Compositions comprising 3, 4-methylenedioxymethylamphetamine optionally in combination with N-acylethanolamine and uses thereof

Abstract

The present disclosure relates to compositions comprising 3, 4-methylenedioxy methyl amphetamine (MDMA), or a salt thereof, and MDMA, or a pharmaceutically acceptable salt thereof, in combination with N-acylethanolamine, or a pharmaceutically acceptable salt thereof (e.g., a pharmaceutically acceptable salt thereof). The present invention relates to pharmaceutical compositions comprising a combination of N, N '-dihydroxybutyramide ("PEA") and at least one pharmaceutically acceptable carrier and / or excipient and their use in methods of treating post-traumatic stress disorder (PTSD), anxiety and eating disorders by administering the composition in a therapeutically effective amount to a subject in need thereof.

Description

[0001] Cross-reference to related applications This application claims the priority benefit of U.S. Provisional Patent Application No. 63 / 485,110, filed February 15, 2023, the contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure relates to compositions and methods for enhancing the therapeutic effects of 3,4-methylenedioxymethamphetamine (MDMA) or a pharmaceutically acceptable salt thereof and / or reducing its side effects. This disclosure provides pharmaceutical compositions comprising MDMA or a pharmaceutically acceptable salt thereof, or pharmaceutical compositions comprising a combination of MDMA or a pharmaceutically acceptable salt thereof with N-acylethanolamine or a pharmaceutically acceptable salt thereof (e.g., palmitoylethanolamide (“PEA”)), and methods thereof for use in a variety of suitable therapeutic indications, including but not limited to post-traumatic stress disorder (PTSD), anxiety, and eating disorders. Background Technology

[0003] 3,4-Methylenedioxymethamphetamine (MDMA) induces serotonin release primarily by binding to the presynaptic serotonin transporter and plays a role in enhancing fear memory extinction, modulating fear memory reconsolidation, and enhancing social behavior. The chemical structure of MDMA is as follows: MDMA-assisted therapy has been proven effective in managing severe post-traumatic stress disorder (PTSD). (Mitchell et al., MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med 27, 1025–1033 (2021)).

[0004] Controlled clinical trials have also demonstrated that MDMA can produce sustained and clinically significant beneficial effects in treating social anxiety (e.g., in people with autism) and anxiety associated with life-threatening illnesses such as cancer. (Danforth et al., Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: arandomized, double-blind, placebo-controlled pilotstudy. Psychopharmacology (2018)). Additionally, MDMA-assisted therapy may have a potentially beneficial role in eating disorders and in significantly reducing symptoms of eating disorders such as active clearance and low body weight. (Brewerton et al., MDMA-assisted therapy significantly reduces eating disorder symptoms in arandomized placebo-controlled trial of adults with severe PTSD. Journal of psychiatric research Vol. 149 (2022): 128-135).

[0005] N-Acylethanolamines (NAEs) are lipid-derived signaling molecules. They are formed when one of several types of acyl groups is attached to the nitrogen atom of an ethanolamine. Examples of N-acylethanolamines include arachidonic acid ethanolamine (an amide of arachidonic acid (20:4 ω-6) and ethanolamine), N-palmitoylethanolamine (an amide of palmitic acid (16:0) and ethanolamine), N-oleoylethanolamine (an amide of oleic acid (18:1) and ethanolamine), N-stearoylethanolamine (an amide of stearic acid (18:0) and ethanolamine), and N-docosahexaenoic acid ethanolamine (an amide of docosahexaenoic acid (22:6) and ethanolamine).

[0006] Palmitoyl ethanolamide (PEA, also known as N-(2-hydroxyethyl)hexadecanoamide; hydroxyethyl palmitamide; hexadecanoamide ethanol; N-palmitoyl ethanolamine; and palmitoyl ethanolamide) is an endogenous fatty acid amide belonging to the nuclear factor agonist class. The chemical structure of PEA is: PEA has been shown to bind to receptors in the cell nucleus (nuclear receptors) and exert a variety of biological functions associated with chronic pain and inflammation. Studies have shown that PEA interacts with different non-CB1 / CB2 receptors, suggesting that PEA utilizes a unique “parallel” endocannabinoid signaling system. Increasing evidence suggests that the production and inactivation of PEA can occur independently of the production and inactivation of AEA and 2-AG, further supporting this view. Most of PEA’s biological effects on cells can be attributed to its affinity for PPARs (particularly PPAR-α and PPAR-γ). PEA has been shown to have affinity for cannabinoid-like G-coupled receptors GPR55 and GPR119, as well as transient receptor potential vanillin type 1 receptor (TRPV1). PEA has been shown to possess anti-inflammatory, anti-nociceptive, neuroprotective, and anticonvulsant properties. Summary of the Invention

[0007] In some embodiments, this disclosure provides pharmaceutical compositions comprising 3,4-methylenedioxymethamphetamine (MDMA) or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure provides methods for preventing and / or treating a variety of disorders responsive to MDMA treatment, such as post-traumatic stress disorder (PTSD), anxiety, and eating disorders.

[0008] In some embodiments, this disclosure provides pharmaceutical compositions comprising a combination of MDMA or a pharmaceutically acceptable salt thereof with N-acylethanolamine or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, these combinations comprise a specific molar ratio between the active agents and / or their dosage and can be used in a variety of methods. In some embodiments, this disclosure provides methods for preventing and / or treating a variety of disorders that respond to MDMA treatment, such as post-traumatic stress disorder (PTSD), anxiety, and eating disorders.

[0010] In some embodiments, the molar ratio of MDMA to N-acylethanolamine is between about 1:0.2 and about 1:5. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is between about 1:0.5 and about 1:2. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is between about 1:15 and about 1:1800. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is between about 1:25 and about 1:450. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is between about 1:50 and about 1:100. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:50. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:100. Each possibility represents a single embodiment of this disclosure.

[0011] In some embodiments, the pharmaceutical composition comprises about 50-200 mg of MDMA or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.2 mg / kg body weight to 5 mg / kg body weight of MDMA or a pharmaceutically acceptable salt thereof. Each possibility represents a single embodiment of this disclosure.

