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WO2024178082A2 - Composition of opioid receptor modulator and mdma for use thereof - Google Patents

Composition of opioid receptor modulator and mdma for use thereof Download PDF

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Publication number
WO2024178082A2
WO2024178082A2 PCT/US2024/016673 US2024016673W WO2024178082A2 WO 2024178082 A2 WO2024178082 A2 WO 2024178082A2 US 2024016673 W US2024016673 W US 2024016673W WO 2024178082 A2 WO2024178082 A2 WO 2024178082A2
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Prior art keywords
opioid receptor
receptor modulator
agent
disorder
amount
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French (fr)
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WO2024178082A3 (en
Inventor
John KRYSTAL
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Freedom Biosciences Inc
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Freedom Biosciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • the agent comprises a 3,4- Methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), N- ethyl-3,4-methylenedioxyamphetamine (MDEA), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha-ethyl-N-methylphenethylamine (MBDB), 1-Benzofuran- 5-ylpropan-2-amine (5-APB), 1-(benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB), 6-(2- aminopropyl)benzofuran (6-APB), 1-(benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N-methylcathinone (methylone), 4-methylmethcathinone (mephedrone), gamma-Hydroxybutyric acid (GHB), ⁇ -Meth
  • MDMA
  • the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta-opioid receptor modulator.
  • the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist.
  • the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, naltrindole, UPHIT ((1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide), DIPPA (2-(3,4-dichlorophenyl)- N-methyl-N-[(1S)- 1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide), JDTic ((3R)-7-Hydroxy-N- [(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl]-1
  • the agent comprises 3,4-Methylenedioxymethamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • MDMA 3,4-Methylenedioxymethamphetamine
  • the agent comprises 3,4- methylenedioxyamphetamine (MDA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • MDA 3,4- methylenedioxyamphetamine
  • MDEA N-ethyl-3,4-methylenedioxyamphetamine
  • MDEA N-ethyl-3,4-methylenedioxyamphetamine
  • the opioid receptor modulator is present in an amount of about 1-150 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-50 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-30 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-20 mg.
  • the agent is present in an amount of about 0.1-200 mg. In some embodiments, the agent is present in an amount of about 0.2-100 mg. In some embodiments, the agent is present in an amount of about 0.2-10 mg. In some embodiments, the agent is present in an amount of about 0.2-1 mg.
  • the present disclosure also provides a method for treating, ameliorating or preventing a disease or disorder in a subject in need thereof comprising administering the pharmaceutical composition disclosed herein.
  • An additional aspect of the present disclosure provides a kit comprising an opioid receptor modulator and an agent, wherein the agent comprises a 3,4-Methylenedioxy methamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric WSGR Docket No.60906-708601 isomer thereof, or any combination thereof.
  • the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta-opioid receptor modulator.
  • the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist.
  • the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, naltrindole, UPHIT ((1S,2S)-trans-2-Isothiocyanato-4,5- dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide), DIPPA (2-(3,4- dichlorophenyl)- N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1- pyrrolidinyl)ethyl]acetamide), JDTic ((3R)-7-Hydroxy-N-[(2S)-1-[(3R
  • the agent comprises 3,4-Methylenedioxymethamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • MDMA 3,4-Methylenedioxymethamphetamine
  • MDA 3,4- methylenedioxyamphetamine
  • the agent WSGR Docket No.60906-708601 comprises N-ethyl-3,4-methylenedioxyamphetamine (MDEA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • MDEA N-ethyl-3,4-methylenedioxyamphetamine
  • the opioid receptor modulator is present in an amount of about 1-150 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-50 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-30 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-20 mg. [11] In some embodiments, the agent is present in an amount of about 0.1-200 mg.
  • the agent is present in an amount of about 0.2-100 mg. In some embodiments, the agent is present in an amount of about 0.2-10 mg. In some embodiments, the agent is present in an amount of about 0.2-1 mg.
  • the agent comprises a 3,4-Methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), N-ethyl-3,4-methylenedioxyamphetamine (MDEA), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha- ethyl-N-methylphenethylamine (MBDB), 1-Benzofuran-5-ylpropan-2-amine (5-APB), 1- (benzofuran-5-yl)-N-methylpropan-2-amine
  • the opioid receptor modulator and the agent are administered concurrently. In some embodiments, the opioid receptor modulator and the agent are administered separately. In some embodiments, the opioid receptor modulator and the agent are administered sequentially. [14] In some embodiments, the opioid receptor modulator is administered once per day, twice per day, or three times per day. In some embodiments, the opioid receptor modulator is administered once per week, twice per week, or three times per week. In some embodiments, the opioid receptor modulator is administered once per month, twice per month, or three times per month. In some embodiments, the agent is administered once per day, twice per day, or three times per day. In some embodiments, the agent is administered once per week, twice per week, or three times per week.
  • the agent is administered once per month, twice per month, or three times per month.
  • the opioid receptor modulator is administered to the subject by a route selected from the group consisting of intranasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous.
  • the agent is administered to the subject by a route selected from the group consisting of intranasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous.
  • administration of the opioid receptor modulator prevents, ameliorates, or minimizes abuse of the agent by the subject, wherein the abuse is contributed by a behavioral effect of the agent including agent liking, agent craving, or agent seeking.
  • the agent comprises 3,4-methylenedioxymethamphetamine (MDMA), 3,4- methylenedioxyamphetamine (MDA), N-ethyl-3,4-methylenedioxyamphetamine (MDEA), 3,4- methylenedioxy-N-hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha-ethyl-N- methylphenethylamine (MBDB), 1-Benzofuran-5-ylpropan-2-amine (5-APB), 1-(benzofuran-5- yl)-N-methylpropan-2-amine (5-MAPB), 6-(2-aminopropyl)benzofuran (6-APB), 1- (benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N- methylcathinone (methylone), 4-methylmethcathinone (mephedrone), gamma-Hydroxybutyric acid (GHB), ⁇ -
  • the disease or disorder is selected from the group consisting of major depressive disorder, major depressive disorder, major depressive episode in bipolar disorder (bipolar depression), bipolar I disorder, bipolar II disorder, persistent depressive disorder (dysthymia), disruptive mood dysregulation disorder, major depressive disorder (including major depressive episode), resistant depressive disorder, partially responsive depressive disorder, substance use disorder (with or without anxiety or depressive disorder), alcohol use disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, anxiety disorder, generalized anxiety disorder, social anxiety disorder (social phobia), specific phobia, panic disorder, agoraphobia, separation anxiety disorder, selective mutism, substance-induced anxiety disorder, medication-induced anxiety disorder, anxiety disorder due to another medical condition, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, obsessive compulsive disorder, bulimia nervosa, anorexia ner
  • the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta-opioid receptor modulator.
  • the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist.
  • the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, naltrindole, UPHIT ((1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide), DIPPA (2-(3,4-dichlorophenyl)- N-methyl-N-[(1S)- 1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide), JDTic ((3R)-7-Hydroxy-N- [(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl]-1
  • the agent comprises 3,4-Methylenedioxymethamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the agent comprises 3,4- methylenedioxyamphetamine (MDA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the agent comprises N-ethyl-3,4-methylenedioxyamphetamine (MDEA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the opioid receptor modulator is present in an amount of about 1-150 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-50 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-30 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-20 mg. [21] In some embodiments, the agent is present in an amount of about 0.1-200 mg. In some embodiments, the agent is present in an amount of about 0.2-100 mg. In some embodiments, the agent is present in an amount of about 0.2-10 mg. In some embodiments, the agent is present in an amount of about 0.2-1 mg.
  • FIG.1 shows naloxone effects in intravenous self-administration of 3,4- methylenedioxymethamphetamine (MDMA), according to some embodiments of the present disclosure.
  • FIG.2 shows naltrexone effects in intravenous self-administration of MDMA, according to some embodiments of the present disclosure.
  • Opioid receptor modulators provide effective treatments for acute and chronic pain. Opioid receptor modulators are opioid antagonists so that they bind to opioid receptors. The opioid receptors in the central nervous system (CNS) have each class having subtype receptors.
  • Opioid receptor modulators can reverse and block the effects of the opioids, such as heroin, morphine, and oxycodone. They reduce and suppress opioid cravings. There is no abuse and diversion potential with opioid receptor modulators.
  • opioid receptor modulators particularly naltrexone and naloxone, have been approved by the U.S. Food and Drug administration for the treatment of opioid use disorder and alcohol use disorder.
  • MDMA 3,4-Methylene-dioxymethamphetamine
  • ecstasy or molly is a widely abused recreational drug. It is known to cause psychostimulation and can induce hallucination and long-term neuropsychiatric behaviors, including depression and psychosis.
  • FDA “breakthrough therapy” status after Phase 2 clinical trials.
  • MDMA shows promise for treating major depressive disorder by rapidly releasing and increasing levels of serotonin and dopamine in the brain.
  • Recent studies show that MDMA has the potential to act as a rapid-acting antidepressant via its modulation of the 5- hydroxytryptamine (5-HT) system and as an augmentation strategy in cognitive therapy.
  • 5- hydroxytryptamine 5 hydroxytryptamine
  • MDMA also has the potential for the treatment of post-traumatic stress disorder (PTSD).
  • PTSD post-traumatic stress disorder
  • MDMA rapidly increases availability of extracellular 5-HT at the synapse, mirroring the action of commonly prescribed antidepressants.
  • SSRIs selective serotonin reuptake inhibitors
  • MDMA could offer instantaneous relief. This rapid onset is an attractive prospect for treatment-resistant depression (TRD).
  • TRD treatment-resistant depression
  • MDMA has potential of the rapid treatment of depression and PTSD, access to MDMA is constrained by concerns about their abuse liability and the possibility that it may worsen other addictions. Such risks limit the contexts in which MDMA may be administered, reduce the number of providers interested in delivering the treatment, and decrease the number of patients eligible to.
  • Empathogen and entactogen are a class of psychoactive drugs that produce distinctive emotional and social effects similar to those of MDMA.
  • This class of the drugs comprises 3,4-methylenedioxyamphetamine (MDA, ‘Love'), N-ethyl-3,4- methylenedioxyamphetamine (MDEA, ‘Eve'), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha-ethyl-N-methylphenethylamine (MBDB, "EDEN” or "Methyl-J”), 1-Benzofuran-5-ylpropan-2-amine (5-APB), 1-(benzofuran-5-yl)-N-methylpropan- 2-amine (5-MAPB), 6-(2-aminopropyl)benzofuran (6-APB), 1-(benzofuran-6-yl)-N- methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N-methylcathinone (methylone, "MDMC”, “ ⁇ k-MDMA” and "M1”), 4-methylmethcathinone (mephedrone, 4-
  • the present disclosure provides an innovative pharmaceutical composition and a method thereof.
  • the pharmaceutical composition and the method thereof disclosed herein may be also applied to MDA, MDEA, MDOH, MBDB, 5-APB, 5-MAPB, 6-APB, 6-MAPB, methylone, mephedrone, GHB, ⁇ MT, ⁇ ET, and MDAI.
  • compositions comprising an opioid receptor modulator and an agent, wherein the agent comprises a 3,4- methylenedioxymethamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • MDMA 3,4- methylenedioxymethamphetamine
  • Any opioid receptor modulator known in the art is contemplated within the present application.
  • the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta-opioid receptor modulator.
  • the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist.
  • the opioid receptor modulator comprises a mu-opioid receptor modulator.
  • the opioid receptor WSGR Docket No.60906-708601 modulator comprises a kappa-opioid receptor modulator.
  • the opioid receptor modulator comprises a delta-opioid receptor modulator.
  • the agent comprises 3,4-methylenedioxyamphetamine (MDA, ‘Love'), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the agent comprises N-ethyl-3,4- methylenedioxyamphetamine (MDEA, ‘Eve'), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • MDEA N-ethyl-3,4- methylenedioxyamphetamine
  • the agent comprises 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH) , any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the agent comprises 3,4-methylenedioxy-alpha-ethyl-N-methylphenethylamine (MBDB, "EDEN” or “Methyl-J”) , any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the agent comprises 1- Benzofuran-5-ylpropan-2-amine (5-APB) , any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the agent comprises 1- (benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB) , any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the agent comprises 6-(2-aminopropyl)benzofuran (6-APB), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the agent comprises 1-(benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the agent comprises 3,4-methylenedioxy-N-methylcathinone (methylone, "MDMC”, “ ⁇ k-MDMA” and “M1"), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the agent comprises 4- methylmethcathinone (mephedrone, 4-MMC, and 4-methylephedrone), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the agent comprises gamma-Hydroxybutyric acid (GHB), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the agent comprises ⁇ -Methyltryptamine ( ⁇ MT), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the agent comprises ⁇ -Ethyltryptamine ( ⁇ ET), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • ⁇ ET ⁇ -Ethyltryptamine
  • MDAI 5,6-methylenedioxy-2-aminoindane
  • the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, naltrindole, UPHIT WSGR Docket No.60906-708601 ((1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide), DIPPA (2-(3,4-dichlorophenyl)- N-methyl-N-[(1S)- 1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide), JDTic ((3R)-7-Hydroxy-N- [(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin
  • the compound is naltrexone, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • administration of the opioid receptor modulator prevents, ameliorates, or minimizes abuse of the agent by the subject, wherein the abuse is contributed by a behavioral effect of the agent including agent liking, agent craving, or agent seeking.
