WO2025010308A2

WO2025010308A2 - Mdma enantiomer compositions and methods for modulating aggression response

Info

Publication number: WO2025010308A2
Application number: PCT/US2024/036639
Authority: WO
Inventors: Glenn Short; Carrie BOWEN
Original assignee: Empathbio Inc
Current assignee: Empathbio Inc
Priority date: 2023-07-03
Filing date: 2024-07-03
Publication date: 2025-01-09
Anticipated expiration: 2026-01-03
Also published as: WO2025010308A3

Abstract

Disclosed are pharmaceutical compositions and formulations of enantiomerically enriched or pure 3,4-methylenedioxymethamphetamine (MDMA) and methods for modulating aggression response behaviors that may be associated with a disorder and/or disease.

Description

Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

MDMA ENANTIOMER COMPOSITIONS AND METHODS FOR MODULATING AGGRESSION RESPONSE

Cross-Reference To Related Applications

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63/524,735, filed July 3, 2023, which is hereby incorporated by reference in its entirety for all purposes.

BACKGROUND

[0002] 3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine analog targeting neurotransmitter systems within the brain. MDMA is a ring-substituted derivative of phenethylamine with a chiral center. There are two stereoisomers of MDMA: S(+)-MDMA and R(-)-MDMA. Phenethylamines including MDMA are known to have psychoactive and stimulant effects, and MDMA has been evaluated clinically for a number of potential therapeutic indications. Depending on the indication, the activity and acute effects of the different MDMA compositions (R(-) enriched, S(+) enriched, and racemic mixture) is unpredictable and can vary widely. In some cases, a specific form or forms of MDMA can be associated with specific adverse effects.

[0003] The term aggression response behavior refers to a number actions and/or personality traits that can result in physical and psychological harm to oneself as well as others. As such, effective compositions that can manage, modulate, or otherwise reduce aggression response are of great importance.

[0004] The present disclosure provides compositions and methods that are effective in modulating aggression response by providing enantiomerically enriched compositions of MDMA, i.e., compositions comprising specific ratios of the R(-) and S(+) enantiomers (up to enantiomerically pure R(-)-MDMA or S(+)-MDMA).

SUMMARY

[0005] The present disclosure provides compositions comprising enantiomerically enriched or pure R(-)-MDMA (or S(+)-MDMA) or a pharmaceutically acceptable salt thereof and the use of such compositions in methods for treating aggression response behaviors.

[0006] In aspects, the disclosure provides methods of treating aggression in a subject who has a disease or disorder associated with aggression, comprising administering to the subject a Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) composition comprising administering a therapeutically effective amount of an enantiomerically enriched or pure 3, 4-methylenedi oxymethamphetamine (MDMA) or a pharmaceutically acceptable salt thereof .

[0007] In aspects, the disclosure provides methods of reducing aggression in a subject comprising administering to the subject a therapeutically effective amount of a composition comprising an enantiomerically enriched or pure MDMA or a pharmaceutically acceptable salt thereof.

[0008] In aspects, the disclosure provides methods of treating aggression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an enantiomerically enriched or pure MDMA or a pharmaceutically acceptable salt thereof.

[0009] In aspects, the method is effective for the treatment of aggression in a subject who has a social anxiety disorder (SAD). In embodiments, the method is effective for the treatment of aggression in a subject who has autism spectrum disorder (ASD).

[0010] In embodiments, the methods comprise administering a composition comprising an enantiomerically enriched or pure MDMA comprising R(-)-MDMA in excess relative to S(+)- MDMA. In embodiments, the amount of R(-)-MDMA in the enantiomerically enriched or pure MDMA comprises at least 50.1% of the total amount of MDMA and up to about 99.99% or 100% of the total amount of MDMA.

[0011] In embodiments, the methods comprise administering a composition comprising an enantiomerically enriched or pure MDMA comprising S(+)-MDMA in excess relative to R(- )-MDMA. In embodiments, the amount of S(+)-MDMA in the enantiomerically enriched or pure MDMA comprises at least 50.1% of the total amount of MDMA and up to about 99.99% or 100% of the total amount of MDMA.

[0012] In embodiments, the methods comprise administering an effective amount of the enantiomerically enriched or pure MDMA in a range from about 0.1 mg/kg to about 350 mg/kg. [0013] Other aspects and embodiments will be apparent to one skilled in the art in light of the detailed description and Examples that follow.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 shows aggressive behavior (latency to first attack, number of attacks, and duration of attacks) in socially isolated male NMRI mice administered racemic MDMA HC1 Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) at 3, 5.6, or 7.8 mg/kg free base by intraperitoneal (i.p.) administration, compared to vehicle and risperidone (“RISP”) positive control.

[0015] FIG. 2 shows aggressive behavior (latency to first attack, number of attacks, and duration of attacks) in mice administered R-MDMA HC1 at 10, 17, or 30 mg/kg (i.p.), compared to vehical and risperidone (“RISP”) positive control.

[0016] FIG. 3 shows aggressive behavior (latency to first attack, number of attacks, and duration of attacks) in mice administered R-MDMA HC1 at 1, 3, or 10 mg/kg (i.p.), compared to vehical and risperidone (“RISP”) positive control.

[0017] FIG. 4 shows aggressive behavior (latency to first attack, number of attacks, and duration of attacks) in mice administered S-MDMA HC1 at 1, 3, or 10 mg/kg (i.p.), compared to vehicle and risperidone (“RISP”) positive control.

DETAILED DESCRIPTION

[0018] Racemic MDMA, consistent with its known 5 -HT -increasing activity, has been reported to modulate aggression response behaviors in mammals (see, e.g., Kirilly E, et al., Acute and long-term effects of a single dose of MDMA on aggression in Dark Agouti rats. Int J Neuropsychopharmacol . 2006 Feb;9(l):63-76.), however racemic MDMA may exert unwanted side effects. The efficacy of the individual MDMA enantiomers R(-) or S(+) MDMA in modulating or reducing aggression has not been characterized. Accordingly, the present disclosure provides compostions and methods for treating or reducing aggression in a subject in need thereof with enantiomerically enriched or pure MDMA compositions.

[0019] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

I. Definitions

[0020] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, ... ”, “about 50” means a range extending to less Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50.5.

[0021] The terms “administer,” “administering” or “administration” as used herein refer to administering a compound or pharmaceutically acceptable salt of the compound or a composition or formulation comprising the compound or pharmaceutically acceptable salt of the compound to a subject.

[0022] The terms “aggression,” “aggression response,” “aggressive behavior(s),” and/or “aggression response behavior(s),” are used interchangeably and refer to one or more intentional or unintentional observable or reported acts, thoughts, or responses characterized as inflicting discomfort, damage, or other harm upon an object, one’s self, or another individual. As used herein, aggression covers a range of behavioral disturbances or disorders, including, but not limited to, irritability, impulsivity, hypervigilance and hyperarousal. Aggression or an aggression response may occur reactively or without provocation. In humans, aggression can be caused by various factors and stimuli such as, for example, environmental triggers or by disorders or diseases giving rise to or associated with aggressive behavior or feelings that can give rise to aggression and/or aggressive behavior (e.g., emotions like fear, frustration, anger, feelings of stress, disrespect, dominance, or pleasure). Aggression can manifest in a variety of forms, which may be expressed physically, verbally, or non-verbally and can include predatory and anti -predatory aggression, defensive aggression, dominance aggression, resident-intruder aggression, maternal aggression, species specific aggression, sex- related aggression, territorial aggression, isolation-induced aggression, irritable aggression, and brain-stimulation-induced aggression. Human aggression may be generally classified with two subtypes: (1) controlled-instrumental subtype (purposeful or goal oriented); and (2) reactive-impulsive subtype (often elicits uncontrollable actions that are inappropriate or undesirable). As such, aggression and/or aggression response(s) may be associated with, or identified and/or diagnosed by, any symptoms that are commonly associated with feelings of aggression or aggressive behaviors. Some non-limiting examples include, feelings of anger, frustration, hypervigilance, or fear or combinations thereof, violent behavior, abusive language, functional impairment (e.g., personal and/or professional functional impairment), degradation or impairment of social association, connection, or affiliation between the subject aggressor and one or more persons (i.e., impairment/degradation of interpersonal relationships; difficulty concentrating, thinking, or performing daily tasks, and the like). Aggression and/or aggression response behavior(s) can be identified using any technique, test, or evaluation Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) generally known in the art that can provide a general rating scale of such behavior over a period or several periods of time. Non-limiting examples include observational diagnoses (e.g. clinical or non-clinical diagnosis) that can evaluate one or more categories of behavior (e.g., verbal aggression, aggression against inanimate objects, aggression against oneself, and aggression against others). In some non-limiting embodiments aggression and/or aggression response can be evaluated using an aggression scale such as, for example, the Modified Overt Aggression Scale, (“MOAS”).

[0023] The terms “effective amount” and “therapeutically effective amount” are used interchangeably in this disclosure and refer to an amount of a compound, or a salt thereof, (or pharmaceutical composition containing the compound or salt) that, when administered to a subject, is capable of performing the intended result.

[0024] The term “MDMA,” without any further description, refers to a mix of S(+)-3,4- methylenedi oxymethamphetamine and R(-)-3,4-methylenedi oxymethamphetamine, including recemic MDMA. MDMA has a chiral center and two stereoisomers, S(+)-MDMA and R(-)- MDMA. The enantiomers have been shown to impact the monoaminergic targets of MDMA differently and can have different toxicologic and pharmacologic properties, but not in a predictable manner. As described herein, enantiomerically enriched or enantiomerically pure MDMA comprise an unequal amount of the R(-)-MDMA and S(+)-MDMA enantiomers and can range from 50.1% enriched in one enantiomer and up to about an enantiomerically pure form of the enantiomer (e.g., 99.5% or greater (i.e., 100%) enrichment in one enantiomer).

[0025] The phrase “pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0026] The term “salts” as used herein embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases. Salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Base addition salts include but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'- Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e. g., lysine and arginine di cyclohexylamine and the like. Examples of metal salts include lithium, sodium, potassium, magnesium, calcium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0027] The term “therapeutic effect” as used herein refers to a desired or beneficial effect provided by the method and/or the composition.

