Compositions Comprising Non-Racemic Mixtures of (R)-3,4-Methylenedioxymethamphetamine and (S)-3,4-Methylenedioxymethamphetamine or (R)N-Methyl-1,3-Benzodioxolylbutanamine and (S)N-Methyl-1,3-Benzodioxolylbutanamine, and Uses Thereof

Abstract

The present application includes compositions comprising non-racemic mixtures of compounds of formula (R)-I or salts and / or solvates thereof with (S)-I or salts and / or solvates thereof, where (R)-I or salts and / or solvates thereof are present in the composition in a greater amount as enantiomeric equivalents compared to (S)-I or salts and / or solvates thereof. Methods of using these compositions, for example, to treat psychiatric disorders, are also included. Compounds of formula (R)-I and (S)-I include enantiomers of 3,4-methylenedioxymethamphetamine (MDMA) and N-methyl-1,3-benzodioxolylbutanamine (MBDB). Methods of treating various diseases, disorders, or conditions using a therapeutically effective amount of (R)-MDMA or pharma-ceutically acceptable salts and / or solvates thereof are also included in the present application. [Formula 1] JPEG2024531437000021.jpg59133

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority to co-pending U.S. Provisional Patent Application No. 63 / 235,460, filed August 20, 2021, and co-pending U.S. Provisional Patent Application No. 63 / 298,820, filed January 12, 2022, the contents of both of which are incorporated by reference in their entireties herein.

[0002] This application relates to compositions comprising non-racemic mixtures of 3,4-methylenedioxymethamphetamine (MDMA) and N-methyl-1,3-benzodioxolylbutanamine (MBDB), and methods of using these compositions in therapeutic treatments. This application further includes various novel therapeutic treatments using (R)-MDMA. [Background technology]

[0003] 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as Ecstasy (E) or Molly, is a psychoactive drug first developed by Merck in 1912. MDMA is often used recreationally today. However, MDMA's first use was as an adjunct to psychotherapy. More recently, MDMA has been studied in a variety of clinical trials, for example investigating MDMA-assisted psychotherapy for post-traumatic stress disorder (PTSD), anxiety associated with advanced illness, and social anxiety in autistic adults. MDMA has now been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) for the treatment of PTSD.

[0004] MDMA is commonly available and consumed as a racemate. Racemates of MDMA are also known to have potential adverse effects such as hyperthermia and neurotoxicity. However, studies have shown qualitative differences in the effects of MDMA isomers. Evidence suggests that the R isomer of MDMA may offer an improved therapeutic index while maintaining some of the therapeutic effects of MDMA racemate with a reduced side effect profile (Pitts et al., Psychopharmacology 235,377-392,2018; Curry et al., Neuropharmacology. 2018 January;128:196-206; Huot et al., Journal of Neuroscience, 2011,31(19)7190-7198; Setola et al., Mol. Pharmacol. 63:1223-1229,2003). Further investigations are needed to determine the therapeutic potential of MDMA enantiomers.

[0005] N-Methyl-1,3-benzodioxolylbutanamine (MBDB), commonly known as Eden or Methyl-J, is an analog of MDMA with an ethyl group instead of a methyl group attached to the alpha carbon next to the amine. Like MDMA, MBDB is also classified as an entactogen. MBDB is also commonly available and consumed as a racemate. Therefore, further investigation of the prosocial, therapeutic and toxicological effects of each enantiomer or MBDB is also needed. Summary of the Invention [Problem to be solved by the invention]

[0006] 3,4-Methylenedioxymethamphetamine (MDMA) is commonly administered as a racemate. The effects of racemic MDMA on social behavior in humans have been studied. Racemic MDMA is known to exhibit adverse effects such as hyperthermia and neurotoxicity, and has potential for drug abuse. The R enantiomer of MDMA ((R)-MDMA) has been shown to have prosocial effects with a lower risk of adverse effects such as neurotoxicity and hypothermia. However, the S enantiomer of MDMA ((S)-MDMA), the more potent enantiomer, is known to have stimulant activity but more adverse effects. Use of (R)-MDMA alone would result in loss of stimulant activity and any synergistic effects provided by the S enantiomer. [Means for solving the problem]

[0007] Therefore, the applicant will investigate various non-racemic mixtures of the enantiomers of MDMA, including a higher amount of the R enantiomer, to develop compositions that contain a sufficient amount of the R enantiomer to achieve the desired prosocial effects while reducing the occurrence of adverse effects such as hyperthermia and neurotoxicity of the S enantiomer, and further contain a sufficient amount of the S enantiomer for therapeutic efficacy. The compositions of the present application will also have low potential for drug abuse. Similar studies will be performed on the enantiomers of N-methyl-1,3-benzodioxolylbutanamine (MBDB). Through these detailed studies, the applicant will develop compositions that contain an optimal range of ratios of the two enantiomers of these beneficial therapeutic compounds to provide the desired efficacy while minimizing the undesirable effects associated with the current use of the racemic mixture.

[0008] In this application, the applicant also describes new therapeutic uses of the (R)-enantiomers of MDMA and MBDB, including use as treatments for autism spectrum disorders, clinical depression in palliative patients, and substance use disorders (e.g., opioid use disorder).

[0009] Thus, the present application includes compositions comprising non-racemic mixtures of compounds of formula (R)-I or salts and / or solvates thereof and (S)-I or salts and / or solvates thereof.

[0010] [ka]

[0011] In the formula, R 1 is CH 3 or CH 2 CH 3 and (R)-I or a salt and / or solvate thereof is present in the composition in a greater amount as an enantiomeric equivalent compared to (S)-I or a salt and / or solvate thereof.

[0012] The present application also includes a method for reducing adverse side effects of treatment with a racemic mixture of a compound of formula I, or a pharma- ceutical acceptable salt and / or solvate thereof.

[0013] [ka]

[0014] During the ceremony, R 1 CH 3 and C.H. 2 CH 3 Selected from: The methods include administering a therapeutically effective amount of one or more compositions of the present application to a subject in need thereof.

[0015] The present application includes methods of treating diseases, disorders, or conditions that benefit from treatment with a racemic mixture of a compound of Formula I, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0016] [ka]

[0017] During the ceremony, R 1 CH 3 and C.H. 2 CH 3 is selected from The methods include administering a therapeutically effective amount of one or more compositions of the present application to a subject in need thereof.

[0018] The application also includes a method for treating a disease, disorder, or condition that would benefit from treatment with racemic MDMA, or a pharma- ceutically acceptable salt and / or solvate thereof, comprising administering to a subject in need thereof a therapeutically effective amount of (R)-MDMA, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0019] Other features and advantages of the present application will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating embodiments of the present application, are given by way of illustration only, and the claims should not be limited by these embodiments, but should be accorded the broadest interpretation consistent with the description as a whole.

[0020] The present application will now be described in more detail with reference to the accompanying drawings and tables. [Brief description of the drawings]

[0021] [Figure 1] The two-dimensional molecular structures of methamphetamine (left structure) and 3,4-methylenedioxymethamphetamine (MDMA) (right structure) are shown. The arrows indicate the chiral carbons in each structure that give rise to the enantiomers.

[0022] [Diagram 2] FIG. 13 is a graph showing total entries into the test compartment during each phase of the social preference procedure in C57 (filled bars) and BTBR (open bars) mice that received saline injections prior to novelty, sociability, and social novelty (Soc Nov) testing.

[0023] [Diagram 3] Graphs depict baseline strain differences in preference during each stage of the social preference sequence in C57 (solid bars) and BTBR (open bars) mice that received saline injections prior to testing. Bars represent group means and error bars represent standard error of the mean (SEM). Note that both strains show comparable indifference during the novelty preference control test (top graph), but consistent with an autistic-like phenotype, BTBR mice show social avoidance during the social stage (middle graph) and social novelty stage (bottom graph).

[0024] [Figure 4] FIG. 1 is a graph showing the effect of saline (open squares) or various doses of methamphetamine (circles), racemic MDMA (Comparative Composition 1, closed diamonds), S(+)-MDMA (Comparative Composition 3, up-pointing triangles) or R(-)-MDMA (Exemplary Composition 7, down-pointing triangles) on compartment entry during social novelty testing in C57 mice (left graph) and BTBR mice (right graph). Doses are expressed in mg / kg and are shown on a logarithmic scale.

[0025] [Diagram 5] Graphs showing the effect of saline (open squares) or various doses of methamphetamine (circles), racemic MDMA (Comparative Composition 1, closed diamonds), S(+)-MDMA (Comparative Composition 3, up-pointing triangles) or R(-)-MDMA (Exemplary Composition 7, down-pointing triangles) on the time spent with the dummy mouse during a novelty preference test in C57 mice (left graph) and BTBR mice (right graph). Symbols represent group means and error bars represent SEM, except where the SEM is smaller than the size of the symbol. The dashed line indicates no difference in the compartment containing the dummy versus the compartment containing an empty cup. Doses are expressed in mg / kg and are shown on a logarithmic scale. Note that C57 and BTBR receiving saline behave essentially identically in this test, showing a slight preference for the novel dummy mouse.

[0026] [Figure 6] Graphs showing the effect of saline (open squares) or various doses of methamphetamine (circles), racemic MDMA (Comparative Composition 1, closed diamonds), S(+)-MDMA (Comparative Composition 3, up-pointing triangles) or R(-)-MDMA (Exemplary Composition 7, down-pointing triangles) on time spent with a stranger mouse during a novelty preference test in C57 mice (left graph) and BTBR mice (right graph). Symbols represent group means and error bars represent SEM, except where the SEM is smaller than the size of the symbol. Dashed lines indicate no difference between compartments containing a stranger mouse versus compartments containing a dummy. Doses are expressed in mg / kg and are shown on a logarithmic scale. Note that saline-treated BTBRs exhibit the expected autistic-like social avoidance in this test, showing avoidance of strangers.

[0027] [Figure 7] Graphs showing the effect of saline (open squares) or various doses of methamphetamine (circles), racemic MDMA (Comparative Composition 1, closed diamonds), S(+)-MDMA (Comparative Composition 3, up-pointing triangles) or R(-)-MDMA (Exemplary Composition 7, down-pointing triangles) on time spent with a novel mouse during a social novelty preference test in C57 mice (left graph) and BTBR mice (right graph). Symbols represent group means and error bars represent SEM, except where the SEM is smaller than the size of the symbol. Dashed lines indicate no difference between the compartment containing the new novel mouse versus the compartment containing the now familiar mouse. Doses are expressed in mg / kg and are shown on a logarithmic scale. Note that saline-treated BTBRs exhibit the expected autistic-like social avoidance in this test, showing avoidance of the novel mouse.

[0028] [Figure 8]Graphs showing the effects of saline (squares), racemic MDMA (Comparative Composition 1, filled and open circles), S(+)-MDMA (Comparative Composition 3, filled circles), R(-)-MDMA (Exemplary Composition 7, open circles) and Exemplary Composition 2(i) (80% R(-)-MDMA and 20% S(+)-MDMA, grey circles) on compartment entry (top left graph), novelty preference (top right graph), sociality (bottom left graph) and social novelty preference (bottom right graph) in C57 mice at doses up to 10 mg / kg.

[0029] [Figure 9] Graph showing the effect of saline (shaded bars) and 3.0 mg / kg MDMA at specific enantiomeric ratios on novelty preference in C57 mice (left graph) versus BTBR mice (right graph): saline (shaded bars, first bar from the left), 100% S(+)-MDMA (Comparative Composition 3, second bar from the left), racemic MDMA (50% R(-)-MDMA and 50% S(+)-MDMA, Comparative Composition 1, third bar from the left), Exemplary Composition 2(i) (80% R(-)-MDMA and 20% S(+)-MDMA, fourth bar from the left) and 100% R(-)-MDMA (Exemplary Composition 7, fifth bar from the left). Thus, the total dose of drug remains the same (3.0 mg / kg), but the enantiomeric composition of the administered dose differs between groups.

[0030] [Figure 10]1 shows the effect of saline and MDMA (3.0 mg / kg) at specific enantiomeric ratios on sociality in C57 mice (left graph) and BTBR mice (right graph): saline (shaded bar, first bar from the left), 100% S(+)-MDMA (Comparative Composition 3, second bar from the left), racemic MDMA (50% R(-)-MDMA and 50% S(+)-MDMA, Comparative Composition 1, third bar from the left), Exemplary Composition 2(i) (80% R(-)-MDMA and 20% S(+)-MDMA, fourth bar from the left), and 100% R(-)-MDMA (Exemplary Composition 7, fifth bar from the left). Darker bars indicate more S-MDMA and lighter bars indicate more R-MDMA. The total dose of drug remains the same (3.0 mg / kg), but the enantiomeric composition of the administered dose differs between groups.

[0031] [Figure 11] Graph showing the effect of saline and 3.0 mg / kg MDMA at specific enantiomer ratios on the social novelty preference test (preference for a novel, unfamiliar mouse over a familiar mouse) in c57 mice (left graph) and BTBR mice (right graph): saline (shaded bar, first bar from the left), 100% S(+)-MDMA (Comparative Composition 3, second bar from the left), racemic MDMA (50% R(-)-MDMA and 50% S(+)-MDMA, Comparative Composition 1, third bar from the left), Exemplary Composition 2(i) (80% R(-)-MDMA and 20% S(+)-MDMA, fourth bar from the left) and 100% R(-)-MDMA (Exemplary Composition 7, fifth bar from the left). Darker bars indicate more S-MDMA and lighter bars indicate more R-MDMA. Thus, although the total dose of drug remained the same (3.0 mg / kg), the enantiomeric composition of the administered dose differed between groups.

[0032] [Figure 12]Graphs showing the effect of saline (shaded bars) and 3.0 mg / kg MDMA at specific enantiomer ratios on the number of entries into two separate compartments (a proxy measure of exploratory behavior / locomotor activity) assessed during a social novelty preference test in C57 mice (left graph) and BTBR mice (right graph): saline (shaded bars, first bar from the left), 100% S(+)-MDMA (Comparative Composition 3, second bar from the left), racemic MDMA (50% R(-)-MDMA and 50% S(+)-MDMA, Comparative Composition 1, third bar from the left), Exemplary Composition 2(i) (80% R(-)-MDMA and 20% S(+)-MDMA, fourth bar from the left) and 100% R(-)-MDMA (Exemplary Composition 7, fifth bar from the left).

[0033] [Figure 13] Graphs showing the effect of saline injections on core temperature (left panels) and locomotor activity (right panels) in C57 (filled circles) and BTBR mice (filled circles). Symbols represent group means, and error bars represent SEM, except where the SEM is smaller than the size of the symbol. The bars below each panel indicate when the room lights were turned on or off.

[0034] [Figure 14] The effect of various doses of racemic MDMA (e.g., Comparative Composition 1) on core temperature in C57 mice (filled circles) and BTBR mice (open circles). Symbols represent group means, and error bars represent SEM, except where the SEM is smaller than the size of the symbol. The bars below each panel indicate when the room lights were turned on or off.

[0035] [Figure 15]Figure 1 shows the effect of various doses of racemic MDMA (50% R(-)-MDMA and 50% S(+)-MDMA, Comparative Composition 1) on locomotor activity in C57 (filled circles) and BTBR mice (open circles). Symbols represent group means and error bars represent SEM, except where the SEM is smaller than the size of the symbol. The bars below each panel indicate when the room lights were turned on or off. Because lethality was expected at the 100 mg / kg dose, injections at this dose were administered at the start of the work day and with the room lights on, and therefore continued for the duration of the data traces shown here.

[0036] [Figure 16] Figure 1 shows the effect of various doses (3 mg / kg, 10 mg / kg, 18 mg / kg, 30 mg / kg) of S-MDMA (Comparative Composition 3) on core temperature in C57 mice (filled circles) and BTBR mice (open circles). Symbols represent group means and error bars represent SEM, except where the SEM is smaller than the size of the symbol. The bars below each panel indicate when the room lights were turned on or off.

[0037] [Figure 17] Figure 1 shows the effect of various doses (3 mg / kg, 10 mg / kg, 18 mg / kg, 30 mg / kg) of S-MDMA (e.g., Comparative Composition 3) on locomotor activity in C57 mice (filled circles) and BTBR mice (open circles). Symbols represent group means, and error bars represent SEM, except where the SEM is smaller than the size of the symbol. The bars below each panel indicate when the room lights were turned on or off.

[0038] [Figure 18]Figure 1 shows the locomotor effects of 0.3 mg / kg (top left), 1 mg / kg (top right graph), and 3 mg / kg of the u-opioid agonist fentanyl in C57 mice (filled circles) versus BTBR mice (open circles). The bottom right graph shows the dose-effect function of the locomotor effect on total activity 4 hours after injection. Symbols represent group means, and error bars represent SEM unless the SEM is smaller than the size of the symbol. Doses are expressed in mg / kg and are shown on a logarithmic scale. Asterisks indicate significant differences from saline, and pound signs indicate significant differences between strains within doses.

[0039] [Figure 19] Figure 1 shows the locomotor effects of 0.3 mg / kg (top left), 1 mg / kg (top right graph), and 3 mg / kg of S-methamphetamine in C57 mice (filled circles) versus BTBR mice (open circles). The bottom right graph shows the dose-effect function of the locomotor effect on total activity 4 hours after injection. Symbols represent group means, and error bars represent SEM, except where the SEM is smaller than the size of the symbol. Doses are expressed in mg / kg and are shown on a logarithmic scale.

[0040] [Figure 20] Figure 1 shows the effect of 10 mg / kg MDMA at ratios of 0% R(-)-MDMA vs. 100% S(+)-MDMA (solid circles, e.g., Comparative Composition 3), 50% R(-)-MDMA vs. 50% S(+)-MDMA (half-white / half-black circles, e.g., Comparative Composition 1), 80% R(-)-MDMA vs. 20% S(+)-MDMA (gray circles, e.g., Exemplary Composition 2(i)), or 100% R(-)-MDMA vs. 0% S(+)-MDMA (open circles, e.g., Exemplary Composition 7) on core temperature in C57 mice (left) and BTBR mice (right). Symbols represent group means, error bars represent SEM, except where the SEM is smaller than the size of the symbol. The bottom panel represents a summary plot of core temperature where the time-activity data from the top figures (0 to 240 min) have been collapsed into bars to allow visualization of the effect of MDMA enantiomers on core temperature.

[0041] [Figure 21] The effects of 10 mg / kg MDMA at ratios of 0% R(-)-MDMA vs. 100% S(+)-MDMA (black circles, e.g., Comparative Composition 3), 50% R(-)-MDMA vs. 50% S(+)-MDMA (half-white / half-black circles, e.g., Comparative Composition 1), 80% R(-)-MDMA vs. 20% S(+)-MDMA (gray circles, e.g., Exemplary Composition 2(i)), or 100% R(-)-MDMA vs. 0% S(+)-MDMA (open circles, e.g., Exemplary Composition 7) on locomotor activity in c57 mice (left) and BTBR mice (right). Symbols represent group means, error bars represent SEM, except where the SEM is smaller than the size of the symbol. The lower panel represents a summary plot of locomotor activity in which the time-activity data from the upper figures (0 to 240 min) have been collapsed into bars to allow visualization of the effects of MDMA enantiomers on locomotor activity.