  • the agent comprises 3,4-methylenedioxymethamphetamine (MDMA), 3,4- methylenedioxyamphetamine (MDA, ‘Love'), N-ethyl-3,4-methylenedioxyamphetamine (MDEA, ‘Eve'), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 3,4-methylenedioxy- alpha-ethyl-N-methylphenethylamine (MBDB, "EDEN” or "Methyl-J”), 1-Benzofuran-5- ylpropan-2-amine (5-APB), 1-(benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB), 6-(2- aminopropyl)benzofuran (6-APB), 1-(benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N-methylcathinone (methylone, "MDMC”, “ ⁇ k-MDMA” and "M1"),
  • the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and WSGR Docket No.60906-708601 an opioid receptor partial agonist.
  • the opioid receptor modulator is an opioid receptor antagonist.
  • the opioid receptor modulator is an opioid receptor negative allosteric modulator.
  • the opioid receptor modulator is an opioid receptor partial agonist.
  • Non-limiting examples of opioid receptor modulators useful within the methods of the present application are recited herein, and include any salt, solvate, enantiomer, tautomer, stereoisomer, and/or geometric isomer thereof, or any mixtures thereof.
  • the opioid receptor modulator may be naltrexone (also known as 17-(cyclopropylmethyl)-4,5 ⁇ - epoxy- 3,14-dihydroxymorphinan-6-one).
  • the opioid receptor modulator may be long-acting naltrexone (extended-release naltrexone, e.g., Vivitrol ® ).
  • the opioid receptor modulator may be naloxone (also known as (4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-prop-2-enyl-2,4,5,6,7a,13-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinoline-7-one, Narcan, Evzio, or Nyxoid).
  • the opioid receptor modulator may be long-acting naloxone (extended-release naloxone).
  • the opioid receptor modulator may be nalmefene (also known as 17-cyclopropylmethyl-4,5 ⁇ -epoxy-6-methylenemorphinan-3,14-diol, nalmetrene, or Selincro). In certain embodiments, the opioid receptor modulator may be long-acting nalmefene (extended-release nalmefene).
  • the opioid receptor modulator may be nalodeine (also known as N-allylnorcodeine, or (4R,4aR,7S,7aR,12bS)-9-methoxy-3-prop-2- enyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol).
  • the long-acting naltrexone has a longer serum half-life than naltrexone.
  • the long-acting naloxone has a longer serum half-life than naloxone.
  • the long-acting nalmefene has a longer serum half-life than nalmefene.
  • the opioid receptor modulator may be naltrindole, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination highly selective delta opioid receptor antagonist having a structure of .
  • the opioid receptor modulator may be UPHIT ((1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • UPHIT ((1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide
  • any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof or any combination thereof.
  • UPHIT is a kappa opioid receptor modulator having a structure of .
  • the opioid receptor modulator may be DIPPA (2-(3,4-dichlorophenyl)- N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1- pyrrolidinyl)ethyl]acetamide), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • DIPPA is a kappa opioid receptor modulator having a structure of .
  • the opioid receptor modulator may be JDTic ((3R)-7-Hydroxy-N-[(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1- yl]-3-methylbutan-2-yl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • JDTic ((3R)-7-Hydroxy-N-[(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1- yl]-3-methylbutan-2-yl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide), any salt, solvate,
  • JDTic is a kappa opioid receptor antagonist having a structure of
  • the opioid receptor WSGR Docket No.60906-708601 modulator may be Nor-BNI (Norbinaltorphimine), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • Nor-BNI Nor-BNI (Norbinaltorphimine), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • Nor-BNI Nor-BNI (Norbinaltorphimine) is a kappa opioid receptor antagonist .
  • the opioid receptor modulator may be GNTI (5’-Guanidinonaltrindole), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • GNTI 5’-Guanidinonaltrindole
  • the opioid receptor modulator may be CERC-501 (4-(4- ⁇ [(2S)-2-(3,5- Dimethylphenyl)-1-pyrrolidinyl]methyl ⁇ phenoxy)-3-fluorobenzamide), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • CERC-501 4-(4- ⁇ [(2S)-2-(3,5- Dimethylphenyl)-1-pyrrolidinyl]methyl ⁇ phenoxy)-3-fluorobenzamide
  • any salt solvate
  • enantiomer tautomer
  • stereoisomer stereoisomer
  • geometric isomer thereof or any combination thereof.
  • CERC-501 (4-(4- ⁇ [(2S)-2-(3,5-Dimethylphenyl)-1- pyrrolidinyl] -3- is a kappa opioid receptor antagonist having a structure of .
  • the opioid receptor WSGR Docket No.60906-708601 modulator may be PF-4455242 (2-methylN-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4- yl)methyl)propan-1-amine), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • PF- 4455242 (2-methylN-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine) is a kappa opioid receptor antagonist having a structure .
  • the opioid receptor modulator may be AZ-MTAB (3- [[(3-endo)-8-[(5- methyl-2-thienyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]oxy]-benzamide), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • AZ-MTAB [[(3-endo)-8-[(5- methyl-2-thienyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]oxy]-benzamide
  • any salt solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • AZ-MTAB (3- [[(3-endo)-8-[(5-methyl-2- thienyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]oxy]-benzamide) is a kappa opioid receptor antagonist having a structure .
  • the opioid receptor modulator may be Arodyn (Ac[Phe 1,2,3 , Arg 4 , D-Ala 8 ]dynorphin A-(1–11) amide), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • Arodyn (Ac[Phe 1,2,3 , Arg 4 , D- Ala 8 ]dynorphin A-(1–11) amide) is a kappa opioid receptor antagonist.
  • the opioid receptor modulator may be Zyklophin (N-Benzyl-L-tyrosylglycylglycyl-N- [(3S,6S,9S,12S)-6-[(2S)-2-butanyl]-3-( ⁇ (2S)-5-carbamimidamido-1-[(2S)-2- ⁇ [(2S)-1,6-diamino- 1-oxo-2-hexanyl]carbamoyl ⁇ -1-pyrrolidinyl]-1-oxo-2-pentanyl ⁇ carbamoyl)-9-(3- carbamimidamidopropyl)-5,8,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-12-yl]-L- phenylalaninamide), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • Buprenorphine ((2S)-2-[(5R,6R,7R,14S)-9 ⁇ -cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6- methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol) is a kappa opioid receptor antagonist.
  • the opioid receptor modulator may be CYX-5, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • CYX-5 is a delta opioid receptor antagonist having a structure .
  • the opioid receptor modulator may be eluxadoline, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • eluxadoline is a delta opioid receptor antagonist.
  • the opioid receptor modulator may be D24M (C75H92N12O14), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • D24M C75H92N12O14
  • the opioid may any enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • FBNTI is a delta opioid receptor antagonist.
  • the opioid receptor modulator may be BOM (benzylideneoxymorphone), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • BOM benzylideneoxymorphone
  • the opioid receptor modulator may be naldemedine (Symproic R ), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • naldemedine is a mu opioid receptor anatagonist having a structure of .
  • the opioid receptor modulator may be ICI- 174,864 (N, N-diallyl-Tyr-Aib-Aib-Phe-Leu, C 38 H 53 N 5 O 7 ), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • ICI-174,864 N, N-diallyl-Tyr-Aib-Aib-Phe-Leu, C 38 H 53 N 5 O 7
  • the opioid receptor modulator may be naltriben, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • naltriben is a delta opioid receptor antagonist having a structure of WSGR Docket No.60906-708601
  • the opioid receptor modulator may be NCGC00485585-01, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the opioid receptor modulator may be NCGC00114968-02, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • Sakamuru et al. J Chem Inf Model.2021 Jun 28; 61(6): 2675– a mu opioid receptor antagonist having a structure of .
  • the opioid receptor modulator may be NCGC00485288-01, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the opioid receptor modulator may be NCGC00106344-01, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • NCGC00106344-01 is a kappa opioid receptor antagonist having a structure of WSGR Docket No.60906-708601 embodiments, the opioid receptor modulator may be enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Sakamuru et al.
  • the opioid receptor modulator may be cyclopropylsulfonamide 9f (17-(Cyclopropylsulfonyl)-6,7- didehydro-4,5 ⁇ -epoxyindolo[2′,3′:6,7]morphinan-3,14 ⁇ -diol), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the opioid receptor modulator may be cyclopropylsulfonamide 9f (17-(Cyclopropylsulfonyl)-6,7- didehydro-4,5 ⁇ -epoxyindolo[2′,3′:6,7]morphinan-3,14 ⁇ -diol), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the opioid receptor modulator may be phenethylsulfonamide 9e (6,7-Didehydro-4,5 ⁇ -epoxy-17-((2- phenylethyl)sulfonyl)indolo[2′,3′:6,7]morphinan-3,14 ⁇ -diol), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the opioid receptor modulator may be Methylnaltrexone (Relistor), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the opioid receptor modulator may be Naloxegol (Movantik), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Urits et al. (Psychopharmacol Bull.2020; 50(3): 97–118), Naloxegol (Movantik) is a mu opioid receptor antagonist. [40] In some embodiments, the opioid receptor modulator is present in an amount of about 1-150 mg in the pharmaceutical composition.
  • the opioid receptor modulator is present in an amount of about 5-50 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-30 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-20 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 mg in the pharmaceutical composition.
  • the opioid receptor modulator is present in an amount of no more than about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 1-150, 5-140, 10- 130, 15-120, 20-110, 25-100, 30-95, 35-90, 40-85, 45-80, 50-75, 55-70, or 60-65 mg in the pharmaceutical composition. [41] In some embodiments, the agent is present in an amount of about 0.1-200 mg in the pharmaceutical composition.
  • the agent is present in an amount of about 0.2-100 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-10 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-1 m in the pharmaceutical composition. In some embodiments, the agent is present in an amount of at least about 0.1, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg in the pharmaceutical composition.
  • the agent is present in an amount of no more than about 0.1, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.1-200, 0.5-190, 1-180, 5-170, 10-160, 20-150, 30-140, 40-130, 50-120, 60-110, 70-100, or 80-90 mg in the pharmaceutical composition.
  • Salts and isoforms [42] The compounds described herein may form salts with acids and/or bases, and such salts are included in the present application. In some embodiments, the salts are pharmaceutically acceptable salts.
  • salts embraces addition salts of free acids and/or WSGR Docket No.60906-708601 bases that are useful within the methods of the present application.
  • pharmaceutically acceptable salt refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present application, such as for example utility in process of synthesis, purification or formulation of compounds useful within the methods of the present application.
  • Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • inorganic acids examples include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate).
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, ⁇
  • Suitable pharmaceutically acceptable base addition salts of compounds of the present application include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
  • Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (also known as N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
  • the compounds of the present application may possess one or more stereocenters, and each stereocenter may exist independently in either the (R) or (S) configuration.
  • compounds described herein are present in optically active or racemic forms.
  • the compounds described herein encompass racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.
  • Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • a compound illustrated herein by WSGR Docket No.60906-708601 the racemic formula further represents either of the two enantiomers or mixtures thereof, or in the case where two or more chiral center are present, all diastereomers or mixtures thereof.
  • the compounds of the present application may exist as tautomer. All tautomers are included within the scope of the compounds recited herein.
  • Compounds described herein also include isotopically labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 S. In some embodiments, substitution with heavier isotopes such as deuterium affords greater chemical stability. Isotopically labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • Method of Treatment also provides a method for treating, ameliorating, or preventing a disease or disorder in a subject in need thereof.
  • the method comprises administering the pharmaceutical composition described herein to the subject.
  • the pharmaceutical composition comprising an opioid receptor modulator and an agent.