[0028] The term “treating” as used herein with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating can be improving, or at least partially ameliorating a disorder or an associated symptom of a disorder.

II. Compositions

[0029] In aspects, the present disclosure provides compositions comprising R(-)- and/or S(+)-MDMA in enantiomerically enriched or enantiomerically pure forms to provide treatment of one or more aggression response behaviors in a subject in need thereof.

[0030] In embodiments, the compositions of the disclosure comprise a non-racemic mixture of R(-)-MDMA and S(+)-MDMA. In embodiments, the composition comprises MDMA enriched in the R(-)-MDMA enantiomer, relative to the S(+)-MDMA enantiomer. In embodiments wherein R(-)-MDMA is in excess compared to S(+)-MDMA, the compositions comprise a weight ratio of R(-)-MDMA to S(+)-MDMA that is greater than 1. In embodiments, the compositions comprise a weight ratio of R(-)-MDMA to S(+)-MDMA ranging from about 50.1 :49.9 to about 100:0 (e.g., about 51 :49, about 52:48, about 53:47, about 54:46, about 55:45, about 56:44, about 57:43, about 58:42, about 59:41, about 60:40, about 61 :39, about 62:38, about 63:37, about 64:36 , about 65:35, about 66:34, about 67:33, about 68:32, about 69:31, about 70:30, about 71 :29, about 72:28, about 73:27, about 74:26, about 75:25, about 76:24, Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) about 77:23, about 78:22, about 79:21, about 80:20, about 81 : 19, about 82: 18, about 83: 17, about 84: 16, about 85: 15, about 86: 14, about 87: 13, about 88: 12, about 89: 11, about 90: 10, about 91 :9, about 92:8, about 93:7, about 94:6, about 95:5, about 96:4, about 97:3, about 98:2, about 99: 1, about 99.5:0.5, about 99.9:0.1, or about 100:0, among other ratios within these enumerated ratios).

[0031] In embodiments, the compositions of the disclosure comprise R(-)-MDMA in an enantiomeric enrichment (or purity) of > 90%, > 95%, > 96%, > 97%, > 98%, > 99%, > 99.5%,

> 99.9%, > 99.99%, or 100% (i.e., relative to total MDMA).

[0032] In embodiments, the compositions of the disclosure comprise a weight ratio of R(- )-MDMA to S(+)-MDMA ranging from about 90: 10 to about 100:0 (e.g., a weight ratio of R(- )-MDMAto S(+)-MDMA ofabout 90: 10, about 91 :9, about 92:8, about 93:7, about 94:6, about 95:5, about 96:4, about 97:3, about 98:2, about 99: 1, about 99.5:0.5, about 99.9:0.1, or about 100:0). In embodiments, the compositions comprise a weight ratio of R(-)-MDMA to S(+)- MDMA ranging from about 99: 1 to 100:0. In embodiments, the weight ratio of R(-)-MDMA to S(+)-MDMA comprises about 99.1 :0.9, about 99.2:0.8, about 99.3:0.7, about 99.4:0.6, about 99.5:0.5, about 99.6:0.4, about 99.7:0.3, about 99.8:0.2, about 99.9:0.1, or about 100:0.

[0033] In embodiments, the compositions of the disclosure comprise MDMA enriched in the S(+)-MDMA enantiomer, relative to the R(-)-MDMA enantiomer. In embodiments, the compositions comprise a weight ratio of R(-)-MDMA to S(+)-MDMA ranging from about 49.9:50.1 to about 0: 100 (e.g., about 49:51, about 48:52: about 47:53, about 46:54, about 45:55, about 44:56, about 43:57, about 42:58, about 41 :59, about 40:60, about 39:61, about 38:62, about 37:63, about 36:64, about 35:65, about 34:66, about 33:67, about 32:68, about 31 :69, about 30:70, about 29:71, about 28:72, about 27:73, about 26:74, about 25:75, about 24:76, about 23:77, about 22:78, about 21 :79, about 20:80, about 19:81, about 18:82, about 17:83, about 16:84, about 15:85, about 14:86, about 13:87, about 12:88, about 11 :89, about 10:90, about 9:91, about 8:92, about 7:93, about 6:94, about 5:95, about 4:96, about 3:97, about 2:98, about 1 :99, about 0.5:99.5, about 0.1 :99.9, or about 0: 100, among other ratios within these enumerated ratios).

[0034] In embodiments, the compositions of the disclosure comprise S(+)-MDMA in an enantiomeric enrichment (or purity) of > 90%, > 95%, > 96%, > 97%, > 98%, > 99%, > 99.5%,

> 99.9%, > 99.99%, or 100% (i.e., relative to total MDMA).

[0035] In aspects, the compositions of the disclosure comprise a weight ratio of R(-)- MDMA to S(+)-MDMA ranging from about 10:90 to about 0: 100 (e.g., a weight ratio of R(-)- Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

MDMA to S(+)-MDMA of about 10:90, about 9:91, about 8:92, about 7:93, about 6:94, about 5:95, about 4:96, about 3:97, about 2:98, about 1 :99, about 0.5:99.5, about 0.1 :99.1, or about 0: 100). In embodiments, the compositions of the disclosure comprise a weight ratio of R(-)- MDMA to S(+)-MDMA ranging from about 1 :99 to 0: 100. In embodiments, the weight ratio of R(-)-MDMA to S(+)-MDMA comprises about 0.9:99.1, about 0.8:99.2, about 0.7:99.3, about 0.6:99.4, about 0.5:99.5, about 0.4:99.6, about 0.3:99.7, about 0.2:99.8, about 0.1 :99.9, or about 0: 100.

[0036] In embodiments, the composition comprises about 90-100% R(-)-MDMA and about 0-10% S(+)-MDMA. In embodiments, the composition comprises about 91-100% R(-)- MDMA and about 0-9% S(+)- MDMA. In embodiments, the composition comprises about 92- 100% R(-)-MDMA and about 0-8% S(+)- MDMA. In embodiments, the composition comprises about 93-100% R(-)-MDMA and about 0-7% S(+)- MDMA. In embodiments, the composition comprises about 94-100% R(-)-MDMA and about 0-6% S(+)- MDMA. In embodiments, the composition comprises about 95-100% R(-)-MDMA and about 0-5% S(+)- MDMA. In embodiments, the composition comprises about 96-100% R(-)-MDMA and about 0-4% S(+)- MDMA. In embodiments, the composition comprises about 97-100% R(-)-MDMA and about 0-3% S(+)- MDMA. In embodiments, the composition comprises about 98-100% R(-)-MDMA and about 0-2% S(+)-MDMA. In embodiments, the composition comprises about 99-100% R(-)-MDMA and about 0-1% S(+)- MDMA.

[0037] In embodiments, the composition comprises about 90-100% S(+)-MDMA and about 0-10% R(-)-MDMA. In embodiments, the composition comprises about 91-100% S(+)- MDMA and about 0-9% R(-)-MDMA. In embodiments, the composition comprises about 92- 100% S(+)-MDMA and about 0-8% R(-)-MDMA. In embodiments, the composition comprises about 93-100% S(+)-MDMA and about 0-7% R(-)-MDMA. In embodiments, the composition comprises about 94-100% S(+)-MDMA and about 0-6% R(-)-MDMA. In embodiments, the composition comprises about 95-100% S(+)-MDMA and about 0-5% R(-)-MDMA. In embodiments, the composition comprises about 96-100% S(+)-MDMA and about 0-4% R(-)- MDMA. In embodiments, the composition comprises about 97-100% S(+)-MDMA and about 0-3% R(-)-MDMA. In embodiments, the composition comprises about 98-100% S(+)-MDMA and about 0-2% R(-)-MDMA. In embodiments, the composition comprises 99-100% S(+)- MDMA and 0-1% R(-)-MDMA.

III. Methods of Use Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

[0038] In accordance with the disclosure, provided herein are methods of treating aggression in a subject who has a disease or disorder associated with aggression, comprising administering to the subject a therapeutically effective amount of any of the compositions described herein. In embodiments, provided herein are methods of reducing aggression in a subject comprising administering to the subject a therapeutically effective amount of any of the compositions described herein. In embodiments, provided herein are methods of treating aggression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the compositions described herein.

[0039] In embodiments, the present disclosure provides methods of treating aggression that is associated with one or more CNS (i.e., neurological) disorders or diseases. As referred to herein, a “neurological disorder or disease” refers to any condition, disorder, or disease involving the nervous system, for example, diseases that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system. In embodiments, a neurological disease or disorder comprises: a neuropsychiatric disorder, such as depression (including severe depression such as treatment-resistant depression (TRD), major depressive disorder (MDD) and persistent depressive disorder), alexithymia, catatonic depression, a depressive disorder due to a medical condition, postpartum depression, premenstrual dysphoric disorder, seasonal affective disorder, anxiety, anxiety disorder, social anxiety disorder (SAD), general anxiety disorder (GAD), avolition disorder, bipolar disorder (including bipolar I disorder and bipolar II disorder), post-traumatic stress disorder (PTSD), body dysmorphic disorder, abnormalities of mood or emotion, including the above conditions, dysthymia, schizoaffective disorder, schizophrenia and other psychotic disorders, panic disorder, traumatic stress disorders, phobic disorders, and personality disorders with abnormal mood, such as borderline personality disorder, schizoid and schizotypal disorders, suicide ideation, rumination/unproductive repetitive thoughts negatively impacting one’s behavior, mood, and/or ability to focus, obsessive-compulsive disorder, addiction (including substance use disorders, such as addiction to nicotine, alcohol, cocaine, opioids, amphetamine, methamphetamine, heroin, morphine, phencyclidine, 3,4-methylenedioxy-methamphetamine, as well as other addictive substances), addictive behavior (including eating, gambling, sex, pornography, videogames, work, exercise, spiritual obsession, self-harm, travel and shopping addiction, etc.), eating disorders (including anorexia nervosa, bulimia nervosa and binge eating disorder), pain (including pain associated with migraine or headache or chronic pain), Prolonged Grief Disorder, paranoid personality Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) disorder, Autoimmune OCD (adult), behavioral symptom s/anxiety in Fragile X (adult), or Xenomelia. Within the broad scope of neurological diseases, a “neurodegenerative disease” refers to a neurological disease marked by the loss of nerve cells or damage to nerve cells, including non-limiting examples of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), tauopathies (including frontotemporal dementia), Huntington's disease, Vascular dementia, Lewy body disease (LBD), Down dementia, and the like. Further non-limiting examples of neurological diseases include headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro- ophthalmological conditions, movement disorders, demyelinating diseases, spinal cord disorders, disorders of peripheral nerves, muscle and neuromuscular junctions, Angelman syndrome, fragile X syndrome, Rett syndrome, among others. In embodiments, a neurologicla disorder comprises a neurodevelopmental disorder, including non-limiting examples of attention-deficit/hyperactivity disorder (ADHD), autism, learning disabilities, intellectual disability (also known as mental retardation), or conduct disorders. In embodiments, addiction, mental illness, psychiatric disorders, and personality disorders are also included within the scope of neurological disorders and diseases, and thus include a broad scope of conditions such as those discussed herein and as generally known in the art.

