time (-10 minutes), the DMT infusion may be aborted.

Tachycardia

Heart rate and oxygenation will be monitored continuously throughout the session using the pulse oximeter. In event of symptomatic drug-induced tachycardia (HR > 100 bpm) for a significant period of time (-10 minutes) - if associated with hypotension we mayincrease the rate of normal saline infusion.

To provide further perspective, the 120 bpm parameter is well within the recommended target heart rate range for aerobic exercise. The target heart rate recommended to achieve during aerobic exercise is 50 to 85 percent of an individual’s maximum heart rate (HRmax). The latter is calculated as 220 - age (in years). Thus, the HRmax for the oldest allowable subjects in the study (age 65 years) would be 220-65= 155 bpm, 35 bpm higher than the 120 bpm that we are using as a guideline. If heart rate sustains >120 associated with psychological distress, the infusion may be aborted.

Hypotension

The frequency of monitoring will be increased to less than every five minutes apart (e.g, every two minutes) until the BP is stable and within appropriate range. In the event of drug-induced hypotension (SBP/DBP < 90/60) with clinical symptoms (e g., lightheadedness, dizziness, feeling faint, blurred or fading vision, nausea, and change in mental status), DMT infusion will be aborted and the subject reclined to Trendelenburg position, and increase the rate of normal saline infusion, as well as measure blood pressure more frequently (q2-q5 minutes) until resolution. If hypotension persists beyond 10 minutes, or the subject has clinical symptoms despite these interventions, the rapid response team will be called.

Bradycardia Heart rate and oxygenation will be monitored continuously throughout the session. In the event of sustained bradycardia (HR < 60) associated with symptoms, the rate of normal saline infusion will be increased. If bradycardia persists despite intervention, the DMT infusion may be aborted. If bradycardia persists beyond 10 minutes despite these interventions, the rapid response team will be called.

If a subject experiences significant physiological changes (see above) after the administration of DMT, abortion of the infusion will be considered.

The following subject-level stopping rules will be applied for physiological changes:

If a participant has sustained hypertension requiring antihypertensives or the need for a code (rapid response), the infusion will be stopped. Sustained high blood pressure is defined as 3 consecutive recordings of systolic and/or diastolic blood pressure greater than 50 mm and 40 mg Hg, respectively. Likewise, if a participant has hypotension requiring increased IV fluids, pressors, positioning in Trendelenberg position, or the need for a code (rapid response), the infusion will be stopped.

If a participant has sustained tachycardia requiring medications (e.g., labetolol) or the need for a code (rapid response), the infusion will be stopped. Sustained tachycardia is defined as 3 consecutive recordings or 10 minutes of heart rate > 90% of the subject’s individualized target heart rate (HRmax). If a participant has sustained bradycardia requiring increased IV fluids, pressors, positioning in Trendelenberg position, or the need for a code (rapid response), the infusion will be stopped.

Worsening depression and drug discontinuation

Subjects with Major Depressive Disorder (MDD) enrolled in this study must have failed to achieve an adequate antidepressant response to a therapeutic dose of at least one antidepressant medication for at least a six-week trial. If a potential subject is still on that medication (despite inadequate response) and wishes to participate in this study, they would be required to taper off this medication. However, this is not a research procedure and will be left to the discretion of the subject’s primary provider. Even assuming that the subject did not have an adequate response to the medication, discontinuing the medication may result in worsening of depressive symptoms, hence the patient will be monitored by their primary clinician who will guide the discontinuation of the medication. Other drug discontinuation symptoms are commonly experienced and are seen to some extent with all antidepressants. These symptoms may be: affective (e.g., irritability); gastrointestinal (e.g, nausea); neuromotor (e.g., ataxia); vasomotor (e.g.. diaphoresis); neurosensory (e.g., paraesthesia); and other neurological (e.g., increased dreaming).

Phlebotomy and IV Placement

Bruising, infection, and thrombosis can occur with placement of the intravenous line. Procedures will be performed by experienced personnel using good clinical technique. An approximate 30 mL of blood will be drawn prior to the start of the experiment (during screening), approximately 60 mL per test day, and 10 mL per follow-up. These volumes are well within Red Cross blood standards.

Pregnancy

DMT administration may pose unknown risks to the unborn fetus. For added safety, all female subjects will be screened for pregnancy and asked about use of birth control before randomization and again before each session. Female subjects who are pregnant or who do not use adequate birth control will not partake (or will cease to partake) in the study.