  • the agent comprises a 3,4-methylenedioxymethamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • MDMA 3,4-methylenedioxymethamphetamine
  • the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta-opioid receptor modulator.
  • the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist.
  • the opioid receptor modulator is an opioid receptor antagonist.
  • the opioid receptor modulator is an opioid receptor negative allosteric modulator.
  • the opioid receptor modulator is an opioid receptor partial agonist.
  • the opioid receptor modulator comprises a kappa-opioid receptor modulator.
  • the opioid receptor modulator comprises a delta-opioid receptor modulator.
  • the agent comprises 3,4-methylenedioxyamphetamine (MDA, ‘Love'), N-ethyl-3,4-methylenedioxyamphetamine (MDEA, ‘Eve'), 3,4-methylenedioxy-N- hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha-ethyl-N-methylphenethylamine (MBDB, "EDEN” or "Methyl-J”), 1-Benzofuran-5-ylpropan-2-amine (5-APB), 1-(benzofuran- 5-yl)-N-methylpropan-2-amine (5-MAPB), 6-(2-aminopropyl)benzofuran (6-APB), 1- (benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N- methyl
  • opioid receptor modulators useful within the methods of the present application are recited in the Pharmaceutical Composition section, and include any salt, solvate, enantiomer, tautomer, stereoisomer, and/or geometric isomer thereof, or any mixtures thereof.
  • the opioid receptor modulator and the agent are administered concurrently to the subject. In some cases, the opioid receptor modulator and the agent are administered separately to the subject. In some cases, the opioid receptor modulator and the agent are administered sequentially to the subject.
  • the opioid receptor modulator is administered once per day, twice per day, or three times per day. In some cases, the opioid receptor modulator is administered once per day. In some cases, the opioid receptor modulator is administered twice per day.
  • the opioid receptor modulator is administered three times per day. In some cases, the opioid receptor modulator is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week. In some cases, the opioid receptor modulator is administered once per week. In some cases, the opioid receptor modulator is administered twice per week. In some cases, the opioid receptor modulator is administered three times per week. In some cases, the opioid receptor modulator is administered four times per week. In some cases, the opioid receptor modulator is administered five times per week. In some cases, the opioid receptor modulator is administered six times per week. In some cases, the opioid receptor modulator is administered seven times per week.
  • the opioid receptor modulator is administered once per month, twice per month, three times per month, four times per month, five times per month, or ten times per month. In some cases, the opioid receptor modulator is administered once per month. In some cases, the opioid receptor modulator is administered twice per month. In some cases, the opioid receptor WSGR Docket No.60906-708601 modulator is administered three times per month. In some cases, the opioid receptor modulator is administered four times per month. In some cases, the opioid receptor modulator is administered five times per month. In some cases, the opioid receptor modulator is administered ten times per month. [54] In some cases, the agent is administered once per day, twice per day, or three times per day. In some cases, the agent is administered once per day.
  • the agent is administered twice per day. In some cases, the agent is administered three times per day. In some cases, the agent is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week. In some cases, the agent is administered once per week. In some cases, the agent is administered twice per week. In some cases, the agent is administered three times per week. In some cases, the agent is administered four times per week. In some cases, the agent is administered five times per week. In some cases, the agent is administered six times per week. In some cases, the agent is administered seven times per week.
  • the agent is administered once per month, twice per month, three times per month, four times per month, five times per month, or ten times per month. In some cases, the agent is administered once per month. In some cases, the agent is administered twice per month. In some cases, the agent is administered three times per month. In some cases, the agent is administered four times per month. In some cases, the agent is administered five times per month. In some cases, the agent is administered ten times per month. [55] In some cases, the pharmaceutical composition described herein is administered once per day, twice per day, or three times per day. In some cases, the pharmaceutical composition described herein is administered once per day. In some cases, the pharmaceutical composition described herein is administered twice per day.
  • the pharmaceutical composition described herein is administered three times per day. In some cases, the pharmaceutical composition described herein is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week. In some cases, the pharmaceutical composition described herein is administered once per week. In some cases, the pharmaceutical composition described herein is administered twice per week. In some cases, the pharmaceutical composition described herein is administered three times per week. In some cases, the pharmaceutical composition described herein is administered four times per week. In some cases, the pharmaceutical composition described herein is administered five times per week. In some cases, the pharmaceutical composition described herein is administered six times per week. In some cases, the pharmaceutical composition described herein is administered seven times per week.
  • the pharmaceutical composition described herein is administered once per month, twice per month, three times per month, four WSGR Docket No.60906-708601 times per month, five times per month, or ten times per month. In some cases, the pharmaceutical composition described herein is administered once per month. In some cases, the pharmaceutical composition described herein is administered twice per month. In some cases, the pharmaceutical composition described herein is administered three times per month. In some cases, the pharmaceutical composition described herein is administered four times per month. In some cases, the pharmaceutical composition described herein is administered five times per month. In some cases, the pharmaceutical composition described herein is administered ten times per month.
  • the opioid receptor modulator is administered to the subject by a route selected from the group consisting of intranasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous.
  • the opioid receptor modulator is administered to the subject by an intranasal route.
  • the opioid receptor modulator is administered to the subject by an inhalational route.
  • the opioid receptor modulator is administered to the subject by a topical route.
  • the opioid receptor modulator is administered to the subject by an oral route.
  • the opioid receptor modulator is administered to the subject by a buccal route. In some cases, the opioid receptor modulator is administered to the subject by a rectal route. In some cases, the opioid receptor modulator is administered to the subject by a pleural route. In some cases, the opioid receptor modulator is administered to the subject by a peritoneal route. In some cases, the opioid receptor modulator is administered to the subject by a vaginal route. In some cases, the opioid receptor modulator is administered to the subject by an intramuscular route. In some cases, the opioid receptor modulator is administered to the subject by a subcutaneous route. In some cases, the opioid receptor modulator is administered to the subject by a transdermal route.
  • the opioid receptor modulator is administered to the subject by an epidural route. In some cases, the opioid receptor modulator is administered to the subject by an intratracheal route. In some cases, the opioid receptor modulator is administered to the subject by an otic route. In some cases, the opioid receptor modulator is administered to the subject by an intraocular route. In some cases, the opioid receptor modulator is administered to the subject by an intrathecal route. In some cases, the opioid receptor modulator is administered to the subject by an intravenous route.
  • the agent is administered to the subject by a route selected from the group consisting of intranasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous.
  • agent is administered to the subject by an intranasal WSGR Docket No.60906-708601 route.
  • the agent is administered to the subject by an inhalational route.
  • the agent is administered to the subject by a topical route.
  • the agent is administered to the subject by an oral route.
  • the agent is administered to the subject by a buccal route. In some cases, the agent is administered to the subject by a rectal route. In some cases, the agent is administered to the subject by a pleural route. In some cases, the agent is administered to the subject by a peritoneal route. In some cases, the agent is administered to the subject by a vaginal route. In some cases, the agent is administered to the subject by an intramuscular route. In some cases, the agent is administered to the subject by a subcutaneous route. In some cases, the agent is administered to the subject by a transdermal route. In some cases, the agent is administered to the subject by an epidural route. In some cases, the agent is administered to the subject by an intratracheal route.
  • the agent is administered to the subject by an otic route. In some cases, the agent is administered to the subject by an intraocular route. In some cases, the agent is administered to the subject by an intrathecal route. In some cases, the agent is administered to the subject by an intravenous route. [58] In some cases, the pharmaceutical composition described herein is administered to the subject by a route selected from the group consisting of intranasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous.
  • the pharmaceutical composition described herein is administered to the subject by an intranasal route. In some cases, the pharmaceutical composition described herein is administered to the subject by an inhalational route. In some cases, the pharmaceutical composition described herein is administered to the subject by a topical route. In some cases, the pharmaceutical composition described herein is administered to the subject by an oral route. In some cases, the pharmaceutical composition described herein is administered to the subject by a buccal route. In some cases, the pharmaceutical composition described herein is administered to the subject by a rectal route. In some cases, the pharmaceutical composition described herein is administered to the subject by a pleural route. In some cases, the pharmaceutical composition described herein is administered to the subject by a peritoneal route.
  • the pharmaceutical composition described herein is administered to the subject by a vaginal route. In some cases, the pharmaceutical composition described herein is administered to the subject by an intramuscular route. In some cases, the pharmaceutical composition described herein is administered to the subject by a subcutaneous route. In some cases, the pharmaceutical composition described herein is administered to the subject by a transdermal route. In some cases, the pharmaceutical composition described herein is administered to the subject by an epidural route. In some cases, the pharmaceutical composition described herein is administered to the subject by an WSGR Docket No.60906-708601 intratracheal route. In some cases, the pharmaceutical composition described herein is administered to the subject by an otic route. In some cases, the pharmaceutical composition described herein is administered to the subject by an intraocular route.
  • the pharmaceutical composition described herein is administered to the subject by an intrathecal route. In some cases, the pharmaceutical composition described herein is administered to the subject by an intravenous route. [59] In some cases, administration of the opioid receptor modulator prevents, ameliorates, or minimizes abuse of the agent by the subject, wherein the abuse is contributed by a behavioral effect of the agent including agent liking, agent craving, or agent seeking. In some cases, administration of the opioid receptor modulator prevents, ameliorates, or minimizes abuse of the MDMA by the subject, wherein the abuse is contributed by a behavioral effect of the MDMA including MDMA liking, MDMA craving, or MDMA seeking.
  • the disease or disorder is selected from the group consisting of major depressive disorder, major depressive disorder, major depressive episode in bipolar disorder (bipolar depression), bipolar I disorder, bipolar II disorder, persistent depressive disorder (dysthymia), disruptive mood dysregulation disorder, major depressive disorder (including major depressive episode), resistant depressive disorder, partially responsive depressive disorder, substance use disorder (with or without anxiety or depressive disorder), alcohol use disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, anxiety disorder, generalized anxiety disorder, social anxiety disorder (social phobia), specific phobia, panic disorder, agoraphobia, separation anxiety disorder, selective mutism, substance-induced anxiety disorder, medication-induced anxiety disorder, anxiety disorder due to another medical condition, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, obsessive compulsive disorder, bulimia nervosa, anorexia nervo
  • the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist. In some embodiments, the opioid receptor modulator is an opioid receptor antagonist. In some embodiments, the opioid receptor modulator is an opioid receptor negative allosteric modulator. In some embodiments, the opioid receptor modulator is an opioid receptor partial agonist. [62] In some embodiments, the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the compound is naltrexone, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the opioid receptor modulator is present in an amount of about 1-150 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-50 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-30 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-20 mg in the pharmaceutical composition.
  • the opioid receptor modulator is present in an amount of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of no more than about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 mg in the pharmaceutical composition.
  • the opioid receptor modulator is present in an amount of about 1-150, 5-140, 10- 130, 15-120, 20-110, 25-100, 30-95, 35-90, 40-85, 45-80, 50-75, 55-70, or 60-65 mg in the pharmaceutical composition.
  • the agent is present in an amount of about 0.1-200 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-100 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-10 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-1 m in the pharmaceutical composition.
  • the agent is present in an amount of at least about 0.1, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of no more than about 0.1, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg in the pharmaceutical composition.
  • the agent is present in an amount of about 0.1-200, 0.5-190, 1-180, 5-170, 10-160, 20-150, 30-140, 40-130, 50-120, 60-110, 70-100, or 80-90 mg in the pharmaceutical composition.
  • Kits [65] Additional aspect of this disclosure provides a kit comprising an opioid receptor modulator and an agent.
  • the agent comprises a 3,4- Methylenedioxymethamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • MDMA 3,4- Methylenedioxymethamphetamine
  • the agent comprises 3,4-methylenedioxyamphetamine (MDA, ‘Love'), N-ethyl-3,4-methylenedioxyamphetamine (MDEA, ‘Eve'), 3,4-methylenedioxy-N- hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha-ethyl-N-methylphenethylamine (MBDB, "EDEN” or "Methyl-J”), 1-Benzofuran-5-ylpropan-2-amine (5-APB), 1-(benzofuran- 5-yl)-N-methylpropan-2-amine (5-MAPB), 6-(2-aminopropyl)benzofuran (6-APB), 1- (benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N- methylcathinone (methylone, "MDMC”, “ ⁇ k-MDMA” and "M1
  • the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta-opioid receptor modulator.
  • the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist.
  • the opioid receptor modulator is an opioid receptor antagonist.
  • the opioid receptor modulator is an opioid receptor negative allosteric modulator.
  • the opioid receptor modulator is an opioid receptor partial agonist.