[0012] In some embodiments, the pharmaceutical composition comprises about 200-1800 mg of N-acylethanolamine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 250 mg, about 500 mg, about 750 mg, about 1000 mg, or about 1500 mg of N-acylethanolamine or a pharmaceutically acceptable salt thereof. Each possibility represents a single embodiment of this disclosure.

[0013] In some embodiments, the N-acylethanolamine is selected from N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexylamide, palmitoylbutyramide, palmitoylisopropamide, oleoylethanolamine (OEA), palmitoylisopropamide (PIA), salts thereof, and any combination thereof. Each possibility represents a single embodiment of this disclosure. In some embodiments, the N-acylethanolamine is PEA or a pharmaceutically acceptable salt thereof. In some embodiments, the N-acylethanolamine consists of PEA or a pharmaceutically acceptable salt thereof. In some embodiments, the N-acylethanolamine consists of PEA.

[0014] In some embodiments, the pharmaceutical composition is formulated for systemic administration. In some embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalation, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. Each possibility represents a separate embodiment of this disclosure. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for oral mucosal administration. In some embodiments, the pharmaceutical composition is formulated for nasal administration. In some embodiments, the pharmaceutical composition is formulated for sublingual administration.

[0015] In another aspect, this disclosure also provides a dosage unit comprising or composed of the above-described pharmaceutical composition.

[0016] In some embodiments, the dosage unit comprises the above-described pharmaceutical composition. In some embodiments, the dosage unit is composed of the above-described pharmaceutical composition. In some embodiments, the dosage unit is formulated as a gel, powder, or spray. In some embodiments, the dosage unit is formulated as a gel. In some embodiments, the dosage unit is formulated as a powder. In some embodiments, the dosage unit is formulated as a spray.

[0017] In other embodiments, this disclosure relates to a method of treating PTSD, comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising MDMA or a pharmaceutically acceptable salt thereof, thereby treating the disorder.

[0018] In other embodiments, this disclosure relates to a method of treating anxiety, comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising MDMA or a pharmaceutically acceptable salt thereof, thereby treating the disorder.

[0019] In other embodiments, this disclosure relates to a method of treating alcohol poisoning, comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising LSD or a pharmaceutically acceptable salt thereof, thereby treating the condition.

[0020] In other embodiments, this disclosure relates to a method of treating an eating disorder, comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising LSD or a pharmaceutically acceptable salt thereof, thereby treating the disorder.

[0021] In some implementations, a therapeutically effective amount of a pharmaceutical composition containing MDMA or a pharmaceutically acceptable salt thereof is administered to a subject to treat PTSD.

[0022] In some implementations, a therapeutically effective amount of a pharmaceutical composition containing MDMA or a pharmaceutically acceptable salt thereof is administered to a subject to treat anxiety.

[0023] In some implementations, a therapeutically effective amount of a pharmaceutical composition containing MDMA or a pharmaceutically acceptable salt thereof is administered to a subject to treat an eating disorder.

[0024] In some implementations, a therapeutically effective amount of a pharmaceutical composition comprising a combination of MDMA or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered to a subject to treat PTSD.

[0025] In some implementations, a therapeutically effective amount of a pharmaceutical composition comprising a combination of MDMA or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered to a subject to treat anxiety.

[0026] In some embodiments, a therapeutically effective amount of a pharmaceutical composition comprising a combination of MDMA or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof is administered to a subject to treat an eating disorder or symptoms associated with an eating disorder.

[0027] In some embodiments, N-acylethanolamine enhances the therapeutic efficacy of MDMA or a pharmaceutically acceptable salt thereof compared to the same pharmaceutical composition without N-acylethanolamine. In some embodiments, N-acylethanolamine reduces the required therapeutic dose of MDMA or a pharmaceutically acceptable salt thereof compared to the same pharmaceutical composition without N-acylethanolamine. In some embodiments, N-acylethanolamine reduces at least one of the side effects of MDMA or a pharmaceutically acceptable salt thereof compared to the same pharmaceutical composition without N-acylethanolamine. In some embodiments, N-acylethanolamine expands the therapeutic window of MDMA or a pharmaceutically acceptable salt thereof compared to the same pharmaceutical composition without N-acylethanolamine. In some embodiments, PEA or a salt thereof enhances the therapeutic efficacy of MDMA or a salt thereof compared to the same pharmaceutical composition without PEA (or a pharmaceutically acceptable salt thereof). In some embodiments, PEA (or a pharmaceutically acceptable salt thereof) reduces the required therapeutic dose of MDMA (or a pharmaceutically acceptable salt thereof) compared to the same pharmaceutical composition without PEA (or a pharmaceutically acceptable salt thereof). In some embodiments, PEA (or a pharmaceutically acceptable salt thereof) reduces at least one of the side effects of MDMA (or a pharmaceutically acceptable salt thereof) compared to the same pharmaceutical composition without PEA (or a pharmaceutically acceptable salt thereof). In some embodiments, PEA (or a pharmaceutically acceptable salt thereof) expands the therapeutic window of MDMA (or a pharmaceutically acceptable salt thereof) compared to the same pharmaceutical composition without PEA (or a pharmaceutically acceptable salt thereof).

[0028] In some embodiments of the above methods, MDMA or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof are contained in the same pharmaceutical composition. In some embodiments of the above methods, MDMA and N-acylethanolamine or a pharmaceutically acceptable salt thereof are contained in different pharmaceutical compositions.

[0029] In some embodiments of the above methods, the administration of MDMA and N-acylethanolamine or a pharmaceutically acceptable salt thereof is repeated three times daily. In some embodiments of the above methods, the administration of MDMA and N-acylethanolamine or a pharmaceutically acceptable salt thereof is repeated twice daily. In some embodiments of the above methods, the administration of MDMA and N-acylethanolamine or a pharmaceutically acceptable salt thereof is repeated once daily. In some embodiments of the above methods, the administration of MDMA and N-acylethanolamine or a pharmaceutically acceptable salt thereof is repeated every two days. In some embodiments of the above methods, the administration of MDMA and N-acylethanolamine or a pharmaceutically acceptable salt thereof is repeated every three days.