EEG Procedures

Brain waves are recorded by attaching electrodes (small plastic discs) to the scalp, using either individual electrodes or electrodes embedded in a nylon cap. The scalp must be carefully scrubbed to ensure proper electrode contact and to minimize electrical impedance. The electrode placement procedure may be uncomfortable at times, but not painful. There is a risk of infection and local skin irritation from electrode attachment.

To minimize these risks, careful preparation of skin surfaces using sterile supplies is conducted before attachment of electrodes, and we use standard procedures to clean the electrode cap after each study using a special bactericidal cleanser. In addition, the duration of electrode attachment rarely exceeds 3 hours, minimizing the development of skin irritation. There is a very low risk of developing an allergic reaction to the electrode conductive gel, which contains chemicals similar to human sweat. In the electrophysiological laboratories the risk of irritation, infection, or allergic reaction is very small (less than 1%). In addition to the above risks, if auditory stimuli are presented via headphones, some of the sounds may be loud. However, the noise level of these sounds is below the threshold that could damage hearing. No risks are associated with the visual stimuli presented during recording of EEG. Overall, the risks of the EEG measures are minimal. Abuse potential

The abuse potential of DMT is low. Inferring from the Global Drug Survey results. DMT is the least likely psychedelic to be used. This would suggest that it has low abuse liability. The findings of the GDS are consistent with previous research which suggests that hallucinogenic substances rarely lead to a strong urge to use more and have low' abuse potential.

Studies in nonhuman pnmates suggest that that administration of tryptamine derivatives such as mescaline, psilocybin or DMT have weak reinforcing effects, or alternatively, mixed reinforcing and aversive effects.

Risk for abuse potential is minimized via subject selection, estimation of abuse potential, and estimation of actual use. Subject Selection: Subjects will be screened for history of alcohol or substance abuse and current alcohol and substance use and abuse. Subjects w ill be excluded for recent history (past 3 months) of alcohol or substance use disorder excluding caffeine and nicotine. Subjects will be excluded for lifetime history of hallucinogen use disorder and/or for regular use or misuse of serotonergic hallucinogens including DMT, psilocybin, LSD. and related compounds. Estimation of Abuse Potential: abuse potential of DMT will be prospectively estimated by asking subjects at the end of each test day how⁷ much they liked the drug effects, how much they w ould be willing to pay for the experience, and the likelihood that they would seek out another similar experience. Estimation of Actual Use: For the 8 weeks after the last DMT session, we will ask subjects whether they have used DMT.

General Procedure

Before study participation, subjects will undergo careful psychiatric and physical screening. In healthy controls, a family member or close friend will be contacted to confirm the history provided by the potential research subject. For depressed subjects, their treating clinician will also be contacted to confirm the diagnosis of major depression; subjects will sign a release of information for these purposes. During each test session, research nurses, research assistants, and the study physician will be available to provide support, verbal reassurance, and consistent reality testing for individuals. If subjects experience intolerable distress while intoxicated, an anxiolytic (lorazepam) will be available in intravenous form, an antipsychotic (risperidone) will be available in oral form, antihypertensives will be available in oral (captopril) or intravenous form (labetalol). and an antiemetic (ondansetron) will be available in oral or intravenous form. In the event of continued intolerable effects of DMT, the subject may be brought to the Emergency Department on premises at the West Haven Veterans Affairs Hospital for further management and close monitoring.

At the end of each test day, a study physician will approve the discharge of subjects from the Neurobiological Studies Unit. Subjects will not drive home; as part of the qualifying criteria they will have to arrange for transportation (e.g., friend, family, taxi). Subjects will be provided a telephone number to reach an on-call research psychiatrist 24 hours/day should unpleasant effects occur after they have left the testing facility.

All subjects will be evaluated approximately the next day following drug administration to determine whether exposure to DMT in the experimental setting resulted in any negative sequelae. They will also be evaluated at approximately 1, 2, 4 weeks, and 6 months for further follow-up.

Adverse Events

An adverse event (AE) is any physical or clinical change or disease experienced by the subject at any time during the course of the study, whether or not considered to be related to the use of the study drug. This includes the onset of new illness and the exacerbation of pre-existing conditions. A serious adverse event is any event that is fatal, is life-threatening (defined as immediate risk of death from the AE as it occurred), is significantly or permanently disabling, or requires inpatient hospitalization or prolongs hospitalization. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

Grading

For the severity of adverse events, the following definitions will be used: mild (z.e., awareness of sign, symptom, or event, but easily tolerated); moderate (i.e., discomfort enough to cause interference with usual activity and may warrant intervention); severe (i.e., incapacitating with inability to do usual activities or significantly affects clinical status, and warrants intervention); and life-threatening (i.e., immediate risk of death).