  • the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the compound is naltrexone, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • opioid receptor modulators useful within the methods of the present application are recited herein, and include any salt, solvate, enantiomer, tautomer, stereoisomer, and/or geometric isomer thereof, or any mixtures thereof.
  • the opioid receptor modulator is naltrexone (also known as 17-(cyclopropylmethyl)-4,5 ⁇ -epoxy- 3,14-dihydroxymorphinan-6-one).
  • the opioid receptor modulator is long-acting naltrexone (extended-release naltrexone, e.g., Vivitrol ® ).
  • the opioid receptor modulator is naloxone (also known as (4R,4aS,7aR,12bS)-4a,9-dihydroxy-3- prop-2-enyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one, Narcan, Evzio, or Nyxoid).
  • the opioid receptor modulator is long- acting naloxone (extended-release naloxone).
  • the opioid receptor modulator is nalmefene (also known as 17-cyclopropylmethyl-4,5 ⁇ -epoxy-6- WSGR Docket No.60906-708601 methylenemorphinan-3,14-diol, nalmetrene, or Selincro).
  • the opioid receptor modulator is long-acting nalmefene (extended-release nalmefene).
  • the opioid receptor modulator is nalodeine (also known as N-allylnorcodeine, or (4R,4aR,7S,7aR,12bS)-9-methoxy-3-prop-2-enyl-2,4,4a,7,7a,13-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinoline-7-ol).
  • the long-acting naltrexone has a longer serum half-life than naltrexone.
  • the long-acting naloxone has a longer serum half-life than naloxone.
  • the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, naltrindole, UPHIT ((1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide), DIPPA (2-(3,4-dichlorophenyl)- N-methyl-N-[(1S)- 1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide), JDTic ((3R)-7-Hydroxy-N- [(2S)-1-[(3R,4R
  • the compound is naltrexone, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof.
  • the opioid receptor modulator is present in an amount of about 1-150 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-50 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-30 mg in the WSGR Docket No.60906-708601 pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-20 mg in the pharmaceutical composition.
  • the opioid receptor modulator is present in an amount of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of no more than about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 mg in the pharmaceutical composition.
  • the opioid receptor modulator is present in an amount of about 1-150, 5-140, 10- 130, 15-120, 20-110, 25-100, 30-95, 35-90, 40-85, 45-80, 50-75, 55-70, or 60-65 mg in the pharmaceutical composition.
  • the agent is present in an amount of about 0.1-200 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-100 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-10 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-1 m in the pharmaceutical composition.
  • the agent is present in an amount of at least about 0.1, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of no more than about 0.1, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg in the pharmaceutical composition.
  • the agent is present in an amount of about 0.1-200, 0.5-190, 1-180, 5-170, 10-160, 20-150, 30-140, 40-130, 50-120, 60-110, 70-100, or 80-90 mg in the pharmaceutical composition.
  • determining As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise.
  • a sample includes a plurality of samples, including mixtures thereof.
  • a “subject” can be a biological entity containing expressed genetic materials.
  • the biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa.
  • the subject can be tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro.
  • the subject can be a mammal.
  • the mammal can be a human.
  • the subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.
  • the term “about” a number refers to that number plus or minus 10% of that number.
  • the term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.
  • treatment or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient.
  • Beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit.
  • a therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated.
  • a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • a prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.
  • Example 1 Intravenous (IV) MDMA self -administration (SA)
  • SA Sprague-Dawley (SD) rats were used on a cocaine intravenous (IV) self- administration (SA). A small group of these cocaine-experienced animals were then tested with MDMA SA followed by a within subject test of naloxone (10 mg/kg).
  • Protocol of cocaine-experienced animals (i) 10-14 days of 0.5mg/kg cocaine IV SA followed by 8-10 days of cocaine extinction and (ii)1 day memory-reconsolidation test, 1 day cue reinstatement testing, 14 days of withdrawal, 1 day long-term cue reinstatement, and 1 day conditioned reinforcement (CR) test.
  • Test Protocol In 24 hrs after the above CR test, animals were placed on sessions with 0.25mg/kg of MDMA-IV-SA. These were 2hr sessions over a period of approximately 3 weeks to generate stable MDMA-IV-SA. There were only 4 animals that showed stable responding that were ultimately tested with the naloxone/naltrexone.

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Abstract

Provided is a pharmaceutical composition comprising an opioid receptor modulator and an agent. Methods for treating, ameliorating, or preventing a disease or disorder in a subject in need thereof by administering the pharmaceutical composition disclosed are also provided herein.

Description

WSGR Docket No.60906-708601 COMPOSITION OF OPIOID RECEPTOR MODULATOR AND MDMA FOR USE THEREOF CROSS REFERENCE [1] This application claims the benefits of U.S. Provisional Application No.63/486,270 filed February 22, 2023 which is incorporated herein by reference in the entirety for all purposes. SUMMARY [2] Provided herein is a pharmaceutical composition comprising an opioid receptor modulator and an agent. In some embodiments, the agent comprises a 3,4- Methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), N- ethyl-3,4-methylenedioxyamphetamine (MDEA), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha-ethyl-N-methylphenethylamine (MBDB), 1-Benzofuran- 5-ylpropan-2-amine (5-APB), 1-(benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB), 6-(2- aminopropyl)benzofuran (6-APB), 1-(benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N-methylcathinone (methylone), 4-methylmethcathinone (mephedrone), gamma-Hydroxybutyric acid (GHB), α-Methyltryptamine (αMT), α-Ethyltryptamine (αET), or 5,6-methylenedioxy-2-aminoindane (MDAI), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [3] In some embodiments, the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta-opioid receptor modulator. In some embodiments, the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist. In some embodiments, the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, naltrindole, UPHIT ((1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide), DIPPA (2-(3,4-dichlorophenyl)- N-methyl-N-[(1S)- 1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide), JDTic ((3R)-7-Hydroxy-N- [(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl]-1,2,3,4- tetrahydroisoquinoline-3-carboxamide), Nor-BNI (Norbinaltorphimine), GNTI (5’- Guanidinonaltrindole), CERC-501 (4-(4-{[(2S)-2-(3,5-Dimethylphenyl)-1- pyrrolidinyl]methyl}phenoxy)-3-fluorobenzamide), PF-4455242 (2-methylN-((2′-(pyrrolidin-1- ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine), AZ-MTAB (3- [[(3-endo)-8-[(5-methyl-2- thienyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]oxy]-benzamide), Arodyn (Ac[Phe1,2,3,Arg4, D- WSGR Docket No.60906-708601 Ala8]dynorphin A-(1–11) amide), Zyklophin (N-Benzyl-L-tyrosylglycylglycyl-N- [(3S,6S,9S,12S)-6-[(2S)-2-butanyl]-3-({(2S)-5-carbamimidamido-1-[(2S)-2-{[(2S)-1,6-diamino- 1-oxo-2-hexanyl]carbamoyl}-1-pyrrolidinyl]-1-oxo-2-pentanyl}carbamoyl)-9-(3- carbamimidamidopropyl)-5,8,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-12-yl]-L- phenylalaninamide), Buprenorphine ((2S)-2-[(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy- 6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol), CYX-5, eluxadoline, D24M, FBNTI, BOM (benzylideneoxymorphone), naldemedine, ICI-174,864, naltriben, NCGC00485585-01, NCGC00114968-02, NCGC00485288-01, NCGC00106344-01, NCGC00386726-01, cyclopropylsulfonamide 9f (17-(Cyclopropylsulfonyl)-6,7-didehydro-4,5α- epoxyindolo[2′,3′:6,7]morphinan-3,14β-diol, SYK-839), phenethylsulfonamide 9e (6,7- Didehydro-4,5α-epoxy-17-((2-phenylethyl)sulfonyl)indolo[2′,3′:6,7]morphinan-3,14β-diol, SYK-901), Methylnaltrexone (Relistor), Naloxegol (Movantik), and any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [4] In some embodiments, the agent comprises 3,4-Methylenedioxymethamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some embodiments, the agent comprises 3,4- methylenedioxyamphetamine (MDA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some embodiments, the agent comprises N-ethyl-3,4-methylenedioxyamphetamine (MDEA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [5] In some embodiments, the opioid receptor modulator is present in an amount of about 1-150 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-50 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-30 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-20 mg. [6] In some embodiments, the agent is present in an amount of about 0.1-200 mg. In some embodiments, the agent is present in an amount of about 0.2-100 mg. In some embodiments, the agent is present in an amount of about 0.2-10 mg. In some embodiments, the agent is present in an amount of about 0.2-1 mg. [7] The present disclosure also provides a method for treating, ameliorating or preventing a disease or disorder in a subject in need thereof comprising administering the pharmaceutical composition disclosed herein. [8] An additional aspect of the present disclosure provides a kit comprising an opioid receptor modulator and an agent, wherein the agent comprises a 3,4-Methylenedioxy methamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric WSGR Docket No.60906-708601 isomer thereof, or any combination thereof. In some embodiments, the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta-opioid receptor modulator. In some embodiments, the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist. In some embodiments, the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, naltrindole, UPHIT ((1S,2S)-trans-2-Isothiocyanato-4,5- dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide), DIPPA (2-(3,4- dichlorophenyl)- N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1- pyrrolidinyl)ethyl]acetamide), JDTic ((3R)-7-Hydroxy-N-[(2S)-1-[(3R,4R)-4-(3- hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl]-1,2,3,4- tetrahydroisoquinoline-3-carboxamide), Nor-BNI (Norbinaltorphimine), GNTI (5’- Guanidinonaltrindole), CERC-501 (4-(4-{[(2S)-2-(3,5-Dimethylphenyl)-1- pyrrolidinyl]methyl}phenoxy)-3-fluorobenzamide), PF-4455242 (2-methylN-((2′-(pyrrolidin-1- ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine), AZ-MTAB (3- [[(3-endo)-8-[(5-methyl-2- thienyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]oxy]-benzamide), Arodyn (Ac[Phe1,2,3,Arg4, D- Ala8]dynorphin A-(1–11) amide), Zyklophin (N-Benzyl-L-tyrosylglycylglycyl-N- [(3S,6S,9S,12S)-6-[(2S)-2-butanyl]-3-({(2S)-5-carbamimidamido-1-[(2S)-2-{[(2S)-1,6-diamino- 1-oxo-2-hexanyl]carbamoyl}-1-pyrrolidinyl]-1-oxo-2-pentanyl}carbamoyl)-9-(3- carbamimidamidopropyl)-5,8,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-12-yl]-L- phenylalaninamide), Buprenorphine ((2S)-2-[(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy- 6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol), CYX-5, eluxadoline, D24M, FBNTI, BOM (benzylideneoxymorphone), naldemedine, ICI-174,864, naltriben, NCGC00485585-01, NCGC00114968-02, NCGC00485288-01, NCGC00106344-01, NCGC00386726-01, cyclopropylsulfonamide 9f (17-(Cyclopropylsulfonyl)-6,7-didehydro-4,5α- epoxyindolo[2′,3′:6,7]morphinan-3,14β-diol, SYK-839), phenethylsulfonamide 9e (6,7- Didehydro-4,5α-epoxy-17-((2-phenylethyl)sulfonyl)indolo[2′,3′:6,7]morphinan-3,14β-diol, SYK-901), Methylnaltrexone (Relistor), Naloxegol (Movantik), and any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [9] In some embodiments, the agent comprises 3,4-Methylenedioxymethamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some embodiments, the agent comprises 3,4- methylenedioxyamphetamine (MDA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some embodiments, the agent WSGR Docket No.60906-708601 comprises N-ethyl-3,4-methylenedioxyamphetamine (MDEA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [10] In some embodiments, the opioid receptor modulator is present in an amount of about 1-150 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-50 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-30 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-20 mg. [11] In some embodiments, the agent is present in an amount of about 0.1-200 mg. In some embodiments, the agent is present in an amount of about 0.2-100 mg. In some embodiments, the