[0030] In some embodiments, this disclosure relates to a pharmaceutical composition comprising MDMA (or a pharmaceutically acceptable salt thereof) and N-acylethanolamine (or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable carrier and / or excipient.

[0031] In some embodiments, the pharmaceutical composition is a unit dosage form composition. In other embodiments, the pharmaceutical composition is a solid unit dosage form composition. In still other embodiments, the pharmaceutical composition is a liquid unit dosage form composition. In yet another embodiment, the pharmaceutical composition is packaged as a single unit dose or as multiple single unit doses.

[0032] In a further embodiment, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient. In other embodiments, the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate, or syrup.

[0033] In some embodiments, the pharmaceutical composition is a unit dosage form composition in the methods of this disclosure. In other embodiments, the amount of MDMA or a pharmaceutically acceptable salt thereof in the unit dosage form is in the range of about 50-200 mg. In some embodiments, the amount of MDMA is in the range of about 0.2 mg / kg body weight to 5 mg / kg body weight. In some embodiments, the pharmaceutical composition is administered orally. In some embodiments, the pharmaceutical composition is administered intravenously.

[0034] Further embodiments of this disclosure and its full scope will become apparent from the detailed description given below. However, while the detailed description and specific examples indicate preferred embodiments of this disclosure, they are given by way of illustration only, as various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from this detailed description. Detailed Implementation

[0035] definition: When listing a range of values, it is intended to cover every value and subrange within that range. For example, "C1-C6 alkyl" is intended to cover C1, C2, C3, C4, C5, C6 ... 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0036] "Isomers" refer to compounds that have the same number and type of atoms and therefore the same molecular weight, but differ in the spatial arrangement or configuration of the atoms.

[0037] "Stereoisomers" or "optical isomers" refer to stable isomers that have at least one chiral atom or restricted rotation to produce a plane of asymmetry (e.g., certain biphenyls, dienes, and spirocyclic compounds) and can rotate plane-polarized light. Because of the presence of asymmetric centers and other chemical structures in the compounds of this disclosure, stereoisomerism can occur, and therefore this disclosure covers stereoisomers and mixtures thereof. The compounds of this disclosure and their salts contain asymmetric carbon atoms and therefore may exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. Typically, such compounds are prepared as racemic mixtures. However, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., single enantiomers or diastereomers, or as mixtures rich in stereoisomers. As discussed in more detail below, individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral center or by preparing a mixture of enantiomers followed by separation or resolution (such as converting to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, using chiral resolving agents, or direct separation of enantiomers on a chiral column). Starting compounds with specific stereochemistry are commercially available or prepared by the methods described below and resolved using techniques well known in the art.

[0038] As is well known in the art, the biological and pharmacological activities of a compound are sensitive to its stereochemistry. Therefore, for example, enantiomers often exhibit distinctly different biological activities, including differences in pharmacokinetic properties (including metabolism, protein binding, etc.) and pharmacological properties (including the type, degree, and toxicity of the activity exhibited). Therefore, those skilled in the art will understand that when one enantiomer is enriched relative to another, or when one enantiomer is isolated from another, its activity may be higher or it may exhibit beneficial effects. Furthermore, based on the knowledge of this disclosure and the prior art, those skilled in the art will know how to isolate, enrich, or selectively prepare enantiomers of the compounds disclosed herein.

[0039] Therefore, although racemic forms of drugs can be used, they are generally less effective than administering an equal amount of the enantiomerically pure drug; in fact, in some cases, an enantiomer may be pharmacologically inactive and will only act as a simple diluent. For example, although ibuprofen was previously administered in racemic form, only the S-isomer of ibuprofen has been shown to be effective as an anti-inflammatory agent (however, in the case of ibuprofen, although the R-isomer is inactive, it is converted to the S-isomer in vivo, therefore, the racemic form of the drug has a slower onset of action than the pure S-isomer). Furthermore, enantiomers may have different biological activities. For example, S-penicillamine is a treatment for chronic arthritis, while R-penicillamine is toxic. In fact, some purified enantiomers are advantageous over racemic ones because purified single isomers have been reported to have faster transdermal penetration rates than racemic mixtures. See U.S. Patent Nos. 5,114,946 and 4,818,541.

[0040] In some embodiments, the compound is a racemic mixture of (S)- and (R)- isomers. In other embodiments, this document provides a compound mixture in which the individual compounds of the mixture are predominantly in the (S)- or (R)- isomer configuration. For example, the compound mixture has an excess of (S)-enantiomers of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or higher. In other embodiments, the compound mixture has an excess of (S)-enantiomers of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to greater than about 99.5%, greater than about 99% to about 99.5%, or higher. In other embodiments, the compound mixture has an (R)-enantiomer purity of greater than about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or higher. In some other embodiments, the compound mixture has an excess of (R)-enantiomers of more than about 55% to about 99.5%, more than about 60% to about 99.5%, more than about 65% to about 99.5%, more than about 70% to about 99.5%, more than about 75% to about 99.5%, more than about 80% to about 99.5%, more than about 85% to about 99.5%, more than about 90% to about 99.5%, more than about 95% to about 99.5%, more than about 96% to about 99.5%, more than about 97% to about 99.5%, more than about 98% to more than about 99.5%, more than about 99% to about 99.5%, or higher.

[0041] Individual stereoisomers of the compounds disclosed herein can be prepared from commercially available starting materials containing an asymmetric center or a stereogenic center, or by preparing a racemic mixture followed by a resolution method well known to those skilled in the art. These resolution methods include, for example: (1) attaching an enantiomer mixture to a chiral auxiliary agent, separating the resulting diastereomer mixture by recrystallization or chromatography, and releasing an optically pure product from the auxiliary agent; (2) salting with an optically active resolving agent; or (3) directly separating a mixture of optically enantiomers on a chiral chromatographic column. The stereoisomer mixture can also be resolved into its component stereoisomers by well-known methods such as chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallizing the compound into a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereoisomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0042] Therefore, if one enantiomer has higher pharmacological activity, lower toxicity, or better distribution in vivo than another enantiomer, preferential administration of that enantiomer will be more beneficial for treatment. In this way, the treated patient will be exposed to a lower total dose of the drug and a lower dose of the enantiomer that may be toxic or an inhibitor of the other enantiomer.