[0040] In embodiments, the present disclosure provides methods of treating aggression that is associated with an anxiety disorder. In embodiments, the anxiety disorder is one or more of generalized anxiety disorder, phobia, social anxiety disorder (SAD), social phobia, panic disorder, panic attack, post-traumatic stress disorders (PTSD), separation anxiety disorder, selective mutism, agoraphobia, or an anxiety disorder induced by a substance/medication or due to another medical condition. Psychopathologies such as anxiety- and depression-related disorders are often characterized by impaired social behaviors including excessive aggression and violence. Excessive aggression and violence likely develop as a consequence of generally disturbed emotional regulation, such as abnormally high or low levels of anxiety. Previous studies indicate an overlap between brain circuitries and neurochemical systems regulating aggression and anxiety. Neumann ID, et al., Aggression and anxiety: social context and neurobiological links. Front Behav Neurosci . 2010 Mar 30;4: 12.

[0041] In embodiments, the present disclosure provides methods of treating aggression that is associated with social anxiety disorder (SAD). SAD, also known as social phobia, is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others (American Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

Psychiatric Association, 1994a). Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person’s normal routine, occupational or academic functioning, or social activities or relationships. Recent research has revealed a subtype of individuals with social anxiety disorder (SAD) who tend to display relatively high amounts of aggression and experience more severe social anxiety and dysfunction compared to individuals in the prototypical SAD group. Kashdan, T. B. & McKnight, P. E. (2010), The darker side of social anxiety: When aggressive impulsivity prevails over shy inhibition. Current Directions in Psychological Science, 19, 47-50.

[0042] In embodiments, the present disclosure provides methods of treating aggression in a subject who has been diagnosed as having SAD as defined by the Diagnostic and Statistical Manual of Mental Disorders — Fifth Edition (DSM-V), published by the American Psychiatric Association, Washington D.C.. In embodiments, the present disclosure provides methods of treating aggression in a subject who have been diagnosed as having SAD based upon the administration of any of the following tests: Liebowitz Social Anxiety Scale (LSAS), CGI- Severity of Illness scale, Social Phobia Inventory (SPIN) total score, social Connectedness Scale, Internalized Shame Scale, Quick Inventory of Depressive Symptomatology (QIDS), Columbia Suicide Severity Rating Scale, Self-Compassion Scale (SCS) total score, Psychotomimetic States Inventory (PSI), Challenging Experience Questionnaire (CEQ) total score, Emotional Breakthrough Inventory (EBI) total score, Mystical Experience Questionnaire, EQL-5D, Hamilton Rating Scale for Anxiety (HAM-A), Hamilton Rating Scale for Depression (HAM-D), axis V Social and Occupational Functioning Assessment Scale of DSM-IV, axis II (ICD-10) World Health Organization Disability Assessment, Schedule 2 (DAS-2), Sheehan Disability Scales, Schneier Disability Profile, World Health Organization Quality of Life- 100 (WHOQOL-lOO), Quality of Life Inventory (QOLI), European Quality of Life 5-Dimensions scale or other tests as described in Bobes, J. (1998), How is recovery from social anxiety disorder defined? The Journal of Clinical Psychiatry, 59(Suppl 17), 12-19, which is incorporated herein by reference.

[0043] In embodiments, the present disclosure provides methods of treating aggression that is associated with a psychiatric disorder. The term “psychiatric disorder” refers to a condition, disorder, or disease of the mind and includes diseases and disorders listed in the Diagnostic and Statistical Manual of Mental Disorders — Fifth Edition (DSM-V), published by the Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

American Psychiatric Association, Washington D.C.. Psychiatric disorders include anxiety disorders (e.g., acute stress disorder agoraphobia, generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social anxiety disorder or social phobia, and specific phobia), childhood disorders, (e.g., attentiondeficit/ hyperactivity disorder, conduct disorder, disruptive mood dysregulation disorder, and oppositional defiant disorder), eating disorders (e.g., anorexia nervosa and bulimia nervosa), mood disorders (e.g., depression, bipolar disorder, cyclothymic disorder, dysthymic disorder, and major depressive disorder), personality disorders (e.g., antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, schizoid personality disorder, and schizotypal personality disorder), psychotic disorders (e.g., brief psychotic disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, schizophrenia, and shared psychotic disorder), substance-related disorders (e.g., alcohol dependence, amphetamine dependence, cannabis dependence, cocaine dependence, hallucinogen dependence, inhalant dependence, nicotine dependence, opioid dependence, phencyclidine dependence, and sedative dependence), adjustment disorder, autism, delirium, dementia, multiinfarct dementia, learning and memory disorders (e.g., amnesia and age-related memory loss), and Tourette's disorder, among others.

[0044] In embodiments, the present disclosure provides methods of treating aggression that is associated with autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder characterized by persistent difficulties in social communication and social interaction, coupled with restricted, repetitive patterns of behavior or interest. Research indicates that aggression rates may be higher in individuals with ASD compared to those with other developmental disabilities. Fitzpatrick SE, et al., Aggression in autism spectrum disorder: presentation and treatment options. Neuropsychiatr Dis Treat. 2016 Jun 23; 12: 1525-38.

[0045] In embodiments, the present disclosure provides methods of treating aggression in a subject who has or suffers from a disease or disorder that is associated with one or more symptoms associated with aggression. In embodiments, the methods in accordance with the disclosure are used to reduce one or more symptoms associated with aggression including, but not limited to, verbal aggression, physical aggression, passive aggression, rage, irritability, tension, racing thoughts, poor communication, hostility, impulsivity (e.g., emotional Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) impulsivity), tremors, heart, palpitations, frustration, moodiness, restlessness, hypervigilance, and/or hyperarousal, or any combination thereof.

III. Dosage Regimens

[0046] Generally, the compositions of the present disclosure are administered in a therapeutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0047] In embodiments, the effective amount of the enantiomerically enriched or pure MDMA composition to be administered in accordance with the methods described herein comprises about 1 mg to about 1000 mg MDMA, or an equivalent amount of the pharmaceutically acceptable salt thereof, per dose based on a 60 kg mammal subject, (e.g., a human subject). In embodiments, the therapeutically effective amount comprises about 1 mg to about 750 mg MDMA, or an equivalent amount of the pharmaceutically acceptable salt thereof, per dose. In embodiments, the therapeutically effective amount comprises about 5 mg to about 500 mg, or about 10 mg to about 400 mg, or about 25 mg to about 300 mg, or about 75 mg to about 225 mg, or about 75 mg to about 850 mg, or about 250 mg to about 850 mg MDMA, or an equivalent amount of the pharmaceutically acceptable salt thereof,. In embodimetns, the therapeutically effective amount comprises about 250 mg to about 350 mg MDMA, or an equivalent amount of the pharmaceutically acceptable salt thereof. In embodiments, the therapeutically effective amount comprises about 25 mg to 50 mg MDMA, or an equivalent amount of the pharmaceutically acceptable salt thereof, (e.g., about 20 mg, about 15 mg, about 10 mg, about 5 mg, about 1 mg, about 0.1 mg, about 0.01 mg, or about 0.001 mg). In embodiments, the therapeutically effective amount comprises about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about