agent is present in an amount of about 0.2-10 mg. In some embodiments, the agent is present in an amount of about 0.2-1 mg. [12] Also provided herein is a method for treating, ameliorating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject an opioid receptor modulator and an agent, wherein the agent comprises a 3,4-Methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), N-ethyl-3,4-methylenedioxyamphetamine (MDEA), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha- ethyl-N-methylphenethylamine (MBDB), 1-Benzofuran-5-ylpropan-2-amine (5-APB), 1- (benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB), 6-(2-aminopropyl)benzofuran (6-APB), 1-(benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N- methylcathinone (methylone), 4-methylmethcathinone (mephedrone), gamma-Hydroxybutyric acid (GHB), α-Methyltryptamine (αMT), α-Ethyltryptamine (αET), or 5,6-methylenedioxy-2- aminoindane (MDAI), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [13] In some embodiments, the opioid receptor modulator and the agent are administered concurrently. In some embodiments, the opioid receptor modulator and the agent are administered separately. In some embodiments, the opioid receptor modulator and the agent are administered sequentially. [14] In some embodiments, the opioid receptor modulator is administered once per day, twice per day, or three times per day. In some embodiments, the opioid receptor modulator is administered once per week, twice per week, or three times per week. In some embodiments, the opioid receptor modulator is administered once per month, twice per month, or three times per month. In some embodiments, the agent is administered once per day, twice per day, or three times per day. In some embodiments, the agent is administered once per week, twice per week, or three times per week. In some embodiments, the agent is administered once per month, twice per month, or three times per month. WSGR Docket No.60906-708601 [15] In some embodiments, the opioid receptor modulator is administered to the subject by a route selected from the group consisting of intranasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous. In some embodiments, the agent is administered to the subject by a route selected from the group consisting of intranasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous. [16] In some embodiments, administration of the opioid receptor modulator prevents, ameliorates, or minimizes abuse of the agent by the subject, wherein the abuse is contributed by a behavioral effect of the agent including agent liking, agent craving, or agent seeking. In some cases, the agent comprises 3,4-methylenedioxymethamphetamine (MDMA), 3,4- methylenedioxyamphetamine (MDA), N-ethyl-3,4-methylenedioxyamphetamine (MDEA), 3,4- methylenedioxy-N-hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha-ethyl-N- methylphenethylamine (MBDB), 1-Benzofuran-5-ylpropan-2-amine (5-APB), 1-(benzofuran-5- yl)-N-methylpropan-2-amine (5-MAPB), 6-(2-aminopropyl)benzofuran (6-APB), 1- (benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N- methylcathinone (methylone), 4-methylmethcathinone (mephedrone), gamma-Hydroxybutyric acid (GHB), α-Methyltryptamine (αMT), α-Ethyltryptamine (αET), or 5,6-methylenedioxy-2- aminoindane (MDAI), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [17] In some embodiments, the disease or disorder is selected from the group consisting of major depressive disorder, major depressive disorder, major depressive episode in bipolar disorder (bipolar depression), bipolar I disorder, bipolar II disorder, persistent depressive disorder (dysthymia), disruptive mood dysregulation disorder, major depressive disorder (including major depressive episode), resistant depressive disorder, partially responsive depressive disorder, substance use disorder (with or without anxiety or depressive disorder), alcohol use disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, anxiety disorder, generalized anxiety disorder, social anxiety disorder (social phobia), specific phobia, panic disorder, agoraphobia, separation anxiety disorder, selective mutism, substance-induced anxiety disorder, medication-induced anxiety disorder, anxiety disorder due to another medical condition, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, obsessive compulsive disorder, bulimia nervosa, anorexia nervosa, binge eating disorder, and posttraumatic stress disorder. WSGR Docket No.60906-708601 [18] In some embodiments, the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta-opioid receptor modulator. In some embodiments, the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist. In some embodiments, the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, naltrindole, UPHIT ((1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide), DIPPA (2-(3,4-dichlorophenyl)- N-methyl-N-[(1S)- 1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide), JDTic ((3R)-7-Hydroxy-N- [(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl]-1,2,3,4- tetrahydroisoquinoline-3-carboxamide), Nor-BNI (Norbinaltorphimine), GNTI (5’- Guanidinonaltrindole), CERC-501 (4-(4-{[(2S)-2-(3,5-Dimethylphenyl)-1- pyrrolidinyl]methyl}phenoxy)-3-fluorobenzamide), PF-4455242 (2-methylN-((2′-(pyrrolidin-1- ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine), AZ-MTAB (3- [[(3-endo)-8-[(5-methyl-2- thienyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]oxy]-benzamide), Arodyn (Ac[Phe1,2,3,Arg4, D- Ala8]dynorphin A-(1–11) amide), Zyklophin (N-Benzyl-L-tyrosylglycylglycyl-N- [(3S,6S,9S,12S)-6-[(2S)-2-butanyl]-3-({(2S)-5-carbamimidamido-1-[(2S)-2-{[(2S)-1,6-diamino- 1-oxo-2-hexanyl]carbamoyl}-1-pyrrolidinyl]-1-oxo-2-pentanyl}carbamoyl)-9-(3- carbamimidamidopropyl)-5,8,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-12-yl]-L- phenylalaninamide), Buprenorphine ((2S)-2-[(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy- 6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol), CYX-5, eluxadoline, D24M, FBNTI, BOM (benzylideneoxymorphone), naldemedine, ICI-174,864, naltriben, NCGC00485585-01, NCGC00114968-02, NCGC00485288-01, NCGC00106344-01, NCGC00386726-01, cyclopropylsulfonamide 9f (17-(Cyclopropylsulfonyl)-6,7-didehydro-4,5α- epoxyindolo[2′,3′:6,7]morphinan-3,14β-diol, SYK-839), phenethylsulfonamide 9e (6,7- Didehydro-4,5α-epoxy-17-((2-phenylethyl)sulfonyl)indolo[2′,3′:6,7]morphinan-3,14β-diol, SYK-901), Methylnaltrexone (Relistor), Naloxegol (Movantik), and any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [19] In some embodiments, the agent comprises 3,4-Methylenedioxymethamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some embodiments, the agent comprises 3,4- methylenedioxyamphetamine (MDA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some embodiments, the agent comprises N-ethyl-3,4-methylenedioxyamphetamine (MDEA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. WSGR Docket No.60906-708601 [20] In some embodiments, the opioid receptor modulator is present in an amount of about 1-150 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-50 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-30 mg. In some embodiments, the opioid receptor modulator is present in an amount of about 5-20 mg. [21] In some embodiments, the agent is present in an amount of about 0.1-200 mg. In some embodiments, the agent is present in an amount of about 0.2-100 mg. In some embodiments, the agent is present in an amount of about 0.2-10 mg. In some embodiments, the agent is present in an amount of about 0.2-1 mg. [22] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. INCORPORATION BY REFERENCE [23] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS [24] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which: [25] FIG.1 shows naloxone effects in intravenous self-administration of 3,4- methylenedioxymethamphetamine (MDMA), according to some embodiments of the present disclosure. [26] FIG.2 shows naltrexone effects in intravenous self-administration of MDMA, according to some embodiments of the present disclosure. WSGR Docket No.60906-708601 DETAILED DESCRIPTION [27] While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed. [28] Opioid receptor modulators provide effective treatments for acute and chronic pain. Opioid receptor modulators are opioid antagonists so that they bind to opioid receptors. The opioid receptors in the central nervous system (CNS) have each class having subtype receptors. These receptor classes are known as a mu (μ)-opioid receptor, a delta (δ)-opioid receptor, and a kappa (κ)-opioid receptor. Opioid receptor modulators can reverse and block the effects of the opioids, such as heroin, morphine, and oxycodone. They reduce and suppress opioid cravings. There is no abuse and diversion potential with opioid receptor modulators. Members of opioid receptor modulators, particularly naltrexone and naloxone, have been approved by the U.S. Food and Drug administration for the treatment of opioid use disorder and alcohol use disorder. [29] 3,4-Methylene-dioxymethamphetamine (MDMA), also known as ecstasy or molly, is a widely abused recreational drug. It is known to cause psychostimulation and can induce hallucination and long-term neuropsychiatric behaviors, including depression and psychosis. However, it has been granted FDA “breakthrough therapy” status after Phase 2 clinical trials. MDMA shows promise for treating major depressive disorder by rapidly releasing and increasing levels of serotonin and dopamine in the brain. Recent studies show that MDMA has the potential to act as a rapid-acting antidepressant via its modulation of the 5- hydroxytryptamine (5-HT) system and as an augmentation strategy in cognitive therapy. MDMA also has the potential for the treatment of post-traumatic stress disorder (PTSD). MDMA rapidly increases availability of extracellular 5-HT at the synapse, mirroring the action of commonly prescribed antidepressants. Compared to first-line treatments for depression, such as selective serotonin reuptake inhibitors (SSRIs), that typically take about 6 weeks to produce optimum therapeutic change, MDMA could offer instantaneous relief. This rapid onset is an attractive prospect for treatment-resistant depression (TRD). [30] MDMA is still a controlled substance in most countries. MDMA is neurotoxic, primarily to serotonergic neurons, and induces degeneration of neuronal fibers in rodents and primates. MDMA overdose can produce hyperthermia, with subsequent muscle break down resulting in hyperkalaemia and organ failure. It can have dangerous effects on the cardiovascular, neurologic, renal, and hepatic systems. The potential for MDMA toxicity exists with every ingestion. There exists a long-felt need for an effective means of preventing the WSGR Docket No.60906-708601 symptoms associated with toxicity of MDMA or MDMA-related drugs. While MDMA has potential of the rapid treatment of depression and PTSD, access to MDMA is constrained by concerns about their abuse liability and the possibility that it may worsen other addictions. Such risks limit the contexts in which MDMA may be administered, reduce the number of providers interested in delivering the treatment, and decrease the number of patients eligible to. [31] Empathogen and entactogen are a class of psychoactive drugs that produce distinctive emotional and social effects similar to those of MDMA. This class of the drugs comprises 3,4-methylenedioxyamphetamine (MDA, ‘Love'), N-ethyl-3,4- methylenedioxyamphetamine (MDEA, ‘Eve'), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha-ethyl-N-methylphenethylamine (MBDB, "EDEN" or "Methyl-J”), 1-Benzofuran-5-ylpropan-2-amine (5-APB), 1-(benzofuran-5-yl)-N-methylpropan- 2-amine (5-MAPB), 6-(2-aminopropyl)benzofuran (6-APB), 1-(benzofuran-6-yl)-N- methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N-methylcathinone (methylone, "MDMC", "βk-MDMA" and "M1"), 4-methylmethcathinone (mephedrone, 4-MMC, and 4- methylephedrone), gamma-Hydroxybutyric acid (GHB), α-Methyltryptamine (αMT), α- Ethyltryptamine (αET), or 5,6-methylenedioxy-2-aminoindane (MDAI). Most all drugs in this class are of the psychedelic phenethylamine family and contains a substituted amphetamine core. [32] To effectively use MDMA as a rapid-acting antidepressant and for the treatment of PTSD, the present disclosure provides an innovative pharmaceutical composition and a method thereof. In some cases, the pharmaceutical composition and the method thereof disclosed herein may be also applied to MDA, MDEA, MDOH, MBDB, 5-APB, 5-MAPB, 6-APB, 6-MAPB, methylone, mephedrone, GHB, αMT, αET, and MDAI. Pharmaceutical Compositions [33] In one aspect, the present disclosure provides a pharmaceutical composition comprising an opioid receptor modulator and an agent, wherein the agent comprises a 3,4- methylenedioxymethamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. Any opioid receptor modulator known in the art is contemplated within the present application. In some cases, the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta-opioid receptor modulator. In some cases, the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist. In some cases, the opioid receptor modulator