[0043] As used herein, the nomenclature of compounds, including organic compounds, can be given using common names, IUPAC, IUBMB, or CAS recommended nomenclature. If a name is given, those skilled in the art can systematically deduce the compound structure using nomenclature conventions or commercially available software such as CHEMDRAW. TM (Cambridgesoft Corporation, USA) to easily determine the structure of compounds. Chemical names are derived using PerkinElmerChemDraw. ® Professional version 17 generated.

[0044] The compounds disclosed herein may contain one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers, such as geometric isomers, enantiomers, or diastereomers. When used herein, the term "stereoisomer" includes all geometric isomers, enantiomers, or diastereomers. These compounds may be represented by the symbols "R" or "S," depending on the configuration of the substituents surrounding the carbon atom of the stereoisomer source. This disclosure covers various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be indicated in nomenclature by "(±)", but those skilled in the art will recognize that the structure may implicitly represent the chiral center. In some embodiments, an enantiomer or stereoisomer that substantially does not contain the corresponding enantiomer may be provided.

[0045] In one aspect, this disclosure provides a pharmaceutical composition comprising a mixture of a therapeutically effective amount of MDMA (or a pharmaceutically acceptable salt thereof) and at least one N-acylethanolamine (or a pharmaceutically acceptable salt thereof).

[0046] In another aspect, this disclosure provides a pharmaceutical composition comprising a mixture of a therapeutically effective amount of MDMA (or a pharmaceutically acceptable salt thereof) and at least one N-acylethanolamine (or a pharmaceutically acceptable salt thereof), wherein the molar ratio between MDMA and N-acylethanolamine (or a pharmaceutically acceptable salt thereof) is between about 1:0.2 and about 1:2000.

[0047] As used herein, “pharmaceutical composition” means a formulation of the active agent described herein with other chemical components such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism. As used herein, the expression “pharmaceuticalally acceptable carrier” means a carrier, excipient, or diluent that will not cause significant irritation to a living organism and will not eliminate the biological activity and properties of the administered compound. Adjuvants are also included under these expressions.

[0048] As used herein, the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of the active ingredient. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, oils (such as vegetable oils or fish oils), and polyethylene glycol.

[0049] As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or medium that is administered with a compound. Such drug carriers can be sterile liquids, such as water and oil. Water or aqueous solutions of saline, as well as aqueous solutions of dextran and glycerol, are preferred as carriers, especially for injectable solutions. Suitable drug carriers are described in EW Martin's "Remington's Pharmaceutical Sciences," 18th edition.

[0050] As used herein, the term "pharmaceutical acceptable" refers to molecular entities and compositions that are physiologically tolerable and generally do not produce allergic reactions or similar toxicities when administered to an individual. Preferably, and particularly in the case of formulations intended for human use, the term "pharmaceutical acceptable" may refer to those approved by a regulatory agency (e.g., the U.S. Food and Drug Administration) or listed in a recognized pharmacopoeia for animal use (e.g., the United States Pharmacopeia).

[0051] As used herein, the term "N-acylethanolamine" generally refers to a type of fatty acid amide, a lipid-derived signaling molecule formed when one of several types of acyl groups is attached to the nitrogen atom of an ethanolamine. These amides can conceptually be formed from fatty acids and ethanolamines, releasing a water molecule, but known biosynthesis uses a specific phospholipase D to cleave the phospholipid unit from N-acylphosphatidylethanolamine. The suffixes -amine and -amide in these names each refer to the single nitrogen atom of the ethanolamine that links the compounds together: in ethanolamine it is called "amine" because it is considered to be the free terminal nitrogen in that subunit; while it is called "amide" when it is considered to be associated with the adjacent carbonyl group of the acyl subunit. In this application, the names of these compounds may appear as "amide" or "amine". The term "ethanolamine" is used in a general sense and is intended to include monoethanolamine, diethanolamine, triethanolamine, and mixtures thereof.

[0052] As used herein, the term “derivative” refers to a compound whose core structure is the same as or very similar to that of an N-acylethanolamine compound but has chemical or physical modifications (such as different or additional side groups).

[0053] As used herein, “salt” refers to any form of active ingredient in which the active ingredient is in ionic form and coupled to an antiion (cation or anion) or in solution. This also includes complexes of the active ingredient with other molecules and ions, particularly complexes formed through ionic interactions.

[0054] In some embodiments, the molar ratio of MDMA to N-acylethanolamine (or a pharmaceutically acceptable salt thereof) is between about 1:0.2 and about 1:5. In some embodiments, the molar ratio of MDMA to N-acylethanolamine (or a pharmaceutically acceptable salt thereof) is between about 1:0.22 and about 1:4.5, between about 1:0.25 and about 1:4, between about 1:0.28 and about 1:3.5, between about 1:0.33 and about 1:3, between about 1:0.4 and about 1:2.5, between about 1:0.5 and about 1:2, or about 1:1. Each possibility represents a separate embodiment of this disclosure.

[0055] In some embodiments, the molar ratio between MDMA and N-acylethanolamine (or a pharmaceutically acceptable salt thereof) is between about 1:15 and about 1:1800. In some embodiments, the molar ratio between MDMA and N-acylethanolamine is between about 1:16 and about 1:1700, about 1:17 and about 1:1600, about 1:18 and about 1:1500, about 1:19 and about 1:1400, about 1:20 and about 1:1300, about 1:21 and about 1:1200, about 1:22 and about 1:1100, about 1:23 and about 1:1000, about 1:24 and about 1:900, about 1:15 and about 1:800, about 1:16 and about 1:700, about 1:17 and about 1:600, about 1:18 and about 1:500, about 1:19 and about 1:490, about 1:20 and about 1:480, about 1:21 and about 1:470, or about 1:22 and about 1:460. Each possibility represents a separate embodiment of this disclosure. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is between about 1:25 and about 1:450. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is between about 1:10 and about 1:500, about 1:15 and about 1:450, about 1:20 and about 1:400, about 1:25 and about 1:350, about 1:30 and about 1:300, about 1:35 and about 1:250, about 1:40 and about 1:200, or about 1:45 and about 1:150. Each possibility represents a separate embodiment of this disclosure. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is between about 1:50 and about 1:100. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:10. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:20. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:30. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:40. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:50. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:60. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:70. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:80. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:90. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:100. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:110. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:120.In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:130. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:140. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:150. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:160. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:170. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:180. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:190. In some embodiments, the molar ratio of MDMA to N-acylethanolamine is about 1:200. In some embodiments, the molar ratio between MDMA and N-acylethanolamine is at least about 1:10, at least about 1:20, at least about 1:30, at least about 1:40, at least about 1:50, at least about 1:60, at least about 1:70, at least about 1:80, at least about 1:90, or at least about 1:100. Each possibility represents a separate embodiment of this disclosure.