[0042] [Figure 22] The effect of 30 mg / kg MDMA at ratios of 0% R(-)-MDMA vs. 100% S(+)-MDMA (solid circles, e.g., Comparative Composition 3), 50% R(-)-MDMA vs. 50% S(+)-MDMA (half-white / half-black circles, e.g., Comparative Composition 1), 80% R(-)-MDMA vs. 20% S(+)-MDMA (gray circles, e.g., Exemplary Composition 2(i)), or 100% R(-)-MDMA vs. 0% S(+)-MDMA (open circles, e.g., Exemplary Composition 7) on core temperature in C57 mice (left) and BTBR mice (right). Symbols represent group means, error bars represent SEM, except where the SEM is smaller than the size of the symbol. The bottom panel represents a summary plot of core temperature where the time-activity data from the top figures (0 to 240 min) have been collapsed into bars to allow visualization of the effect of MDMA enantiomers on core temperature.

[0043] [Diagram 23]The effects of 30 mg / kg MDMA at ratios of 0% R(-)-MDMA vs. 100% S(+)-MDMA (black circles, e.g., Comparative Composition 3), 50% R(-)-MDMA vs. 50% S(+)-MDMA (half-white / half-black circles) (e.g., Comparative Composition 1), 80% R(-)-MDMA vs. 20% S(+)-MDMA (gray circles, e.g., Exemplary Composition 2(i)), or 100% R(-)-MDMA vs. 0% S(+)-MDMA (open circles, e.g., Exemplary Composition 7) on locomotor activity in C57 mice (top left) and BTBR mice (top right). Symbols represent group means, error bars represent SEM, except where the SEM is smaller than the size of the symbol. The bottom panel represents a summary plot of locomotor activity in which the time-activity data from the top figures (0 to 240 min) have been collapsed into bars to allow visualization of the effects of MDMA enantiomers on locomotor activity.

[0044] [Figure 24] Figure 1 shows the locomotor effects of saline or various doses of racemic MDMA (left panel, e.g., Comparative Composition 1) or S-MDMA (right panel, e.g., Comparative Composition 3) in C57 mice (filled circles) and BTBR mice (open circles). Symbols represent group means, and error bars represent SEM, except where the SEM is smaller than the size of the symbol. Doses are expressed in mg / kg and are shown on a logarithmic scale. Numbers adjacent to the points indicate the number of animals that died within 8 hours of drug administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] I. Definition Unless otherwise indicated, the definitions and embodiments set forth in this section and other sections are intended to be applicable to all embodiments and aspects of the application described herein where they are appropriate, as would be understood by one of skill in the art.

[0046] For purposes of understanding the scope of this application, the term "comprising" and its derivatives as used herein are intended to be open-ended terms that specify the presence of stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers, and / or steps. The above also applies to words of similar meaning, such as the terms "including," "having," and their derivatives.

[0047] As used herein, the term "composition of the application" refers to any composition comprising a non-racemic mixture of the compounds of formula (R)-I and (S)-I and / or salts and / or solvates thereof as described herein, as well as any composition comprising (R)-I and / or salts and / or solvates thereof as described herein.

[0048] As used herein, the term "consisting of" and its derivatives are intended to be closed terminology specifying the presence of stated features, elements, components, groups, integers, and / or steps, but excluding the presence of other unrecited features, elements, components, groups, integers, and / or steps.

[0049] As used herein, the term "consisting essentially of" is intended to specify the presence of a stated feature, element, component, group, integer, and / or step, as well as things that do not materially affect the basic and novel characteristic(s) of the feature, element, component, group, integer, and / or step.

[0050] As used herein, terms of degree such as "substantially," "about," and "approximately" refer to a reasonable amount of deviation from the modified term so that the end result is not materially altered. These terms of degree should be construed to include a deviation of at least ±5% of the modified term if such deviation does not negate the meaning of the word it modifies.

[0051] As used in this application, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0052] In embodiments that include an "additional" or "second" component, the second component, as used herein, is chemically distinct from the other component or the first component. A "third" component is distinct from the other component, the first component, and the second component, and further recited or "additional" components are similarly distinct.

[0053] As used herein, the term "and / or" means that the listed items may be present or used either individually or in any combination. In effect, the term means that "at least one" or "one or more" of the listed items are used or present.

[0054] As used herein, the term "subject" includes all members of the animal kingdom, including mammals, and suitably refers to humans. Thus, the methods of the present application are applicable to both human therapy and veterinary applications.

[0055] As used herein, the term "MDMA" refers to the compound having the IUPAC name: 1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine, or the chemical name: 3,4-methylenedioxymethamphetamine, and having the chemical formula:

[0056] [ka]

[0057] As used herein, the term "(R)-MDMA" refers to the compound having the IUPAC name: (2R)-1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine, or the chemical name: (R)-3,4-methylenedioxymethamphetamine, and having the chemical formula:

[0058] [ka]

[0059] As used herein, the term "(S)-MDMA" refers to the compound having the IUPAC name: (2S)-1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine, or the chemical name: (S)-3,4-methylenedioxymethamphetamine, and having the chemical formula:

[0060] [ka]

[0061] As used herein, the term "MBDB" refers to the compound having the IUPAC name: 1-(1,3-benzodioxol-5-yl)-N-methylbutan-2-amine, or the chemical name: N-methyl-1,3-benzodioxolylbutanamine, and having the chemical formula:

[0062] [ka]

[0063] As used herein, the term "(R)-MBDB" refers to the compound having the IUPAC name: (2R)-1-(1,3-benzodioxol-5-yl)-N-methylbutan-2-amine, or the chemical name: (R)-N-methyl-1,3-benzodioxolylbutanamine, and having the chemical formula:

[0064] [ka]

[0065] As used herein, the term "(S)-MBDB" refers to the compound having the IUPAC name: (2S)-1-(1,3-benzodioxol-5-yl)-N-methylbutan-2-amine, or the chemical name: (S)-N-methyl-1,3-benzodioxolylbutanamine, and having the chemical formula:

[0066] [ka]

[0067] As used herein, the term "pharmaceutical composition" refers to a composition of matter for pharmaceutical use.

[0068] The term "medicinal use" means adapted for the treatment of a subject.

[0069] The term "pharmaceutical acceptable" means compatible with the treatment of a subject.

[0070] The term "pharmaceutical acceptable salt" means an acid addition salt that is suitable or compatible with the treatment of a subject.

[0071] Acid addition salts suitable for or compatible with the treatment of a subject are any non-toxic organic or inorganic acid addition salts of any of the base compounds.

[0072] The term "solvate" as used herein means a compound or a salt of a compound wherein molecules of a suitable solvent are incorporated into the crystal lattice, said suitable solvent being physiologically acceptable at the dosage administered.

[0073] As used herein, the term "therapeutically effective amount" of a composition of the present application or (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof refers to an amount sufficient to effect beneficial or desired results, including clinical results, when administered to a subject; thus, "therapeutically effective amount" or its synonyms depend on the context in which it is applied. Thus, as used herein, "therapeutically effective amount" is intended to mean an amount of a compound or composition sufficient to treat, prevent or inhibit a disease or condition. The amount of a given compound or composition of the present application that corresponds to such an amount will vary depending on a variety of factors, such as the given compound or composition, pharmaceutical formulation, route of administration, type of disease or disorder, identity of the subject being treated, etc., but can nevertheless be routinely determined by one of ordinary skill in the art.

[0074] As used herein, the term "administered" refers to the application or administration of a therapeutically effective amount of a composition of (R)-MDMA, a pharma- ceutical acceptable salt and / or solvate thereof to a cell, either in a cell culture or in a subject.

[0075] The terms "to treat", "treating" and "treatment" as used herein and well understood in the art refer to an approach to obtain beneficial or desired results, including clinical results. Examples of beneficial or desired clinical results for any disease, disorder or condition include, but are not limited to, reduction in extent, stabilized (i.e., not worsening), prevention of spread, delay or slowing of progression, improvement or palliation of a condition, and remission (whether partial or total), whether detectable or undetectable. "To treat", "treating" and "treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment. As used herein, "to treat", "treating" and "treatment" also include prophylactic treatment.

[0076] "Palliating" a disease, disorder, or condition means reducing the severity and / or undesirable clinical signs of the disease, disorder, or condition and / or slowing or prolonging the time course of progression compared to not treating the disease, disorder, or condition.

[0077] As used herein, the terms "prevention" or "prophylaxis," or their equivalents, refer to a reduction in the risk or probability that a patient will suffer from a disease, disorder, or condition, or will exhibit symptoms associated with a disease, disorder, or condition.

[0078] As used herein, the term "on-time" refers to the duration of the anti-Parkinsonian effect of L-DOPA.

[0079] For example, when used in relation to the treatment methods, uses, compositions and / or kits of the present application, a subject, e.g., a subject "in need thereof", is a subject who has been diagnosed and / or treated for a disease, disorder or condition that would benefit from the administration of a composition of the present application or (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof.

[0080] The term "enantiomeric equivalent" as used herein refers to the molar amount of each enantiomer of the compound of formula I, i.e., the base compound of (R)-I and (S)-I, regardless of whether the enantiomer is present as a salt and / or solvate. Thus, the percentage of enantiomeric equivalent of each of (R)-I and (S)-I is defined by the molar amount of either (R)-I or (S)-I divided by the total molar amount of both (R)-I and (S)-I. The amount of any anion-forming salt and / or solvate-forming solvent is excluded and is not considered in determining the percentage of enantiomeric equivalent of each of (R)-I and (S)-I.

[0081] II. Non-racemic Compositions of the Present Application The present application includes compositions comprising non-racemic mixtures of compounds of formula (R)-I or salts and / or solvates thereof and (S)-I or salts and / or solvates thereof.

[0082] [ka]

[0083] In the formula, R 1 is CH 3 or CH 2 CH 3 and (R)-I or a salt and / or solvate thereof is present in the composition in a greater amount as an enantiomeric equivalent compared to (S)-I or a salt and / or solvate thereof.

[0084] In some embodiments, the composition comprises from about 70% to about 99% enantiomeric equivalent weight of the compound of formula (R)-I or its salt and / or solvate and from about 1% to about 30% enantiomeric equivalent weight of the compound of formula (S)-I or its salt and / or solvate.

[0085] In some embodiments, the composition comprises from about 70% to about 79.9% by enantiomeric equivalent of the compound of formula (R)-I or its salt and / or solvate and from about 20.1% to about 30% by enantiomeric equivalent of the compound of formula (S)-I or its salt and / or solvate.

[0086] In some embodiments, the composition comprises about 70% to about 75% enantiomeric equivalent weight of a compound of formula (R)-I or a salt and / or solvate thereof and 25% to about 30% enantiomeric equivalent weight of a compound of formula (S)-I or a salt and / or solvate thereof.

[0087] In some embodiments, the composition comprises about 75% to about 79.9% by enantiomeric equivalent of the compound of formula (R)-I or its salt and / or solvate and about 20.1% to about 25% by enantiomeric equivalent of the compound of formula (S)-I or its salt and / or solvate.

[0088] In some embodiments, the composition comprises from about 80% to about 89.9% enantiomeric equivalent weight of the compound of formula (R)-I or its salt and / or solvate and from about 10.1% to about 20% enantiomeric equivalent weight of the compound of formula (S)-I or its salt and / or solvate.

[0089] In some embodiments, the composition comprises about 80% to about 85% enantiomeric equivalent of Formula (R)-I or a salt and / or solvate thereof and about 15% to about 20% enantiomeric equivalent of Formula (S)-I or a salt and / or solvate thereof.

[0090] In some embodiments, the composition comprises about 80% by enantiomeric equivalent of Formula (R)-I or a salt and / or solvate thereof and about 20% by enantiomeric equivalent of Formula (S)-I or a salt and / or solvate thereof.

[0091] In some embodiments, the composition comprises from about 85% to about 89.9% enantiomeric equivalent weight of the compound of formula (R)-I or its salt and / or solvate and from about 10.1% to about 15% enantiomeric equivalent weight of the compound of formula (S)-I or its salt and / or solvate.

[0092] In some embodiments, the composition comprises about 90% to about 99% enantiomeric equivalent weight of the compound of formula (R)-I or its salt and / or solvate and about 1% to about 10% enantiomeric equivalent weight of the compound of formula (S)-I or its salt and / or solvate.

[0093] In some embodiments, the compositions comprise about 90% to about 95% enantiomeric equivalent of a compound of formula (R)-I or a salt and / or solvate thereof and about 5% to about 10% enantiomeric equivalent of a compound of formula (S)-I or a salt and / or solvate thereof.

[0094] In some embodiments, the compositions comprise from about 95% to about 99% enantiomeric equivalent of a compound of formula (R)-I or a salt and / or solvate thereof and from about 1% to about 5% enantiomeric equivalent of a compound of formula (S)-I or a salt and / or solvate thereof.

[0095] In some embodiments, R 1 CH 3 and the compound of formula (R)-I is (R)-3,4-methylenedioxymethamphetamine ((R)-MDMA) and the compound of formula (S)-I is (S)-3,4-methylenedioxymethamphetamine ((S)-MDMA).

[0096] In some embodiments, R 1 CH 2 CH 3 and the compound of formula (R)-I is (R)-N-methyl-1,3-benzodioxolylbutanamine ((R)-MBDB) and the compound of formula (S)-I is (S)-N-methyl-1,3-benzodioxolylbutanamine ((S)-MBDB).

[0097] (R)-MDMA and (S)-MDMA(R 1 CH 3 Compounds of formula (R)-I and compounds of formula (S)-I, where R is a 1-methyl-1,2-diphenyl-2-propanediol, and S is a 1-methyl-1,2-diphenyl-2-propanediol, can be prepared by various synthetic processes. The selection of a particular process is within the understanding of a person skilled in the art. For example, (R)-MDMA and (S)-MDMA can be prepared by the methods disclosed in, for example, Dunlap et al. (2018), ACS Chem Neurosci; 9(10): 2408-2427; Llabres et al. (2014), European J. of Med. Chem. 81(2014) 35-46; Huot et al. (2011), J Neurosci. (2011) May 11; 31(19): 7190-7198 and Felim et al., Chem Res Toxicol. 2010 23(1): 211-9.

[0098] (R)-MBDB and (S)-MBDB(R 1 CH 2 CH3 Compounds of formula (R)-I and compounds of formula (S)-I, which are represented by the formula (R)-I and (S)-I, can be prepared by various synthetic processes. The selection of a particular process is within the understanding of a person skilled in the art. For example, (R)-MBDB and (S)-MBDB can be prepared by the above-mentioned method for preparing (R)-MDMA and (S)-MDMA, or the method disclosed in co-pending US Provisional Application No. 63 / 201,609, US Provisional Application No. 63 / 203,099, US Provisional Application No. 63 / 201,610, and US Provisional Application No. 63 / 203,101.

[0099] Alternatively, compounds of formula (R)-I and compounds of formula (S)-I can be obtained using enantiomer separation methods known in the art, for example, using chromatography, crystallization or other such methods for isolating individual enantiomers from a racemic mixture.

[0100] In some embodiments, the compound of formula (R)-I and / or the compound of formula (S)-I are provided as salts. The selection of suitable salts can be performed by those skilled in the art. Acids that are generally considered suitable for the formation of pharma-ceutically acceptable salts from base pharmaceutical compounds are discussed, for example, by P.Stahl et al., Camille G. (eds.) and Handbook of Pharmaceutical Salts.Properties, Selection and Use.(2002) Zurich:Wiley VCH; S.Berge et al., Journal of Pharmaceutical Sciences 1977 66(1)1-19; P.Gould, International J.of Pharmaceutics(1986)33 201-217; Anderson et al., The Practice of Medicinal Chemistry(1996), Academic Press, New York; and The Orange Book (Food&Drug Administration, Washington, DC (online)).

[0101] In some embodiments, the acid addition salt suitable for or compatible with the treatment of a subject is any non-toxic organic or inorganic acid addition salt.Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids.Examples of such organic acids are, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In some embodiments, exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates ("mesylates"), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylates), and the like. In some embodiments, the salts are present in either hydrated, solvated, or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally exhibit higher melting points compared to their free base forms.

[0102] Salts of compounds of formula (R)-I or formula (S)-I can be formed by methods known to those skilled in the art, for example, by reacting (R)-I or (S)-I with an amount of acid, such as an equivalent amount, in a medium in which the salt precipitates or in an aqueous medium, followed by lyophilization.

[0103] In some embodiments, the compound of formula (R)-I and / or the compound of formula (S)-I are provided as solvates. Solvates include, for example, those prepared with pharma- ceutically acceptable solvents. Such solvents include, for example, water (the resulting solvates are called hydrates), ethanol, and the like. Suitable solvents are physiologically acceptable at the dosage administered.

[0104] In general, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. Selection of appropriate conditions for forming a particular solvate can be performed by one of ordinary skill in the art.

[0105] The compounds of formula (R)-I and compounds of formula (S)-I, or pharma- ceutically acceptable salts and / or solvates thereof, may further exist in different polymorphic forms, and any polymorph or mixture thereof is contemplated and included within the scope of this application.

[0106] In some embodiments, the compound of formula (R)-I and the compound of formula (S)-I are both in free base form. In some embodiments, the compound of formula (R)-I and the compound of formula (S)-I are both in acid salt form.

[0107] The compounds of formula (R)-I and compounds of formula (S)-I and / or salts and / or solvates thereof are suitably formulated into pharmaceutical compositions for administration to a subject in a biologically compatible form suitable for in vivo administration. Thus, in one embodiment, the composition of the present application is a pharmaceutical composition and further comprises one or more pharma- ceutically acceptable carriers.

[0108] The pharmaceutical compositions of the present application may be administered to a subject in a variety of forms depending on the route of administration selected, as will be appreciated by those skilled in the art. For example, the compositions of the present application may be administered orally, by inhalation, parenterally, bucally, sublingually, nasally, rectally, vaginally, by patch, pump, minipump, topically or transdermally, and the pharmaceutical compositions may be formulated accordingly. In some embodiments, administration is by pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000-20th edition) and The United States Pharmacopeia: The National Formulary, published in 1999 (USP 24 NF19).

[0109] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary (e.g., by use of an aerosol), intrathecal, rectal, and topical (including use of a patch or other transdermal delivery device) modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.

[0110] In some embodiments, the compositions of the present application may be orally administered, for example, with an inert diluent or an assimilable edible carrier, or may be enclosed in a hard or soft shell gelatin capsule, or may be compressed into tablets, or may be directly incorporated into dietary foods. For oral therapeutic administration, the compositions may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions or suspensions, and the like. In the case of tablets, the carriers used include lactose, corn starch, sodium citrate, and salts of phosphoric acid. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets are coated by methods well known in the art. For tablets, capsules, caplets, pellets or granules for oral administration, pH-sensitive enteric coatings such as Eudragits™, designed to control the release of the active ingredient, are optionally used. Oral dosage forms also include modified release formulations, such as immediate release formulations and timed release formulations. Examples of modified release formulations include, for example, sustained release (SR), extended release (ER, XR or XL), timed or time-limited release, controlled release (CR), or continuous release (CR or contin), used in the form of, for example, coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, aggregated particles such as, for example, molecular sieve-type particles, or fine hollow permeable fiber bundles or chopped hollow permeable fibers aggregated or held in fibrous packets. Timed release compositions can be formulated, for example, in liposomes, or in liposomes where the composition is protected with a differentially degradable coating by microencapsulation, multiple coatings, etc.Liposomal delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine. Carriers or diluents useful for oral administration in capsule form include lactose and dried cornstarch.