comprises a mu-opioid receptor modulator. In some cases, the opioid receptor WSGR Docket No.60906-708601 modulator comprises a kappa-opioid receptor modulator. In some cases, the opioid receptor modulator comprises a delta-opioid receptor modulator. [34] In some cases, the agent comprises 3,4-methylenedioxyamphetamine (MDA, ‘Love'), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some cases, the agent comprises N-ethyl-3,4- methylenedioxyamphetamine (MDEA, ‘Eve'), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some cases, the agent comprises 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH) , any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some cases, the agent comprises 3,4-methylenedioxy-alpha-ethyl-N-methylphenethylamine (MBDB, "EDEN" or "Methyl-J”) , any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some cases, the agent comprises 1- Benzofuran-5-ylpropan-2-amine (5-APB) , any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some cases, the agent comprises 1- (benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB) , any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some cases, the agent comprises 6-(2-aminopropyl)benzofuran (6-APB), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some cases, the agent comprises 1-(benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some cases, the agent comprises 3,4-methylenedioxy-N-methylcathinone (methylone, "MDMC", "βk-MDMA" and "M1"), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some cases, the agent comprises 4- methylmethcathinone (mephedrone, 4-MMC, and 4-methylephedrone), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some cases, the agent comprises gamma-Hydroxybutyric acid (GHB), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some cases, the agent comprises α-Methyltryptamine (αMT), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some cases, the agent comprises α-Ethyltryptamine (αET), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some cases, the agent comprises 5,6-methylenedioxy-2-aminoindane (MDAI), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [35] In some cases, the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, naltrindole, UPHIT WSGR Docket No.60906-708601 ((1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide), DIPPA (2-(3,4-dichlorophenyl)- N-methyl-N-[(1S)- 1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide), JDTic ((3R)-7-Hydroxy-N- [(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl]-1,2,3,4- tetrahydroisoquinoline-3-carboxamide), Nor-BNI (Norbinaltorphimine), GNTI (5’- Guanidinonaltrindole), CERC-501 (4-(4-{[(2S)-2-(3,5-Dimethylphenyl)-1- pyrrolidinyl]methyl}phenoxy)-3-fluorobenzamide), PF-4455242 (2-methylN-((2′-(pyrrolidin-1- ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine), AZ-MTAB (3- [[(3-endo)-8-[(5-methyl-2- thienyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]oxy]-benzamide), Arodyn (Ac[Phe1,2,3,Arg4, D- Ala8]dynorphin A-(1–11) amide), Zyklophin (N-Benzyl-L-tyrosylglycylglycyl-N- [(3S,6S,9S,12S)-6-[(2S)-2-butanyl]-3-({(2S)-5-carbamimidamido-1-[(2S)-2-{[(2S)-1,6-diamino- 1-oxo-2-hexanyl]carbamoyl}-1-pyrrolidinyl]-1-oxo-2-pentanyl}carbamoyl)-9-(3- carbamimidamidopropyl)-5,8,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-12-yl]-L- phenylalaninamide), Buprenorphine ((2S)-2-[(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy- 6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol), CYX-5, eluxadoline, D24M, FBNTI, BOM (benzylideneoxymorphone), naldemedine, ICI-174,864, naltriben, or any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some cases, the compound is naltrexone, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [36] In some cases, administration of the opioid receptor modulator prevents, ameliorates, or minimizes abuse of the agent by the subject, wherein the abuse is contributed by a behavioral effect of the agent including agent liking, agent craving, or agent seeking. In some cases, the agent comprises 3,4-methylenedioxymethamphetamine (MDMA), 3,4- methylenedioxyamphetamine (MDA, ‘Love'), N-ethyl-3,4-methylenedioxyamphetamine (MDEA, ‘Eve'), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 3,4-methylenedioxy- alpha-ethyl-N-methylphenethylamine (MBDB, "EDEN" or "Methyl-J”), 1-Benzofuran-5- ylpropan-2-amine (5-APB), 1-(benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB), 6-(2- aminopropyl)benzofuran (6-APB), 1-(benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N-methylcathinone (methylone, "MDMC", "βk-MDMA" and "M1"), 4- methylmethcathinone (mephedrone, 4-MMC, and 4-methylephedrone), gamma-Hydroxybutyric acid (GHB), α-Methyltryptamine (αMT), α-Ethyltryptamine (αET), or 5,6-methylenedioxy-2- aminoindane (MDAI), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [37] In some embodiments, the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and WSGR Docket No.60906-708601 an opioid receptor partial agonist. In some embodiments, the opioid receptor modulator is an opioid receptor antagonist. In some embodiments, the opioid receptor modulator is an opioid receptor negative allosteric modulator. In some embodiments, the opioid receptor modulator is an opioid receptor partial agonist. [38] Non-limiting examples of opioid receptor modulators useful within the methods of the present application are recited herein, and include any salt, solvate, enantiomer, tautomer, stereoisomer, and/or geometric isomer thereof, or any mixtures thereof. In certain embodiments, the opioid receptor modulator may be naltrexone (also known as 17-(cyclopropylmethyl)-4,5α- epoxy- 3,14-dihydroxymorphinan-6-one). In certain embodiments, the opioid receptor modulator may be long-acting naltrexone (extended-release naltrexone, e.g., Vivitrol®). In certain embodiments, the opioid receptor modulator may be naloxone (also known as (4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-prop-2-enyl-2,4,5,6,7a,13-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinoline-7-one, Narcan, Evzio, or Nyxoid). In certain embodiments, the opioid receptor modulator may be long-acting naloxone (extended-release naloxone). In certain embodiments, the opioid receptor modulator may be nalmefene (also known as 17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol, nalmetrene, or Selincro). In certain embodiments, the opioid receptor modulator may be long-acting nalmefene (extended-release nalmefene). In certain embodiments, the opioid receptor modulator may be nalodeine (also known as N-allylnorcodeine, or (4R,4aR,7S,7aR,12bS)-9-methoxy-3-prop-2- enyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol). In some embodiments, the long-acting naltrexone has a longer serum half-life than naltrexone. In some embodiments, the long-acting naloxone has a longer serum half-life than naloxone. In some embodiments, the long-acting nalmefene has a longer serum half-life than nalmefene. [39] In certain embodiments, the opioid receptor modulator may be naltrindole, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination highly selective delta opioid receptor antagonist having a structure of
Figure imgf000013_0001
. In certain embodiments, the opioid receptor modulator may be UPHIT ((1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research WSGR Docket No.60906-708601 paper reported by Carlezon et al. (Depress Anxiety.2016 October ; 33(10): 895–906. doi:10.1002/da.22500), UPHIT is a kappa opioid receptor modulator having a structure of
Figure imgf000014_0001
. In certain embodiments, the opioid receptor modulator may be DIPPA (2-(3,4-dichlorophenyl)- N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1- pyrrolidinyl)ethyl]acetamide), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Carlezon et al. (Depress Anxiety.2016 October ; 33(10): 895–906. doi:10.1002/da.22500), DIPPA is a kappa opioid receptor modulator having a structure of
Figure imgf000014_0002
. In certain embodiments, the opioid receptor modulator may be JDTic ((3R)-7-Hydroxy-N-[(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1- yl]-3-methylbutan-2-yl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Carlezon et al. (Depress Anxiety.2016 October ; 33(10): 895–906. doi:10.1002/da.22500), JDTic is a kappa opioid receptor antagonist having a
Figure imgf000014_0003
structure of In certain embodiments, the opioid receptor WSGR Docket No.60906-708601 modulator may be Nor-BNI (Norbinaltorphimine), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Carlezon et al. (Depress Anxiety.2016 October ; 33(10): 895–906. doi:10.1002/da.22500), Nor-BNI (Norbinaltorphimine) is a kappa opioid receptor antagonist . In certain embodiments, the
Figure imgf000015_0001
opioid receptor modulator may be GNTI (5’-Guanidinonaltrindole), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Carlezon et al. (Depress Anxiety.2016 October ; 33(10): 895–906. doi:10.1002/da.22500), GNTI (5’-Guanidinonaltrindole) is a kappa opioid receptor antagonist having a structure
Figure imgf000015_0003
. In certain embodiments, the opioid receptor modulator may be CERC-501 (4-(4-{[(2S)-2-(3,5- Dimethylphenyl)-1-pyrrolidinyl]methyl}phenoxy)-3-fluorobenzamide), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Carlezon et al. (Depress Anxiety.2016 October ; 33(10): 895–906. doi:10.1002/da.22500), CERC-501 (4-(4-{[(2S)-2-(3,5-Dimethylphenyl)-1- pyrrolidinyl] -3- is a kappa opioid receptor antagonist having
Figure imgf000015_0002
a structure of . In certain embodiments, the opioid receptor WSGR Docket No.60906-708601 modulator may be PF-4455242 (2-methylN-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4- yl)methyl)propan-1-amine), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Carlezon et al. (Depress Anxiety.2016 October ; 33(10): 895–906. doi:10.1002/da.22500), PF- 4455242 (2-methylN-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine) is a kappa opioid receptor antagonist having a structure . In
Figure imgf000016_0001
certain embodiments, the opioid receptor modulator may be AZ-MTAB (3- [[(3-endo)-8-[(5- methyl-2-thienyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]oxy]-benzamide), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Carlezon et al. (Depress Anxiety.2016 October ; 33(10): 895–906. doi:10.1002/da.22500), AZ-MTAB (3- [[(3-endo)-8-[(5-methyl-2- thienyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]oxy]-benzamide) is a kappa opioid receptor antagonist having a structure
Figure imgf000016_0002
. certain embodiments, the opioid receptor modulator may be Arodyn (Ac[Phe1,2,3, Arg4, D-Ala8]dynorphin A-(1–11) amide), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Carlezon et al. (Depress Anxiety.2016 October ; 33(10): 895–906. doi:10.1002/da.22500), Arodyn (Ac[Phe1,2,3, Arg4, D- Ala8]dynorphin A-(1–11) amide) is a kappa opioid receptor antagonist. In certain embodiments, the opioid receptor modulator may be Zyklophin (N-Benzyl-L-tyrosylglycylglycyl-N- [(3S,6S,9S,12S)-6-[(2S)-2-butanyl]-3-({(2S)-5-carbamimidamido-1-[(2S)-2-{[(2S)-1,6-diamino- 1-oxo-2-hexanyl]carbamoyl}-1-pyrrolidinyl]-1-oxo-2-pentanyl}carbamoyl)-9-(3- carbamimidamidopropyl)-5,8,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-12-yl]-L- phenylalaninamide), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Carlezon et al. (Depress Anxiety.2016 October ; 33(10): 895–906. doi:10.1002/da.22500), Zyklophin (N- Benzyl-L-tyrosylglycylglycyl-N-[(3S,6S,9S,12S)-6-[(2S)-2-butanyl]-3-({(2S)-5- carbamimidamido-1-[(2S)-2-{[(2S)-1,6-diamino-1-oxo-2-hexanyl]carbamoyl}-1-pyrrolidinyl]- WSGR Docket No.60906-708601 1-oxo-2-pentanyl}carbamoyl)-9-(3-carbamimidamidopropyl)-5,8,11,14-tetraoxo-1,4,7,10- tetraazacyclotetradecan-12-yl]-L-phenylalaninamide) is a kappa opioid receptor antagonist having a structure
Figure imgf000017_0001
In certain embodiments, the opioid receptor modulator may be Buprenorphine ((2S)-2-[(5R,6R,7R,14S)- 9α-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6-methoxymorphinan-7-yl]-3,3- dimethylbutan-2-ol), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Carlezon et al. (Depress Anxiety.2016 October ; 33(10): 895–906. doi:10.1002/da.22500), Buprenorphine ((2S)-2-[(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6- methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol) is a kappa opioid receptor antagonist. In certain embodiments, the opioid receptor modulator may be CYX-5, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Imam et al. (Pharmacological Reports, 2023. https://doi.org/10.1007/s43440-023-00446-8), CYX-5 is a delta opioid receptor antagonist
Figure imgf000017_0002
having a structure . In certain embodiments, the opioid receptor modulator may be eluxadoline, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Boinpally et al. (Clin Pharmacol Drug Dev.2022 Nov;11(11):1341-1348), eluxadoline is a delta opioid receptor antagonist. In certain embodiments, the opioid receptor modulator may be D24M (C75H92N12O14), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Olson et al. (J. Med. Chem.2018, 61, 14, 6075–6086) and Boinpally et al.(Behav Brain Res.2021 Jan 15;397:112953. doi:10.1016/j.bbr.2020.112953), D24M (C75H92N12O14) is a mu and delta opioid WSGR Docket No.60906-708601 receptor antagonist having a structure of .