[0056] In some embodiments, the pharmaceutical composition comprises about 0.5-10 mg of MDMA or a salt thereof. In some embodiments, the pharmaceutical composition comprises about 1-9.5 mg, about 1.5-9 mg, about 2-8.5 mg, about 2.5-8 mg, about 3-7.5 mg, about 3.5-7 mg, about 4-6.5 mg, about 4.5-6 mg, or about 5-5.5 mg of MDMA or a salt thereof. In some embodiments, the pharmaceutical composition comprises about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg of MDMA or a salt thereof. Each possibility represents a single embodiment of this disclosure. In some embodiments, the pharmaceutical composition comprises less than about 0.5 mg, less than about 1 mg, less than about 1.5 mg, less than about 2 mg, less than about 2.5 mg, less than about 3 mg, less than about 3.5 mg, less than about 4 mg, less than about 4.5 mg, less than about 5 mg, less than about 5.5 mg, less than about 6 mg, less than about 6.5 mg, less than about 7 mg, less than about 7.5 mg, less than about 8 mg, less than about 8.5 mg, less than about 9 mg, less than about 9.5 mg, or about 10 mg of MDMA or a pharmaceutically acceptable salt thereof. Each possibility represents a separate embodiment of this disclosure. In some embodiments, the pharmaceutical composition comprises about 0.5 mg to about 1 mg, about 0.5 mg to about 1.5 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 2.5 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 3.5 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 4.5 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 5.5 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 6.5 mg, about 0.5 mg to about 7 mg, about 0.5 mg to about 7.5 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 8.5 mg, about 0.5 mg to about 9 mg, or about 0.5 mg to about 9.5 mg of MDMA or a pharmaceutically acceptable salt thereof. Each possibility represents a single embodiment of this disclosure.

[0057] In some embodiments, the pharmaceutical composition comprises about 200-1800 mg of N-acylethanolamine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 250-1550 mg, about 300-1200 mg, about 350-950 mg, about 400-700 mg, about 450-600 mg, or about 500-550 mg of N-acylethanolamine or a pharmaceutically acceptable salt thereof. Each possibility represents a single embodiment of this disclosure. In some embodiments, the pharmaceutical composition comprises at least about 50 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, at least about 300 mg, at least about 350 mg, at least about 400 mg, at least about 450 mg, at least about 500 mg, at least about 550 mg, at least about 600 mg, at least about 650 mg, at least about 700 mg, at least about 750 mg, at least about 800 mg, at least about 850 mg, at least about 900 mg, at least about 950 mg, at least about 1000 mg, at least about 1050 mg, at least about 1100 mg, at least about 1150 mg, at least about 1200 mg, at least about 1250 mg, at least about 1300 mg, at least about 1350 mg, at least about 1400 mg, at least about 1450 mg, at least about 1500 mg, at least about 1550 mg, at least about 1600 mg. mg, at least about 1650 mg, at least about 1700 mg, at least about 1750 mg, or at least about 1800 mg N-acylethanolamine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, or about 1800 mg. N-acylethanolamine or a pharmaceutically acceptable salt thereof. Each possibility represents a single embodiment of this disclosure.

[0058] In some embodiments, the N-acylethanolamine is selected from N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexylamide, palmitoylbutyramide, palmitoylisopropamide, oleoylethanolamine (OEA), palmitoylisopropamide (PIA), pharmaceutically acceptable salts thereof, and any combination thereof. Each possibility represents a single embodiment of this disclosure. In some embodiments, the N-acylethanolamine is PEA or a pharmaceutically acceptable salt thereof. In some embodiments, the N-acylethanolamine consists of PEA or a pharmaceutically acceptable salt thereof. In some embodiments, the N-acylethanolamine consists of PEA.

[0059] In some embodiments, the pharmaceutical composition is formulated for systemic administration. In some embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, sublingual, inhalation, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for oral, oral mucosal, nasal, or sublingual administration. Each possibility represents a separate embodiment of this disclosure. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for oral mucosal administration. In some embodiments, the pharmaceutical composition is formulated for nasal administration. In some embodiments, the pharmaceutical composition is formulated for sublingual administration.

[0060] The techniques for formulating and administering pharmaceuticals are well known in the art and can be found, for example, in "Remington's Pharmaceutical Sciences" by Mack Publishing Co., Easton, Pennsylvania. The pharmaceutical compositions disclosed herein can be manufactured by methods well known in the art, such as conventional methods of mixing, dissolving, granulating, forming into sugar-coated pellets, grinding into fine powder, emulsifying, encapsulating, embedding, or lyophilizing.

[0061] For oral administration, pharmaceutical compositions can be readily formulated by combining the active compound with a pharmaceutically acceptable carrier well known in the art. Such carriers enable the pharmaceutical composition to be formulated into tablets, pills, sugar-coated pills, capsules, liquids, gels, syrups, pastes, suspensions, etc., for oral administration. Pharmacological preparations for oral use can be prepared using solid excipients, optionally by grinding the resulting mixture and processing it into granular mixtures after adding suitable excipients as needed to obtain tablets or sugar-coated pill cores. In particular, suitable excipients include: fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose; and / or physiologically acceptable polymers, such as polyvinylpyrrolidone (PVP). If desired, disintegrants, such as croscarmellose, agar, or alginate or its salts, such as sodium alginate, can be added.