[0111] In some embodiments, liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be suitably provided as a dry product for reconstitution with water or other suitable vehicle(s) before use. When aqueous suspensions and / or emulsions are administered orally, the compositions of the present application are suitably suspended or dissolved in an oily phase in combination with an emulsifying and / or suspending agent. If desired, specific sweetening and / or flavoring and / or coloring agents are added. In some embodiments, such liquid preparations for oral administration are prepared by conventional means using pharma- ceutical acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0112] In some embodiments, the compositions of the present application are formulated as solid or semi-solid compositions. In some embodiments, the compositions of the present application are formulated as tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions or suspensions. In some embodiments, the compositions of the present application are formulated as tablets or capsules. In some embodiments, the compositions of the present application are formulated as tablets.

[0113] The compositions of the present application can also be lyophilized and the resulting lyophilizates used, for example, for the preparation of injectable products.

[0114] In some embodiments, the compositions of the present application are administered parenterally. For example, solutions of the compositions of the present application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Those skilled in the art will know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compositions of the present application are usually prepared, and the pH of the solution is suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids are delivered by ocular delivery systems known in the art, such as applicators or eyedroppers. In some embodiments, such formulations include a mucosal mimetic such as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose or polyvinyl alcohol, a preservative such as sorbic acid, EDTA or benzyl chromium chloride, and a diluent or carrier in the usual amount. In the case of pulmonary administration, the diluent or carrier is selected to be appropriate to allow the formation of an aerosol.

[0115] In some embodiments, the compositions of the present application are formulated for parenteral administration by injection, including using conventional catheterization or infusion. Injectable compositions are provided, for example, in unit dosage form (e.g., ampoules) or in multi-dose containers, with the addition of a preservative. In some embodiments, the compositions are formulated as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, containing formulating agents such as suspending, stabilizing and / or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compositions of the present application are suitably in sterile powder form for reconstitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0116] MDMA (±) 3,4-methylenedioxymethamphetamine, "Ecstasy") is reported to be used recreationally to increase empathy, sociality, and interpersonal closeness. Through clinical and some animal studies, MDMA metabolism is known to be quite complex. It involves two main hepatic metabolic pathways: (1) O-demethylation, e.g., to produce (±)-4-hydroxy-3-methoxymethamphetamine (HMMA), and / or glucuronide / sulfate conjugates; (2) N-dealkylation, deamination, and oxidation of the corresponding benzoic acid derivatives conjugated with glycine, e.g., to produce (±)-3,4-methylenedioxyamphetamine (MDA) and 3,4-dihydroxymethamphetamine (DHMA), (±)-3,4-dihydroxyamphetamine (HHA) (Baumann MH et al., Drug Metab Dispos. 2009;37(11):2163-70).

[0117] Significant differences in the Cmax of MDMA in rats based on the route of delivery have been observed (Baumann MH et al. Drug Metab Dispos. 2009;37(11):2163-70). At 2 mg / kg, maximum MDMA concentrations were approximately 200 ng / ml via the intraperitoneal (210 ng / ml) and subcutaneous (196 ng / ml) routes, but lower via the oral route (46 ng / ml). At the higher dose (10 mg / kg), the Cmax via the intraperitoneal (2257 ng / ml) and subcutaneous (1130 ng / ml) routes of administration was higher than the oral route (966 ng / ml).

[0118] It is also known that the (R)- and (S)-enantiomers of racemic 3,4-methylenedioxymethamphetamine (MDMA) show different dose-concentration curves. MDMA, MDA, DHMA, DHMA sulfate, HMMA, HMMA sulfate, and HMMA glucuronide have been shown to be excreted in substantial amounts in human urine (Schwaninger AE et al., Biochem Pharmacol. 2012;83(1):131-8). After creatinine normalization, statistically significant differences between the two enantiomers (R- and S- of the individual metabolites) were observed for all compounds except HMMA sulfate. Higher R-enantiomer Cmax was observed for MDMA, DHMA, and HMMA sulfate, whereas the S-enantiomer was higher for DHMA sulfate, HMMA, HMMA glucuronide, and MDA. Error! Reference source not found.

[0119] The oral mucosa is occasionally used as a site of drug absorption. Sublingual administration, in which a tablet or lozenge is completely dissolved in the oral cavity, takes advantage of the permeability of the oral epithelium and is the route of administration for several potent lipophilic drugs, such as nitroglycerin and oxytocin, as well as the oral sedative triazolam.

[0120] MDMA has demonstrated efficacy in Phase 3 trials for treating post-traumatic stress disorder (PTSD) via MDMA-assisted psychotherapy. It has a complex pharmacology and is known to affect multiple receptors in the brain.

[0121] In some embodiments, intranasal administration is believed to provide both direct and indirect routes to the delivery of psychopharmacological agents to the central nervous system (CNS). Direct nose-to-brain transport via the olfactory and trigeminal nerve pathways after intranasal deposition and absorption into the olfactory and respiratory epithelium provides a non-invasive means of avoiding the blood-brain barrier (BBB), which is an obstacle to drug delivery to the CNS. In some embodiments, compared to other routes of administration (e.g., oral administration), intranasal administration offers ease of use, reduced systemic exposure, faster drug onset, increased compliance, and improved bioavailability by avoiding first-pass metabolism (Keller et al., Drug Deliv. and Transl. Res. 12, 735-757 (2022)).

[0122] Thus, in some embodiments, sublingual and intranasal administration avoids drug destruction, in some embodiments, sublingual and intranasal administration avoids drug destruction by bypassing stomach acid and intestinal and hepatic enzymes.

[0123] In some embodiments, sublingual and intranasal absorption is more efficient compared to intestinal uptake, for example, when using oral administration, hi some embodiments, the onset of drug effect using sublingual or intranasal administration is faster compared to the onset of the same drug effect using oral administration.

[0124] In some embodiments, better drug absorption and metabolic profile is achieved using sublingual or intranasal administration compared to oral administration.In some embodiments, liver metabolism is more suppressed using sublingual or intranasal administration compared to oral administration.In some embodiments, a lower dose of active ingredient, e.g. MDMA, is used to achieve a biological effect by sublingual or intranasal administration compared to the dose of active ingredient to achieve the same biological effect by oral administration.In some embodiments, sublingual or intranasal administration provides better bioavailability and a better safety profile for active ingredient, e.g. MDMA, compared to oral administration.

[0125] Thus, in some embodiments, compositions comprising non-racemic mixtures of compounds of formula (R)-I or salts and / or solvates thereof and (S)-I or salts and / or solvates thereof as described above are formulated for intranasal administration or use.

[0126] Thus, in some embodiments, the present application also includes intranasal compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof.

[0127] [ka]

[0128] In the formula, R 1 is CH 3 or CH 2 CH 3 and (R)-I or a salt and / or solvate thereof is present in the composition in a greater amount as an enantiomeric equivalent compared to (S)-I or a salt and / or solvate thereof.

[0129] In some embodiments, the amounts or enantiomeric equivalents of the compounds of formula (R) or salts and / or solvates thereof and (S)-I or salts and / or solvates thereof in the non-racemic mixture in the intranasal composition are as described above.

[0130] In some embodiments, a composition comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof is for use or administration in the treatment of any of the diseases, disorders, or conditions described herein.

[0131] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders. For intranasal administration or administration by inhalation, the compositions of the present application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the subject, or as an aerosol spray presentation from a pressurized container or nebulizer. Aerosol compositions typically contain a solution or fine suspension of the compositions of the present application in a physiologically acceptable aqueous or non-aqueous solvent, and are usually provided in single or multiple doses in a sterile form in a sealed container, usually in the form of a cartridge or refill for use with an atomizing device, for example. Alternatively, the sealed container is an integrated dispensing device, such as a single-dose nasal inhaler or aerosol dispenser, with a metering valve intended for disposal after use. When the dosage form includes an aerosol dispenser, it includes a propellant, which is, for example, a compressed gas, such as compressed air, or an organic propellant, such as a fluorochlorohydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the composition of the present application. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are formulated, for example, containing a powder mix of the composition of the present application and a suitable powder base, such as lactose or starch. The aerosol dosage form can also take the form of a pump-atomiser.

[0132] In some embodiments, an intranasal pharmaceutical composition comprising a non-racemic mixture of a compound of Formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof is formulated as an aerosol for use with a pump sprayer.

[0133] In some embodiments, the intranasal pharmaceutical composition comprising the non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates is a powder. In some embodiments, the powder is a dry powder. In some embodiments, the dry powder is formulated to be reconstituted with a suitable vehicle before use or administration. In some embodiments, the suitable vehicle is sterile pyrogen-free water.

[0134] In some embodiments, the powder is formulated for use or administration in an inhaler or insufflator. Thus, in some embodiments, the dry powder is formulated for use or administration in capsules and cartridges for use in an inhaler or insufflator.

[0135] In some embodiments, the dry powder further comprises a suitable powder base, hi some embodiments, the suitable powder base comprises lactose or starch.

[0136] In some embodiments, the intranasal pharmaceutical composition comprising a non-racemic mixture of the compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof further comprises water. Thus, in some embodiments, the intranasal pharmaceutical composition comprising a non-racemic mixture of the compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof further comprises water and is an aqueous intranasal pharmaceutical composition.

[0137] In some embodiments, the intranasal pharmaceutical composition comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof is a solution, suspension or emulsion. In some embodiments, the intranasal pharmaceutical composition comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof is a solution.

[0138] In some embodiments, the aqueous intranasal pharmaceutical composition comprising a non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates is formulated for administration to the nose in the form of drops. In some embodiments, the aqueous intranasal pharmaceutical composition comprising a non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates is formulated for administration as a nasal spray. In some embodiments, the nasal spray is delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray presentation from a pressurized container or nebulizer. In some embodiments, the aqueous intranasal pharmaceutical composition comprising a non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates is formulated as an aerosol for use with a pump sprayer.

[0139] In some embodiments, water is present in the intranasal pharmaceutical composition in an amount of about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 33% to about 75%, about 55% to about 70%, or about 55% to about 65% by weight of the composition. In some embodiments, water is present in an amount of about 50%, about 60%, about 65%, or about 70% by weight of the composition. In some embodiments, water is present in an amount of about 55% to about 65% by weight of the composition. In some embodiments, water is about 60% by weight of the composition.

[0140] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, in which the compositions of the present application are formulated with a carrier such as sugar, acacia, tragacanth, or gelatin, and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.

[0141] In some embodiments, the compositions of the present application are formulated for sublingual administration or use.

[0142] Thus, in some embodiments, the present application also includes sublingual compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof.

[0143] [ka]

[0144] In the formula, R 1 is CH 3 or CH 2 CH 3 and (R)-I or a salt and / or solvate thereof is present in the composition in a greater amount as an enantiomeric equivalent compared to (S)-I or a salt and / or solvate thereof.

[0145] In some embodiments, the amount or enantiomeric equivalent of a compound in a non-racemic mixture in the sublingual composition of the present application is as described above.

[0146] In some embodiments, the sublingual composition comprising the non-racemic mixture is used to treat any of the diseases, disorders, or conditions described herein.

[0147] In some embodiments, the sublingual composition is formulated as a tablet, drop, strip, spray, lozenge, or effervescent tablet.

[0148] Suppository forms of the compositions of the present application are useful for vaginal, urethral and rectal administration. Such suppositories are generally constructed from a mixture of materials that are solid at room temperature but melt at body temperature. Materials commonly used to make such vehicles include, but are not limited to, theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. For further discussion of suppository dosage forms, see, for example, Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533.

[0149] In some embodiments, the compositions of the present application comprise from about 40 mg to about 180 mg of both the compound of formula (R)-I and the compound of formula (S)-I and / or salts and / or solvates thereof. In some embodiments, the compositions of the present application comprise 40 mg, 60 mg, 75 mg, 80 mg, 100 mg, 120 mg, or 125 mg of both the compound of formula (R)-I and the compound of formula (S)-I and / or salts and / or solvates thereof. In some embodiments, depending on the mode of administration, the compositions of the present application are pharmaceutical compositions comprising from about 0.05% to about 99% by weight or from about 0.10% to about 70% by weight of both the compound of formula (R)-I and the compound of formula (S)-I and / or salts and / or solvates thereof and from about 1% to about 99.95% by weight or from about 30% to about 99.90% by weight of one or more pharma- ceutical acceptable carriers, all weight percentages being based on the total composition.

[0150] In some embodiments, the compound of formula (R)-I and the compound of formula (S)-I and / or salts and / or solvates thereof are present in the composition in an effective amount, e.g., an effective amount for treating or preventing a disease, disorder, or condition that would benefit from treatment with a racemic mixture of the compound of formula I and / or a pharma- ceutical acceptable salt and / or solvate thereof, or that would benefit from psychotherapy in combination with a racemic mixture of the compound of formula I and / or a pharma- ceutical acceptable salt and / or solvate thereof. In some embodiments, the effective amount is determined as described in the Methods and Uses section below.

[0151] In some embodiments, the compositions of the present application are pharmaceutical compositions comprising an additional therapeutic agent and, optionally, one or more pharma- ceutical acceptable carriers. In some embodiments, the additional therapeutic agent is a known agent useful for treating a disease, disorder, or condition that would benefit from treatment with a racemic mixture of the compound of formula I and / or its pharma- ceutical acceptable salts and / or solvates, or that would benefit from treatment with psychotherapy in combination with a racemic mixture of the compound of formula I and / or its pharma- ceutical acceptable salts and / or solvates.

[0152] III. Methods and Uses of the Present Application (i) Methods and Uses of the Compositions of the Present Application In some embodiments, the compositions of the present application, including pharmaceutical compositions, can be used in methods to reduce adverse side effects of treatment with a racemic mixture of a compound of formula I or a pharma- ceutically acceptable salt and / or solvate thereof.

[0153] [ka]

[0154] During the ceremony, R 1 CH 3 and C.H. 2 CH 3 is selected from The methods include administering to a subject in need thereof a therapeutically effective amount of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof as described above.

[0155] The present application further includes the use of one or more compositions comprising a non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates as described above and (S)-I or its salts and / or solvates for reducing the adverse side effects of treatment with a racemic mixture of formula I or a pharmacokinetically acceptable salt and / or solvate thereof, the use of one or more compositions comprising a non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates as described above and (S)-I or its salts and / or solvates for preparing a medicament for reducing the adverse side effects of treatment with a racemic mixture of formula I or a pharmacokinetically acceptable salt and / or solvate thereof, and one or more compositions comprising a non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates as described above and (S)-I or its salts and / or solvates for use in reducing the adverse side effects of treatment with a racemic mixture of formula I or a pharmacokinetically acceptable salt and / or solvate thereof.

[0156] In some embodiments, the adverse side effects are selected from one or more of neurotoxicity, hyperthermia, and substance use disorder. In some embodiments, the substance use disorder is drug abuse or drug dependence. In some embodiments, the substance use disorder is drug abuse of the compound of formula I.

[0157] In some embodiments, the adverse side effects are selected from one or more of hyperthermia and neurotoxicity.

[0158] Reports suggest that long-term use of MDMA can result in cardiac valve fibrosis and dysfunction, such as valvular heart disease (VHD) (Setola et al., Mol. Pharmacol. 63:1223-1229, 2003). Thus, in some embodiments, the adverse side effect is cardiotoxicity. In some embodiments, the cardiotoxicity is cardiac valve fibrosis and dysfunction. In some embodiments, the cardiotoxicity is valvular heart disease. Thus, in some embodiments, the adverse side effect is valvular heart disease.

[0159] The present application also includes methods of treating diseases, disorders, or conditions that benefit from treatment with a racemic mixture of a compound of Formula I, or a pharma- ceutical acceptable salt and / or solvate thereof.

[0160] [ka]

[0161] During the ceremony, R 1 CH 3 and C.H. 2 CH 3 is selected from The methods include administering to a subject in need thereof a therapeutically effective amount of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof as described above.

[0162] The present application further relates to the use of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof as described above for treating a disease, disorder or condition that would benefit from treatment with a racemic mixture of a compound of formula I or a pharma- ceutical acceptable salt and / or solvate thereof; the use of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof as described above for the preparation of a medicament for treating a disease, disorder or condition that would benefit from treatment with a racemic mixture of a compound of formula I or a pharma- ceutical acceptable salt and / or solvate thereof as described above; The present invention also includes the use of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof as described above with (S)-I or a salt and / or solvate thereof, as well as one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof as described above with (S)-I or a salt and / or solvate thereof for use in treating a disease, disorder or condition that would benefit from treatment with a racemic mixture of a compound of formula I or a pharma- ceutically acceptable salt and / or solvate thereof.

[0163] In some embodiments, R 1 CH 3 and the compound of formula I in the methods and uses defined above is racemic 3,4-methylenedioxymethamphetamine (MDMA).

[0164] In some embodiments, R 1 CH 2 CH 3 and the compound of formula I in the methods and uses defined above is racemic N-methyl-1,3-benzodioxolylbutanamine (MBDB).

[0165] The applicant has shown that S(+)-MDMA and racemic compositions of MDMA induce a dose-dependent increase in temperature in BTBR mice. However, exemplary compositions including compounds of formula (R)-I or salts and / or solvates thereof and non-racemic mixtures of (S)-I or salts and / or solvates thereof and compositions of pure R(-)-MDMA did not induce a significant effect on core temperature. Hyperthermia is known to result in cell damage and neurotoxicity (Walter and Carraretto, Crit Care. 2016 Jul 14; 20(1): 199).

[0166] Thus, in some embodiments, administration or use of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof as described above results in fewer adverse side effects compared to treatment with a racemic mixture of a compound of formula I or a pharma- ceutically acceptable salt and / or solvate thereof.

[0167] Thus, in some embodiments, the present application includes methods of treating a disease, disorder, or condition that would benefit from treatment with a racemic mixture of a compound of formula I, or a pharma- ceutical acceptable salt and / or solvate thereof.