Attribution

The investigator must also assess the relationship of any adverse event to the use of the study drug, based on available information, using the following guidelines: unrelated (i.e., adverse event(s) was clearly not related to the investigational agents(s)); unlikely (z.e., adverse event(s) was doubtfully related to investigational agent(s)); possible (i.e., adverse event(s) may have been related to investigational agent(s)); probable (z.e., adverse event(s) was likely related to investigational agent(s)); and definite (z.e., adverse event(s) was clearly related to investigational agent(s) or other intervention).

Monitoring and reporting of adverse events

Subjects will be questioned, examined, or both by the investigator or his designee for evidence of adverse events. Questions will be general, such as, “How have you been feeling since your last visit?'’ The presence or absence of specific adverse events will not be solicited from subjects. All adverse events will be recorded in the subject’s medical record, research records, or both. The onset and end dates, severity, and relationship to the study drug will be recorded for each adverse event. The severity of the adverse event will be assessed according to the described grading system. Any action or outcome (e.g., hospitalization, discontinuation of the study, etc.) will also be recorded for each adverse event.

All serious adverse events such as deaths, hospitalizations, and unexpected toxicity also will be reported to the HSS as well as our local hospital risk management committee under expedited reporting, i.e., immediately by telephone as the information is available to us, followed by written report within 48 hours. The procedures for written reporting include written documentation using the clinical notes related to the adverse event and specific forms detailing the event with a sign-off by all appropriate supervisory personnel. Communication of recommendations and decisions are made back to the investigator in a timely manner.

Example 2: Pilot study

Enrollment occurred over a period of about 7 months. From the 52 individuals who were initially considered for the study and for a telephone screen (FIG. 5), 14 were selected for an in-person screening visit, and 12 (3 HC and 9 with cunent MDD) were enrolled in the trial. 2 MDD participants dropped out before randomization. Amongst the 7 MDD participants who received DMT, 4 w ere self-referred and 3 were clinician-referred. Participants’ demographic and clinical characteristics are shown in FIGs. 6A-6B. Three of 7 MDD participants met criteria for severe depression at baseline (HAMD-17 score > 24) while the remaining four met criteria for moderate severity depression (HAMD-17 score 17 to < 24). As a prerequisite to participation, all MDD participants w ere engaged in treatment including psychotherapy and were not taking any antidepressant medication that could interfere with DMT effects. Except for one participant (one month), all the others had last taken antidepressants more than three months before their first test day. Only one MDD participant withdrew taking antidepressants in order to participate. The study was halted when the batch of DMT expired.

Participants reported overall tolerability (0 = intolerable to 100 = well-tolerated) as 89.80 (SD 12.95) for the 0.1 mg/kg dose session and 71.11 (SD 24.52) for the 0.3 mg/kg dose session (difference -17.78 [95% CI -32.81 to -2.75] t = -2.72. p = 0.026) (FIG. 4).

After completion of the 0.1 mg/kg dose session, all participants reported willingness to return for the second dose session (0.3 mg/kg). Furthermore, on completion of the first dose session (0. 1 mg/kg), the study psychiatrists determined that all the participants who completed the first dosing session were appropriate for continuation to the second dose day based on a review of the self-reported effects, study -clinician observed effects, cardiovascular parameters, participants debriefing, and clearance testing.

DMT increased systolic and diastolic blood pressure, and heart rate (FIGs. 7A-7C); while there was a significant time effect for both doses, there were no significant dose or dose-time effects.

Post-hoc analyses revealed statistically significant increases in systolic pressure at the +5, +10, and +15 minute time points relative to baseline; significant increases in diastolic pressure at +5, +10, +15, +20, and +30 minutes relative to baseline; and significant increases in heart rate at the +5 minute time point relative to baseline (Table 3).

Table 3. Dose-related effects of DMT on blood pressure and heart rate

The most common adverse events (AEs) were transient anxiety prior to administration and drug onset (n = 6). transient headache (n = 2) during onset and after resolution of drug effects, and transient hypertension (n = 2) before dose and during onset of effects (FIGs. 8A- 8B). Some of the AEs were deemed definitely related to DMT effects while others were deemed unrelated. There was one serious adverse event in a female participant who had significant asymptomatic bradycardia and hypotension that was addressed by placing the participant in Trendelenburg position and increasing intravenous saline. None of the participants experienced any clinically relevant psychotic symptoms. All participants passed a standard field sobriety test and pre-dose baseline-matched Mini-Mental Status Exam prior to discharge. No rescue medications were used during any dosing session to address psychological or physiologic adverse events reported.