[0062] The term "oral administration" refers to any method of administration in which the active agent can be administered by swallowing, chewing, sucking, or drinking oral dosage forms. Examples of solid dosage forms include regular tablets, multilayer tablets, capsules, capsule-type tablets, etc., which substantially do not release the drug in the mouth or oral cavity.

[0063] Sugar-coated pill cores are provided with a suitable coating. For this purpose, a concentrated sugar solution can be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments can be added to the coating of the tablets or sugar-coated pills to identify or characterize different combinations of active compound dosages.

[0064] Orally administered pharmaceutical compositions include hard or soft-sealed capsules made of gelatin and plasticizers such as glycerin or sorbitol. The capsules may contain an active ingredient mixed with a filler such as lactose, a binder such as starch, a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, a stabilizer may be added. All formulations intended for oral administration should be dose-appropriate for the chosen route of administration. For buccal and sublingual administration, the composition may be in tablet or lozenge form, formulated in a conventional manner or in a binder carrier. Alternatively, the active ingredient may be in powder form to be reconstituted with a suitable medium (e.g., a sterile, pyrogen-free aqueous solution) prior to use.

[0065] Pharmaceutical compositions suitable for use in the context of this disclosure include compositions in which an active ingredient is contained in an amount that effectively achieves the intended purpose. More specifically, a “therapeuticly effective amount” refers to an amount of active ingredient that effectively prevents, alleviates, or improves symptoms or side effects of a disease or condition, or prolongs the survival of a treated subject. The determination of a therapeutically effective amount is entirely within the competence of those skilled in the art, especially when referenced to the detailed disclosure provided herein. More specifically, a “therapeuticly effective amount of a mixture” refers to an amount of at least two active ingredients, wherein each of said active ingredients may be independently absent from a therapeutically effective amount, or wherein neither of said active ingredients may be present in a therapeutically effective amount, yet the mixture effectively prevents, alleviates, or improves symptoms or side effects of a disease or condition, or prolongs the survival of a treated subject. As used herein, the term “mixture” refers to a non-covalent combination of two molecules.

[0066] For any formulation used in the methods of this disclosure, the dose or therapeutically effective amount can initially be estimated from in vitro, in vivo, and cell culture assays. For example, the dose can be formulated in animal models to achieve the desired concentration or titer. This information can be used to more precisely determine the useful dose in humans. The dose of each compound in the claimed combinations depends on several factors, including: the method of administration, the disease to be treated, the severity of the disease, whether the disease is to be treated or prevented, and the age, weight, and health status of the person to be treated. Additionally, pharmacogenomic information (the effect of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of the treatment) for a particular patient may influence the dose used. Continuous daily dosing may not be necessary; treatment regimens may require cycles during which no drug is administered, or treatment may be provided as needed during acute exacerbations of the disease. Dose escalation may or may not be necessary; treatment regimens may require dose reduction. The toxicity and efficacy of the active ingredients described herein can be determined using standard pharmaceutical procedures in vitro, in cell cultures, or in laboratory animals. Data obtained from these in vitro and cell culture assays, as well as from animal studies, can be used to develop dose ranges for human use. The dose may vary depending on the dosage form and route of administration used. Individual physicians can choose the exact formulation, route of administration, and dosage based on the patient's condition (see, for example, Fingl, E. et al. (1975), "The Pharmacological Basis of Therapeutics," Ch. 1, p. 1). Depending on the severity and responsiveness of the disease to be treated, administration may be a single or multiple doses, lasting from several days to several weeks, or until a cure or reduction of the disease state is achieved.

[0067] In another aspect, this disclosure also provides a dosage unit comprising or composed of the above-described pharmaceutical composition.

[0068] In some embodiments, the dosage unit comprises the above-described pharmaceutical composition. In some embodiments, the dosage unit is composed of the above-described pharmaceutical composition. In some embodiments, the dosage unit is formulated as a gel, powder, or spray. In some embodiments, the dosage unit is formulated as a gel. In some embodiments, the dosage unit is formulated as a powder. In some embodiments, the dosage unit is formulated as a spray.

[0069] In another aspect, this disclosure also provides pharmaceutical compositions or dosage units as described above for use in methods of preventing or treating diseases suitable for prevention or treatment by MDMA or its pharmaceutically acceptable salts.

[0070] As used herein, the term “treatment” includes, but is not limited to, any one or more of the following: eliminating, alleviating, inhibiting, weakening, blocking, suppressing, reducing, delaying, stopping, mitigating or preventing one or more symptoms or side effects of the disease or ailment of this disclosure.

[0071] The term "acute" refers to a disease with a relatively short but severe course.

[0072] As used herein, the term "chronic" refers to the duration of the disease or ailment described in this disclosure, which may be weeks, months, or possibly years. The severity of the disease or ailment can be distinguished based on a variety of factors such as the patient's age, body temperature, season, and type of disease.

[0073] As used in this document with respect to a value, multiple values, or a range of values ​​defined by a minimum and a maximum value, the term “about” refers to a value that is 10% lower and / or higher than the corresponding value, multiple values, or range of values. For example, the expression “about 1” refers to “0.9 to 1.1”, the expression “about 1 or 2” refers to “0.9 to 1.1 or 1.8 to 2.2”, and the expression “about 1 to about 2” refers to “0.9 to 2.2”.

[0074] The terms “comprises / comprising”, “includes / including”, “have”, and their variant forms all refer to “including but not limited to”.

[0075] The term "composed of" means "including and limited to".

[0076] The term "consistently of" means that a composition, method, or microcapsule may contain additional ingredients, steps, and / or components, but only if such additional ingredients, steps, and / or components do not substantially alter the essential and novel characteristics of the claimed composition, method, or structure.

[0077] As used herein, unless the context clearly specifies otherwise, the singular forms “a / an,” “an,” and “the” include plural references. For example, the terms “a compound” or “at least one compound” can include multiple compounds, including mixtures thereof.

[0078] Toxicity and efficacy can be determined using standard drug procedures in cell cultures or laboratory animals, such as those used to determine LD50. 50 (The dose that is lethal to 50% of the population) and ED 50 (The dose that is effective in 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as the ratio LD50. 50 / ED 50 Compositions exhibiting a high therapeutic index are preferred.