[0168] [ka]

[0169] During the ceremony, R 1 CH 3 and C.H. 2 CH 3 is selected from The method comprises administering to a subject in need thereof a therapeutically effective amount of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof as described above; The methods further include fewer adverse side effects as compared to treatment with a racemic mixture of the compound of formula I, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0170] The present application further relates to the use of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof as described above, for treating a disease, disorder or condition that would benefit from treatment with a racemic mixture of a compound of formula I or a pharmacokinetic or kinetically acceptable salt and / or solvate thereof, which would have fewer adverse side effects compared to treatment with a racemic mixture of a compound of formula I or a pharmacokinetic or kinetically acceptable salt and / or solvate thereof, for treating a disease, disorder or condition that would benefit from treatment with a racemic mixture of a compound of formula I or a pharmacokinetic or kinetically acceptable salt and / or solvate thereof, which would have fewer adverse side effects compared to treatment with a racemic mixture of a compound of formula I or a pharmacokinetic or kinetically acceptable salt and / or solvate thereof, and the use of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof as described above and (S)-I or a salt and / or solvate thereof for the preparation of a medicament having fewer adverse side effects as compared to treatment with a racemic mixture of a compound of formula I or a pharma- ceutical acceptable salt and / or solvate thereof, as well as one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof as described above and (S)-I or a salt and / or solvate thereof for use in treating a disease, disorder or condition that benefits from treatment with a racemic mixture of a compound of formula I or a pharma-ceutical acceptable salt and / or solvate thereof and having reduced adverse side effects as compared to treatment with a racemic mixture of a compound of formula I or a pharma-ceutical acceptable salt and / or solvate thereof.

[0171] In some embodiments, the adverse side effects are selected from one or more of neurotoxicity, hyperthermia, and substance use disorder. In some embodiments, the substance use disorder is drug abuse or drug dependence. In some embodiments, the substance use disorder is drug abuse of the compound of formula I.

[0172] In some embodiments, the adverse side effect is selected from one or more of hyperthermia and neurotoxicity, hi some embodiments, the adverse side effect is hyperthermia.

[0173] In some embodiments, the disease, disorder or condition that would benefit from treatment with a racemic mixture of a compound of formula I or a pharma- ceutically acceptable salt and / or solvate thereof is any disease, disorder or condition that would benefit from psychotherapy, including, but not limited to, one or more of post-traumatic stress disorder (PTSD), social anxiety disorder, depression, alcohol addiction, and eating disorders.

[0174] In some embodiments, one or more compositions comprising a non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates are administered or used in combination with psychotherapy to treat a disease, disorder, or condition. In some embodiments, the one or more compositions improve the effectiveness of psychotherapy. In some embodiments, the psychotherapy is for a psychiatric disorder.

[0175] In some embodiments, the disease, disorder or condition that benefits from treatment with the racemic mixture of the compound of formula I or its pharma- ceutically acceptable salt and / or solvate is one or more psychiatric disorders. In some embodiments, the one or more psychiatric disorders are selected from one or more of anxiety disorders, mood disorders, developmental disorders, substance use disorders and addictions, eating disorders, personality disorders and psychotic disorders. In some embodiments, the substance use disorder is drug abuse or drug dependence.

[0176] In some embodiments, the anxiety disorder is selected from one or more of obsessive-compulsive disorder (OCD), social anxiety disorder, phobia, panic disorder, and post-traumatic stress disorder (PTSD). In some embodiments, the anxiety disorder is social anxiety disorder. In some embodiments, the anxiety disorder is PTSD.

[0177] In some embodiments, the mood disorder is selected from one or both of depression and bipolar disorder.

[0178] In some embodiments, the developmental disorder is selected from autism spectrum disorder (ASD). In some embodiments, the developmental disorder is Asperger's syndrome.

[0179] In some embodiments, the substance use disorder and addiction is selected from one or more of alcoholism, drug abuse, drug addiction, and compulsive gambling. In some embodiments, the drug addiction is opioid addiction. In some embodiments, the substance use disorder is opioid use disorder.

[0180] In some embodiments, the eating disorder is selected from anorexia and bulimia.

[0181] In some embodiments, the personality disorder is selected from borderline personality disorder and dependent personality disorder.

[0182] In some embodiments, the psychotic disorder is selected from schizophrenia and other disorders that cause detachment from reality.

[0183] In some embodiments, the one or more psychiatric disorders are selected from one or more of autism spectrum disorder (ASD), depression, and substance abuse. In some embodiments, the depression is clinical depression, for example in a palliative care subject.

[0184] In some embodiments, the one or more psychiatric disorders are selected from post-traumatic stress disorder (PTSD), eating disorders, and alcoholism. In some embodiments, the one or more psychiatric disorders is post-traumatic stress disorder (PTSD).

[0185] In some embodiments, the one or more psychiatric disorders are selected from autism spectrum disorder (ASD), depression, and substance use disorder. In some embodiments, the depression is clinical depression, for example in palliative care subjects. In some embodiments, the substance use disorder is opioid use disorder.

[0186] In some embodiments, the disease, disorder or condition that would benefit from treatment with a racemic mixture of a compound of formula I, or a pharma- ceutically acceptable salt and / or solvate thereof, is an autism spectrum disorder.

[0187] In some embodiments, the autism spectrum disorder is selected from autism, Asperger's syndrome, childhood disintegrative disorder, Rett syndrome, and pervasive developmental disorder not otherwise specified.

[0188] The present application also includes a method of treating one or more symptoms of autism spectrum disorder, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof as described above.

[0189] The present application further includes the use of one or more compositions comprising a non-racemic mixture of the compound of formula (R)-I or a salt and / or solvate thereof as described above and (S)-I or a salt and / or solvate thereof for treating one or more symptoms of autism spectrum disorder, the use of one or more compositions comprising a non-racemic mixture of the compound of formula (R)-I or a salt and / or solvate thereof as described above and (S)-I or a salt and / or solvate thereof for preparing a medicament for treating one or more symptoms of autism spectrum disorder, and one or more compositions comprising a non-racemic mixture of the compound of formula (R)-I or a salt and / or solvate thereof as described above and (S)-I or a salt and / or solvate thereof for use in treating one or more symptoms of autism spectrum disorder.

[0190] In some embodiments, the one or more symptoms of an autism spectrum disorder are selected from generalized anxiety, clinical anxiety, irritability, inappropriate speech, stereotypies, social withdrawal, repetitive behaviors, and hyperactivity.

[0191] In some embodiments, one or more symptoms of autism spectrum disorder are selected from stereotypy and social withdrawal. In some embodiments, one or more symptoms of autism spectrum disorder are stereotypy. In some embodiments, one or more symptoms of autism spectrum disorder are social withdrawal. Thus, in some embodiments, the composition comprising the non-racemic mixture of the compound of formula (R)-I or its salt and / or solvate and (S)-I or its salt and / or solvate above is for use in promoting prosocial activity.

[0192] The applicant has shown that a composition comprising a non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates promotes prosocial behavior in an in vivo mouse model of autism spectrum disorder. It has further been shown that a composition comprising a non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates does not affect locomotor activity in a mouse model of autism spectrum disorder. The applicant has shown that racemic compositions of S(+)-MDMA and MDMA induce a dose-dependent increase in temperature in BTBR mice. However, an exemplary composition comprising a non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates and a composition of pure R(-)-MDMA did not induce a significant effect on core temperature. Hyperthermia is known to cause cell damage and neurotoxicity (Walter and Carraretto, Crit Care. 2016 Jul 14;20(1):199)

[0193] Furthermore, it has been shown that mouse stereotypies or hyperstimulation are observed in mice administered S-MDMA and high doses of racemic MDMA, but not in compositions comprising non-racemic mixtures of the compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof as described above.

[0194] Thus, in some embodiments, the administration or use of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof described above to treat one or more symptoms of an autism spectrum disorder results in fewer adverse side effects compared to treatment with a racemic mixture of a compound of formula I or a pharma- ceutically acceptable salt and / or solvate thereof.

[0195] Accordingly, the present application also includes methods of treating one or more symptoms of autism spectrum disorder with fewer adverse side effects as compared to treatment with a racemic mixture of a compound of formula I or a pharma- ceutically acceptable salt and / or solvate thereof.

[0196] [ka]

[0197] During the ceremony, R 1 CH 3 and C.H. 2 CH 3 is selected from The methods include administering to a subject in need thereof a therapeutically effective amount of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof as described above.

[0198] The present application further relates to the use of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof as described above, for treating one or more symptoms of autism spectrum disorder and having fewer adverse side effects as compared to treatment with a racemic mixture of a compound of formula I or a pharma- ceutical acceptable salt and / or solvate thereof; and the preparation of a medicament for treating one or more symptoms of autism spectrum disorder and having fewer adverse side effects as compared to treatment with a racemic mixture of a compound of formula I or a pharma-ceutical acceptable salt and / or solvate thereof. and one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof as described above and (S)-I or a salt and / or solvate thereof for use in treating one or more symptoms of autism spectrum disorder and reducing adverse side effects compared to treatment with a racemic mixture of a compound of formula I or a pharmacologic agent.

[0199] In some embodiments, the one or more symptoms of autism spectrum disorder are selected from stereotypies and social withdrawal, and the adverse side effects are selected from hyperthermia, stereotypies, and neurotoxicity. In some embodiments, the one or more symptoms of autism spectrum disorder are selected from stereotypies and social withdrawal, and the adverse side effects are selected from hyperthermia and neurotoxicity. In some embodiments, the one or more symptoms of autism spectrum disorder are selected from stereotypies and social withdrawal, and the adverse side effects are selected from hyperthermia.

[0200] In some embodiments, autism spectrum disorder, as defined by DSM-IV, includes one or more symptoms selected from the following: (i) qualitative impairment in social interaction; (ii) qualitative impairment in communication; and (iii) restricted, repetitive and stereotyped patterns of behaviors, interests and activities.

[0201] In some embodiments, the one or more symptoms are selected from a qualitative impairment in social interaction.

[0202] In some embodiments, the qualitative impairment in social interaction includes one or more of: (a) a marked impairment in the use of multiple non-verbal behaviors, including gaze, facial expression, body posture, and gestures, to regulate social interactions; an inability to form peer relationships appropriate to developmental level; (b) a lack of initiative to share enjoyment, interests, or achievements with others (e.g., by a lack of showing, bringing, or pointing out objects of interest); or (c) a lack of social or emotional reciprocity.

[0203] In some embodiments, the qualitative impairments in communication include one or more of: delayed or complete lack of development of spoken language (without attempts to compensate through alternative modes of communication such as gestures or body language); in individuals with adequate speech, significant impairment in the ability to initiate or sustain conversation with others; stereotyped and repetitive use of language or idiosyncratic language; and lack of varied and spontaneous pretend or social imitative play appropriate to the developmental level.

[0204] In some embodiments, restricted, repetitive and stereotyped patterns of behavior, interests, and activities include one or more of the following: comprehensive preoccupation with one or more stereotyped and restricted interest patterns that are abnormal in either intensity or concentration; apparently inflexible adherence to specific non-functional routines or rituals; stereotyped and repetitive motor habits (e.g., hand or finger flaps or twists or complex whole-body movements); persistent preoccupation with parts of an object.

[0205] In some embodiments, one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof, as described above, are administered or used as a second agent or "add-on" therapy.

[0206] In some embodiments, one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof, as described above, are administered before, during and / or after psychotherapy. In some embodiments, one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof, as described above, and (S)-I or a salt and / or solvate thereof, as described above, are administered during and / or after psychotherapy.

[0207] In some embodiments, the psychotherapy is selected from behavioral psychotherapy, exposure-based psychotherapy, cognitive psychotherapy, and psychodynamically-oriented psychotherapy.

[0208] In some embodiments, the disease, disorder, or condition that would benefit from treatment with a racemic mixture of the compound of formula I or a pharma- ceutically acceptable salt and / or solvate thereof is any disease, disorder, or condition that would benefit from treatment with L-3,4-dihydroxyphenylalanine (L-DOPA).

[0209] In some embodiments, one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates are administered or used in combination with L-DOPA to treat a disease, disorder, or condition that benefits from treatment with L-DOPA. In some embodiments, one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates improve the efficacy of L-DOPA. In some embodiments, one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates are administered or used in combination with L-DOPA to improve the efficacy of L-DOPA.

[0210] In some embodiments, the disease, disorder or condition that would benefit from treatment with L-DOPA is Parkinson's disease.

[0211] The present application also includes methods for treating Parkinson's disease, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compositions comprising a non-racemic mixture of the compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof as described above.

[0212] The present application further includes the use of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof as described above and (S)-I or a salt and / or solvate thereof for treating Parkinson's disease, the use of one or more compositions of the present application for preparing a medicament for treating Parkinson's disease, and one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof as described above and (S)-I or a salt and / or solvate thereof for use in treating Parkinson's disease.

[0213] In some embodiments, one or more compositions comprising a non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates are administered or used in combination with L-DOPA to treat Parkinson's disease. In some embodiments, one or more compositions improve the effectiveness of L-DOPA to treat Parkinson's disease. In some embodiments, one or more compositions comprising a non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates are administered or used in combination with L-DOPA to improve the effectiveness of L-DOPA to treat Parkinson's disease.

[0214] In some embodiments, one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof improve the efficacy of L-DOPA by reducing L-DOPA-induced dyskinesia.

[0215] Thus, in some embodiments, the disease, disorder, or condition that would benefit from treatment with a racemic mixture of a compound of formula I or a pharma- ceutically acceptable salt and / or solvate thereof is dyskinesia, hi some embodiments, the dyskinesia is L-DOPA-induced dyskinesia.

[0216] In some embodiments, one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof improve the efficacy of L-DOPA by increasing the duration of the anti-Parkinson's benefit (e.g., on-time) of L-DOPA. In some embodiments, one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof improve the efficacy of L-DOPA by increasing the duration of the anti-Parkinson's benefit of L-DOPA without disabling dyskinesias.

[0217] In some embodiments, one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof improve the efficacy of L-DOPA by reducing L-DOPA-induced Parkinson's psychosis.

[0218] Thus, in some embodiments, the disease, disorder or condition that would benefit from treatment with a racemic mixture of a compound of formula I or a pharma- ceutically acceptable salt and / or solvate thereof is L-DOPA-induced Parkinson's psychosis.

[0219] "Reducing L-DOPA-induced dyskinesia" or "reducing L-DOPA-induced Parkinson's psychosis" refers to any reduction in the magnitude, whether detectable or undetectable, of dyskinesia, stabilization (i.e., not worsening), delay or slowing of progression, amelioration or alleviation, and remission (whether partial or total), in the presence of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof, as described above, and (S)-I or a salt and / or solvate thereof, as compared to otherwise identical conditions, except in the absence of one or more compositions of the present application.

[0220] "Increasing the duration of the anti-Parkinson's effect of L-DOPA" means any increase in the duration of the anti-Parkinson's effect of L-DOPA compared to otherwise identical conditions except in the absence of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof as described above.

[0221] "Increasing the duration of the anti-Parkinsonian effect of L-DOPA without disabling dyskinesias" means any increase in the duration of the anti-Parkinsonian effect of L-DOPA without disabling dyskinesias compared to otherwise identical conditions except in the absence of one or more compositions comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof as described above.

[0222] The skilled artisan will appreciate that methods for the assessment of L-DOPA induced dyskinesia and / or psychosis are well known in the art, such as those found in, for example, Fox et al., 2006 Arch Neurol 63:1343-1344; Gomez-Ramirez et al., 2006, Mov Disord 21:839-846; Visanji et al., 2006, Mov Disord 21:1879-1891; Huot et al., Journal of Neuroscience, 2011, 31(19)7190-7198, and Fox et al., 2010 Can J Neurol Sci 37:86-95).

[0223] In some embodiments, the amount of a given composition comprising a non-racemic mixture of a compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof, as described above, that corresponds to an effective amount will vary depending on factors such as the given composition(s), pharmaceutical formulation, route of administration, type of condition, disease or disorder, identity of the subject being treated, and the like, but can nevertheless be routinely determined by one of skill in the art. In one embodiment, an effective amount is an amount that manifests as an improvement or reduction in symptoms of any disease, disorder or condition following treatment therewith, particularly compared to symptoms of the disease, disorder or condition without treatment.

[0224] In some embodiments, the composition comprising the non-racemic mixture of the compound of formula (R)-I or its salt and / or solvate and (S)-I or its salt and / or solvate is administered at least once a week. In some embodiments, the composition comprising the non-racemic mixture of the compound of formula (R)-I or its salt and / or solvate and (S)-I or its salt and / or solvate is administered about once every two weeks, about once every three weeks, or about once a month. In some embodiments, the composition comprising the non-racemic mixture of the compound of formula (R)-I or its salt and / or solvate and (S)-I or its salt and / or solvate is administered about once a week to about once a day. In some embodiments, the composition of the present application is administered two, three, four, five, or six times a day. The length of the treatment period depends on various factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of the composition applied, and / or a combination thereof.

[0225] It will also be understood that the effective dosage of the composition comprising the non-racemic mixture of the compound of formula (R)-I or its salt and / or solvate and (S)-I or its salt and / or solvate used for treatment may increase or decrease over the course of a particular treatment regimen. Changes in dosage may occur and be evident by standard diagnostic assays known in the art. In some cases, long-term administration is required. For example, the composition comprising the non-racemic mixture of the compound of formula (R)-I or its salt and / or solvate and (S)-I or its salt and / or solvate is administered to a subject in an amount and for a period sufficient to treat the subject.

[0226] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat. Thus, the compositions, methods and uses of the present application are directed to both human and veterinary diseases, disorders and conditions.

[0227] The composition comprising the non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates described above is used alone or in combination with other known agents useful for treating diseases, disorders or conditions that benefit from psychotherapeutic treatment. When used in combination with other agents useful for treating diseases, disorders or conditions that benefit from psychotherapeutic treatment, it is an embodiment in which the composition comprising the non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates described above is administered contemporaneously with these agents. As used herein, "contemporaneous administration" of two substances to a subject means providing each of the two substances such that both of them are active in the individual at the same time. The exact details of administration depend on the pharmacokinetics of the substances in the presence of each other and may include administering the substances within a few hours of each other, or even administering one substance within 24 hours of the other, if the pharmacokinetics are appropriate. Designing an appropriate dosing regimen is routine for one of ordinary skill in the art. In certain embodiments, the agents are administered substantially simultaneously, i.e., within minutes of each other, or in a single composition containing all the agents. A further embodiment of the present application is that the combination of agents is administered to the subject asynchronously.

[0228] The dosage of the composition comprising the non-racemic mixture of the compound of formula (R)-I or its salts and / or solvates and (S)-I or its salts and / or solvates described above varies depending on many factors, such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of symptoms, the frequency of treatment and type of concurrent treatment, if any, and the clearance rate of the compound in the subject being treated. Those skilled in the art can determine the appropriate dosage based on the above factors. In some embodiments, the composition of the present application is initially administered at an appropriate dosage that is adjusted as necessary depending on the clinical response.

[0229] (ii) Methods and Uses of (R)-MDMA The R enantiomer of MDMA ((R)-MDMA) has been shown to have an improved toxicological profile while retaining the therapeutic efficacy of MDMA racemate.

[0230] Thus, (R)-MDMA can be used in a method that has fewer adverse side effects of treatment with racemic MDMA or a pharma- ceutically acceptable salt and / or solvate thereof, the method comprising administering a therapeutically effective amount of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof to a subject in need thereof.

[0231] The application further includes the use of (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof for reducing the adverse side effects of treatment with racemic MDMA or a pharma- ceutical acceptable salt and / or solvate thereof; the use of (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof for preparing a medicament for reducing the adverse side effects of treatment with racemic MDMA or a pharma- ceutical acceptable salt and / or solvate thereof, and the use of (R)-MDMA for use in reducing the adverse side effects of treatment with racemic MDMA or a pharma- ceutical acceptable salt and / or solvate thereof.