DMT’s acute psychedelic effects typically became detectable between 2 and 5 minutes of administration, peaked between 5-10 minutes after dosing, and completely subsided by 30 minutes. While there were no significant scores on any of the 23 -item VAS psychedelic effects at baseline, scores increased with both doses at the +30 minute rating. Peak change in VAS psychedelic composite score was 13. 16 (SD 1 1.91) for the 0.1 mg/kg session and 55.83 (SD 23.89) for the 0.3 mg/kg dose (difference 42.67 [95% CI 33.30 to 52.03]; z = 4.11; p < 0.0001; Hedge’s g = 2.2) (Table 4).

Table 4. Dose-related peak change in subjective effects

VAS. visual analog scale; PSI, psychotomimetic states inventory.

There were significant dose-related differences on 16 of the 23- items (FDR correction, q = 0.05) (Table 5). The top five ranked items with significant dose- related differences (p, adjusted < 0.01) were ‘intensity' of experience' (p = 0.002), ‘complex visual images’ (p = 0.004), ‘experienced different reality /dimension’ (p = 0.006), ‘things looked strange’ (p = 0.008), and ‘imagination was very vivid’ (p = 0.01) (Table 5; FIG. 10).

Table 5. Dose-related peak change from baseline in VAS psychedelic effects

FDR correction **p. adjusted <0.01; *p. adjusted <0.036

Mean peak change in Psychotomimetic States Inventory' (PSI) scale total score was 7.33 (SD 7.62) for the 0.1 mg/kg session and 31.67 (16.57) for the 0.3 mg/kg session (difference 24.33; 95% CI 12.74 to 35.94; t = 4.84: p = 0.001; Hedge’s g = 1.89). The dose- related difference on peak change in PSI subscales was significant only for the perceptual disturbance subscale (p < 0.005) (Table 6).

Table 6. Dose-related peak change in psychotomimetic effects

Peak change in VAS anxiety scale administered to all participants was 2.56 (SD 31.8) on the 0. 1 mg/kg session and 29.67 (SD 39.96) on the 0.3 mg/kg session; (difference 27. 11 [ 95% CI -14.30 to 68.53] z = 1.1 , p = 0.26). Peak change in VAS depression administered only to MDD participants was 6.83 (SD 28.94) for the 0. 1 mg/kg session and 14.83 (SD 37.79) on the 0.3 mg/kg session (difference 8.00 [95% CI -41.47 to 57.47] z = 0.11, p = 0.92 (FIGs. 9A-9B).

On measures of drug desirability, participants reported overall willingness to use DMT as 24.00 (SD 17.91) for the 0. 1 mg/kg session and 22.44 (SD 22.72) for the 0.3 mg/kg session; (difference -1.56 [ 95% CI: -16.74 to 13.62] z = -0.14, p = 0.90). Participants monetized the value of drug effects (scale from 0 - 100 dollars) as 25.56 (SD 29.07) for the 0. 1 mg/kg session and 24.78 (SD 33.36) for the 0.3 mg/kg session; (difference -0.78 [95% CI -32.38 to 33.94] z = -0. 14, p = 0.89) (Table 7). Table 7. Desirability of DMT

Most MDD participants showed a nominal reduction in depression severity on the HAMD-17 after the 0. 1 mg/kg session (FIG. 1, Table 8). HAMD-17 depression scores were significantly reduced from baseline (23.86 (SD 4.45)) to post-0.3 mg/kg session (20.20 (SD 7.82)); (difference -4.5 (95% CI: -7.80 to -1.20J t = -3.50, p = 0.017; Hedge’s g = 0.75).

Difference in HAMD-17 was also significant between the 0.1 mg/kg session and 0.3 mg/kg session; (difference -3.5 [95% CI: -6.87 to -0.013] t = -2.67, p = 0.044). One treatmentresistant MDD participant who experienced a significant improvement in depression, requested additional dosing.

Table 8. Change in Hamilton Depression Rating Scale (17 item) Scores Between the

Baseline, 0.1 mg/kg and 0.3 mg/kg DMT

HAMD was completed at baseline and 1 day after each test day. Effect sizes and P values reflect the results of a paired sample t test that compared scores between baseline and Day 1 after each test day. *One subject was withdrawn administratively before completing the 2^nd test day (0.3 mg/kg).

To the knowledge of the inventors, this is the first report of the safety, tolerability, and efficacy of DMT in MDD. Intravenous DMT can be safely administered to and tolerated by individuals with moderate to severe, treatment-resistant MDD, and it may have next day antidepressant properties.