33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about

40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about

47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about

54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about

61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg, about

68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg, about Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 101 mg, about 102 mg, about 103 mg, about 104 mg, about 105 mg, about 106 mg, about 107 mg, about 108 mg, about 109 mg, about 110 mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115 mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, about 120 mg, about 121 mg, about 122 mg, about 123 mg, about 124 mg, about 125 mg, about 126 mg, about 127 mg, about 128 mg, about 129 mg, about 130 mg, about 131 mg, about 132 mg, about 133 mg, about 134 mg, about 135 mg, about 136 mg, about 137 mg, about 138 mg, about 139 mg, about 140 mg, about 141 mg, about 142 mg, about 143 mg, about 144 mg, about 145 mg, about 146 mg, about 147 mg, about 148 mg, about 149 mg, about 150 mg, about 151 mg, about 152 mg, about 153 mg, about 154 mg, about 155 mg, about 156 mg, about 157 mg, about 158 mg, about 159 mg, about 160 mg, about 161 mg, about 162 mg, about 163 mg, about 164 mg, about 165 mg, about 166 mg, about 167 mg, about 168 mg, about 169 mg, about 170 mg, about 171 mg, about 172 mg, about 173 mg, about 174 mg, about 175 mg, about 176 mg, about 177 mg, about 178 mg, about 179 mg, about 180 mg, about 181 mg, about 182 mg, about 183 mg, about 184 mg, about 185 mg, about 186 mg, about 187 mg, about 188 mg, about 189 mg, about 190 mg, about 191 mg, about 192 mg, about 193 mg, about 194 mg, about 195 mg, about 196 mg, about 197 mg, about 198 mg, about 199 mg, about 200 mg, about 201 mg, about 202 mg, about 203 mg, about 204 mg, about 205 mg, about 206 mg, about 207 mg, about 208 mg, about 209 mg, about 210 mg, about 211 mg, about 212 mg, about 213 mg, about 214 mg, about 215 mg, about 216 mg, about 217 mg, about 218 mg, about 219 mg, about 220 mg, about 221 mg, about 222 mg, about 223 mg, about 224 mg, about 225 mg, about 226 mg, about 227 mg, about 228 mg, about 229 mg, about 230 mg, about 231 mg, about 232 mg, about 233 mg, about 234 mg, about 235 mg, about 236 mg, about 237 mg, about 238 mg, about 239 mg, about 240 mg, about 241 mg, about 242 mg, about 243 mg, about 244 mg, about 245 mg, about 246 mg, about 247 mg, about 248 mg, about 249 mg, about 250 mg, about 251 mg, about 252 mg, about 253 mg, about 254 mg, about 255 mg, about 256 mg, about 257 mg, about 258 mg, about 259 mg, about 260 mg, about 261 mg, about 262 mg, about 263 mg, about 264 mg, about 265 mg, about 266 mg, about 267 mg, about 268 mg, about 269 mg, about 270 mg, about 271 mg, about 272 mg, about 273 mg, about 274 mg, about 275 mg, about 276 mg, about 277 mg, about 278 mg, about 279 mg, about 280 mg, about 281 mg, about 282 mg, about 283 mg, about 284 mg, about 285 mg, about 286 Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) mg, about 287 mg, about 288 mg, about 289 mg, about 290 mg, about 291 mg, about 292 mg, about 293 mg, about 294 mg, about 295 mg, about 296 mg, about 297 mg, about 298 mg, about 299 mg, or about 300 mg, or more MDMA, or an equivalent amount of the pharmaceutically acceptable salt thereof.

[0048] In embodiments, the therapeutically effective amount of the enantiomerically enriched or pure MDMA compositions disclosed herein comprises about 0.01 mg/kg to about 20 mg/kg MDMA, or an equivalent amount of the pharmaceutically acceptable salt thereof, per dose (e.g., about 1 mg/kg to about 15 mg/kg, about 5 mg/kg to about 15 mg/kg, about 10 mg/kg to about 20 mg/kg, about 3 mg/kg to about 15 mg/kg, or about 3 mg/kg to about 5 mg/kg MDMA, or an equivalent amount of the pharmaceutically acceptable salt thereof).

[0049] In embodiments, the therapeutically effective amount of enantiomerically enriched or pure MDMA comprises ranging from about 0.001 mg/kg to 50 mg/kg MDMA, or an equivalent amount of the pharmaceutically acceptable salt thereof, (e.g., about 0.001 mg/kg, about 0.01 mg/kg, about 0.1 mg/kg, about 0.25 mg/kg, about 0.5 mg/kg, about 0.75 mg/kg, about 1.0 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 1.75 mg/kg, about 2.0 mg/mg, about 2.25 mg/kg, about 2.5 mg/kg, about 2.75 mg/kg, about 3.0 mg/kg, about 3.25 mg/kg, about 3.5 mg/kg, about 3.75 mg/kg, about 4.0 mg/kg, about 4.25 mg/kg, about 4.5 mg/kg, about 4.75 mg/kg, about 5.0 mg/kg, about 5.25 mg/kg, about 5.5 mg/kg, about 5.75 mg/kg, about 6.0 mg/kg, about 6.25 mg/kg, about 6.5 mg/kg, about 6.75 mg/kg, about 7.0 mg/kg, about 7.25 mg/kg, about 7.5 mg/kg, about 7.75 mg/kg, about 8.0 mg/kg, about 8.5 mg/kg, about 9.0 mg/kg, about 9.5 mg/kg, about 10.0 mg/kg, about 10.5 mg/kg, about 11.0 mg/kg, about 11.5 mg/kg, about 12.0 mg/kg, about 12.5 mg/kg, about 13.0 mg/kg, about 13.5 mg/kg, about 14.0 mg/kg, about 15.5 mg/kg, about 16.0 mg/kg, about 16.5 mg/kg, about 17.0 mg/kg, about 17.5 mg/kg, about 18.0 mg/kg, about 18.5 mg/kg, about 19.0 mg/kg, about 19.5 mg/kg, about 20.0 mg/kg, about 20.5 mg/kg, about 21 mg/kg, about 22, about mg/kg, about 23, about mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, about 30 mg/kg, about 31 mg/kg, about 32, about mg/kg, about 33, about mg/kg, about 34 mg/kg, about 35 mg/kg, about 36 mg/kg, about 37 mg/kg, about 38 mg/kg, about 39 mg/kg, about 40 mg/kg, about 41 mg/kg, about 42, about mg/kg, about 43, about mg/kg, about 44 mg/kg, about 45 mg/kg, about 46 mg/kg, about 47 mg/kg, about 48 mg/kg, about 49 mg/kg, or about 50 mg/kg MDMA, or an equivalent amount of the pharmaceutically acceptable salt thereof). Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

[0050] In embodiments, the effective amounts are provided as a single dose or on regular schedule, i.e., on a daily, weekly, monthly, or yearly basis or on an irregular schedule with varying administration days, weeks, months, etc. To reduce the occurrence of possible side effect associated with the dose, an effective amount may be provided as a split dose, where the single dose is split into two doses, that are administered apart, usually over several hours. For example, a single dose may be split into two doses, administered about 1 hour apart, about 2 hours apart, about 3 hours apart, about 4 hours apart, about 5 hours apart, about 6 hours apart, about 7 hours apart, about 8 hours apart, or more.

[0051] In embodiments, the therapeutically effective amount for the first dose is higher than the therapeutically effective amount for one or more of the subsequent doses. In emobidments, the therapeutically effective amount for the first dose is lower than the therapeutically effective amount for one or more of the subsequent doses.

[0052] In embodiments, equivalent dosages are administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every 2 weeks, about every 3 weeks, about every month, about every 2 months, about every 3 months and about every 6 months. The number and frequency of dosages corresponding to a completed course of therapy will be determined according to the judgment of a health-care practitioner.

[0053] In embodiments, dosing regimens of the disclosure include a titration period. In embodiments, the titration period comprises a period of time of about 1 month to about 24 months; about 1 month to about 21 months; about 1 month to about 18 months; about 1 month to about 15 months; about 1 month to about 12 months; about 1 month to about 9 months; about 1 month to about 6 months; about or 1 month to about 3 months. In embodiments, a titration period comprises a time of about: 3 months to about 24 months; about 3 months to about 21 months; about 3 months to about 18 months; about 3 months to about 15 months; about 3 months to about 12 months; about 3 or months to about 6 months. In embodiments, a titration period comprises a time of about: 6 months to about 24 months; about 6 months to about 21 months; about 6 months to about 18 months; about 6 months to about 15 months; or about 6 months to about 12 months. In embodiments, a titration period comprises a time of about: 2 months to about 4 months; about 2 months to about 7 months; about 2 months to about 8 months; about 4 months to about 8 months; about 5 months to about 7 months; or about 5 months to about 8 months, including all ranges therein. In embodiments, the titration period Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) comprises a period of time of about 1 to about 6 months. In embodiments, the titration period comprises a period of time of about 3 to about 6 months. In embodiments, the titration period comprises a period of time of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, or about 24 months, including all ranges therein. In embodiments, the titration period comprises a period of time of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, or about 24 weeks, including all ranges therein. In embodiments, the titration period comprises a period of time of about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, or about 24 days, including all ranges therein.

[0054] In embodiments, a starting dose administered during a titration period described herein is lower than the amount of a maintenance dose administered after a titration period. In embodiments, a starting dose administered during a titration period described herein is higher than the amount of a maintenance dose administered after a titration period. In embodiments, the maintenance dose is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% of the starting dose. In embodiments, the maintenance dose is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% of the starting dose. In embodiments, when the patient experiences side effects after administering the maintenance dose, the maintenance dose is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% of the intial maintenance dose. [0055] In embodiments, the maintenance dose is administered for about 1 month to about 24 months; about 1 month to about 21 months; about 1 month to about 18 months; about 1 Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) month to about 15 months; about 1 month to about 12 months; about 1 month to about 9 months; about 1 month to about 6 months; about or 1 month to about 3 months. In embodiments, the maintenance dose is administered for about 3 months to about 24 months; about 3 months to about 21 months; about 3 months to about 18 months; about 3 months to about 15 months; about 3 months to about 12 months; about 3 or months to about 6 months. In embodiments, the maintenance dose is administered for about 6 months to about 24 months; about 6 months to about 21 months; about 6 months to about 18 months; about 6 months to about 15 months; about or 6 months to about 12 months. In embodiments, the maintenance dose is administered for 2 months to about 4 months; about 2 months to about 7 months; about 2 months to about 8 months; about 4 months to about 8 months; about 5 months to about 7 months; or about 5 months to about 8 months, including all ranges therein. In embodiments, the maintenance dose is administered for about 1 to about 6 months. In embodiments, the maintenance dose is administered for about 3 to about 6 months. In embodiments, the maintenance dose is administered for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, or about 24 months, including all ranges therein. In embodiments, the maintenance dose is administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, or about 24 weeks, including all ranges therein. In embodiments, the maintenance dose is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, or about 24 days, including all ranges therein. embodiments

IV. Combination Therapies Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

[0056] In embodiments, the methods in accordance with the disclosure comprise administering a second therapy, such as, for example, one or more selective serotonin reuptake inhibitors (SSRIs) such as those typically administered for the treatment of psychological conditions such as major depressive disorder, anxiety disorders, and the like. In embodiments, the SSRI comprises fluoxetine, paroxetine, sertraline, escitalopram or citalopram.

[0057] In embodiments, a second therapy comprises a form of psychotherapy such as, for example, cognitive processing therapy (CPT), cognitive behavioral therapy (CBT), prolonged exposure therapy (PET), brief eclectic psychotherapy (BEP), narrative exposure therapy (NAT), or eye-movement desensitization, or reprocessing (EMDR).