[0232] In some embodiments, the adverse side effects are selected from one or more of neurotoxicity, hyperthermia, and substance use disorder. In some embodiments, the substance use disorder is drug abuse or drug dependence. In some embodiments, the substance use disorder is drug abuse of the compound of formula I.

[0233] Thus, in some embodiments, the adverse side effects are one or more of hyperthermia and neurotoxicity.

[0234] Reports suggest that long-term use of MDMA may result in cardiac valve fibrosis and dysfunction, such as valvular heart disease (VHD).Accordingly, in some embodiments, the adverse side effect is cardiotoxicity.In some embodiments, the cardiotoxicity is cardiac valve fibrosis and dysfunction.In some embodiments, the cardiotoxicity is valvular heart disease.Accordingly, in some embodiments, the adverse side effect is valvular heart disease.

[0235] Thus, (R)-MDMA may be useful, for example, in the treatment of a variety of diseases, disorders or conditions that would benefit from treatment with racemic MDMA or a pharma- ceutically acceptable salt and / or solvate thereof.

[0236] Accordingly, the present application also includes a method for treating a disease, disorder or condition that would benefit from treatment with racemic MDMA, or a pharma- ceutically acceptable salt and / or solvate thereof, comprising administering a therapeutically effective amount of (R)-MDMA, or a pharma- ceutically acceptable salt and / or solvate thereof, to a subject in need thereof.

[0237] The application further includes the use of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof for treating a disease, disorder or condition that would benefit from treatment with racemic MDMA or a pharma- ceutically acceptable salt and / or solvate thereof, the use of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof for the preparation of a medicament for treating a disease, disorder or condition that would benefit from treatment with racemic MDMA or a pharma- ceutically acceptable salt and / or solvate thereof, and (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof for use to treat a disease, disorder or condition that would benefit from treatment with racemic MDMA or a pharma- ceutically acceptable salt and / or solvate thereof.

[0238] The applicant has shown that racemic compositions of S(+)-MDMA and MDMA induce a dose-dependent increase in temperature in BTBR mice. However, exemplary compositions including non-racemic mixtures of the compound of formula (R)-I or its salts and / or solvates with (S)-I or its salts and / or solvates and compositions of pure R(-)-MDMA did not induce a significant effect on core temperature. Hyperthermia is known to result in cell damage and neurotoxicity (Walter and Carraretto, Crit Care. 2016 Jul 14; 20(1): 199).

[0239] In some embodiments, administration or use of (R)-MDMA, or a pharma- ceutically acceptable salt and / or solvate thereof, results in fewer adverse side effects compared to treatment with racemic MDMA, or a pharma-ceutically acceptable salt and / or solvate thereof.

[0240] Thus, in some embodiments, the present application provides a method of treating a disease, disorder, or condition that would benefit from treatment with racemic MDMA or a pharma- ceutical acceptable salt and / or solvate thereof, and that has fewer adverse side effects compared to treatment with racemic MDMA or a pharma- ceutical acceptable salt and / or solvate thereof, comprising: The present invention includes methods comprising administering a therapeutically effective amount of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof to a subject in need thereof.

[0241] The application further includes the use of (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof for treating a disease, disorder or condition that would benefit from treatment with racemic MDMA or a pharma- ceutical acceptable salt and / or solvate thereof, which has fewer adverse side effects compared to treatment with racemic MDMA or a pharma- ceutical acceptable salt and / or solvate thereof, the use of (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof for the preparation of a medicament for treating a disease, disorder or condition that would benefit from treatment with racemic MDMA or a pharma- ceutical acceptable salt and / or solvate thereof, which has fewer adverse side effects compared to treatment with racemic MDMA or a pharma- ceutical acceptable salt and / or solvate thereof, and (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof for use in treating a disease, disorder or condition that would benefit from treatment with racemic MDMA or a pharma- ceutical acceptable salt and / or solvate thereof, which has fewer adverse side effects compared to treatment with racemic MDMA or a pharma- ceutical acceptable salt and / or solvate thereof.

[0242] In some embodiments, the adverse side effects are selected from one or more of neurotoxicity, hyperthermia, and substance use disorder. In some embodiments, the substance use disorder is drug abuse or drug dependence. In some embodiments, the substance use disorder is drug abuse of the compound of formula I.

[0243] In some embodiments, the adverse side effect is selected from one or more of hyperthermia and neurotoxicity, hi some embodiments, the adverse side effect is hyperthermia.

[0244] In some embodiments, the disease, disorder, or condition that would benefit from treatment with racemic MDMA or a pharma- ceutically acceptable salt and / or solvate thereof is any disease, disorder, or condition that would benefit from psychotherapy, including, but not limited to, one or more of post-traumatic stress disorder (PTSD), social anxiety disorder, depression, alcohol addiction, and eating disorders.

[0245] In some embodiments, (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof is administered or used in combination with psychotherapy to treat a disease, disorder, or condition. In some embodiments, (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof improves the effectiveness of psychotherapy. In some embodiments, the psychotherapy is for a psychiatric disorder.

[0246] In some embodiments, the disease, disorder or condition that benefits from treatment with racemic MDMA or its pharma- ceutically acceptable salts and / or solvates is one or more psychiatric disorders. In some embodiments, the one or more psychiatric disorders are selected from one or more of anxiety disorders, mood disorders, developmental disorders, substance use disorders and addictions, eating disorders, personality disorders, and psychotic disorders. In some embodiments, the substance use disorder is drug abuse or drug dependence.

[0247] In some embodiments, the anxiety disorder is selected from one or more of obsessive-compulsive disorder (OCD), social anxiety disorder, phobia, panic disorder, and post-traumatic stress disorder (PTSD). In some embodiments, the anxiety disorder is social anxiety disorder. In some embodiments, the anxiety disorder is PTSD.

[0248] In some embodiments, the mood disorder is selected from one or both of depression and bipolar disorder.

[0249] In some embodiments, the developmental disorder is selected from autism spectrum disorder (ASD). In some embodiments, the developmental disorder is Asperger's syndrome.

[0250] In some embodiments, the substance use disorder and addiction is selected from one or more of alcoholism, drug abuse, drug addiction, and compulsive gambling. In some embodiments, the drug addiction is opioid addiction. In some embodiments, the substance use disorder is opioid use disorder.

[0251] In some embodiments, the eating disorder is selected from anorexia and bulimia.

[0252] In some embodiments, the personality disorder is selected from borderline personality disorder and dependent personality disorder.

[0253] In some embodiments, the psychotic disorder is selected from schizophrenia and other disorders that cause detachment from reality.

[0254] In some embodiments, the one or more psychiatric disorders are selected from one or more of autism spectrum disorder (ASD), depression, and substance abuse. In some embodiments, the depression is clinical depression, for example in a palliative care subject.

[0255] In some embodiments, the one or more psychiatric disorders are selected from post-traumatic stress disorder (PTSD), eating disorders, and alcoholism. In some embodiments, the one or more psychiatric disorders is post-traumatic stress disorder (PTSD).

[0256] In some embodiments, the one or more psychiatric disorders are selected from autism spectrum disorder (ASD), depression, and substance abuse. In some embodiments, the depression is clinical depression, for example in palliative care subjects. In some embodiments, the substance use disorder is opioid use disorder.

[0257] In some embodiments, the disease, disorder or condition that would benefit from treatment with racemic MDMA, or a pharma- ceutically acceptable salt and / or solvate thereof, is an autism spectrum disorder.

[0258] In some embodiments, the autism spectrum disorder is selected from autism, Asperger's syndrome, childhood disintegrative disorder, Rett syndrome, and pervasive developmental disorder not otherwise specified.

[0259] The application also includes a method of treating one or more symptoms of an autism spectrum disorder, comprising administering a therapeutically effective amount of (R)-MDMA, or a pharma- ceutically acceptable salt and / or solvate thereof, to a subject in need thereof.

[0260] The application further includes the use of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof for treating one or more symptoms of autism spectrum disorder, the use of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof for preparing a medicament for treating one or more symptoms of autism spectrum disorder, and (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof for use to treat one or more symptoms of autism spectrum disorder.

[0261] In some embodiments, the one or more symptoms are selected from generalized anxiety, clinical anxiety, irritability, inappropriate speech, stereotypies, social withdrawal, repetitive behaviors, and hyperactivity.

[0262] In some embodiments, one or more symptoms of autism spectrum disorder are selected from stereotypies and social withdrawal. In some embodiments, one or more symptoms of autism spectrum disorder are stereotypies. In some embodiments, one or more symptoms of autism spectrum disorder are social withdrawal. Thus, in some embodiments, (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof is for use in promoting prosocial activity.

[0263] Applicants have shown that (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof promotes prosocial behavior in an in vivo mouse model of autism spectrum disorder. It has further been shown that compositions comprising the above-mentioned (R)-MDMA and non-racemic mixtures of the compound of formula (R)-I or a salt and / or solvate thereof with (S)-I or a salt and / or solvate thereof do not affect locomotor activity in a mouse model of autism spectrum disorder. Applicants have shown that racemic compositions of S(+)-MDMA and MDMA induce a dose-dependent increase in temperature in BTBR mice. However, exemplary compositions comprising the compound of formula (R)-I or a salt and / or solvate thereof and non-racemic mixtures of (S)-I or a salt and / or solvate thereof and compositions of pure R(-)-MDMA did not induce a significant effect on core temperature. Hyperthermia is known to cause cell damage and neurotoxicity (Walter and Carraretto, Crit Care. 2016 Jul 14;20(1):199)

[0264] Furthermore, it has been shown that mouse stereotypies or hyperstimulation are observed in mice administered S-MDMA and high doses of racemic MDMA, but not in compositions comprising non-racemic mixtures of the compound of formula (R)-I or a salt and / or solvate thereof and (S)-I or a salt and / or solvate thereof as described above.

[0265] Thus, in some embodiments, administration or use of (R)-MDMA, or a pharma- ceutically acceptable salt and / or solvate thereof, results in fewer adverse side effects compared to treatment with racemic MDMA, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0266] Thus, the present application also provides a method of treating one or more symptoms of an autism spectrum disorder with fewer adverse side effects compared to treatment with racemic MDMA or a pharma- ceutical acceptable salt and / or solvate thereof, comprising: The present invention includes methods comprising administering a therapeutically effective amount of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof to a subject in need thereof.

[0267] The application further includes uses of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof for treating one or more symptoms of autism spectrum disorder, which have fewer adverse side effects compared to treatment with racemic MDMA or a pharma- ceutically acceptable salt and / or solvate thereof, uses of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof for the preparation of a medicament for treating one or more symptoms of autism spectrum disorder, which have fewer adverse side effects compared to treatment with racemic MDMA or a pharma- ceutically acceptable salt and / or solvate thereof, and (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof for use in treating one or more symptoms of autism spectrum disorder, which have fewer adverse side effects compared to treatment with racemic MDMA or a pharma- ceutically acceptable salt and / or solvate thereof.

[0268] In some embodiments, the one or more symptoms of autism spectrum disorder are selected from stereotypies and social withdrawal, and the adverse side effects are selected from hyperthermia, stereotypies, and neurotoxicity. In some embodiments, the one or more symptoms of autism spectrum disorder are selected from stereotypies and social withdrawal, and the adverse side effects are selected from hyperthermia and neurotoxicity. In some embodiments, the one or more symptoms of autism spectrum disorder are selected from stereotypies and social withdrawal, and the adverse side effects are selected from hyperthermia.

[0269] In some embodiments, autism spectrum disorder, as defined by DSM-IV, includes one or more symptoms selected from the following: (i) qualitative impairment in social interaction; (ii) qualitative impairment in communication; and (iii) restricted, repetitive and stereotyped patterns of behaviors, interests and activities.

[0270] In some embodiments, the one or more symptoms are selected from a qualitative impairment in social interaction.

[0271] In some embodiments, the qualitative impairment in social interaction includes one or more of: (a) a marked impairment in the use of multiple non-verbal behaviors, including gaze, facial expression, body posture, and gestures, to regulate social interactions; an inability to form peer relationships appropriate to developmental level; (b) a lack of initiative to share enjoyment, interests, or achievements with others (e.g., by a lack of showing, bringing, or pointing out objects of interest); or (c) a lack of social or emotional reciprocity.

[0272] In some embodiments, the qualitative impairments in communication include one or more of: delayed or complete lack of development of spoken language (without attempts to compensate through alternative modes of communication such as gestures or body language); in individuals with adequate speech, significant impairment in the ability to initiate or sustain conversation with others; stereotyped and repetitive use of language or idiosyncratic language; and lack of varied and spontaneous pretend or social imitative play appropriate to the developmental level.

[0273] In some embodiments, restricted, repetitive and stereotyped patterns of behavior, interests, and activities include one or more of the following: comprehensive preoccupation with one or more stereotyped and restricted interest patterns that are abnormal in either intensity or concentration; apparently inflexible adherence to specific non-functional routines or rituals; stereotyped and repetitive motor habits (e.g., hand or finger flaps or twists or complex whole-body movements); persistent preoccupation with parts of an object.

[0274] In some embodiments, (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof is administered or used as a second agent or "add-on" therapy.

[0275] In some embodiments, (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof is administered before, during and / or after psychotherapy. In some embodiments, (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof is administered during and / or after psychotherapy.

[0276] In some embodiments, the psychotherapy is selected from behavioral psychotherapy, exposure-based psychotherapy, cognitive psychotherapy, and psychodynamically-oriented psychotherapy.

[0277] The application also includes a method for treating Parkinson's disease comprising administering a therapeutically effective amount of (R)-MDMA, or a pharma- ceutical acceptable salt and / or solvate thereof, to a subject in need thereof.

[0278] The application further includes the use of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof for treating Parkinson's disease, the use of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof for preparing a medicament for treating Parkinson's disease, and (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof for use to treat Parkinson's disease.

[0279] In some embodiments, the (R)-MDMA has an enantiomeric purity of greater than 99%.

[0280] In some embodiments, the amount of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof that corresponds to an effective amount will vary depending on factors such as the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one of skill in the art. In one embodiment, an effective amount is an amount that manifests as an improvement or reduction in the symptoms of any disease, disorder or condition following treatment therewith, particularly as compared to the symptoms of the disease, disorder or condition without treatment.

[0281] In one embodiment, (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof is administered at least once a week. However, in another embodiment, (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof is administered to the subject from about once every two weeks, three weeks, or a month. In another embodiment, (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof is administered from about once a week to about once a day. In another embodiment, (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof is administered 2, 3, 4, 5, or 6 times a day. The length of the treatment period depends on various factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof, and / or combinations thereof. It will also be understood that the effective dosage of (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof used for treatment may increase or decrease over the course of a particular treatment regimen. Dosage variations may occur and be evident by standard diagnostic assays known in the art. In some cases, chronic administration may be necessary. For example, (R)-MDMA or a pharma-ceutically acceptable salt and / or solvate thereof is administered to the subject in an amount and for a duration sufficient to treat the subject.

[0282] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human. In one embodiment, the subject is a non-human animal. In one embodiment, the subject is a dog. In one embodiment, the subject is a cat. Thus, the methods and uses of the present application are directed to both human and veterinary diseases, disorders and conditions.

[0283] (R)-MDMA or its pharma- ceutical acceptable salts and / or solvates are used alone or in combination with other known agents useful for treating diseases, disorders, or conditions that would benefit from psychotherapeutic treatment. When used in combination with other agents useful for treating diseases, disorders, or conditions that would benefit from psychotherapeutic treatment, it is an embodiment in which (R)-MDMA or its pharma- ceutical acceptable salts and / or solvates are administered contemporaneously with these agents. As used herein, "contemporaneous administration" of two agents to a subject means providing each of the two agents such that they are both active in the individual at the same time. The exact details of administration depend on the pharmacokinetics of the two agents in the presence of each other, and may even include administering the two agents within a few hours of each other, or administering one agent within 24 hours of the other, if the pharmacokinetics are appropriate. Designing an appropriate administration regimen is routine for one of ordinary skill in the art. In certain embodiments, the two agents are administered substantially simultaneously, i.e., within minutes of each other, or in a single composition containing both agents. A further embodiment of the present application is that the combination of agents is administered to the subject asynchronously.

[0284] The dosage of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof will vary depending on many factors, such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of symptoms, the frequency of treatment and type of co-treatment, if any, and the clearance rate of (R)-MDMA or a pharma-ceutically acceptable salt and / or solvate thereof in the subject being treated. One of skill in the art will be able to determine the appropriate dosage based on the above factors.

[0285] In some embodiments, the dosage of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof is about 40 mg to about 180 mg. In some embodiments, the dosage of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof is about 40 mg, about 60 mg, about 75 mg, about 80 mg, about 100 mg, about 120 mg, or about 125 mg. In some embodiments, depending on the mode of administration, the compositions of the present application are pharmaceutical compositions comprising about 0.05% to about 99% by weight or about 0.10% to about 70% by weight of (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof and about 1% to about 99.95% by weight or about 30% to about 99.90% by weight of one or more pharma- ceutical acceptable carriers, all weight percentages being based on the total composition.

[0286] (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof is suitably formulated in a conventional manner into a composition using one or more carriers. Accordingly, the present application also includes compositions comprising (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof and a carrier. The compounds of the present application are suitably formulated into pharmaceutical compositions for administration to a subject in a biologically compatible form suitable for in vivo administration. Accordingly, the present application further includes pharmaceutical compositions comprising (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof and a pharma- ceutical acceptable carrier.

[0287] In an embodiment of the application, a pharmaceutical composition of (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof is used for the treatment of any of the diseases, disorders or conditions described herein.

[0288] (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof may be administered to a subject in a variety of forms depending on the route of administration selected, as will be appreciated by those of skill in the art, such as the various dosage forms and routes of administration described in the "Non-racemic Compositions of the Present Application" section above.

[0289] Significant differences in the Cmax of MDMA based on the route of delivery have been observed in rats (Baumann MH et al. Drug Metab Dispos. 2009;37(11):2163-70). At 2 mg / kg, maximum MDMA concentrations were approximately 200 ng / ml via the intraperitoneal (210 ng / ml) and subcutaneous (196 ng / ml) routes, but lower via the oral route (46 ng / ml). At the higher dose (10 mg / kg), the Cmax via the intraperitoneal (2257 ng / ml) and subcutaneous (1130 ng / ml) routes of administration was higher than that via the oral route (966 ng / ml).

[0290] It is also known that the (R)- and (S)-enantiomers of racemic 3,4-methylenedioxymethamphetamine (MDMA) show different dose-concentration curves. MDMA, MDA, DHMA, DHMA sulfate, HMMA, HMMA sulfate, and HMMA glucuronide have been shown to be excreted in substantial amounts in human urine (Schwaninger AE et al., Biochem Pharmacol. 2012;83(1):131-8). After creatinine normalization, statistically significant differences between the two enantiomers ((R)- and (S)- of the individual metabolites) were observed for all compounds except HMMA sulfate. Higher R-enantiomer Cmax was observed for MDMA, DHMA, and HMMA sulfate, whereas the S-enantiomer was higher for DHMA sulfate, HMMA, HMMA glucuronide, and MDA. Error! Reference source not found.