[0079] Data obtained from cell culture assays or animal studies can be used to determine dosage ranges for human use. Therapeutic doses obtained in one animal model can be converted to doses used in another animal (including humans) using conversion factors known in the art (see, for example, Freireich et al.). Cancer Chemother. Reports 50(4):219-244 (1966) and the equivalent surface area dose factor in the table below).

[0080] Table 1. Equivalent Surface Area Dose Factor The preferred dosage of such compounds includes ED. 50 And within a range of circulating concentrations with very low or no toxicity. Dosage may vary within this range depending on the dosage form and route of administration. Generally, the therapeutically effective dose may vary depending on the subject's age, disease, sex, and the severity of the subject's medical condition. Dosage may be determined by a physician and adjusted as needed to accommodate observed therapeutic effects.

[0081] Those skilled in the art will recognize that in vivo and in vitro tests using appropriate, known and generally accepted cell and / or animal models can predict the ability of an investigational compound to treat or prevent a given condition.

[0082] Those skilled in the art should also recognize that human clinical trials (including first-in-human trials, dose range trials, and efficacy trials) conducted in healthy patients and / or patients with a given condition can be performed using methods well known in the clinical and medical fields.

[0083] In some embodiments, this disclosure provides pharmaceutical compositions comprising MDMA or pharmaceutically acceptable salts thereof. In some embodiments, this disclosure provides methods for preventing and / or treating a variety of disorders responsive to MDMA treatment, such as post-traumatic stress disorder (PTSD), anxiety, and eating disorders.

[0084] In some embodiments, this disclosure provides pharmaceutical compositions comprising a combination of MDMA or a pharmaceutically acceptable salt thereof with N-acylethanolamine or a pharmaceutically acceptable salt thereof. These combinations are defined in part by a specific molar ratio between the active agents and / or their dosage and can be used in a variety of methods. In some embodiments, this disclosure provides methods for preventing and / or treating a variety of disorders that respond to MDMA treatment, such as post-traumatic stress disorder (PTSD), anxiety, and eating disorders.

[0085] One or more embodiments of this disclosure include the following embodiments 1 to 39: 1. A pharmaceutical composition comprising 3,4-methylenedioxymethylamphetamine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier and / or excipient.

[0086] 2. The pharmaceutical composition of embodiment 1, wherein the composition is a unit dosage form composition.

[0087] 3. The pharmaceutical composition of embodiment 2, wherein the pharmaceutical composition is a solid unit dosage form composition.

[0088] 4. The pharmaceutical composition of embodiment 2, wherein the pharmaceutical composition is a liquid unit dosage form composition.

[0089] 5. The pharmaceutical composition of embodiment 2, wherein the pharmaceutical composition is packaged as a single unit dose or as multiple single unit doses.

[0090] 6. The pharmaceutical composition of embodiment 2, wherein the unit dosage form comprises 50-200 mg of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof.

[0091] 7. The pharmaceutical composition of Embodiment 2, wherein the unit dosage form comprises 0.2 mg / kg body weight to 5 mg / kg body weight of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof.

[0092] 8. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition is formulated for oral administration, sublingual administration or intravenous administration.

[0093] 9. A method for treating post-traumatic stress disorder, the method comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising 3,4-methylenedioxymethylamphetamine or a pharmaceutically acceptable salt thereof.

[0094] 10. A method for treating anxiety, the method comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof.

[0095] 11. A method for treating an eating disorder, the method comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof.

[0096] 12. The method of embodiment 9, 10 or 11, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

[0097] 13. The method of embodiment 9, 10 or 11, wherein the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate or syrup.

[0098] 14. The method of embodiment 9, 10 or 11, wherein the pharmaceutical composition is a unit dosage form composition.

[0099] 15. The method of embodiment 9, 10 or 11, wherein the amount of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof in the unit dosage form is in the range of about 50-200 mg.

[0100] 16. The method of embodiment 9, 10 or 11, wherein the amount of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof in the unit dosage form is in the range of about 0.2 mg / kg body weight to 5 mg / kg body weight.

[0101] 17. The method of embodiment 9, 10 or 11, wherein the pharmaceutical composition is administered orally or intravenously.

[0102] 18. A pharmaceutical composition comprising 3,4-methylenedioxymethylamphetamine or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or excipient.

[0103] 19. The pharmaceutical composition of embodiment 18, wherein the composition is a unit dosage form composition.

[0104] 20. The pharmaceutical composition of embodiment 19, wherein the pharmaceutical composition is a solid unit dosage form composition.

[0105] 21. The pharmaceutical composition of embodiment 19, wherein the pharmaceutical composition is a liquid unit dosage form composition.

[0106] 22. The pharmaceutical composition of embodiment 19, wherein the pharmaceutical composition is packaged as a single unit dose or as multiple single unit doses.

[0107] 23. The pharmaceutical composition of embodiment 19, wherein the unit dosage form comprises 50-200 mg of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof.

[0108] 24. The pharmaceutical composition of embodiment 19, wherein the unit dosage form comprises 0.2 mg / kg body weight to 5 mg / kg body weight of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof.

[0109] 25. The pharmaceutical composition of embodiment 19, wherein the unit dosage form comprises 50 mg to 1800 mg of N-acylethanolamine or a pharmaceutically acceptable salt thereof.

[0110] 26. The pharmaceutical composition of embodiment 18, wherein the pharmaceutical composition is formulated for oral or intravenous administration.

[0111] 27. A method for treating post-traumatic stress disorder, the method comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising 3,4-methylenedioxymethylamphetamine or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof.

[0112] 28. A method for treating anxiety, the method comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising 3,4-methylenedioxymethylamphetamine or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof.

[0113] 29. A method for treating an eating disorder, the method comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising 3,4-methylenedioxymethylamphetamine or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof.

[0114] 30. The method of embodiment 27, 28 or 29, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

[0115] 31. The method of embodiment 27, 28 or 29, wherein the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate or syrup.

[0116] 32. The method of embodiment 27, 28 or 29, wherein the pharmaceutical composition is a unit dosage form composition.