[0058] In embodiments, the combination therapies comprise administration of the active agents together in the same admixture, or in separate admixtures. In embodiments, the combination therapies comprise two, three, or more active agents. In embodiments, the combination therapies result in an additive effect on the treatment of the conditions, symptoms, diseases associated with aggression. In embodiments, the combination therapies result in a synergisitc effect on the treatment of the conditions, symptoms, diseases associated with aggression.

V. Formulations

[0059] In emobidments, the pharmaceutical compositions of the disclosure are formulated in a variety of unit dosage forms depending upon the method and route of administration. In embodiments, the methods include any route of administration such as, for example, oral, parenteral (intravenous (i.v.), intraperitoneal (i.p.), intramuscular (i.m.), intrathecal, or subcutaneous, (s.c.) injections), sublingual, buccal, rectal, vaginal, ocular, otic, nasal, inhalation, nebulization, cutaneous/topical, transmucosal or transdermal administration. Suitable unit dosage forms, include, but are not limited to, liquids, powders, tablets, pills, capsules, lozenges, sprays, granules, etc., and also include conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles and, if desired, other active ingredients. As used herein, and as known in the art, the term parenteral injection includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like.

[0060] In embodiments, the pharmaceutical compositions of the disclosure are formulated in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) elixirs. Compositions intended for oral use are prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide palatable preparations. Tablets contain the active ingredient (i.e., MDMA enantiomer(s)) in admixture) with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. In embodiments, the excipients comprise inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and/or lubricating agents, for example magnesium stearate, stearic acid or talc. In emboddiments, the tablet are uncoated. In embodiments, the tablets are coated by known techniques. In embodimetns, coatings are prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.

[0061] In embodiments, the formulations for oral use comprise hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. In embodiments, the formulations for oral use comprise soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

[0062] In embodiments, the formulations of the disclosure comprise aqueous suspensions comprising the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions. In embodiments, the excipients comprise suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, for example a naturally-occurring phosphatide, such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyl eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. In embodiments, the aqueous suspensions comprise one or more preservatives, for example ethyl, or n-propyl p- Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and/or one or more sweetening agents, such as sucrose or saccharin.

[0063] In embodiments, the formulations of the disclosure comprise oily suspensions comprising the active ingredients suspended in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. In embodiments, the oily suspensions comprise a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. In embodiments, the oil suspensions comprises sweetening agents and flavoring agents to provide palatable oral preparations. In embodiments, the oily suspensions are preserved by the addition of an anti-oxidant such as ascorbic acid.

[0064] In embodiments, the dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water comprise the active ingredients in admixture with a dispersing or wetting agent described herein, a suspending agent described herein and one or more preservatives. In embodiments, additional excipients, for example sweetening, flavoring and coloring agents, are included.

[0065] In embodiments, pharmaceutical compositions in accordance with the disclosure are formulated in the form of oil-in-water emulsions. In embodiments, the oily phase is a vegetable oil or a mineral oil or mixtures of these. In embodiments, the emulsifying agents comprise naturally-occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and/or condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. In embodiments, the emulsions comprise sweetening and flavoring agents. In embodiments, syrups and elixirs are formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. In embodimetns, the formulations further comprise a demulcent, a preservative, and flavoring and coloring agents.

[0066] In embodiments, the pharmaceutical compositions may be formulated in the form of a sterile injectable aqueous or oleaginous suspension. In embodiments, the suspension is formulated according to the known art using those suitable dispersing or wetting agents and suspending agents described herein. In embodiments, the sterile injectable preparation is a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. [0067] In embodiments, compositions in accordance with the disclosure may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

VII. Clinical Outcome Measures

[0068] In embodiments, the methods of the disclosure lead to reduction in aggression, and/or associated symptoms in subjects. In embodiments, the therapeutic effectiveness of the methods of the disclosure are measured through procedures, methodologies, or techniques for assessing aggression known to those skilled in the art. In embodiments, clinical efficacies are measured by improvements of one or more of the following scores: Modified Overt Aggression Scale (MOAS); Neuropsychiatric Inventory (NPI) agitation/aggression domain; NPI total; Composite of NPI agitation/aggression, irritability/lability, aberrant motor behavior, and anxiety domains (NPI4A); Composite of NPI agitation/aggression, irritability/lability, aberrant motor behavior, and disinhibition domains (NPI4D); Cornell Scale for Depression in Dementia (CSDD) Score; Mini-Mental State Examination (MMSE); Modified Alzheimer Disease Cooperative Study — Clinical Global Impression of Change (ADCS-CGIC) score of agitation; Patient Global Impression of Change (PGI-C) score of agitation; Aggression Questionnaire (AGQ); Passive Aggression Scale (PAS); Clinical Global Impression-Severity of Aggression scale (CGI- A); Positive and Negative Syndrome Scale-Excited Component (PANSS-EC); Change in Difficulties in Emotion Regulation Scale (DERS); Staff Observation Aggression Scale-Revised (SOAS-R); Aggressive Behavior Risk Assessment Tool for Long-Term Care (AB RAT -L); Aggressive Behavior Scale (ABS); Rating Scale for Aggressive Behaviour in the Elderly (RAGE); Ryden Aggression Scale (RAS); Cohen-Mansfield Agitation Inventory (CMAI); Disruptive Behavior Rating Scales (DBRS); Pittsburgh Agitation Scale (PAS); Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE- AD); and/or Nursing Home Behavior Problem Scale (NHBPS). While the above non-exhaustive list of scores are typical of those that might be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used. Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

[0069] In embodiments, the clinical outcomes are measured as a baseline before the administration, and it continues to be monitored throughout the administration period.

[0070] In embodiments, the methods of the disclsoure lead to a reduction in subject’s MOAS score by at least about 1.5, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, or at least about 40 as compared to baseline.

[0071] In embodiments, the methods of the disclsoure lead to a reduction in subject’s NPI score for agitation/aggression by at least about 1.5, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, or at least about 10 as compared to baseline.

[0072] In embodiments, the methods of the disclsoure lead to a reduction in subject’s total NPI score by at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 30, at least about 40, at least about 50, least about 60, at least about 70, at least about 80, at least about 90, or at least about 100 as compared to baseline.

[0073] In embodiments, the methods of the disclsoure lead to a reduction in subject’s NPI4A score by at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, or at least about 20 as compared to baseline.

[0074] In embodiments, the methods of the disclsoure lead to a reduction in subject’s NPI4D score by at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, or at least about 15 as compared to baseline.

[0075] In embodiments, the methods of the disclsoure lead to a reduction in subject’s CSDD score by at least about 2, at least about 3, at least about 4, at least about 5, at least about Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, or at least about 15 as compared to baseline.

[0076] In embodiments, the methods of the disclsoure lead to a reduction in subject’s MMSE score by at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, or at least about 15 as compared to baseline.

[0077] In embodiments, the methods of the disclsoure lead to an improvement in subject’s ADCS-CGIC score of agitation by at least about 0.5, at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 30, at least about 40, or at least about 50 as compared to baseline.

[0078] In embodiments, the methods of the disclsoure lead to an improvement in subject’s PGI-C score of agitation by at least about 0.5, at least about 1, at least about 2, at least about 3, at least about 4, or at least about 5 as compared to baseline.

[0079] In embodiments, the methods of the disclsoure lead to a reduction in subject’s AGQ score by at least about 1.5, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, at least about 40, at least about 41, at least about 42, at least about 43, at least about 44, at least about 45, at least about 46, at least about 47, at least about 48, at least about 49, or at least about 50 as compared to baseline.

[0080] In embodiments, the methods of the disclsoure lead to a reduction in subject’s PAS score by at least about 1.5, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, or at least about 21 as compared to baseline. Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

[0081] In embodiments, the methods of the disclsoure lead to a reduction in subject’s CGI- A score by at least about 0.5, at least about 1, at least about 1.5, at least about 2, at least about 2.5, at least about 3, at least about 3.5, at least about 4, at least about 4.5, or at least about 5 as compared to baseline.

[0082] In embodiments, the methods of the disclsoure lead to a reduction in subject’s PANSS-EC score by at least about 1.5, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, or at least about 30 as compared to baseline. [0083] In embodiments, the methods of the disclsoure lead to a reduction in subject’s DERS score by at least about 1.5, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, at least about 40, at least about 41, at least about 42, at least about 43, at least about 44, at least about 45, at least about 46, at least about 47, at least about 48, at least about 49, or at least about 50 as compared to baseline.

[0084] In embodiments, the methods of the disclsoure lead to a reduction in subject’s SOAS-R score by at least about 1.5, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21 as compared to baseline.

[0085] In embodiments, the methods of the disclsoure lead to a reduction in subject’s ABRAT-L score by at least about 0.5, at least about 1, at least about 1.5, at least about 2, at least about 2.5, at least about 3, at least about 3.5, at least about 4, at least about 4.5, at least about 5, at least about 5.5, at least about 6, at least about 6.5, at least about 7, at least about 7.5, at least about 8 as compared to baseline. Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

[0086] In embodiments, the methods of the disclsoure lead to a reduction in subject’s ABS score by at least about 1.5, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, or at least about 12 as compared to baseline.

[0087] In embodiments, the methods of the disclsoure lead to a reduction in subject’s RAGE score by at least about 1.5, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, at least about 40, at least about 41, at least about 42, at least about 43, at least about 44, at least about 45, at least about 46, at least about 47, at least about 48, at least about 49, at least about 50, at least about 51, at least about 52, at least about 53, at least about 54, at least about 55, at least about 56, at least about 57, at least about 58, at least about 59, at least about 60, or at least about 61 as compared to baseline.