[0291] The oral mucosa is occasionally used as a site of drug absorption. Sublingual administration, in which a tablet or lozenge is completely dissolved in the oral cavity, takes advantage of the permeability of the oral epithelium and is the route of administration for several potent lipophilic drugs, such as nitroglycerin and oxytocin, as well as the oral sedative triazolam.

[0292] MDMA has demonstrated efficacy in Phase 3 trials for treating post-traumatic stress disorder (PTSD) via MDMA-assisted psychotherapy. It has a complex pharmacology and is known to affect multiple receptors in the brain.

[0293] In some embodiments, intranasal administration is believed to provide both direct and indirect routes to the delivery of psychopharmacological agents to the central nervous system (CNS). Direct nose-to-brain transport via the olfactory and trigeminal nerve pathways after intranasal deposition and absorption into the olfactory and respiratory epithelium provides a non-invasive means of avoiding the blood-brain barrier (BBB), which is an obstacle to drug delivery to the CNS. Furthermore, in some embodiments, compared to other routes of administration (e.g., oral administration), intranasal administration offers ease of use, reduced systemic exposure, faster drug onset, increased compliance, and improved bioavailability by avoiding first-pass metabolism (Keller et al., Drug Deliv. and Transl. Res. 12, 735-757 (2022)).

[0294] Thus, in some embodiments, sublingual and intranasal administration avoids drug destruction, in some embodiments, sublingual and intranasal administration avoids drug destruction by bypassing stomach acid and intestinal and hepatic enzymes.

[0295] In some embodiments, sublingual and intranasal absorption is more efficient compared to intestinal uptake, for example, when using oral administration, hi some embodiments, the onset of drug effect using sublingual or intranasal administration is faster compared to the onset of the same drug effect using oral administration.

[0296] In some embodiments, better drug absorption and metabolic profile is achieved using sublingual or intranasal administration compared to oral administration.In some embodiments, liver metabolism is more suppressed using sublingual or intranasal administration compared to oral administration.In some embodiments, a lower dose of active ingredient, e.g. MDMA, is used to achieve a biological effect by sublingual or intranasal administration compared to the dose of active ingredient to achieve the same biological effect by oral administration.In some embodiments, sublingual or intranasal administration provides better bioavailability and a better safety profile for active ingredient, e.g. MDMA, compared to oral administration.

[0297] Thus, in some embodiments, the (R)-MDMA or pharma- ceutically acceptable salts and / or solvates thereof compositions are formulated for intranasal or sublingual administration or use, hi some embodiments, the (R)-MDMA or pharma-ceutically acceptable salts and / or solvates thereof compositions are formulated for intranasal administration or use.

[0298] Thus, in some embodiments, the present application also includes intranasal compositions comprising (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof.

[0299] In some embodiments, the R enantiomer of MDMA ((R)-MDMA) or a pharma- ceutically acceptable salt and / or solvate thereof is as described above.

[0300] In some embodiments, an intranasal composition comprising (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof is for use or administration in the treatment of any of the diseases, disorders, or conditions described herein.

[0301] In some embodiments, intranasal compositions comprising (R)-MDMA or its pharma- ceutically acceptable salts and / or solvates are conveniently formulated as aerosols, drops, gels and powders. For intranasal administration or administration by inhalation, the compositions of the present application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the subject, or as an aerosol spray presentation from a pressurized container or nebulizer. Aerosol compositions typically comprise a solution or fine suspension of the compositions of the present application in a physiologically acceptable aqueous or non-aqueous solvent, and are usually provided in single or multiple doses in sterile form in a sealed container, usually in the form of a cartridge or refill for use with an atomizing device, for example. Alternatively, the sealed container is an integrated dispensing device, such as a single-dose nasal inhaler or aerosol dispenser, with a metering valve intended for disposal after use. When the dosage form comprises an aerosol dispenser, it contains a propellant, which is, for example, a compressed gas, such as compressed air, or an organic propellant, such as a fluorochlorohydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the composition of the present application. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are formulated, for example, containing a powder mix of the composition of the present application and a suitable powder base, such as lactose or starch. The aerosol dosage form can also take the form of a pump-atomiser.

[0302] In some embodiments, an intranasal composition comprising (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof is formulated as an aerosol for use with a pump sprayer.

[0303] In some embodiments, the intranasal composition comprising (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof is a powder. In some embodiments, the powder is a dry powder. In some embodiments, the dry powder is formulated to be reconstituted with a suitable vehicle prior to use or administration. In some embodiments, the suitable vehicle is sterile pyrogen-free water.

[0304] In some embodiments, the powder is formulated for use or administration in an inhaler or insufflator. Thus, in some embodiments, the dry powder is formulated for use or administration in capsules and cartridges for use in an inhaler or insufflator.

[0305] In some embodiments, the dry powder further comprises a suitable powder base, hi some embodiments, the suitable powder base comprises lactose or starch.

[0306] In some embodiments, the intranasal composition comprising (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof further comprises water. Thus, in some embodiments, the intranasal pharmaceutical composition further comprises water and is an aqueous intranasal pharmaceutical composition.

[0307] In some embodiments, the intranasal composition comprising (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof is a solution, suspension, or emulsion. In some embodiments, the intranasal composition comprising (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof is a solution.

[0308] In some embodiments, the aqueous intranasal composition comprising (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof is formulated for administration to the nose in the form of a nasal drop. In some embodiments, the aqueous intranasal composition comprising (R)-MDMA or a pharma- ceutical acceptable salt and / or solvate thereof is formulated for administration as a nasal spray. In some embodiments, the nasal spray is delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray presentation from a pressurized container or nebulizer. In some embodiments, the aqueous intranasal pharmaceutical composition is formulated as an aerosol for use with a pump sprayer.

[0309] In some embodiments, water is present in the intranasal pharmaceutical composition in an amount of about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 33% to about 75%, about 55% to about 70%, or about 55% to about 65% by weight of the composition. In some embodiments, water is present in an amount of about 50%, about 60%, about 65%, or about 70% by weight of the composition. In some embodiments, water is present in an amount of about 55% to about 65% by weight of the composition. In some embodiments, water is about 60% by weight of the composition.

[0310] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, in which the compositions of the present application are formulated with a carrier such as sugar, acacia, tragacanth, or gelatin, and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.

[0311] In some embodiments, the (R)-MDMA or pharma- ceutically acceptable salts and / or solvates thereof compositions are formulated for sublingual administration or use.

[0312] Thus, in some embodiments, the present application also includes sublingual compositions comprising (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof.

[0313] In some embodiments, the sublingual composition (R)-MDMA or a pharma- ceutically acceptable salt and / or solvate thereof is used or administered in the treatment of any of the diseases, disorders, or conditions described herein.

[0314] In some embodiments, the sublingual composition is formulated as a tablet, drop, strip, spray, lozenge, or effervescent tablet. EXAMPLES

[0315] The following non-limiting examples are illustrative of the present application.

[0316] Example 1: Exemplary Compositions of the Present Application Exemplary Composition 1 (ALA001): 90%-99% (R)-MDMA, 1%-10% (S)-MDMA

[0317] Exemplary Composition 2 (ALA002): 80% to 89.9% (R)-MDMA, 10.1% to 20% (S)-MDMA

[0318] Exemplary composition 2(i): 80% (R)-MDMA and 20% (S)-MDMA. 80% (R)-MDMA and 20% (S)-MDMA were dissolved in physiological 0.9%. Exemplary composition 2(i) was tested in the following examples at various doses, for example 3mg / kg and 10mg / kg.

[0319] Exemplary Composition 3 (ALA003): 70% to 79.9% (R)-MDMA, 20.1% to 30% (S)-MDMA

[0320] Exemplary Composition 4 (ALA004): 90%-99% (R)-MBDB, 1%-10% (S)-MBDB

[0321] Exemplary Composition 5 (ALA005): 80% to 89.9% (R)-MBDB, 10.1% to 20% (S)-MBDB

[0322] Exemplary Composition 6 (ALA006): 70% to 79.9% (R)-MBDB, 20.1% to 30% (S)-MBDB

[0323] Exemplary Composition 7: (R)-MDMA (>99% R enantiomer)

[0324] Comparative composition 1: racemic MDMA

[0325] Comparative composition 2: Racemic MBDB

[0326] Comparative composition 3: (S)-MDMA (>99% S enantiomer)

[0327] In the following in vivo studies, all drugs, (R)-MDMA, (S)-MDMA and control drugs were dissolved in 0.9% saline and administered in a constant volume of 1 ml / 100 g body weight.

[0328] Biological Data Example 2: Behavioral Experiments Social Interaction Test The social interaction test, which has been used to test the effects of MDMA, and in particular the prosocial effects of MDMA, is described in Morley and McGregnor Eur J Pharmacol. 2000;408:41-9 and is used to test the exemplary and comparative compositions of the present application.

[0329] Social interaction tests are conducted twice to familiarize subjects (mice) with the test procedure and to screen for aggressive subjects. During the first session, subjects receive an injection of the exemplary composition of the present application, a comparative composition, or saline, and are isolated in a clean cage for 30 minutes. Each subject is then paired with an unfamiliar weight-matched allogeneic mouse from the same treatment group for 10 minutes in a 30x18cm clear plexiglass test chamber. An experimenter is present during the first test day to separate aggressive subjects. Any subjects that are removed are replaced with new naive subjects so that each treatment condition has an equal number of non-aggressive subjects.

[0330] A second test session is conducted 48 hours later using the same pairs, treatments, and procedures, except that the experimenter is not present in the room during testing. Within the testing arena, subjects are free to move around and interact, allowing for a variety of observable behaviors. On the second test day, social pairings are videotaped and the duration of social behaviors is quantified using JWatcher or BORIS (Friard and Gamba, Methods Ecol Evol. 2016;7(11)1325-1330) by an observer blinded to the experimental conditions. The duration of three behaviors is scored: anogenital investigation (sniffing the anogenital area of ​​the conspecific), general investigation (sniffing outside the anogenital area, grooming, and following the conspecific), and adjacent recumbency (side-by-side contact or huddle behavior). These behaviors are averaged for each pair and then summed to generate a total social interaction score, on which statistical analyses are performed.

[0331] Locomotor behavior The effect of the exemplary compositions and comparative compositions of the present application on locomotor activity is tested in a 45x39x37 cm open field chamber with a 16x16 photocell placed 2.5 cm away from the chamber. Mice are treated with the exemplary compositions of the present application, the comparative compositions or saline (n=13 / group) immediately before being placed in the chamber for 1 hour. Testing is performed in a dark, enclosed space. The cumulative beam breaks of adjacent photocells are recorded as a measure of locomotor activity.

[0332] Fear conditioning and extinction The effects of the exemplary and comparative compositions of the present application on conditioned freezing were assessed using an established protocol previously used to test racemic MDMA (Young et al., 2015, Transl Psychiatry. 5:1-8). For consistency with this previous study, C57BL / 6 mice are used in this experiment. Briefly, mice are exposed to induced fear conditioning on day 1, fear extinction training on day 3, and extinction testing on day 4. Induced fear conditioning consists of a single pairing of a conditioned stimulus (CS) tone (80 dB, 4.5 kHz, 30 s) with a non-conditioned stimulus (US) foot shock (1 mA, 2 s). Extinction training occurs 48 h after conditioning in a novel context. (R)-MDMA, (S)-MDMA, or saline (n=6-7 / group) was administered on day 3, 30 min prior to training. Extinction training consists of a suboptimal regimen of 4C(S) tone re-exposures spaced 45 s apart. Extinction tests are performed 24 hours later to determine the lasting effects of the treatment on conditioned freezing. Extinction tests are performed in the same context as training and follow the same procedures, except that no treatment is administered. Throughout these experiments, freezing rates (conditioned responses) are estimated by scoring the presence or absence of non-respiratory movements every 5 seconds.

[0333] Example 3: Neurotoxicity Testing Neurotoxicity administration and tissue collection In a dosing regimen modified from Itzhak et al., Psychopharmacol. 2003;166:241-248, subjects receive a total of four injections of the exemplary composition of the present application, the comparative composition, or saline, administered twice on two consecutive days, two hours apart. Subjects are isolated during treatment and are returned to their home cages two hours after the second daily administration. After treatment, subjects are divided into two groups. 48 hours after the last injection, subjects in group 1 are anesthetized and transcardially perfused with 4% formaldehyde. Their brains are post-fixed overnight, then immersed in 15% sucrose for 48 hours, frozen in chilled methylbutane, sectioned at 35 μm, and stored at −20° C. until analysis by immunohistochemistry. Subjects in group 2 are euthanized by cervical dislocation 14 days after the last injection. Their brains are removed and the prefrontal cortex, striatum and hippocampus are rapidly dissected and stored at -80°C for subsequent analysis by high performance liquid chromatography (HPLC) or Western blot.

[0334] Temperature monitoring The effect of the exemplary and comparative compositions of the present application on body temperature, given twice at 2-hour intervals, is monitored using a rectal thermometer (n=5 / group). Measurements are taken every 30 minutes at ambient room temperature of 22±2° C. During monitoring, mice are separated into individual holding cages.

[0335] Consideration (R)-MDMA is less neurotoxic than a comparative composition containing a racemic mixture of MDMA.

[0336] The exemplary composition of the present application, ALA001, exhibits a better neurotoxicity profile than a comparative composition containing a racemic mixture of MDMA.

[0337] (R)-MDMA is less neurotoxic than the present application's exemplary composition ALA001, but the present application's exemplary composition ALA001 has a subjective psychological experience that is more similar to a comparative composition comprising a racemic mixture of MDMA.

[0338] Example 4: Studies in a rat model Studies in rat models of autism spectrum disorder Introduction Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder defined by two major behavioral clusters. The first cluster of behaviors is defined by deficits in social communication and social interaction, while the second cluster of behaviors consists of repetitive and inflexible patterns of behavior, interests, and thinking. In 2016, the Autism and Developmental Disabilities Monitoring Network estimated the prevalence of ASD to be 1 in 54 children and stated that ASD is 4.3 times more common among boys compared to girls. Over the past few decades, the reported incidence of ASD has increased in the United States, yet the etiology of ASD is poorly understood. To better understand the neurological basis of ASD, rodent models of ASD have been developed for research. BTBR T+Itpr3tf / J mice (BTBR), originally bred for research on insulin resistance, diabetes-induced nephropathy, and phenylketonuria, were identified approximately 10 years ago as exhibiting strong and consistent autism-related behaviors. Thus, the identification of novel drugs that increase sociality and decrease repetitive behaviors in autistic-like BTBR mice and C57BL / 6J (C57) background stocks would be therapeutically useful in the context of ASD. The bald patches frequently seen on the dorsal flank of BTBR mice are due to the repetitive grooming and "barbering" behaviors exhibited by all mice of this strain, consistent with the high rate of self-directed behaviors characteristic of human ASD. Thus, the ability to remain blind to the strain is challenging.

[0339] In the study described in Example 4, male BTBR and C57 mice were used to evaluate the effects of customized compositions comprising racemic 3,4-methylenedioxymethamphetamine (MDMA) (e.g., Comparative Composition 1, MDMA), its constituent S enantiomer (e.g., Comparative Composition 3, (S)-MDMA) and R enantiomer (e.g., Exemplary Composition 7, (R)-MDMA), and non-racemic mixtures of (R)-MDMA or salts and / or solvates thereof and (S)-MDMA or salts and / or solvates thereof, where the (R)-MDMA or salts and / or solvates thereof are present in the composition in a greater amount as enantiomeric equivalents compared to (S)-MDMA or salts and / or solvates thereof (e.g., Exemplary Composition 2(i)), in autism-related assays of social preference, and in studies of the safety and abuse liability of these drugs. Figure 1 provides the two-dimensional molecular structures of methamphetamine (structure on the left) and 3,4-methylenedioxymethamphetamine (MDMA, structure on the right). Pharmacologically, the enantiomers can have very different biological effects, including quantitative differences in potency and efficacy, as well as qualitative differences in mechanism of action or interoceptive effects. In the case of methamphetamine, the S(+)-enantiomer is an abused psychoactive drug with strong and long-lasting psychoactive effects, whereas the R(-)-enantiomer is over 100-fold less potent to induce any of these effects. In the case of MDMA, both enantiomers induce effects distinct from each other but are active at similar doses. Based on their similar chemical structures, methamphetamine was selected as a positive control compound to compare the effects of MDMA in the social preference test. Both compounds were expected to induce locomotor stimulant effects at high doses, whereas methamphetamine was expected not to induce prosocial effects.

[0340] General animal handling Adult male C57 and BTBR mice were shipped to the University of Arkansas for Medical Sciences from Charles River Laboratories and The Jackson Laboratory, respectively. Upon arrival, mice were housed three per cage according to strain with food and water available ad libitum. Mice were allowed to acclimate to the UAMS facility for at least 48 hours before any experimental procedures were performed.

[0341] Drug Administration: All drugs were dissolved in 0.9% saline and administered at a constant volume of 1 ml / 100 g body weight. All drugs utilized in these studies were synthesized as hydrochloric acid (HCl) salts and therefore were weighed as the salt prior to preparation of all solutions. All drugs at all concentrations are readily soluble in aqueous solutions at normal pH. Injections of all drugs were administered intraperitoneally (IP) to mimic pharmacokinetic parameters typical of oral gavage administration without the behavioral disruptive effects of oral gavage stress.

[0342] social preference test method The assay was performed in adult male C57 and BTBR mice (n=6 per group) in a dedicated controlled room with strict control of environmental light, sound, and human contact. The social preference chamber consisted of two polycarbonate boxes (13.5 cm wide x 22.5 cm high x 31.0 cm deep) floored with rough textured black ABS plastic and connected to each other by 1.25 inch PVC T-joints. An infrared light beam emitter / detector array was attached to each intersection of the T-joints with each preference compartment, breaking the light beam as the mouse crossed the apparatus, either upon entry into or exit from each preference compartment. Beam breaks started or stopped a counter on an interfaced computer, allowing for automated collection of time spent in each compartment. At the end of each trial, data were reported as time spent in each compartment (in seconds), number of entries into each compartment, and average time spent in each compartment after entry. The social preference test was performed in replicates, with each test subject completing four different phases, as described below. Between test sessions, the chambers were disinfected by wiping the interior with a disinfectant product provided by the UAMS Department of Laboratory Animal Medicine. At the end of the week (when all phases of the procedure were completed), each apparatus was disassembled and all parts were disinfected. Neither food nor water was available during the social preference session, but was available in the home cage immediately after.

[0343] Phase 1 - Habituation A single habituation session was conducted prior to preference testing, in which each compartment contained an identical empty wire mesh pencil cup (9.0 cm diameter × 10.5 cm height). During this session, mice were weighed, no injections were administered, and subjects were introduced into the T-junction and allowed to explore both preference compartments for 30 min. This habituation session was conducted as a procedural control to allow the animals to become accustomed to the apparatus and to screen for animals with a strong initial bias towards one of the two compartments. A priori exclusion criteria were established such that subjects who spent more than 75% of their total time in one single preference compartment were excluded from further studies, but no subjects in these studies met this exclusion criterion. To prevent weekend testing, habituation sessions were always conducted on Mondays or Tuesdays.