[0117] 33. The method of embodiment 27, 28 or 29, wherein the amount of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof in the unit dosage form is in the range of about 50-200 mg.

[0118] 34. The method of embodiment 27, 28 or 29, wherein the amount of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof in the unit dosage form is in the range of about 0.2 mg / kg body weight to 5 mg / kg body weight.

[0119] 35. The method of embodiment 27, 28 or 29, wherein the pharmaceutical composition is administered orally or intravenously.

[0120] 36. A pharmaceutical composition according to any of the foregoing embodiments, wherein the N-acylethanolamine is selected from N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexylamide, palmitoylbutyramide, palmitoylisopropamide, oleoylethanolamine (OEA), palmitoylisopropamide (PIA), their salts, and any combination thereof.

[0121] 37. The method of any of the foregoing embodiments, wherein the N-acylethanolamine is selected from N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexylamide, palmitoylbutyramide, palmitoylisopropamide, oleoylethanolamine (OEA), palmitoylisopropamide (PIA), their salts, and any combination thereof.

[0122] 38. A pharmaceutical composition according to any of the foregoing embodiments, wherein the N-acylethanolamine is PEA or a pharmaceutically acceptable salt thereof.

[0123] 39. The method of any of the foregoing embodiments, wherein the N-acylethanolamine is PEA or a pharmaceutically acceptable salt thereof.

Claims

1. A pharmaceutical composition comprising 3,4-methylenedioxymethylamphetamine or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier and / or excipient.

2. The pharmaceutical composition according to claim 1, wherein the composition is a unit dosage form composition.

3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is a solid unit dosage form composition.

4. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is a liquid unit dosage form composition.

5. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition is packaged as a single unit dose or as multiple single unit doses.

6. The pharmaceutical composition of claim 2, wherein the unit dosage form comprises 50-200 mg of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition of claim 2, wherein the unit dosage form comprises 0.2 mg / kg body weight to 5 mg / kg body weight of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is formulated for oral administration, sublingual administration or intravenous administration.

9. A method for treating post-traumatic stress disorder, the method comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof.

10. A method for treating anxiety, the method comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising 3,4-methylenedioxymethylamphetamine or a pharmaceutically acceptable salt thereof.

11. A method for treating an eating disorder, the method comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising 3,4-methylenedioxymethylamphetamine or a pharmaceutically acceptable salt thereof.

12. The method according to claim 9, 10 or 11, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

13. The method according to claim 9, 10 or 11, wherein the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate or syrup.

14. The method according to claim 9, 10 or 11, wherein the pharmaceutical composition is a unit dosage form composition.

15. The method according to claim 9, 10 or 11, wherein the amount of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof in the unit dosage form is in the range of about 50-200 mg.

16. The method according to claim 9, 10 or 11, wherein the amount of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof in the unit dosage form is in the range of about 0.2 mg / kg body weight to 5 mg / kg body weight.

17. The method according to claim 9, 10 or 11, wherein the pharmaceutical composition is administered orally or intravenously.

18. A pharmaceutical composition comprising 3,4-methylenedioxymethylamphetamine or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier and / or excipient.

19. The pharmaceutical composition according to claim 18, wherein the composition is a unit dosage form composition.

20. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition is a solid unit dosage form composition.

21. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition is a liquid unit dosage form composition.

22. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition is packaged as a single unit dose or as multiple single unit doses.

23. The pharmaceutical composition of claim 19, wherein the unit dosage form comprises 50-200 mg of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof.

24. The pharmaceutical composition of claim 19, wherein the unit dosage form comprises 0.2 mg / kg body weight to 5 mg / kg body weight of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof.

25. The pharmaceutical composition of claim 19, wherein the unit dosage form comprises 50 mg to 1800 mg of N-acylethanolamine or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is formulated for oral or intravenous administration.

27. A method for treating post-traumatic stress disorder, the method comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising 3,4-methylenedioxymethylamphetamine or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof.

28. A method for treating anxiety, the method comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising 3,4-methylenedioxymethylamphetamine or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof.

29. A method for treating an eating disorder, the method comprising administering to a subject in need a therapeutically effective amount of a pharmaceutical composition comprising 3,4-methylenedioxymethylamphetamine or a pharmaceutically acceptable salt thereof and N-acylethanolamine or a pharmaceutically acceptable salt thereof.

30. The method according to claim 27, 28 or 29, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier and / or excipient.

31. The method according to claim 27, 28 or 29, wherein the pharmaceutical composition is a free-flowing powder, tablet, capsule, lozenge, liquid, liquid concentrate or syrup.

32. The method according to claim 27, 28 or 29, wherein the pharmaceutical composition is a unit dosage form composition.

33. The method according to claim 27, 28 or 29, wherein the amount of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof in the unit dosage form is in the range of about 50-200 mg.

34. The method according to claim 27, 28 or 29, wherein the amount of 3,4-methylenedioxymethamphetamine or a pharmaceutically acceptable salt thereof in the unit dosage form is in the range of about 0.2 mg / kg body weight to 5 mg / kg body weight.

35. The method according to claim 27, 28 or 29, wherein the pharmaceutical composition is administered orally or intravenously.

36. The pharmaceutical composition according to any of the preceding claims, wherein the N-acylethanolamine is selected from N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexylamide, palmitoylbutyramide, palmitoylisopropamide, oleoylethanolamine (OEA), palmitoylisopropamide (PIA), their salts, and any combination thereof.

37. The method according to any of the preceding claims, wherein the N-acylethanolamine is selected from N-palmitoylethanolamine (PEA), Me-palmitoylethanolamide (Me-PEA), palmitoylcyclohexylamide, palmitoylbutyramide, palmitoylisopropamide, oleoylethanolamine (OEA), palmitoylisopropamide (PIA), their salts, and any combination thereof.

38. The pharmaceutical composition according to any of the preceding claims, wherein the N-acylethanolamine is PEA or a pharmaceutically acceptable salt thereof.

39. The method according to any of the preceding claims, wherein the N-acylethanolamine is PEA or a pharmaceutically acceptable salt thereof.

Images