[0088] In embodiments, the methods of the disclsoure lead to a reduction in subject’s RAS score by at least about 1.5, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, at least about 40, at least about 41, at least about 42, at least about 43, at least about 44, at least about 45, at least about 46, at least about 47, at least about 48, at least about 49, at least about 50, at least about 51, at least about 52, at least about 53, at least about 54, at least about 55, at least about 56, at least about 57, at least about 58, at least about 59, at least about 60, at least about 61, at least about 62, at least about 63, at least about 64, at least about 65, at least about 66, at least about 67, at least about 68, at least about 69, at least about 70, at least about 71, at least about 72, at least about 73, at least about 74, at least about 75, at least about 76, at least about 77, at least about 78, at least about 79, at least about 80, at Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) least about 81, at least about 82, at least about 83, at least about 84, at least about 85, at least about 86, at least about 87, at least about 88, at least about 89, at least about 90, at least about 91, at least about 92, at least about 93, at least about 94, at least about 95, at least about 96, at least about 97, at least about 98, at least about 99, at least about 100, at least about 101, at least about 102, at least about 103, at least about 104, at least about 105, at least about 106, at least about 107, at least about 108, at least about 109, at least about 110, at least about 111, at least about 112, at least about 113, at least about 114, at least about 115, at least about 116, at least about 117, at least about 118, at least about 119, at least about 120, at least about 121, at least about 122, at least about 123, at least about 124, or at least about 125 as compared to baseline. [0089] In embodiments, the methods of the disclsoure lead to a reduction in subject’s CMAI score by at least about 1.5, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, at least about 40, at least about 41, at least about 42, at least about 43, at least about 44, at least about 45, at least about 46, at least about 47, at least about 48, at least about 49, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100, at least about 110, at least about 120, at least about 130, at least about 140, at least about 150, at least about 160, at least about 170, at least about 180, at least about 190, or at least about 200 as compared to baseline.

[0090] In embodiments, the methods of the disclsoure lead to a reduction in subject’s DBRS score by at least about 0.5, at least about 1, at least about 1.5, at least about 2, at least about 2.5, at least about 3, at least about 3.5, at least about 4, at least about 4.5, or at least about 5 as compared to baseline.

[0091] In embodiments, the methods of the disclsoure lead to a reduction in subject’s PAS score by at least about 1.5, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, or at least about 16 as compared to baseline. Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

[0092] In embodiments, the methods of the disclsoure lead to a reduction in subject’s BEHAVE-AD score by at least about 1.5, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, at least about 40, at least about 41, at least about 42, at least about 43, at least about 44, at least about 45, at least about 46, at least about 47, at least about 48, at least about 49, at least about 50, at least about 51, at least about 52, at least about 53, at least about 54, at least about 55, at least about 56, at least about 57, at least about 58, at least about 59, at least about 60, at least about 61, at least about 62, at least about 63, at least about 64, at least about 65, at least about 66, at least about 67, at least about 68, at least about 69, at least about 70, at least about 71, at least about 72, at least about 73, at least about 74, or at least about 75 as compared to baseline.

[0093] In embodiments, the methods of the disclsoure lead to a reduction in subject’s NHBPS score by at least about 1.5, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 26, at least about 27, at least about 28, at least about 29, at least about 30, at least about 31, at least about 32, at least about 33, at least about 34, at least about 35, at least about 36, at least about 37, at least about 38, at least about 39, at least about 40, at least about 41, at least about 42, at least about 43, at least about 44, at least about 45, at least about 46, at least about 47, at least about 48, at least about 49, at least about 50, at least about 51, at least about 52, at least about 53, at least about 54, at least about 55, at least about 56, at least about 57, at least about 58, at least about 59, at least about 60, at least about 61, at least about 62, at least about 63, at least about 64, at least about 65, at least about 66, at least about 67, at least about 68, at least about 69, at least about 70, at least about 71, at least about 72, at least about 73, at least about 74, at least about 75, at least about 76, at least about 77, at least about 78, at least about 79, at least about 80, at least about 81, at least about 82, at least about 83, at least about 84, at least about Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

85, at least about 86, at least about 87, at least about 88, at least about 89, at least about 90, at least about 91, at least about 92, at least about 93, at least about 94, at least about 95, at least about 96, at least about 97, at least about 98, at least about 99, at least about 100, at least about 101, at least about 102, at least about 103, at least about 104, at least about 105, at least about 106, at least about 107, at least about 108, at least about 109, at least about 110, at least about 111, at least about 112, at least about 113, at least about 114, at least about 115, or at least about 116 as compared to baseline.

NUMBERED EMBODIMENTS OF THE DISCLOSURE

[0094] In addition to the disclosure above, the Examples below, and the appended claims, the disclosure sets forth the following numbered embodiments.

[0095] Embodiment 1. A method of treating aggression in a subject who has a disease or disorder associated with aggression, comprising administering to the subject a therapeutically effective amount of a composition comprising an enantiomerically enriched or pure 3,4-methylenedioxymethamphetamine (MDMA) or a pharmaceutically acceptable salt thereof.

[0096] Embodiment 2. A method of reducing aggression in a subject comprising administering to the subject a therapeutically effective amount of a composition comprising an enantiomerically enriched or pure MDMA or a pharmaceutically acceptable salt thereof.

[0097] Embodiment s. A method of treating aggression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an enantiomerically enriched or pure MDMA or a pharmaceutically acceptable salt thereof.

[0098] Embodiment 4. The method of any one of embodiments 1-3, wherein the aggression in the subject comprises irritability, impulsivity, hypervigilance and/or hyperarousal.

[0099] Embodiment 5. The method of embodiment 1, wherein the disease or disorder is a social anxiety disorder (SAD).

[0100] Embodiment 6. The method of embodiment 51, wherein the disease or disorder is an autism spectrum disorder (ASD).

[0101] Embodiment 7. The method of any one of embodiments 1-6, wherein the enantiomerically enriched or pure MDMA comprises R(-)-MDMA in excess relative to S(+)- MDMA. Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

[0102] Embodiment 8. The method of any one of embodiments 1-6, wherein the enantiomerically enriched or pure MDMA comprises S(+)-MDMA in excess compared to R(- )-MDMA.

[0103] Embodiment 9. The method of any one of embodiments 1-8, wherein the therapeutically effective amount comprises a range from about 0.1 mg/kg to about 40 mg/kg.

[0104] Embodiment 10. The method of any one of embodiments 1-8, wherein the therapeutically effective amount comprises a range from about 1 mg/kg to about 20 mg/kg.

[0105] Embodiment 11. The method of any one of embodiments 1-8, wherein the therapeutically effective amount comprises a range from about 25 mg to about 350 mg.

[0106] Embodiment 12. The method of any one of embodiments 1-11, wherein administering the composition comprises injection, oral delivery, transdermal delivery, or transmucosal delivery.

[0107] Embodiment 13. The method of any one of embodiments 1-12, comprising administering enantiomerically enriched or pure MDMA comprising R(-)-MDMA in excess relative to S(+)-MDMA as a single dose.

[0108] Embodiment 14. The method of any one of embodiments 1-12, comprising administering enantiomerically enriched or pure form of MDMA comprising R(-)-MDMA in excess relative to S(+)-MDMA in repeated doses.

[0109] Embodiment 15. The method of any one of embodiments 1-12, comprising administering enantiomerically enriched or pure form of MDMA comprising S(+)-MDMA in excess relative to R(-)-MDMA as a single dose.

[0110] Embodiment 16. The method of any one of embodiments 1-12, comprising administering enantiomerically enriched or pure form of MDMA comprising S(+)-MDMA in excess relative to R(-)-MDMA in repeated doses.

[OHl] Embodiment 17. The method of any one of embodiments 1-16, further comprising administering a second therapy.

[0112] Embodiment 18. The method of embodiment 17, wherein the second therapy comprises a selective serotonin reuptake inhibitor (SSRI) or a form of psychotherapy.

[0113] Embodiment 19. The method of embodiment 18, wherein the SSRI comprises fluoxetine, paroxetine, sertraline, escitalopram or citalopram

[0114] Embodiment 20. The method of embodiment 18, wherein the psychotherapy comprises cognitive processing therapy (CPT), cognitive behavioral therapy (CBT), prolonged Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) exposure therapy (PET), brief eclectic psychotherapy (BEP), narrative exposure therapy (NAT), or eye-movement desensitization or reprocessing (EMDR).

[0115] Embodiment 21. The method of any one of the preceding embodiments, wherein the composition comprising an enantiomerically enriched or pure MDMA comprises a weight ratio of R(-)-MDMA to S(+)-MDMA ranging from about 50.1 :49.9 to about 100:0.

[0116] Embodiment 22. The method of any one of the preceding embodiments, wherein the composition comprising an enantiomerically enriched or pure MDMA comprises a weight ratio of S(+)-MDMA to R(-)-MDMA ranging from about 50.1 :49.9 to about 100:0.

[0117] Embodiment 23. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Modified Overt Aggression Scale (MO AS) by at least about 1.5 as compared to baseline.

[0118] Embodiment 24. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Neuropsychiatric Inventory (NPI) score for agitation/aggression by at least about 1.5 as compared to baseline.

[0119] Embodiment 25. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s total NPI score by at least about 2 as compared to baseline.

[0120] Embodiment 26. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Composite of NPI agitation/aggression, irritability/lability, aberrant motor behavior, and anxiety domains (NPI4A) score by at least about 2 as compared to baseline.

[0121] Embodiment 27. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Composite of NPI agitation/aggression, irritability/lability, aberrant motor behavior, and disinhibition domains (NPI4D) score by at least about 2 as compared to baseline.

[0122] Embodiment 28. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Cornell Scale for Depression in Dementia (CSDD) score by at least about 2 as compared to baseline.

[0123] Embodiment 29. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Mini -Mental State Examination (MMSE) score by at least about 2 as compared to baseline.

[0124] Embodiment 30. The method of any one of the preceding embodiments, wherein the method leads to an improvement in subject’s Modified Alzheimer Disease Cooperative Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

Study — Clinical Global Impression of Change (ADCS-CGIC) score of agitation by at least about 0.5 as compared to baseline.

[0125] Embodiment 31. The method of any one of the preceding embodiments, wherein the method leads to an improvement in subject’s Patient Global Impression of Change (PGI- C) score of agitation by at least about 0.5 as compared to baseline.