[0344] Stage 2 – Novelty Preference One novelty preference session was conducted the day after the habituation test, in which one compartment contained an empty wire mesh cup and the other compartment contained an identical wire mesh cup with a novel dummy mouse inside. The location of the dummy mouse (left or right compartment) was counterbalanced between subjects. The dummy mouse was constructed from a 2.5 inch length of white 3 / 4 inch PVC pipe with a zip tie attached to one end (to mimic a tail) and two red dots painted on the other end (to mimic eyes). During this session, mice were weighed, injections were administered, and they were returned to their home cage for a 30 minute pretreatment period. Mice were then introduced into the T-junction and allowed to explore both preference compartments for 15 minutes. These tests were conducted as procedural controls to ensure that the observed drug effects were not simply due to an enhancement of the mice's innate novelty preference. Novelty preference sessions were always conducted on Tuesdays or Wednesdays to prevent weekend testing.

[0345] Phase 3 - Social Testing One socialization session was conducted the day after the novelty preference test, in which one compartment contained a wire mesh cup with a dummy mouse inside, and the other compartment contained a male naive NIH Swiss mouse inside a previously empty cup. The wire mesh cup allowed visual, olfactory, auditory, and limited tactile contact, but prevented aggressive behavior that could result in injury. The location of the dummy mouse (left or right compartment) remained the same for each subject as during the novelty test on the previous day, thereby counterbalancing the location of the naive mouse across subjects. The naive NIH Swiss mice were similar in mass and appearance to the dummy PVC mice and were housed in a colony facility separately from the experimental subjects (C57 and BTBR mice). The experimental subjects first encountered the naive mouse when they entered the compartment in which they were housed. During this session, the mice were weighed, administered the same injections as the previous day, and returned to their home cages for a 30-minute pretreatment period. The mice were then introduced into the T-junction and allowed to explore both preference compartments for 15 minutes. Social testing was always conducted on Wednesdays or Thursdays to prevent testing on weekends.

[0346] Stage 4 – Social Novelty Preference One social novelty preference session was conducted the day after social testing, with one compartment containing a wire mesh cup with the same NIH Swiss mouse inside as the previous day (now referred to as the "familiar" mouse) and the other compartment containing a new male naive NIH Swiss mouse inside the cup that had previously contained the dummy mouse during social testing. The wire mesh cup allowed visual, olfactory, auditory, and limited tactile contact, but prevented aggressive behavior that could result in injury. The position of the now familiar NIH Swiss mouse (left or right compartment) remained the same for each subject as during social testing on the previous day, thereby counterbalancing the position of the new naive NIH Swiss mouse across subjects. As before, the new naive NIH Swiss mouse was housed in the colony facility separately from the experimental subjects (C57 and BTBR mice) and was first encountered by the experimental subjects when they entered the compartment in which they were housed. During this session, mice were weighed, administered the same injections as the previous day, and returned to their home cages for a 30-minute pretreatment period. Mice were then introduced into the T-junction and allowed to explore both preferred compartments for 15 min. Social novelty testing was always performed on Thursday or Friday to prevent testing on weekends.

[0347] Social Preference Test Results Drug effects on locomotor activity Quantification of total entries into the preferred compartment provided a surrogate measure of the locomotor stimulating effect of various doses of the different test drugs. Since induction of locomotor stimulating effects provides a preference assessment, this established the limits of the drug dose that could be tested in the social preference procedure (because the mice stopped attending to the social stimuli in each compartment and instead spent their time on locomotor behavior). Locomotor activity varied across the different phases of the social preference test, in part because the habituation session was twice as long (30 min) as the novelty, social and social novelty tests (15 min each), but also because the mice emitted high levels of exploratory behavior in the novel environment. Thus, the number of entries decreased as habituation to the test apparatus increased over successive exposures to the chambers.

[0348] Figure 2 shows the above-mentioned decreasing trend of locomotor activity in C57 (solid bars) and BTBR (open bars) in the absence of any drug injection. Baseline differences in locomotor activity were also observed between C57 and BTBR mice in the absence of drug injection, such that BTBR subjects consistently showed more entries during all stages of the social preference procedure.

[0349] Because baseline activity of C57 and BTBR mice did not change from the social test to the social novelty test (the final test phase when mice were maximally habituated to the apparatus), we focused on drug effects during this phase to determine the locomotor stimulatory effects of various treatments. (Note that although entries were collected for all trials, drug effects on entries in earlier phases may be less reliable due to the confounding influence of changes in habituation to the apparatus between phases.)

[0350] In C57 mice (see FIG. 3, black bars), approximately 20 entries were observed following saline administration.

[0351] Injections of methamphetamine (positive control), racemic MDMA (e.g., Comparative Composition 1) and S(+)-MDMA (e.g., Comparative Composition 3) dose-dependently increased entries to over 150, demonstrating locomotor stimulant effects that confounded the assessment of social preference after 3.0 mg / kg methamphetamine, 10.0 mg / kg racemic MDMA (e.g., Comparative Composition 1) and 10.0 mg / kg S(+)-MDMA (e.g., Comparative Composition 3) (see FIG. 4). In contrast, administration of 10.0 mg / kg R(-)-MDMA (e.g., Exemplary Composition 7) did not increase compartment entries.

[0352] However, in BTBR mice (see open bars in Figure 4, right panel), approximately 40 entries were observed after saline administration, consistent with the greater baseline levels of locomotor activity previously described in Figure 2.

[0353] Injection of racemic MDMA (e.g., Comparative Composition 1) dose-dependently increased entries to nearly 100 at 5.6 mg / kg, suggesting a stronger locomotor stimulant effect in BTBR mice than in C57. When a single dose of S(+)-MDMA (e.g., Comparative Composition 3) was tested, 3.0 mg / kg of S(+)-MDMA (e.g., Comparative Composition 3) induced entries nearly equivalent to 3.0 mg / kg of racemic MDMA (e.g., Comparative Composition 1), as in C57 mice. As no dose of racemic MDMA (e.g., Comparative Composition 1) or S(+)-MDMA (e.g., Comparative Composition 3) increased entries to more than 100, all tested doses showed the social preference results described below.

[0354] Drug effects on novelty preference C57 mice (see FIG. 5, left graph) spent approximately equal time in each compartment after administration of saline and did not show a strong preference for the dummy mouse compared to the empty cup. Injection of methamphetamine, S(+)-MDMA (e.g., Comparative Composition 3) or R(-)-MDMA (e.g., Exemplary Composition 7) had no systematic effect on novelty preference, whereas administration of racemic MDMA (e.g., Comparative Composition 1) induced avoidance of the dummy mouse at a dose of 5.6 mg / kg.

[0355] BTBR mice (see Figure 5, right graph), like C57, also did not show a strong preference for the dummy mouse over the empty cup, as approximately equal amounts of time were spent in each compartment after saline administration.

[0356] Doses of racemic MDMA (e.g., Comparative Composition 1) or S(+)-MDMA (e.g., Comparative Composition 3) did not induce any effect on novelty preference. Because none of the test drugs increased novelty preference, any enhancement of social preference in subsequent tests is unlikely to be confounded by novelty-related effects, such as changes in the motivational properties of the novel object (which could otherwise be confounded for prosocial benefits).

[0357] Drug effects on sociality After saline administration, C57 mice spent slightly less time in the compartment containing the unfamiliar mouse than in the compartment containing the dummy, indicating slight avoidance of the unfamiliar mouse (see Figure 6, left graph).

[0358] Injection of methamphetamine or S(+)-MDMA (e.g., Comparative Composition 3) had no systematic effect on sociality, whereas administration of racemic MDMA induced a dose-dependent increase in time spent with a stranger, with a dose of 3.0 mg / kg resulting in a moderate preference for a stranger over a dummy. The greatest effect on sociality was induced by administration of 10.0 mg / kg R(-)-MDMA (e.g., Exemplary Composition 7). Interestingly, these doses of racemic MDMA (e.g., Comparative Composition 3) and R(-)-MDMA (e.g., Exemplary Composition 7), which increased sociality, did not affect locomotor activity (see FIG. 4) or novelty preference (see FIG. 5).

[0359] In BTBR mice (see Figure 3, right bar), the expected autistic-like reduction in sociability was observed after saline administration, where the mice showed strong avoidance of unfamiliar mice. Administration of racemic MDMA induced a biphasic effect on sociability similar to that observed in C57, with the lowest tested dose having no effect and the intermediate dose increasing preference for unfamiliar mice, but these prosocial effects were not observed after injection of the highest dose. Also, similar to C57 mice, a single dose of S(+)-MDMA (e.g., Comparative Composition 3) tested did not alter sociability in BTBR (see Figure 6). In contrast to the dissociation of locomotor effects from prosocial effects observed in C57 mice, BTBR mice showed increased sociability only after administration of a dose of racemic MDMA (e.g., Comparative Composition 1) that increased locomotor activity (as before).

[0360] Drug effects on social novelty preference After saline administration, C57 mice spent slightly more time in the compartment containing the novel unfamiliar mouse than in the compartment containing the now familiar mouse, indicating a slight preference for the novel unfamiliar mouse (see Figure 7, left graph).

[0361] Injection of methamphetamine or S(+)-MDMA (e.g., Comparative Composition 3) had no systematic effect on social novelty preference, whereas administration of racemic MDMA (e.g., Comparative Composition 1) induced a dose-dependent increase in time spent with the stranger mouse, with the 3.0 mg / kg dose resulting in a stronger preference for the stranger mouse over the now familiar mouse.

[0362] As observed in the social test, the greatest effect on social novelty preference was induced by administration of 10.0 mg / kg of R(-)-MDMA (e.g., Exemplary Composition 7). Interestingly, these doses of racemic MDMA (e.g., Comparative Composition 1) and R(-)-MDMA (e.g., Exemplary Composition 7), which strongly increased social novelty preference, did not affect locomotor activity (see FIG. 4) or novelty preference (see FIG. 5).

[0363] In BTBR mice (see Figure 7, right graph), the expected autistic-like social reduction was observed after saline administration, where the mice showed slight avoidance of unfamiliar mice. Administration of all doses of racemic MDMA (e.g., Comparative Composition 1) induced similar effects on social novelty preference, with BTBR mice treated with racemic MDMA (e.g., Comparative Composition 1) showing preference for unfamiliar mice at both doses. Unlike the lack of prosocial effects of S(+)-MDMA (e.g., Comparative Composition 3) observed in C57 mice, a single dose of S(+)-MDMA (e.g., Comparative Composition 3) tested in BTBR mice induced a strong preference for unfamiliar mice. Similarly, in contrast to the dissociation of locomotor effects from prosocial effects observed in C57 mice, BTBR mice showed increased social novelty preference following administration of doses of racemic MDMA (e.g., Comparative Composition 1) and S(+)-MDMA (e.g., Comparative Composition 3) that increased locomotor activity, except for the lowest racemic MDMA (e.g., Comparative Composition 1) dose tested.

[0364] Summary of drug effects in C57 mice Racemic MDMA (e.g., Comparative Composition 1), S-(+)-MDMA (e.g., Comparative Composition 3) stimulated locomotor activity in C57 mice in a dose-dependent manner, with over 100 entries recorded at 10 mg / kg intraperitoneally (see FIG. 8, top left graph). In contrast, even 10 mg / kg of R-(-)MDMA (e.g., Exemplary Composition 7) had no stimulatory effect on locomotor activity in C57. Exemplary Composition 2(i), containing 80% (R)-MDMA and 20% (S)-MDMA administered at higher doses, had some stimulatory effect, but it was substantially lower than that observed with S-MDMA (e.g., Comparative Composition 3) and racemic MDMA (e.g., Comparative Composition 1).

[0365] C57 mice administered 10 mg / kg R-MDMA (e.g., Exemplary Composition 7) spent more time in the compartment containing the new unfamiliar mouse than in the compartment containing the now familiar mouse, demonstrating a strong preference for the new unfamiliar mouse (bottom right graph, FIG. 8). In contrast, even after administration of 3.0 mg / kg and 5.6 mg / kg S-MDMA (e.g., Comparative Composition 3), C57 does not induce a substantial preference for the unfamiliar mouse compared to the now familiar mouse (bottom right graph, FIG. 8). Racemic MDMA (e.g., Comparative Composition 1) showed a biphasic dose-response preference for the unfamiliar mouse over the familiar mouse, with maximum preference demonstrated at the 3 mg / kg dose. Exemplary Composition 2(i) administered at 10 mg / kg induced a strong preference for the unfamiliar mouse without overstimulating the mice, as seen with racemic MDMA (e.g., Comparative Composition 1).

[0366] Drug effects in C57 vs. BTBR mice When we studied the effects of the drug on novelty preference (preference for the novel dummy mouse over an empty cup), the data showed that no systematic effects were observed in any of the strains (see Figure 9). This was a control experiment to ensure that any drug effects observed in subsequent social preference tests were related to truly social behavior as opposed to changes in the salience of the novel stimulus.

[0367] In C57 mice, racemic (50 / 50) MDMA (e.g., Comparative Composition 3), Exemplary Composition 2(i) containing 80% (R)-MDMA and 20% (S)-MDMA d, and pure R-MDMA (e.g., Exemplary Composition 7) induce significant effects on sociality at a dose of 3.0 mg / kg, while the effect of pure S-MDMA (e.g., Comparative Composition 3) is no different from saline (see FIG. 10). For BTBR mice, there appears to be a "dose-dependent" effect, such that the more R-MDMA present in the mixture, the greater the effect (although there may be a plateau, since Exemplary Composition 2(i)- is identical to pure R-MDMA (e.g., Exemplary Composition 7)). Thus, Exemplary Composition 2(i) induces a stronger social response than racemic MDMA (e.g., Comparative Composition 1) and S-MDMA (e.g., Comparative Composition 3).

[0368] For C57 mice, racemic (50 / 50) MDMA, exemplary composition 2(i) (e.g., comparative composition 1), and pure R-MDMA (e.g., exemplary composition 7) induce significant effects on sociality at a dose of 3.0 mg / kg, while the effect of pure S-MDMA (e.g., comparative composition 3) is no different from saline (see FIG. 11). For BTBR mice, there again appears to be a "dose-dependent" effect, with the more R-MDMA present in the mixture the greater the effect, and exemplary composition 2(i) performing roughly similarly to R-MDMA (e.g., exemplary composition 7). It is important to consider this together with the locomotor stimulatory effects captured in FIG. 12. For C57 mice, none of the MDMA formulations significantly altered ingression. In BTBR mice, pure S-MDMA (e.g., Comparative Composition 3) and the racemic mixture (e.g., Comparative Composition 1) increased the number of entries observed at this dose, but no stimulation of locomotor activity was observed with Exemplary Composition 2(i) containing 80% (R)-MDMA and 20% (S)-MDMA, while pure R-MDMA (e.g., Exemplary Composition 7) reduced entries at this dose.

[0369] overview: In summary, it has been demonstrated that S-MDMA (e.g., Comparative Composition 3) and racemic MDMA (e.g., Comparative Composition 3) have a dose-response stimulatory effect on C57 mice (representative of the general population) and BTBR mice (representative of the autistic population), while a higher dose (3 mg / kg) of R-MDMA (e.g., Exemplary Composition 7) suppresses locomotor activity in BTBR mice. Exemplary Composition 2(i), which contains 80% (R)-MDMA and 20% (S)-MDMA, has no effect on locomotor activity in BTBR and C57 mice.

[0370] The effect of Exemplary Composition 2(i) on prosocial behavior is well captured through a social novelty preference test in which mice under the influence of the drug at 3 mg / kg dose (ip) in BTBR and C57 mice strongly prefer to interact and spend time with strange mice over familiar mice, the time spent with strange mice being much longer than that observed under the influence of racemic MDMA (e.g. Comparative Composition 1) and S-MDMA (e.g. Comparative Composition 3).

[0371] B. Radiotelemetry of Core Temperature and Locomotor Activity Testing Methods Radiotelemetry of Core Temperature and Locomotor Activity Testing Methods Monoamine mimetics may affect temperature regulation, particularly amphetamine derivatives such as MDMA, which is perhaps the most widely studied (Freedman et al., Psychopharmacology, (2005) 183, 248-256; Kendrick et al., (1977) Annals of Internal Medicine, 86, 381-387; Parrott, AC (2012) Drug and Alcohol Dependence, 121, 1-9; Docherty & Green, (2010), British Journal of Pharmacology, 160, 1029-1044). Thus, the aim of this study was to study the effect of a drug of interest (object) on core temperature in C57 and BTBR mice. Based on the social preference demonstrated by Exemplary Composition 2(i), the effects of such non-racemic compositions of the present application and (R)-MDMA (Exemplary Composition 7) were included in this study.

[0372] This radiotelemetry was performed in adult male C57 and BTBR mice (n=6 per group) in a dedicated testing room where environmental light, sound, and human contact were strictly controlled.

[0373] Prior to surgical implantation of the radiotelemetry probe, mice were administered 3 mg / kg meloxicam (IP) and anesthesia was induced with 4% inhaled isoflurane and maintained with 1–3% isoflurane (as needed) throughout the procedure at a flow rate of 1.5 liters / min. The abdominal area of ​​each animal was treated with depilatory cream and then disinfected with three alternating scrubs with iodine and alcohol. A rostral-caudal cut approximately 1.5 cm long was made with sterile skin scissors to provide access to the intraperitoneal cavity. Cylindrical glass-encapsulated radiotelemetry probes (model ER-4000 E-Mitter, Mini Mitter, Bend, OR, USA) were then inserted. These probes are 15.5 mm × 6.5 mm and weigh approximately 1 gram. The incisions were closed using reverse-cut 5-0 vicryl absorbable sutures for the muscle layer and 5-0 nylon suture material for the skin layer (skin and muscle layers separately). Surgery was performed at least 7 days prior to the start of experimental conditions to allow time for the incision to heal and for the animals to regain normal body weight. After surgery, all implanted mice were housed individually in Plexiglas cages in the telemetry room for the duration of all experiments. The implanted transmitters generate activity and temperature modulated signals that are transmitted to a receiver (Model ER-4000 Receiver, Mini Mitter Co., Inc.) under each cage. After use, the telemetry probes were removed from the carcass, wiped with alcohol swabs, and stored in a disinfectant solution until reuse.

[0374] At least 7 days after surgical implantation of the radiotelemetry probe, mice in individual home cages were placed on top of the radiotelemetry energy device / receiver, powering the probe and transmitting their data to an interfaced computer. Upon starting an experimental session, the computer collected two types of updated data from the probe at 5-min intervals: core temperature (°C) on one channel and locomotor activity counts (arbitrary units depending on the relative position of the probe on the receiver) on the other. After at least 60 min of baseline data collection, mice were removed from their cages, injected with saline or a given dose of a specific drug, and then returned to their home cages for 24 h of data collection.

[0375] Food and water were always available ad libitum in the home cage. Mice were injected with increasing doses of a given drug, with doses spaced at least 48 hours apart. Since there are few studies of drug effects in BTBR mice, the first drug dose tested sometimes induced unexpectedly large locomotor effects in these animals. In these cases, a lower drug dose was then tested after a washout period of at least 1 day.