The most novel finding of this study was the significant reduction in HAMD-17 scores one day after receiving DMT 0.3 mg/kg in MDD patients who had failed several previous antidepressants trials and who had been chronically ill (average duration of illness was 27 years). The mean reduction in HAMD-17 score was about 4.5 points the day after receiving 0.3 mg/kg. a medium to large effect size (Hedges g= 0.75). Of note, HAMD-17 scores changed nominally the day after the 0. 1 mg/kg dose, and the difference between the two doses was significant, findings that will inform dose-selection for future studies. However, because of the fixed order and the lack of any measure of depression immediately prior to the 0.3 mg kg DMT session, it is not possible to determine the extent to which carryover effects from the 0. 1 mg kg DMT session. Consistent with the known heterogeneity of MDD, some participants had greater reductions in HAMD-17 scores than others. One MDD participant had a profound and sustained improvement in depression (corroborated by her partner) and requested receiving additional doses.

The magnitude of antidepressant effects with DMT were smaller than those reported by Carhart-Harris et al. with psilocybin (The Lancet Psychiatry. 2016;3(7):619-27). A number of differences between the two studies including the samples studied, the setting, augmentation with psychotherapy, the duration of psychedelic effects, the timing of assessments and the route of administration of the drugs, may have accounted for the differences in the magnitude of effects. A direct comparison of the two drugs head on will be necessary' to determine their differences and similarities.

Considerable importance has been given to the centrality' of set and setting in psychedelic treatment models. Recent psychedelic studies are ty pically conducted settings that are adorned with art, plants, flowers, and homey furnishings, painted in warm colors, and lit with muted lighting. Studies often include specific music. Furthermore, psychotherapy is considered an important part of psychedelic treatment. In contrast, this DMT study was conducted in a typical hospital setting, and participants received strategic education and psychological support but minimal psychotherapy, similar to ketamine. Despite the hospital setting and minimal psychotherapy provided in this study, depression scores decreased with DMT. Neither psychedelic/psychotomimetic effects (ASC/PSI) significantly correlated with change in depression score from baseline to post-0.3 mg/kg dose.

The present study’ provides information on the safety and tolerability of DMT in depressed individuals. DMT produced transient dose-related increases in perceptual alterations (FIGs. 10-11, FIGs. 12A-12F, and Table 6). The largest changes were on items of intensity, visual imagery, and alternate reality experience. Participants reported transient increases in anxiety. There were no serious psychiatric adverse events. Consistent with the literature, DMT produced transient increases in blood pressure and heart rate. However, there was one serious adverse event (SAE) of one participant who had precipitous hypotension and bradycardia lasting 5 minutes after receiving 0.3 mg/kg DMT; there were no sequelae. Given that DMT typically increases blood pressure, the serious adverse event (SAE) was determined to be an interaction between the participants’ (undisclosed) history of autonomic instability' and DMT effects. The cardiovascular effects of DMT warrant careful screening for cardiovascular risk factors, and for implementing procedures in place to manage cardiovascular events. Participants reported that the experience was intense and challenging (ASC scale items), and transient increase in anxiety. Yet participants reported that the experience was pleasurable and meaningful (modified ASC scale items), and that they were willing to return to receive IV DMT 0.3 mg/kg. Participants rated the tolerability of the 0. 1 and 0.3 mg/kg doses as 89.80(SD 12.95) and 71.11(SD 24.52), respectively. Furthermore, no participants dropped out from the present study. Collectively taken while intense and challenging, IV DMT was mostly safe and tolerated. Larger studies may be necessary to more fully evaluate the safety and tolerability⁷ of IV DMT.

That immediately after the dosing session, participants were willing to pay only $25 for the experience ($0-100), and reported being less likely to use DMT. suggests that intravenous DMT has low abuse potential.

The strengths of the study include the use of a sub-psychedelic and psychedelic dose, the inclusion of both healthy control and MDD participants, and the study of treatmentresistant MDD.

In conclusion, the findings of this exploratory study provide support for DMT’s tolerability, safety, and potential rapid antidepressant effect. In contrast to other psychedelic treatment models, reductions in depression were observed the day after DMT dosing, and occurred within a typical hospital setting, and without intensive psychotherapy. This intriguing finding suggests it may be easier to implement DMT for the treatment of MDD. Future studies are warranted to replicate the findings and inform the therapeutic potential of DMT. Enumerated Embodiments

The following exemplary’ embodiments are provided, the numbering of which is not to be construed as designating levels of importance:

Embodiment 1 provides a method of treating, preventing, and/or ameliorating depression in a subject in need thereof, the method comprising:

(a) intravenously administering to the subject a first bolus dose of dimethyltryptamine (DMT), or a salt, solvate, or isotopologue thereof, or any mixtures thereof; and

(b) intravenously administering to the subject a second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, by continuous infusion.