[0126] Embodiment 32. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Aggression Questionnaire (AGQ) score by at least about 1.5 as compared to baseline.

[0127] Embodiment 33. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Passive Aggression Scale (PAS) score by at least about 1.5 as compared to baseline.

[0128] Embodiment 34. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Clinical Global Impression-Severity of Aggression scale (CGI- A) score by at least about 1.5 as compared to baseline.

[0129] Embodiment 35. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score by at least about 1.5 as compared to baseline.

[0130] Embodiment 36. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Change in Difficulties in Emotion Regulation Scale (DERS) score by at least about 1.5 as compared to baseline.

[0131] Embodiment 37. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Staff Observation Aggression Scale-Revised (SOAS-R) score by at least about 1.5 as compared to baseline.

[0132] Embodiment 38. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Aggressive Behavior Risk Assessment Tool for Long-Term Care (ABRAT-L) score by at least about 1.5 as compared to baseline.

[0133] Embodiment 39. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Aggressive Behavior Scale (ABS) score by at least about 1.5 as compared to baseline.

[0134] Embodiment 40. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Rating Scale for Aggressive Behaviour in the Elderly (RAGE) score by at least about 1.5 as compared to baseline. Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

[0135] Embodiment 41. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Ryden Aggression Scale (RAS) score by at least about 1.5 as compared to baseline.

[0136] Embodiment 42. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Cohen-Mansfield Agitation Inventory (CMAI) score by at least about 1.5 as compared to baseline.

[0137] Embodiment 43. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Disruptive Behavior Rating Scales (DBRS) score by at least about 1.5 as compared to baseline.

[0138] Embodiment 44. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Pittsburgh Agitation Scale (PAS) score by at least about 1.5 as compared to baseline.

[0139] Embodiment 45. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE- AD) score by at least about 1.5 as compared to baseline.

[0140] Embodiment 46. The method of any one of the preceding embodiments, wherein the method leads to a reduction in subject’s Nursing Home Behavior Problem Scale (NHBPS) score by at least about 1.5 as compared to baseline.

EXAMPLES

[0141] The following examples are provided to further illustrate the embodiments of the present disclosure but are not intended to limit the scope of the embodiments. While they are typical of those that might be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.

Example 1: MDMA forms and effect on aggression response

[0142] The efficacy of the compositions disclosed herein including racemic MDMA and enantiomerically pure forms of MDMA (S(+)-MDMA and R(-)-MDMA) were evaluated for effects on aggression behaviors. Aggressive behaviors in mice were measured using the Resident-Intruder Animal Model. The resident-intruder (RI) test was used to observe offensive responses, typically by using individual housing to induce inter-male aggression in socially- isolated mice. This is a behavior test used to assess the social behavior and aggression in rodents. This test used biting to signify an act of aggression. Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

[0143] Methods: Male mice (aged 10-13 weeks at the beginning of the experiments) were allowed to acclimate to environmental conditions for at least 5 days prior to experimentation. The resident animals were individually housed in polycarbonate cages (floor area = 549 cm²) and the intruder animals were housed in groups of 4-10 in polysulfone cages (floor area = 1500 cm²) under standard conditions (room temperature at 22±2°C; hygrometry at 55±10%; light/dark cycle at 12h/12h; air circulation at 15-20 volumes/hour; water and food ad libitum). [0144] Enrichment for intruder animals consisted of the presence in the cage of cellulose slices and wooden briquettes. Small structures (house type) were added in order to promote nesting. For the resident animals, the enrichment consisted of wooden briquettes. The intruder animals were numbered by marking their tail using indelible markers.

[0145] Four independent dose-response experiments were conducted using male NMRI mice as either resident or intruder mice. (Janvier Labs, Saint-Berthevin, France).

[0146] Independent dose-response experiments evaluated the following MDMA compositions formulated in 0.9% NaCl and administered intraperitoneally (IP). All MDMA was sourced from Curia Global Inc., Albany, NY. Racemic MDMA HC1 at 3, 5.6, and 7.8 mg/kg free base; R(-)-MDMA HC1, at 10, 17 and 30 mg/kg free base; R(-)-MDMA HC1 at 1, 3 and 10 mg/kg free base; or S(+)-MDMA HC1 at 1, 3, 10 mg/kg free base was administered.

[0147] Doses were based on the molecular weight of the free base (correction factor for racemic, R(-) and S(+)-MDMA = 1.189). Risperidone was included in each experiment as a positive reference (0.06 mg/kg; Carbosynth Limited, Compton, UK; ref. FR27737). Risperidone was formulated in 0.9% NaCl with a few drops of 0.1N HC1 and administered subcutaneously (SC). Vehicle, test article or risperidone was administered once, 30 min before Test 3. The volume of administration was 10 mL/kg body weight for IP or SC administration. [0148] The resident mice were kept isolated in their individual home-cage throughout the 3-week experiment. One week after the beginning of the isolation period, two pre-tests (Test 1 and Test 2), spaced by one week, were performed in order to detect the level of aggressivity of each resident. One week after Test 2, drug administration was performed in Test 3.

[0149] At each RI test, the animals to be tested were placed in an experimental room at least 30 minutes before testing. During the 3 RI tests, each socially housed intruder was confronted to one resident for a session of 5 minutes in the resident’s home-cage. After the test, intruder mice were returned to their social group. Latency to first attack, number of attacks and total duration of attacks induced by the resident towards the intruder were recorded by a trained Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) observer using a timer and a counter. An attack was defined as biting the intruder. For each RI test, the resident interacted with a new intruder.

[0150] During Test 1 and Test 2, if a resident was attacked by the intruder, both mice were excluded from the study and not used again. During Test 2, only resident mice displaying at least one attack were included in Test 3. The aggressivity level of each resident mouse was evaluated based on the 3 recorded parameters. Animals that met the inclusion criterion were randomly allocated to experimental groups to ensure similar aggression levels prior to treatment, with a maximum of 12 mice per treatment condition.

[0151] The experimenter scoring the behaviour was not aware of the animal treatment. Testing was performed from 8.00 a.m. to 1.00 p.m. During Tests 1, 2 and 3, the following parameters were measured for resident mice: Latency to first attack(s), Number of attacks, Total duration of attack(s).

[0152] All parameters were analyzed at Biotrial with GraphPad Prism® software (current version). The number of attacks, latency to first attack and total duration of attacks during Test 3 were analyzed as follows: Comparison of the vehicle-treated group versus the Test Item- treated groups using a Kruskal -Wallis test. When group effect was significant, a Mann- Whitney test was used to compare each test article condition versus vehicle. Comparison of vehicle-treated group versus risperidone-treated group utilized a Mann-Whitney test. P<0.05 was set as the level of significance.

Example 1.1 - Effects of racemic MDMA

[0153] A single administration of racemic MDMA significantly and dose-dependently reduced aggressive behaviors, as measured by latency to first attack, number of attacks and total duration of attack, in socially-isolated NMRI mice in the resident-intruder test at all tested doses (Figure 1; *p<0.05, **p<0.01, ***p<0.001 vs. Vehicle). As expected, a single administration of the positive reference compound, 0.06 mg/kg risperidone, significantly decreased aggressive behaviors, as measured by latency to first attack, the number of attacks and total duration of attack, validating the robustness of the experiment (FIG. 1; **p<0.01, ***p<0.001 vs. Vehicle).

[0154] FIG. 1 depicts the effects of racemic MDMA (3, 5.6 and 7.8 mg/kg i.p.) on aggressive behaviors in socially-isolated male NMRI mice (N=12). Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

Example 1.2 - Effects of R(-)-MDMA

[0155] A single administration of R(-)-MDMA (administered i.p., at 10, 17 and 30 mg/kg) significantly reduced aggressive behavior, as measured by latency to first attack, number of attacks and total duration of attack, in socially-isolated NMRI mice in the resident-intruder test at all tested doses (FIG. 2; ***p<0.001 vs. Vehicle). Single administration of the positive reference compound, 0.06 mg/kg risperidone, significantly decreased aggressive behavior, as measured by latency to first attack, the number of attacks and total duration of attack, validating the robustness of the experiment (FIG. 2; ***p<0.001 vs. Vehicle).

[0156] FIG. 2 depicts the effects of R(-)-MDMA (administered i.p., at 10, 17 and 30 mg/kg) on aggressive behavior in socially-isolated male NMRI mice (N=12).

Example 1.3 - Effects of R(-)-MDMA (lower doses)

[0157] A single administration of R(-)-MDMA at lower doses (administered i.p. at 1, 3 and 10 mg/kg) significantly reduced aggressive behavior, as measured by latency to first attack, the number of attacks and total duration of attack, in socially-isolated NMRI mice in the residentintruder test at 3 and 10 mg/kg (FIG. 3; **p<0.01, ***0.001 vs. Vehicle). A single administration of the positive reference compound, 0.06 mg/kg risperidone, significantly decreased aggressive behaviors, as measured by number of attacks and total duration of attack (FIG. 3; ***p<0.001 vs. Vehicle). However, the effect of 0.06 mg/kg risperidone on latency to first attack did not achieve statistical significance compared to vehicle (FIG. 3; p=0.0532). Overall, the significant effects of 0.06 mg/kg risperidone on 2 out of 3 measures of aggressive behavior validates the robustness of the experiment.

[0158] FIG. 3 depicts the effects of R(-)-MDMA (administered i.p. at 1, 3 and 10 mg/kg) on aggressive behavior in socially-isolated male NMRI mice (N=12).

Example 1.4 Effects ofS(+ )-MDMA

[0159] A single administration of S(+)-MDMA (administered i.p. at 1, 3 and 10 mg/kg) significantly reduced aggressive behaviors, as measured by latency to first attack, the number of attacks and total duration of attack, in socially-isolated male NMRI mice in the residentintruder test at 1, 3 and 10 mg/kg (FIG. 4; *p<0.05, **p<0.01, ***p<0.001 vs. Vehicle). A single administration of the positive reference compound, 0.06 mg/kg risperidone, significantly decreased aggressive behaviors, as measured by latency to first attack, the number of attacks Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) and total duration of attack, validating the robustness of the experiment (FIG. 4; ***p<0.001 vs. Vehicle).