Figure imgf000018_0001
In certain embodiments, the opioid may any enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Akgun et al. (Biochemistry 2021, 60, 18, 1413–1419), FBNTI is a delta opioid receptor antagonist. In certain embodiments, the opioid receptor modulator may be BOM (benzylideneoxymorphone), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Mada et al. (Psychopharmacology 237, 3591–3602, 2020), BOM (benzylideneoxymorphone) is a delta opioid receptor antagonist having a structure of
Figure imgf000018_0002
embodiments, the opioid receptor modulator may be naldemedine (SymproicR), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Urits et al. (Psychopharmacol Bull.2020; 50(3): 97–118) and Kanemasa et al. (J Pharmacol Exp Ther. 2020;373(3):438-444), naldemedine is a mu opioid receptor anatagonist having a structure of
Figure imgf000018_0003
. In certain embodiments, the opioid receptor modulator may be ICI- 174,864 (N, N-diallyl-Tyr-Aib-Aib-Phe-Leu, C38H53N5O7), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Hirayama et al. (Curr Top Med Chem.2020;20(31):2889-2902), ICI-174,864 (N, N-diallyl-Tyr-Aib-Aib-Phe-Leu, C38H53N5O7) is a delta opioid receptor antagonist. In certain embodiments, the opioid receptor modulator may be naltriben, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Lever et al. (Eur J Pharmacol.1998;350(2- 3):335-44), naltriben is a delta opioid receptor antagonist having a structure of WSGR Docket No.60906-708601 In certain embodiments, the opioid receptor modulator may be
Figure imgf000019_0001
NCGC00485585-01, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Sakamuru et al. (J Chem Inf Model.2021 Jun 28; 61(6): 01 is a mu, kappa, and delta opioid receptor antagonist having a structure
Figure imgf000019_0002
certain embodiments, the opioid receptor modulator may be NCGC00114968-02, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Sakamuru et al. (J Chem Inf Model.2021 Jun 28; 61(6): 2675– a mu opioid receptor antagonist having a structure of
Figure imgf000019_0003
. embodiments, the opioid receptor modulator may be NCGC00485288-01, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Sakamuru et al. (J Chem Inf Model.2021 Jun 28; 61(6): 01 is a mu, kappa, and
Figure imgf000019_0004
delta opioid receptor antagonist having a structure of . In certain embodiments, the opioid receptor modulator may be NCGC00106344-01, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Sakamuru et al. (J Chem Inf Model.2021 Jun 28; 61(6): 2675–2685), NCGC00106344-01 is a kappa opioid receptor antagonist having a structure of WSGR Docket No.60906-708601 embodiments, the opioid receptor modulator may be
Figure imgf000020_0001
enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Sakamuru et al. (J Chem Inf Model.2021 Jun 28; 61 : NCGC00386726-01 is a kappa opioid receptor antagonist having a structure
Figure imgf000020_0002
certain embodiments, the opioid receptor modulator may be cyclopropylsulfonamide 9f (17-(Cyclopropylsulfonyl)-6,7- didehydro-4,5α-epoxyindolo[2′,3′:6,7]morphinan-3,14β-diol), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Iwamatsu et al. (Molecules.2020 Sep; 25(17): 3792), cyclopropylsulfonamide 9f (17-(Cyclopropylsulfonyl)-6,7-didehydro-4,5α- epoxyindolo[2′,3′:6,7]morphinan-3,14β-diol) is a delta opioid receptor antagonist having a structure of
Figure imgf000020_0003
certain embodiments, the opioid receptor modulator may be phenethylsulfonamide 9e (6,7-Didehydro-4,5α-epoxy-17-((2- phenylethyl)sulfonyl)indolo[2′,3′:6,7]morphinan-3,14β-diol), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Iwamatsu et al. (Molecules.2020 Sep; 25(17): 3792), phenethylsulfonamide 9e (6,7-Didehydro-4,5α-epoxy-17-((2- phenylethyl) 3,14β-diol) is a delta opioid receptor antagonist
Figure imgf000020_0004
having a structure of (R=Phenethyl, SYK-901). In certain embodiments, the opioid receptor modulator may be Methylnaltrexone (Relistor), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Urits et al. (Psychopharmacol Bull.2020; 50(3): 97–118), WSGR Docket No.60906-708601 Methylnaltrexone (Relistor) is a mu opioid receptor antagonist. In certain embodiments, the opioid receptor modulator may be Naloxegol (Movantik), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. As shown in the research paper reported by Urits et al. (Psychopharmacol Bull.2020; 50(3): 97–118), Naloxegol (Movantik) is a mu opioid receptor antagonist. [40] In some embodiments, the opioid receptor modulator is present in an amount of about 1-150 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-50 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-30 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-20 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of no more than about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 1-150, 5-140, 10- 130, 15-120, 20-110, 25-100, 30-95, 35-90, 40-85, 45-80, 50-75, 55-70, or 60-65 mg in the pharmaceutical composition. [41] In some embodiments, the agent is present in an amount of about 0.1-200 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-100 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-10 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-1 m in the pharmaceutical composition. In some embodiments, the agent is present in an amount of at least about 0.1, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of no more than about 0.1, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.1-200, 0.5-190, 1-180, 5-170, 10-160, 20-150, 30-140, 40-130, 50-120, 60-110, 70-100, or 80-90 mg in the pharmaceutical composition. Salts and isoforms [42] The compounds described herein may form salts with acids and/or bases, and such salts are included in the present application. In some embodiments, the salts are pharmaceutically acceptable salts. The term "salts" embraces addition salts of free acids and/or WSGR Docket No.60906-708601 bases that are useful within the methods of the present application. The term "pharmaceutically acceptable salt" refers to salts that possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present application, such as for example utility in process of synthesis, purification or formulation of compounds useful within the methods of the present application. [43] Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. [44] Suitable pharmaceutically acceptable base addition salts of compounds of the present application include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (also known as N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. [45] The compounds of the present application may possess one or more stereocenters, and each stereocenter may exist independently in either the (R) or (S) configuration. In some embodiments, compounds described herein are present in optically active or racemic forms. The compounds described herein encompass racemic, optically active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. A compound illustrated herein by WSGR Docket No.60906-708601 the racemic formula further represents either of the two enantiomers or mixtures thereof, or in the case where two or more chiral center are present, all diastereomers or mixtures thereof. [46] In some embodiments, the compounds of the present application may exist as tautomer. All tautomers are included within the scope of the compounds recited herein. [47] Compounds described herein also include isotopically labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to 2H, 3H, 11C, 13C, 14C, 36Cl, 18F, 123I, 125I, 13N, 15N, 15O, 17O, 18O, 32P, and 35S. In some embodiments, substitution with heavier isotopes such as deuterium affords greater chemical stability. Isotopically labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed. [48] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Method of Treatment [49] This disclosure also provides a method for treating, ameliorating, or preventing a disease or disorder in a subject in need thereof. In some cases, the method comprises administering the pharmaceutical composition described herein to the subject. In some embodiments, the pharmaceutical composition comprising an opioid receptor modulator and an agent. In some embodiments, the agent comprises a 3,4-methylenedioxymethamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. Any opioid receptor modulator known in the art is contemplated within the present application. In some embodiments, the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta-opioid receptor modulator. In some embodiments, the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist. In some embodiments, the opioid receptor modulator is an opioid receptor antagonist. In some embodiments, the opioid receptor modulator is an opioid receptor negative allosteric modulator. In some embodiments, the opioid receptor modulator is an opioid receptor partial agonist. In some cases, the opioid receptor modulator comprises a kappa-opioid receptor modulator. In some cases, the opioid receptor modulator comprises a delta-opioid receptor modulator. WSGR Docket No.60906-708601 [50] In some cases, the agent comprises 3,4-methylenedioxyamphetamine (MDA, ‘Love'), N-ethyl-3,4-methylenedioxyamphetamine (MDEA, ‘Eve'), 3,4-methylenedioxy-N- hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha-ethyl-N-methylphenethylamine (MBDB, "EDEN" or "Methyl-J”), 1-Benzofuran-5-ylpropan-2-amine (5-APB), 1-(benzofuran- 5-yl)-N-methylpropan-2-amine (5-MAPB), 6-(2-aminopropyl)benzofuran (6-APB), 1- (benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N- methylcathinone (methylone, "MDMC", "βk-MDMA" and "M1"), 4-methylmethcathinone (mephedrone, 4-MMC, and 4-methylephedrone), gamma-Hydroxybutyric acid (GHB), α- Methyltryptamine (αMT), α-Ethyltryptamine (αET), or 5,6-methylenedioxy-2-aminoindane (MDAI), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [51] Non-limiting examples of opioid receptor modulators useful within the methods of the present application are recited in the Pharmaceutical Composition section, and include any salt, solvate, enantiomer, tautomer, stereoisomer, and/or geometric isomer thereof, or any mixtures thereof. [52] In some cases, the opioid receptor modulator and the agent are administered concurrently to the subject. In some cases, the opioid receptor modulator and the agent are administered separately to the subject. In some cases, the opioid receptor modulator and the agent are administered sequentially to the subject. [53] In some cases, the opioid receptor modulator is administered once per day, twice per day, or three times per day. In some cases, the opioid receptor modulator is administered once per day. In some cases, the opioid receptor modulator is administered twice per day. In some cases, the opioid receptor modulator is administered three times per day. In some cases, the opioid receptor modulator is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week. In some cases, the opioid receptor modulator is administered once per week. In some cases, the opioid receptor modulator is administered twice per week. In some cases, the opioid receptor modulator is administered three times per week. In some cases, the opioid receptor modulator is administered four times per week. In some cases, the opioid receptor modulator is administered five times per week. In some cases, the opioid receptor modulator is administered six times per week. In some cases, the opioid receptor modulator is administered seven times per week. In some cases, the opioid receptor modulator is administered once per month, twice per month, three times per month, four times per month, five times per month, or ten times per month. In some cases, the opioid receptor modulator is administered once per month. In some cases, the opioid receptor modulator is administered twice per month. In some cases, the opioid receptor WSGR Docket No.60906-708601 modulator is administered three times per month. In some cases, the opioid receptor modulator is administered four times per month. In some cases, the opioid receptor modulator is administered five times per month. In some cases, the opioid receptor modulator is administered ten times per month. [54] In some cases, the agent is administered once per day, twice per day, or three times per day. In some cases, the agent is administered once per day. In some cases, the agent is administered twice per day. In some cases, the agent is administered three times per day. In some cases, the agent is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week. In some cases, the agent is administered once per week. In some cases, the agent is administered twice per week. In some cases, the agent is administered three times per week. In some cases, the agent is administered four times per week. In some cases, the agent is administered five times per week. In some cases, the agent is administered six times per week. In some cases, the agent is administered seven times per week. In some cases, the agent is administered once per month, twice per month, three times per month, four times per month, five times per month, or ten times per month. In some cases, the agent is administered once per month. In some cases, the agent is administered twice per month. In some cases, the agent is administered three times per month. In some cases, the agent is administered four times per month. In some cases, the agent is administered five times per month. In some cases, the agent is administered ten times per month. [55] In some cases, the pharmaceutical composition described herein is administered once per day, twice per day, or three times per day. In some cases, the pharmaceutical composition described herein is administered once per day. In some cases, the pharmaceutical composition described herein is administered twice per day. In some cases, the pharmaceutical composition described herein is administered three times per day. In some cases, the pharmaceutical composition described herein is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or seven times per week. In some cases, the pharmaceutical composition described herein is administered once per week. In some cases, the pharmaceutical composition described herein is administered twice per week. In some cases, the pharmaceutical composition described herein is administered three times per week. In some cases, the pharmaceutical composition described herein is administered four times per week. In some cases, the pharmaceutical composition described herein is administered five times per week. In some cases, the pharmaceutical composition described herein is administered six times per week. In some cases, the pharmaceutical composition described herein is administered seven times per week. In some cases, the pharmaceutical composition described herein is administered once per month, twice per month, three times per month, four WSGR Docket No.60906-708601 times per month, five times per month, or ten times per month. In some cases, the pharmaceutical composition described herein is administered once per month. In some cases, the pharmaceutical composition described herein is administered twice per month. In some cases, the pharmaceutical composition described herein is administered three times per month. In some cases, the pharmaceutical composition described herein is administered four times per month. In some cases, the pharmaceutical composition described herein is administered five times per month. In some cases, the pharmaceutical composition described herein is administered ten times per month. [56] In some cases, the opioid receptor modulator is administered to the subject by a route selected from the group consisting of intranasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous. In some cases, the opioid receptor modulator is administered to the subject by an intranasal route. In some cases, the opioid receptor modulator is administered to the subject by an inhalational route. In some cases, the opioid receptor modulator is