Embodiment 2 provides the method of Embodiment 1, wherein the depression is at least partially treatment-resistant, optionally wherein the depression is fully treatment resistant.

Embodiment 3 provides the method of Embodiment 1 or 2, wherein the depression is a major depressive disorder (MDD).

Embodiment 4 provides the method of any one of Embodiments 1-3, wherein the first bolus dose is administered over a period of about 5 minutes.

Embodiment 5 provides the method of any one of Embodiments 1-4, wherein the first bolus dose comprises about 10 to about 14 mg of DMT. or the salt, solvate, or isotopologue thereof, or any mixtures thereof.

Embodiment 6 provides the method of Embodiment 5, wherein the first bolus dose comprises about 10 mg of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof.

Embodiment 7 provides the method of Embodiment 6, wherein the second dose of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered at a rate of about 0.010 mg/kg/min.

Embodiment 8 provides the method of Embodiment 6 or 7, wherein the second dose of DMT. or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered over a period of about 55 minutes.

Embodiment 9 provides the method of Embodiment 5, wherein the first bolus dose comprises about 14 mg of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof. Embodiment 10 provides the method of Embodiment 9, wherein the second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered at a rate of about 0.015 mg/kg/min.

Embodiment 11 provides the method of Embodiment 9 or 10, wherein the second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered over a period of about 55 minutes.

Embodiment 12 provides the method of any one of Embodiments 1-1 1. wherein the DMT, or the salt, solvate, or isotopically labeled derivative thereof, is substantially pure.

Embodiment 13 provides the method of any one of Embodiments 1-12, wherein the salt of DMT of the first bolus dose and/or the second dose is /V./V-di methyl tr ptamine hemifumurate.

Embodiment 14 provides the method of any one of Embodiments 1-13, wherein the subject is administered a total dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, of less than about 100 mg, optionally wherein the total dose has a range of about 49 mg to about 72 mg.

Embodiment 15 provides the method of any one of Embodiments 1-14. wherein the subject is in a minimally incapacitating psychedelic state, optionally wherein the subject can communicate with another human.

Embodiment 16 provides the method of any one of Embodiments 1-15, wherein psychedelic effects experienced by the subject after the administration last for 60 minutes or less.

Embodiment 17 provides the method of any one of Embodiments 1-1 , wherein steps (a)-(b) are repeated after about six weeks.

Embodiment 18 provides the method of any one of Embodiments 1-17, wherein the subject is not administered a monoamine oxidase inhibitor (MAOI).

Embodiment 19 provides the method of any one of Embodiments 1-18, wherein the subject is further subjected to psychotherapy.

Embodiment 20 provides the method of any one of Embodiments 1-18, wherein the subject is not further subjected to psychotherapy.

Embodiment 21 provides the method of any one of Embodiments 1-20, wherein the subject is further administered a medication for psychological distress or a medication for hypertension.

Embodiment 22 provides the method of any one of Embodiments 1-21. wherein the subject has a Hamilton Rating Scale for Depression (HAMD-17) of 17, or an equivalent thereof on a comparable scale, or higher prior to the administration of the DMT or the salt, solvate, or isotopically labelled derivative thereof, or any mixture thereof.

Embodiment 23 provides the method of Embodiment 22, wherein the HAMD-17 score of the subject is reduced by 3.0 points or more the day after the administration of the DMT or the salt, solvate, or isotopically labelled derivative thereof, or any mixture thereof.

Embodiment 24 provides a kit for treating, preventing, and/or ameliorating depression in a subject, the kit comprising:

(a) dimethyltryptamine (DMT), or a salt, solvate, or isotopically labeled derivative thereof, or any mixture thereof; and

(b) a manual providing instructions for:

(i) intravenous administration of a first bolus administration of DMT, or a salt, solvate, or isotopically labeled derivative thereof to the subject; and

(ii) intravenous administration of a second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, by continuous infusion to the subject.

Embodiment 25 provides the kit of Embodiment 24. wherein the depression is at least partially treatment-resistant, optionally wherein the depression is fully treatment resistant.

Embodiment 26 provides the kit of Embodiment 24 or 25, wherein the depression is a major depressive disorder (MDD).

Embodiment 27 provides the kit of any one of Embodiments 24-26. wherein the manual instructs that the first bolus dose is administered over a period of about 5 minutes.

Embodiment 28 provides the kit of any one of Embodiments 24-27, wherein the manual instructs that the first bolus dose comprises about 10 to about 14 mg of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof.