[0160] FIG. 4 depicts the effects of S(+)-MDMA (i.p. administration at 1, 3 and 10 mg/kg) on aggressive behavior in socially-isolated male NMRI mice (N=12).

[0161] This study examined the effect of enantiomerically pure forms of MDMA (i.e., R(- )-MDMA and S(+)-MDMA) on aggression behaviors, using the mouse resident-intruder test. Given that R(-)-MDMA has known differential activity for SERT inhibition and 5-HT release (and consequently stimulation of 5-HT1 A and 5-HT1B receptors) when compared to both S(+)- MDMA and racemic MDMA, one of skill may expect that the potency and magnitude of the anti-aggression effects of R(-)-MDMA are lower than those of S(+)-MDMA and racemic MDMA.

[0162] The results indicate similarities among racemic MDMA and each of its enantiomers, R(-) and S(+)-MDMA, in that all forms exhibit anti-aggressive effects in a model of socially-isolated male mice. Notably, the data identifies a minimal effective dose for R(-)- MDMA (i.e., 3 mg/kg i.p.), but does not insufficiently define minimal effective doses for racemic MDMA (i.e., <3 mg/kg i.p.) or S(+)-MDMA (i.e., <1 mg/kg i.p.).

[0163] These data lend additional support to the continued development of enantiomerically pure or enantiomerically enriched forms of MDMA for the treatment of disorders that are accompanied by increased aggression, irritability, impulsivity, hypervigilance and/or hyperarousal.

Example 2- Clinical Evaluation of the effects of enantiomerically enriched or pure MDMA on aggression

[0164] A subject who has been diagnosed with a disease or disorder associated with aggression will be administered with a therapeutically effective amount of a composition described herein. The subject will receive the following measures before and after the treatment: Modified Overt Aggression Scale (MOAS); Neuropsychiatric Inventory (NPI) agitation/aggression domain; NPI total; Composite of NPI agitation/aggression, irritability /lability, aberrant motor behavior, and anxiety domains (NPI4A); Composite of NPI agitation/aggression, irritability/lability, aberrant motor behavior, and disinhibition domains (NPI4D); NPI caregiver distress — agitation/aggression domain; Cornell Scale for Depression in Dementia (CSDD) Score; Mini-Mental State Examination (MMSE); Modified Alzheimer Disease Cooperative Study — Clinical Global Impression of Change (ADCS-CGIC) score of Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) agitation; Patient Global Impression of Change (PGI-C) score of agitation; Aggression Questionnaire (AGQ); Passive Aggression Scale (PAS); Clinical Global Impression-Severity of Aggression scale (CGI-A); Positive and Negative Syndrome Scale-Excited Component (PANSS-EC); Change in Difficulties in Emotion Regulation Scale (DERS); Staff Observation Aggression Scale-Revised (SOAS-R); Aggressive Behavior Risk Assessment Tool for Long- Term Care (ABRAT-L); Aggressive Behavior Scale (ABS); Rating Scale for Aggressive Behaviour in the Elderly (RAGE); Ryden Aggression Scale (RAS); Cohen-Mansfield Agitation Inventory (CMAI); Disruptive Behavior Rating Scales (DBRS); Pittsburgh Agitation Scale (PAS); Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE- AD); and/or Nursing Home Behavior Problem Scale (NHBPS). Other procedures, methodologies, or techniques useful for assessing aggression known to those skilled in the art may alternatively be used.

Claims

Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008) CLAIMS What is claimed is:

1. A method of treating aggression in a subject who has a disease or disorder associated with aggression, comprising administering to the subject a therapeutically effective amount of a composition comprising an enantiomerically enriched or pure 3,4- methylenedioxymethamphetamine (MDMA) or a pharmaceutically acceptable salt thereof.

2. A method of reducing aggression in a subject comprising administering to the subject a therapeutically effective amount of a composition comprising an enantiomerically enriched or pure MDMA or a pharmaceutically acceptable salt thereof.

3. A method of treating aggression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an enantiomerically enriched or pure MDMA or a pharmaceutically acceptable salt thereof.

4. The method of any one of claims 1-3, wherein the aggression in the subject comprises irritability, impulsivity, hypervigilance and/or hyperarousal.

5. The method of claim 1, wherein the disease or disorder is a social anxiety disorder (SAD).

6. The method of claim 1, wherein the disease or disorder is an autism spectrum disorder (ASD).

7. The method of any one of claims 1-6, wherein the enantiomerically enriched or pure MDMA comprises R(-)-MDMA in excess relative to S(+)-MDMA.

8. The method of any one of claims 1-6, wherein the enantiomerically enriched or pure MDMA comprises S(+)-MDMA in excess compared to R(-)-MDMA.

9. The method of any one of claims 1-8, wherein the therapeutically effective amount comprises a range from about 0.1 mg/kg to about 40 mg/kg. Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

10. The method of any one of claims 1-8, wherein the therapeutically effective amount comprises a range from about 1 mg/kg to about 20 mg/kg.

11. The method of any one of claims 1-8, wherein the therapeutically effective amount comprises a range from about 25 mg to about 350 mg.

12. The method of any one of claims 1-11, wherein administering the composition comprises injection, oral delivery, transdermal delivery, or transmucosal delivery.

13. The method of any one of claims 1-12, comprising administering the enantiomerically enriched or pure MDMA comprising R(-)-MDMA in excess relative to S(+)-MDMA as a single dose.

14. The method of any one of claims 1-12, comprising administering the enantiomerically enriched or pure MDMA comprising R(-)-MDMA in excess relative to S(+)-in repeated doses.

15. The method of any one of claims 1-12, comprising administering the enantiomerically enriched or pure MDMA comprising S(+)-MDMA in excess relative to R(-)-MDMA as a single dose.

16. The method of any one of claims 1-12, comprising administering enantiomerically enriched or pure MDMA comprising S(+)-MDMA in excess relative to R(-)-MDMA in repeated doses.

17. The method of any one of claims 1-16, further comprising administering a second therapy.

18. The method of claim 17, wherein the second therapy comprises a selective serotonin reuptake inhibitor (SSRI) or a form of psychotherapy. Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

19. The method of claim 18, wherein the SSRI comprises fluoxetine, paroxetine, sertraline, escitalopram or citalopram.

20. The method of claim 18, wherein the psychotherapy comprises cognitive processing therapy (CPT), cognitive behavioral therapy (CBT), prolonged exposure therapy (PET), brief eclectic psychotherapy (BEP), narrative exposure therapy (NAT), or eye-movement desensitization or reprocessing (EMDR).

21. The method of any one of the preceding claims, wherein the composition comprising an enantiomerically enriched or pure MDMA comprises a weight ratio of R(-)-MDMA to S(+)-MDMA ranging from about 50.1 :49.9 to about 100:0.

22. The method of any one of the preceding claims, wherein the composition comprising an enantiomerically enriched or pure MDMA comprises a weight ratio of S(+)-MDMA to R(- )-MDMA ranging from about 50.1 :49.9 to about 100:0.

23. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Modified Overt Aggression Scale (MO AS) by at least about 1.5 as compared to baseline.

24. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Neuropsychiatric Inventory (NPI) score for agitation/aggression by at least about 1.5 as compared to baseline.

25. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s total NPI score by at least about 2 as compared to baseline.

26. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Composite of NPI agitation/aggression, irritability /lability, aberrant motor behavior, and anxiety domains (NPI4A) score by at least about 2 as compared to baseline. Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

27. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Composite of NPI agitation/aggression, irritability /lability, aberrant motor behavior, and disinhibition domains (NPI4D) score by at least about 2 as compared to baseline.

28. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Cornell Scale for Depression in Dementia (CSDD) score by at least about 2 as compared to baseline.

29. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Mini -Mental State Examination (MMSE) score by at least about 2 as compared to baseline.

30. The method of any one of the preceding claims, wherein the method leads to an improvement in subject’s Modified Alzheimer Disease Cooperative Study — Clinical Global Impression of Change (ADCS-CGIC) score of agitation by at least about 0.5 as compared to baseline.

31. The method of any one of the preceding claims, wherein the method leads to an improvement in subject’s Patient Global Impression of Change (PGI-C) score of agitation by at least about 0.5 as compared to baseline.

32. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Aggression Questionnaire (AGQ) score by at least about 1.5 as compared to baseline.

33. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Passive Aggression Scale (PAS) score by at least about 1.5 as compared to baseline.

34. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Clinical Global Impression-Severity of Aggression scale (CGI- A) score by at least about 1.5 as compared to baseline. Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

35. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Positive and Negative Syndrome Scale-Excited Component (PANSS- EC) score by at least about 1.5 as compared to baseline.

36. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Change in Difficulties in Emotion Regulation Scale (DERS) score by at least about 1.5 as compared to baseline.

37. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Staff Observation Aggression Scale-Revised (SOAS-R) score by at least about 1.5 as compared to baseline.

38. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Aggressive Behavior Risk Assessment Tool for Long-Term Care (AB RAT -L) score by at least about 1.5 as compared to baseline.

39. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Aggressive Behavior Scale (ABS) score by at least about 1.5 as compared to baseline.

40. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Rating Scale for Aggressive Behaviour in the Elderly (RAGE) score by at least about 1.5 as compared to baseline.

41. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Ry den Aggression Scale (RAS) score by at least about 1.5 as compared to baseline.

42. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Cohen -Mansfield Agitation Inventory (CMAI) score by at least about 1.5 as compared to baseline. Atty Ref. ATAI-092/01 WO 338067-2474 (EMP-008)

43. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Disruptive Behavior Rating Scales (DBRS) score by at least about 1.5 as compared to baseline.

44. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Pittsburgh Agitation Scale (PAS) score by at least about 1.5 as compared to baseline.

45. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE- AD) score by at least about 1.5 as compared to baseline.

46. The method of any one of the preceding claims, wherein the method leads to a reduction in subject’s Nursing Home Behavior Problem Scale (NHBPS) score by at least about 1.5 as compared to baseline.