[0376] Effect of saline injection on core temperature and (locomotor activity) LMA in C57 and BTBR mice [Establishment of baseline and characteristics of mouse strain] Figure 13 shows saline injection on core temperature (left panel) and locomotor activity (right panel) in C57 (filled circles) and BTBR mice (filled circles). Both strains show a transiently increased core temperature and higher activity levels for approximately 30 minutes after saline administration. Activity also follows a normal circadian pattern for both strains. More locomotor activity was recorded during the subjective dark phase, but interestingly, BTBR mice show higher activity than C57, along with an increase in core temperature that may be due to this higher activity.

[0377] Effect of increasing doses of racemic MDMA injections on core temperature in C57 and BTBR mice 14 shows the effect of various doses (10 mg / kg, 30 mg / kg, 56 mg / kg, 100 mg / kg) of racemic MDMA (e.g., Comparative Composition 1) on core temperature in C57 (filled circles) and BTBR (open circles) mice. Because lethality was expected at the 100 mg / kg dose, injections at this dose were administered under room lights at the start of the work day and therefore continued for the duration of the data traces shown here.

[0378] At 10 mg / kg IP administration, racemic MDMA (e.g., Comparative Composition 1) induced a decrease in core temperature in both C57 and BTBR mice 30 minutes to 1 hour after injection, which then stabilized. Increasing doses gradually increased core temperature in both BTBR and C57 mice, with an approximate 2° C. increase in temperature at 56 mg / kg.

[0379] Effect of increasing doses of racemic MDMA injections on LMA in C57 and BTBR mice Figure 15 shows the effect of various doses of racemic MDMA (e.g., Comparative Composition 1) on locomotor activity in C57 mice (filled circles) and BTBR mice (open circles). The pattern of locomotor activity over time for C57 administered 30 mg / kg, 56 mg / kg, and 100 mg / kg (see 15) is consistent with motor stereotypy: an early increase in activity is observed, followed by a suppression of locomotor activity, and then a "late" increase in activity as MDMA is removed and eliminated. No evidence of motor stereotypy in BTBR was observed at any dose. The increased locomotor effect corresponds to the regulation of temperature, as demonstrated in Figure 14 above.

[0380] Effect of Increasing Doses of S-MDMA Injections on Core Temperature in C57 and BTBR Mice Figure 16 shows the effect of various doses of S-MDMA (e.g., Comparative Composition 3) on core temperature in C57 (filled circles) and BTBR (open circles) mice. Note that the large error bars in the C57 data traces from approximately 5-8 hours post-injection were due to one animal experiencing severe hypothermia prior to expiration. The sudden "jump" in mean temperature is the result of this subject being removed from the group average after death.

[0381] Similar to racemic MDMA (e.g., Comparative Composition 1), S-MDMA (e.g., Comparative Composition 3) induced a dose-dependent increase in temperature in both C57 and BTBR mice, with the key difference being that lower doses of S-MDMA induced stronger changes in core temperature. The jump in core temperature at 18 mg / kg ip of S-MDMA (e.g., Comparative Composition 3) (Figure 16) was greater than that observed at 56 mg / kg ip of racemic MDMA (e.g., Comparative Composition 1) (Figure 14).

[0382] Effect of increasing doses of S-MDMA injections on LMA in C57 and BTBR mice Figure 17 shows the effect of various doses of S-MDMA (e.g., Comparative Composition 3) on locomotor activity in C57 mice (filled circles) and BTBR mice (open circles). The pattern of locomotor activity over time for C57 mice administered 30 mg / kg is consistent with motor stereotypy: an early increase in activity is observed, followed by a suppression of locomotor activity, and then a "late" increase in activity as S(+)-MDMA is removed and eliminated. No evidence of motor stereotypy in BTBR was observed at any dose.

[0383] Locomotor effects of increasing doses of fentanyl in C57 and BTBR mice. Figure 18 shows the locomotor effects of 0.3 mg / kg (top left), 1 mg / kg (top right graph), and 3 mg / kg of the u-opioid agonist fentanyl in C57 mice (filled circles) versus BTBR mice (open circles). Note that unlike the pattern of data observed with racemic MDMA (e.g., Comparative Composition 1) and S(+)-MDMA (e.g., Comparative Composition 1), each dose of fentanyl induced more locomotor activity in C57 mice than in BTBR mice. Thus, BTBR mice are not more sensitive to the locomotor effects of all drugs, but are specifically sensitive to the psychostimulant effects of MDMA-like drugs.

[0384] Locomotor effects of increasing doses of the psychostimulant S-methamphetamine in C57 and BTBR mice. FIG. 19 shows the locomotor effects of S-methamphetamine at 0.3 mg / kg (top left), 1 mg / kg (top right graph), and 3 mg / kg in C57 mice (filled circles) versus BTBR mice (open circles). Note that unlike the pattern of data observed with racemic MDMA and S(+)-MDMA, no significant strain differences were observed at any dose of S(+)-METH. Thus, BTBR mice are not more sensitive to the locomotor effects of all drugs, but are specifically sensitive to the psychostimulant effects of MDMA-like drugs. (Time-activity curves are not shown for 0.3 mg / kg S(+)-methamphetamine, as the effects were not different from saline.)

[0385] Core temperature and locomotor activity effects of 10 mg / kg racemic MDMA vs. S-MDMA vs. R-MDMA vs. comparative composition 2(i) FIG. 20 shows the effect of 10 mg / kg MDMA in the ratios of 0% R(-)-MDMA to 100% S(+)-MDMA (closed circles) (e.g., Comparative Composition 3), 50% R(-)-MDMA to 50% S(+)-MDMA (half-white / half-black circles) (e.g., Comparative Composition 1), 80% R(-)-MDMA to 20% S(+)-MDMA (grey circles) (e.g., Exemplary Composition 2(i)), or 100% R(-)-MDMA to 0% S(+)-MDMA (open circles) (e.g., Exemplary Composition 7) on core temperature in C57 mice (left) and BTBR mice (right). In C57 mice (left), pure S(+)-MDMA (e.g., Comparative Composition 3) induced an increase in temperature, but neither the mixture (e.g., Exemplary Composition 2(i)) nor pure R(-)-MDMA (e.g., Exemplary Composition 7) induced a significant effect on core temperature at this dose. There appears to be a trend for temperature reductions in response to the presence of R(-)-MDMA, but whether these are physiologically relevant to the human population remains to be evaluated.

[0386] In BTBR mice (right), pure S(+)-MDMA (e.g., Comparative Composition 3) induced a similar temperature increase, and the less S(+)-enantiomer present in the mixture, the smaller the effect observed. This pattern is repeated below 30 mg / kg, where significant differences are observed.

[0387] FIG. 21 shows the effect of 10 mg / kg MDMA in the following ratios on locomotor activity in c57 mice (left) and BTBR mice (right): 0% R(-)-MDMA vs. 100% S(+)-MDMA (closed circles) (e.g., Comparative Composition 3), 50% R(-)-MDMA vs. 50% S(+)-MDMA (half-white / half-black circles) (e.g., Comparative Compositions), 80% R(-)-MDMA vs. 20% S(+)-MDMA (grey circles) (e.g., Exemplary Composition 2(i)), or 100% R(-)-MDMA vs. 0% S(+)-MDMA (open circles) (e.g., Exemplary Composition 7). In C57 mice (left), pure S(+)-MDMA (e.g., Comparative Composition 3) induces the greatest locomotor stimulation, and less hyperactivity is observed at this dose with the racemic mixture (e.g., Comparative Composition 1) and the 80R / 20S mixture (e.g., Exemplary Composition 2(i)). Pure R(-)-MDMA (e.g., Exemplary Composition 7) induces a significant locomotor stimulation at this dose. In BTBR mice (right), pure S(+)-MDMA (e.g., Comparative Composition 3) induces a substantially greater stimulation in locomotor activity, and less activity is observed with less S(+)-enantiomer present in the mixture. No significant locomotor stimulation was observed at this dose for pure R(-)-MDMA (e.g., Exemplary Composition 7) and the 80 / 20 mixture (e.g., Exemplary Composition 2(i)).

[0388] Surprisingly, despite the strong locomotor stimulatory effect of S-MDMA (e.g., Comparative Composition 3) in BTBR mice (Figure 21), core temperatures were not significantly different from those observed with racemic MDMA (e.g., Comparative Composition 1) (see Figure 20).

[0389] Core temperature and locomotor activity effects of 30 mg / kg racemic MDMA vs. S-MDMA vs. R-MDMA vs. exemplary composition 2(i) 22 shows the effect of 30 mg / kg MDMA in the ratios of 0% R(-)-MDMA to 100% S(+)-MDMA (black circles) (e.g., Exemplary Composition 7), 50% R(-)-MDMA to 50% S(+)-MDMA (half-white / half-black circles) (e.g., Comparative Composition 1), 80% R(-)-MDMA to 20% S(+)-MDMA (gray circles) (e.g., Exemplary Composition 2(i)), or 100% R(-)-MDMA to 0% S(+)-MDMA (white circles) (e.g., Exemplary Composition 7) on core temperature in C57 mice (left) and BTBR mice (right). In C57 mice (left), pure S(+)-MDMA induces significant hyperthermia, but neither the mixture nor pure R(-)-MDMA induces a significant effect on core temperature at this dose.

[0390] In BTBR mice (right), pure S(+)-MDMA (e.g., Exemplary Composition 3) induced a large hyperthermic response, and the less S(+)-enantiomer present in the mixture, the less hyperthermia was observed. For pure R(-)-MDMA (e.g., Exemplary Composition 7) and the 80 / 20 mixture (e.g., Exemplary Composition 2(i)), no significant effect on core temperature was observed at this dose.

[0391] FIG. 23 shows the effect of 30 mg / kg MDMA in the ratios of 0% R(-)-MDMA vs. 100% S(+)-MDMA (closed circles) (e.g., Comparative Composition 3), 50% R(-)-MDMA vs. 50% S(+)-MDMA (half-white / half-black circles) (e.g., Comparative Composition 1), 80% R(-)-MDMA vs. 20% S(+)-MDMA (grey circles) (e.g., Exemplary Composition 2(i)), or 100% R(-)-MDMA vs. 0% S(+)-MDMA (open circles) (e.g., Exemplary Composition 7) on locomotor activity in C57 mice (top left) and BTBR mice (top right). 30 mg / kg of 100% S(+)-MDMA (e.g., Comparative Composition 3) induces locomotor stereotypy in C57 mice, characterized by an initial increase in activity, followed by a decrease as the animals enter stereotypy, followed by a "second phase" increase in activity as the drug is removed and cleared around 240 minutes after injection. In contrast, the enantiomer mixture (e.g., Exemplary Composition 2(i)) induces only a time-dependent increase in locomotor activity. Interestingly, no stereotypy was observed in BTBR mice.

[0392] In C57 mice (left graph), the racemic mixture (e.g., Comparative Composition 1) and the 80R / 20S mixture (e.g., Exemplary Composition 2(i)) induce higher activity at this dose than pure S(+)-MDMA (e.g., Comparative Composition 3) due to the steric hindrance effect of the S(+)-enantiomer. Pure R(-)-MDMA (e.g., Exemplary Composition 7) did not induce significant locomotor stimulation at this dose.

[0393] In BTBR mice (right), pure S(+)-MDMA induced a large stimulation in locomotor activity, and the less S(+)-enantiomer present in the mixture, the lower the activity observed.No significant locomotor stimulation was observed at this dose for pure R(-)-MDMA (e.g., Exemplary Composition 7).

[0394] Locomotor effects of saline or various doses of racemic MDMA and S-MDMA in C57 and BTBR mice. FIG. 24 shows the locomotor effects of saline or various doses of racemic MDMA (left panel) (e.g., Comparative Composition 1) or S-MDMA (right panel) (e.g., Comparative Composition 3) in C57 mice (filled circles) and BTBR mice (open circles). Both racemic MDMA (e.g., Comparative Composition 1) and S(+)-MDMA (e.g., Comparative Composition 3) induce a classic "inverted U-shaped" dose-effect curve, as high doses induce motor stereotypies, resulting in less total locomotor activity than observed with intermediate doses. Interestingly, the dose-effect curve in BTBR mice does not follow this biphasic pattern for racemic MDMA.

[0395] overview In a pilot Phase 2 clinical trial, Alicia Danforth and Charles Grobb (Danforth et al., Psychopharmacology (Berl). 2018; 235(11): 3137-3148) demonstrated rapid and durable improvement of social anxiety symptoms in autistic adults following MDMA-assisted psychotherapy. However, racemic MDMA also leads to increased core temperature and cardiovascular events, as demonstrated by other researchers. The purpose of this study was to evaluate the safety profile of our exemplary non-racemic compositions of the present application compared to the individual (R) and (S) enantiomers of MDMA and racemic MDMA.

[0396] The following findings were found:

[0397] Both racemic MDMA (e.g., Comparative Composition 1) and S(+)-MDMA (e.g., Comparative Composition 3) induce a classic "inverted U-shaped" dose-effect curve, with high doses inducing motor stereotypies that result in less total locomotor activity than observed with intermediate doses. Interestingly, the dose-effect curves in BTBR mice do not follow this biphasic pattern for racemic MDMA (see FIG. 24).

[0398] Compared to 10 mg / kg, BTBR induces a stronger hyperthermic response to 30 mg / kg S-MDMA (e.g., Comparative Composition 3). Racemic MDMA (e.g., Comparative Composition 1) produces a temperature increase at both doses (10 mg / kg and 30 mg / kg), but it is less pronounced than S-MDMA (see FIG. 22).

[0399] Exemplary composition 2(i)) (regardless of dose) and saline have a temperature change response in BTBR and C57 mice (see Figures 20 and 22).

[0400] Combined with the social preference data described in Part A above, these results elucidate that administration of a non-racemic composition of the present application, such as exemplary composition 2(i)), in BTBR mice causes the mice to overcome their inherent social anxiety without having severe adverse events such as hyperthermia, thereby providing a relatively safe use of MDMA.

[0401] Although the present application has been described with reference to examples, it should be understood that the claims should not be limited by the embodiments described in the examples, but should be accorded the broadest interpretation consistent with the description as a whole.

[0402] All publications, patents, and patent applications are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. In the event that any term in this application is found to have a different definition in a document incorporated herein by reference, the definition provided herein shall serve as the definition of that term.

Claims

1. A non-racemic mixture comprising a compound of formula (R)-I or a salt and / or solvate thereof and a compound of formula (S)-I or a salt and / or solvate thereof, 【Chemical 1】 In the formula, R １ is CH ３ or CH ２ CH ３ and The non-racemic mixture comprises about 70% to about 80% enantiomeric equivalent of the compound of Formula (R)-I or a salt and / or solvate thereof and about 20% to about 30% enantiomeric equivalent of the compound of Formula (S)-I or a salt and / or solvate thereof.

2. The non-racemic mixture of claim 1, comprising about 70% to about 75% enantiomeric equivalent of the compound of formula (R)-I or its salt and / or solvate and 25% to about 30% enantiomeric equivalent of the compound of formula (S)-I or its salt and / or solvate.

3. The non-racemic mixture of claim 1, comprising about 75% to about 79.9% enantiomeric equivalent of the compound of formula (R)-I or its salt and / or solvate and about 20.1% to about 25% enantiomeric equivalent of the compound of formula (S)-I or its salt and / or solvate.

4. The non-racemic mixture of claim 1, comprising about 80% enantiomeric equivalents of formula (R)-I or a salt and / or solvate thereof and about 20% enantiomeric equivalents of formula (S)-I or a salt and / or solvate thereof.

5. The non-racemic mixture of claim 1, comprising about 70% enantiomeric equivalents of formula (R)-I or a salt and / or solvate thereof and about 30% enantiomeric equivalents of formula (S)-I or a salt and / or solvate thereof.

6. The non-racemic mixture of any one of claims 1 to 5, wherein the compound of formula (R)-I is (R)-3,4-methylenedioxymethamphetamine ((R)-MDMA) and the compound of formula (S)-I is (S)-3,4-methylenedioxymethamphetamine ((S)-MDMA). 【Chemistry 2】 7. The non-racemic mixture of any one of claims 1 to 5, wherein the compound of formula (R)-I is (R)-N-methyl-1,3-benzodioxolylbutanamine ((R)-MBDB) and the compound of formula (S)-I is (S)-N-methyl-1,3-benzodioxolylbutanamine ((S)-MBDB). 【Chemistry 3】 8. The non-racemic mixture of claim 6, wherein the (R)-MDMA and the (S)-MDMA are both in the acid salt form.

9. The non-racemic mixture of claim 7, wherein the (R)-MBDB and the (S)-MBDB are both in the acid salt form.

10. A pharmaceutical composition comprising the non-racemic mixture of any one of claims 1 to 5 and one or more pharmaceutically acceptable carriers.

11. The pharmaceutical composition of claim 10, formulated for oral administration.

12. The pharmaceutical composition of claim 10, formulated for intranasal or sublingual administration.

13. The pharmaceutical composition of claim 11, comprising about 40 mg to about 180 mg of the non-racemic mixture.

14. The pharmaceutical composition of claim 11, comprising about 0.05% to about 99% by weight, or about 0.10% to about 70% by weight of said non-racemic mixture, and about 1% to about 99.95% by weight, or about 30% to about 99.90% by weight of one or more pharmaceutically acceptable carriers, wherein all weight percentages are based on the total composition.

15. The pharmaceutical composition of claim 10 for the treatment of a disease, disorder, or condition that would benefit from treatment with racemic 3,4-methylenedioxymethamphetamine (MDMA) or a pharmaceutically acceptable salt and / or solvate thereof.

16. The pharmaceutical composition of claim 15, wherein the treatment with the pharmaceutical composition has a reduced risk of adverse side effects compared to treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof.

17. The disease, disorder or condition that would benefit from treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof is any disease, disorder or condition that would benefit from psychotherapy; or the disease, disorder or condition that would benefit from treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof is one or more psychiatric disorders; or 16. The pharmaceutical composition of claim 15, wherein the disease, disorder, or condition that would benefit from treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof is a disease, disorder, or condition that would benefit from treatment with L-3,4-dihydroxyphenylalanine (L-DOPA), and the use of the pharmaceutical composition is for improving the effectiveness of L-DOPA, or for use in combination with L-DOPA to improve the effectiveness of L-DOPA, for treating the symptoms of the disease, disorder, or condition that would benefit from L-DOPA treatment.

18. The pharmaceutical composition of claim 10 for the treatment of symptoms of one or more diseases, disorders, or conditions that would benefit from treatment with racemic 3,4-methylenedioxymethamphetamine (MDMA) or a pharmaceutically acceptable salt and / or solvate thereof.

19. A pharmaceutical composition comprising (R)-MDMA or a pharmaceutically acceptable salt and / or solvate thereof for treating a disease, disorder or condition that would benefit from treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof.

20. A pharmaceutical composition comprising (R)-MDMA or a pharmaceutically acceptable salt and / or solvate thereof for treating the symptoms of one or more diseases, disorders or conditions that would benefit from treatment with racemic MDMA or a pharmaceutically acceptable salt and / or solvate thereof.

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