Embodiment 29 provides the kit of Embodiment 28, wherein the manual instructs that the first bolus dose comprises about 10 mg of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof.

Embodiment 30 provides the kit of Embodiment 29. wherein the manual instructs that the second dose of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered at a rate of about 0.010 mg/kg/min.

Embodiment 31 provides the kit of Embodiment 29 or 30. wherein the manual instructs that the second dose of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion, is administered over a period of about 55 minutes.

Embodiment 32 provides the kit of Embodiment 29, wherein the manual instructs that the first bolus dose comprises about 14 mg of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof.

Embodiment 33 provides the kit of Embodiment 32. wherein the manual instructs that the second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered at a rate of about 0.015 mg/kg/min.

Embodiment 34 provides the kit of Embodiment 32 or 33. wherein the manual instructs that the second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion, is administered over a period of about 55 minutes.

Embodiment 35 provides the kit of any one of Embodiments 24-34, wherein the DMT, or the salt, solvate, or isotopically labeled derivative thereof, is substantially pure.

Embodiment 36 provides the kit of any one of Embodiments 24-35. wherein the salt of DMT of the first bolus dose and/or the second dose is ;V-dimethyltryptamme hemifumurate.

Embodiment 37 provides the kit of any one of Embodiments 24-36. wherein the manual instructs that the subject is administered a total dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, of less than about 100 mg, optionally wherein the total dose has a range of about 49 mg to about 72 mg.

Embodiment 38 provides the kit of any one of Embodiments 24-37, wherein the manual instructs that administration of the first bolus dose and the second dose are repeated after about six weeks.

Embodiment 39 provides the kit of any one of Embodiments 24-38, wherein the manual instructs that the subject is not administered a monoamine oxidase inhibitor (MAOI).

Embodiment 40 provides the kit of any one of Embodiments 24-39. wherein the manual instructs that the subject is further subjected to psychotherapy.

Embodiment 41 provides the kit of any one of Embodiments 24-39, wherein the manual instructs that the subject is not further subjected to psychotherapy.

Embodiment 42 provides the kit of any one of Embodiments 24-41, w herein the manual instructs that the subject is further administered a medication for psychological distress or a medication for hypertension. Embodiment 43 provides the kit of any one of Embodiments 24-42, wherein the manual provides instructions for using the Hamilton Rating Scale for Depression.

Embodiment 44 provides the kit of any one of Embodiments 24-43, wherein the manual instructs that an initial Hamilton Rating Scale for Depression (HAMD-17) score, or an equivalent thereof, is measured prior to the administration of the DMT or the salt, solvate, or isotopically labelled derivative thereof, or any mixture thereof.

Embodiment 45 provides the kit of any one of Embodiments 24-44. wherein the manual instructs that a second Hamilton Rating Scale for Depression (HAMD-17) score, or an equivalent thereof, is measured about 24 or more hours after the administration of the DMT or the salt, solvate, or isotopically labelled derivative thereof, or any mixture thereof.

The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application.

Claims

CLAIMS What is claimed is:

1. A method of treating, preventing, and/or ameliorating depression in a subject in need thereof, the method comprising:

2. The method of claim 1, wherein the depression is at least partially treatment-resistant, optionally wherein the depression is fully treatment resistant.

3. The method of claim 1 or 2, wherein the depression is a major depressive disorder (MDD).

4. The method of any one of claims 1-3, wherein the first bolus dose is administered over a period of about 5 minutes.

5. The method of any one of claims 1-4, wherein the first bolus dose comprises about 10 to about 14 mg of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof.

6. The method of claim 5, wherein the first bolus dose comprises about 10 mg of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof.

7. The method of claim 6, wherein the second dose of DMT. or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered at a rate of about 0.010 mg/kg/min.

8. The method of claim 6 or 7, wherein the second dose of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered over a period of about 55 minutes.

9. The method of claim 5, wherein the first bolus dose comprises about 14 mg of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof.

10. The method of claim 9, wherein the second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered at a rate of about 0.015 mg/kg/min.

11. The method of claim 9 or 10, wherein the second dose of DMT. or a salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered over a period of about 55 minutes.

12. The method of any one of claims 1-11, wherein the DMT, or the salt, solvate, or isotopically labeled derivative thereof, is substantially pure.

13. The method of any one of claims 1-12, wherein the salt of DMT of the first bolus dose and/or the second dose is A/ -dimethyltryptamine hemifumurate.

14. The method of any one of claims 1-13, wherein the subject is administered a total dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, of less than about 100 mg, optionally wherein the total dose has a range of about 49 mg to about 72 mg.

15. The method of any one of claims 1-14, wherein the subject is in a minimally incapacitating psychedelic state, optionally wherein the subject can communicate with another human.

16. The method of any one of claims 1-15, wherein psychedelic effects experienced by the subject after the administration last for 60 minutes or less.

17. The method of any one of claims 1-16, wherein steps (a)-(b) are repeated after about six weeks.

18. The method of any one of claims 1-17, wherein the subject is not administered a monoamine oxidase inhibitor (MAOI).

19. The method of any one of claims 1-18, wherein the subject is further subjected to psychotherapy.

20. The method of any one of claims 1-18, wherein the subject is not further subjected to psychotherapy.

21. The method of any one of claims 1-20, wherein the subject is further administered a medication for psychological distress or a medication for hypertension.

22. The method of any one of claims 1-21, wherein the subject has a Hamilton Rating Scale for Depression (HAMD-17) of 17, or an equivalent thereof on a comparable scale, or higher prior to the administration of the DMT or the salt, solvate, or isotopically labelled derivative thereof, or any mixture thereof.

23. The method of claim 22. wherein the HAMD-17 score of the subject is reduced by 3.0 points or more the day after the administration of the DMT or the salt, solvate, or isotopically labelled derivative thereof, or any mixture thereof.

24. A kit for treating, preventing, and/or ameliorating depression in a subject, the kit comprising:

(b) a manual providing instructions for:

25. The kit of claim 24, wherein the depression is at least partially treatment-resistant, optionally wherein the depression is fully treatment resistant.

26. The kit of claim 24 or 25, wherein the depression is a major depressive disorder (MDD).

27. The kit of any one of claims 24-26, wherein the manual instructs that the first bolus dose is administered over a period of about 5 minutes.

28. The kit of any one of claims 24-27, wherein the manual instructs that the first bolus dose comprises about 10 to about 14 mg of DMT. or the salt, solvate, or isotopologue thereof, or any mixtures thereof.

29. The kit of claim 28, wherein the manual instructs that the first bolus dose comprises about 10 mg of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof.

30. The kit of claim 29, wherein the manual instructs that the second dose of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered at a rate of about 0.010 mg/kg/min.

31 . The kit of claim 29 or 30, wherein the manual instructs that the second dose of DMT, or the salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion, is administered over a period of about 55 minutes.

32. The kit of claim 29, wherein the manual instructs that the first bolus dose comprises about 14 mg of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof.

33. The kit of claim 32, wherein the manual instructs that the second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion is administered at a rate of about 0.015 mg/kg/min.

34. The kit of claim 32 or 33, wherein the manual instructs that the second dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, which is administered by continuous infusion, is administered over a period of about 55 minutes.

35. The kit of any one of claims 24-34, wherein the DMT, or the salt, solvate, or isotopically labeled derivative thereof, is substantially pure.

36. The kit of any one of claims 24-35, wherein the salt of DMT of the first bolus dose and/or the second dose is Af/V-dimethy I tryptamine hemifumurate.

37. The kit of any one of claims 24-36, wherein the manual instructs that the subject is administered a total dose of DMT, or a salt, solvate, or isotopologue thereof, or any mixtures thereof, of less than about 100 mg, optionally wherein the total dose has a range of about 49 mg to about 72 mg.

38. The kit of any one of claims 24-37, wherein the manual instructs that administration of the first bolus dose and the second dose are repeated after about six weeks.

39. The kit of any one of claims 24-38, wherein the manual instructs that the subject is not administered a monoamine oxidase inhibitor (MAOI).

40. The kit of any one of claims 24-39, wherein the manual instructs that the subject is further subjected to psychotherapy.

41. The kit of any one of claims 24-39, wherein the manual instructs that the subject is not further subjected to psychotherapy.

42. The kit of any one of claims 24-41, wherein the manual instructs that the subject is further administered a medication for psychological distress or a medication for hypertension.

43. The kit of any one of claims 24-42, wherein the manual provides instructions for using the Hamilton Rating Scale for Depression.

44. The kit of any one of claims 24-43, wherein the manual instructs that an initial Hamilton Rating Scale for Depression (HAMD-17) score, or an equivalent thereof, is measured prior to the administration of the DMT or the salt, solvate, or isotopically labelled derivative thereof, or any mixture thereof.

45. The kit of any one of claims 24-44, wherein the manual instructs that a second Hamilton Rating Scale for Depression (HAMD-17) score, or an equivalent thereof, is measured about 24 or more hours after the administration of the DMT or the salt, solvate, or isotopically labelled derivative thereof, or any mixture thereof.