administered to the subject by a topical route. In some cases, the opioid receptor modulator is administered to the subject by an oral route. In some cases, the opioid receptor modulator is administered to the subject by a buccal route. In some cases, the opioid receptor modulator is administered to the subject by a rectal route. In some cases, the opioid receptor modulator is administered to the subject by a pleural route. In some cases, the opioid receptor modulator is administered to the subject by a peritoneal route. In some cases, the opioid receptor modulator is administered to the subject by a vaginal route. In some cases, the opioid receptor modulator is administered to the subject by an intramuscular route. In some cases, the opioid receptor modulator is administered to the subject by a subcutaneous route. In some cases, the opioid receptor modulator is administered to the subject by a transdermal route. In some cases, the opioid receptor modulator is administered to the subject by an epidural route. In some cases, the opioid receptor modulator is administered to the subject by an intratracheal route. In some cases, the opioid receptor modulator is administered to the subject by an otic route. In some cases, the opioid receptor modulator is administered to the subject by an intraocular route. In some cases, the opioid receptor modulator is administered to the subject by an intrathecal route. In some cases, the opioid receptor modulator is administered to the subject by an intravenous route. [57] In some cases, the agent is administered to the subject by a route selected from the group consisting of intranasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous. In some cases, agent is administered to the subject by an intranasal WSGR Docket No.60906-708601 route. In some cases, the agent is administered to the subject by an inhalational route. In some cases, the agent is administered to the subject by a topical route. In some cases, the agent is administered to the subject by an oral route. In some cases, the agent is administered to the subject by a buccal route. In some cases, the agent is administered to the subject by a rectal route. In some cases, the agent is administered to the subject by a pleural route. In some cases, the agent is administered to the subject by a peritoneal route. In some cases, the agent is administered to the subject by a vaginal route. In some cases, the agent is administered to the subject by an intramuscular route. In some cases, the agent is administered to the subject by a subcutaneous route. In some cases, the agent is administered to the subject by a transdermal route. In some cases, the agent is administered to the subject by an epidural route. In some cases, the agent is administered to the subject by an intratracheal route. In some cases, the agent is administered to the subject by an otic route. In some cases, the agent is administered to the subject by an intraocular route. In some cases, the agent is administered to the subject by an intrathecal route. In some cases, the agent is administered to the subject by an intravenous route. [58] In some cases, the pharmaceutical composition described herein is administered to the subject by a route selected from the group consisting of intranasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous. In some cases, the pharmaceutical composition described herein is administered to the subject by an intranasal route. In some cases, the pharmaceutical composition described herein is administered to the subject by an inhalational route. In some cases, the pharmaceutical composition described herein is administered to the subject by a topical route. In some cases, the pharmaceutical composition described herein is administered to the subject by an oral route. In some cases, the pharmaceutical composition described herein is administered to the subject by a buccal route. In some cases, the pharmaceutical composition described herein is administered to the subject by a rectal route. In some cases, the pharmaceutical composition described herein is administered to the subject by a pleural route. In some cases, the pharmaceutical composition described herein is administered to the subject by a peritoneal route. In some cases, the pharmaceutical composition described herein is administered to the subject by a vaginal route. In some cases, the pharmaceutical composition described herein is administered to the subject by an intramuscular route. In some cases, the pharmaceutical composition described herein is administered to the subject by a subcutaneous route. In some cases, the pharmaceutical composition described herein is administered to the subject by a transdermal route. In some cases, the pharmaceutical composition described herein is administered to the subject by an epidural route. In some cases, the pharmaceutical composition described herein is administered to the subject by an WSGR Docket No.60906-708601 intratracheal route. In some cases, the pharmaceutical composition described herein is administered to the subject by an otic route. In some cases, the pharmaceutical composition described herein is administered to the subject by an intraocular route. In some cases, the pharmaceutical composition described herein is administered to the subject by an intrathecal route. In some cases, the pharmaceutical composition described herein is administered to the subject by an intravenous route. [59] In some cases, administration of the opioid receptor modulator prevents, ameliorates, or minimizes abuse of the agent by the subject, wherein the abuse is contributed by a behavioral effect of the agent including agent liking, agent craving, or agent seeking. In some cases, administration of the opioid receptor modulator prevents, ameliorates, or minimizes abuse of the MDMA by the subject, wherein the abuse is contributed by a behavioral effect of the MDMA including MDMA liking, MDMA craving, or MDMA seeking. [60] In some cases, the disease or disorder is selected from the group consisting of major depressive disorder, major depressive disorder, major depressive episode in bipolar disorder (bipolar depression), bipolar I disorder, bipolar II disorder, persistent depressive disorder (dysthymia), disruptive mood dysregulation disorder, major depressive disorder (including major depressive episode), resistant depressive disorder, partially responsive depressive disorder, substance use disorder (with or without anxiety or depressive disorder), alcohol use disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, anxiety disorder, generalized anxiety disorder, social anxiety disorder (social phobia), specific phobia, panic disorder, agoraphobia, separation anxiety disorder, selective mutism, substance-induced anxiety disorder, medication-induced anxiety disorder, anxiety disorder due to another medical condition, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, obsessive compulsive disorder, bulimia nervosa, anorexia nervosa, binge eating disorder, and posttraumatic stress disorder. [61] In some embodiments, the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist. In some embodiments, the opioid receptor modulator is an opioid receptor antagonist. In some embodiments, the opioid receptor modulator is an opioid receptor negative allosteric modulator. In some embodiments, the opioid receptor modulator is an opioid receptor partial agonist. [62] In some embodiments, the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In WSGR Docket No.60906-708601 some embodiments, the compound is naltrexone, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [63] In some embodiments, the opioid receptor modulator is present in an amount of about 1-150 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-50 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-30 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-20 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of no more than about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 1-150, 5-140, 10- 130, 15-120, 20-110, 25-100, 30-95, 35-90, 40-85, 45-80, 50-75, 55-70, or 60-65 mg in the pharmaceutical composition. [64] In some embodiments, the agent is present in an amount of about 0.1-200 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-100 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-10 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-1 m in the pharmaceutical composition. In some embodiments, the agent is present in an amount of at least about 0.1, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of no more than about 0.1, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.1-200, 0.5-190, 1-180, 5-170, 10-160, 20-150, 30-140, 40-130, 50-120, 60-110, 70-100, or 80-90 mg in the pharmaceutical composition. Kits [65] Additional aspect of this disclosure provides a kit comprising an opioid receptor modulator and an agent. In some embodiments, the agent comprises a 3,4- Methylenedioxymethamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. WSGR Docket No.60906-708601 [66] In some cases, the agent comprises 3,4-methylenedioxyamphetamine (MDA, ‘Love'), N-ethyl-3,4-methylenedioxyamphetamine (MDEA, ‘Eve'), 3,4-methylenedioxy-N- hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha-ethyl-N-methylphenethylamine (MBDB, "EDEN" or "Methyl-J”), 1-Benzofuran-5-ylpropan-2-amine (5-APB), 1-(benzofuran- 5-yl)-N-methylpropan-2-amine (5-MAPB), 6-(2-aminopropyl)benzofuran (6-APB), 1- (benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N- methylcathinone (methylone, "MDMC", "βk-MDMA" and "M1"), 4-methylmethcathinone (mephedrone, 4-MMC, and 4-methylephedrone), gamma-Hydroxybutyric acid (GHB), α- Methyltryptamine (αMT), α-Ethyltryptamine (αET), or 5,6-methylenedioxy-2-aminoindane (MDAI), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [67] In some cases, the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta-opioid receptor modulator. In some embodiments, the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist. In some embodiments, the opioid receptor modulator is an opioid receptor antagonist. In some embodiments, the opioid receptor modulator is an opioid receptor negative allosteric modulator. In some embodiments, the opioid receptor modulator is an opioid receptor partial agonist. [68] In some embodiments, the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some embodiments, the compound is naltrexone, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [69] Non-limiting examples of opioid receptor modulators useful within the methods of the present application are recited herein, and include any salt, solvate, enantiomer, tautomer, stereoisomer, and/or geometric isomer thereof, or any mixtures thereof. In certain embodiments, the opioid receptor modulator is naltrexone (also known as 17-(cyclopropylmethyl)-4,5α-epoxy- 3,14-dihydroxymorphinan-6-one). In certain embodiments, the opioid receptor modulator is long-acting naltrexone (extended-release naltrexone, e.g., Vivitrol®). In certain embodiments, the opioid receptor modulator is naloxone (also known as (4R,4aS,7aR,12bS)-4a,9-dihydroxy-3- prop-2-enyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one, Narcan, Evzio, or Nyxoid). In certain embodiments, the opioid receptor modulator is long- acting naloxone (extended-release naloxone). In certain embodiments, the opioid receptor modulator is nalmefene (also known as 17-cyclopropylmethyl-4,5α-epoxy-6- WSGR Docket No.60906-708601 methylenemorphinan-3,14-diol, nalmetrene, or Selincro). In certain embodiments, the opioid receptor modulator is long-acting nalmefene (extended-release nalmefene). In certain embodiments, the opioid receptor modulator is nalodeine (also known as N-allylnorcodeine, or (4R,4aR,7S,7aR,12bS)-9-methoxy-3-prop-2-enyl-2,4,4a,7,7a,13-hexahydro-1H-4,12- methanobenzofuro[3,2-e]isoquinoline-7-ol). In some embodiments, the long-acting naltrexone has a longer serum half-life than naltrexone. In some embodiments, the long-acting naloxone has a longer serum half-life than naloxone. In some embodiments, the long-acting nalmefene has a longer serum half-life than nalmefene. [70] In some embodiments, the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, naltrindole, UPHIT ((1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide), DIPPA (2-(3,4-dichlorophenyl)- N-methyl-N-[(1S)- 1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide), JDTic ((3R)-7-Hydroxy-N- [(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl]-1,2,3,4- tetrahydroisoquinoline-3-carboxamide), Nor-BNI (Norbinaltorphimine), GNTI (5’- Guanidinonaltrindole), CERC-501 (4-(4-{[(2S)-2-(3,5-Dimethylphenyl)-1- pyrrolidinyl]methyl}phenoxy)-3-fluorobenzamide), PF-4455242 (2-methylN-((2′-(pyrrolidin-1- ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine), AZ-MTAB (3- [[(3-endo)-8-[(5-methyl-2- thienyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]oxy]-benzamide), Arodyn (Ac[Phe1,2,3,Arg4, D- Ala8]dynorphin A-(1–11) amide), Zyklophin (N-Benzyl-L-tyrosylglycylglycyl-N- [(3S,6S,9S,12S)-6-[(2S)-2-butanyl]-3-({(2S)-5-carbamimidamido-1-[(2S)-2-{[(2S)-1,6-diamino- 1-oxo-2-hexanyl]carbamoyl}-1-pyrrolidinyl]-1-oxo-2-pentanyl}carbamoyl)-9-(3- carbamimidamidopropyl)-5,8,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-12-yl]-L- phenylalaninamide), Buprenorphine ((2S)-2-[(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy- 6,14-ethano-3- 6- 7-yl]-3,3-dimethylbutan-2-ol), CYX-5
Figure imgf000031_0001
, Pharmacological Reports, 2023. https://doi.org/10.1007/s43440-023-00446-8), eluxadoline (Clin Pharmacol Drug Dev.2022
Figure imgf000031_0002
, J. Med. Chem.2018, 61, 14, 6075–6086; Behav Brain Res.2021 Jan 15;397:112953. doi:10.1016/j.bbr.2020.112953), FBNTI WSGR Docket No.60906-708601 (Biochemistry 2021, 60, 18, 1413–1419), BOM (benzylideneoxymorphone), naldemedine, ICI- 174,864 (N, N-diallyl-Tyr-Aib-Aib-Phe-Leu, C38H53N5O7, Curr Top Med Chem.2020;20(31):2889-2902), naltriben (Eur J Pharmacol.1998 Jun 5;350(2-3):335-44), ), ),
Figure imgf000032_0001
(Cyclopropylsulfonyl)-6,7-didehydro-4,5α-epoxyindolo[2′,3′:6,7]morphinan-3,14β-diol,
Figure imgf000032_0002
839, Molecules.2020 Sep; 25(17): 3792), phenethylsulfonamide 9e (6,7-Didehydro-4,5α-epoxy-17-((2-
Figure imgf000032_0003
phenylethyl)sulfonyl)indolo[2′,3′:6,7]morphinan-3,14β-diol, R=Phenethyl, SYK-901), Methylnaltrexone (Relistor), Naloxegol (Movantik), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. In some embodiments, the compound is naltrexone, any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. [71] In some embodiments, the opioid receptor modulator is present in an amount of about 1-150 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-50 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-30 mg in the WSGR Docket No.60906-708601 pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 5-20 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of no more than about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, or 150 mg in the pharmaceutical composition. In some embodiments, the opioid receptor modulator is present in an amount of about 1-150, 5-140, 10- 130, 15-120, 20-110, 25-100, 30-95, 35-90, 40-85, 45-80, 50-75, 55-70, or 60-65 mg in the pharmaceutical composition. [72] In some embodiments, the agent is present in an amount of about 0.1-200 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-100 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-10 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.2-1 m in the pharmaceutical composition. In some embodiments, the agent is present in an amount of at least about 0.1, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of no more than about 0.1, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg in the pharmaceutical composition. In some embodiments, the agent is present in an amount of about 0.1-200, 0.5-190, 1-180, 5-170, 10-160, 20-150, 30-140, 40-130, 50-120, 60-110, 70-100, or 80-90 mg in the pharmaceutical composition. Definitions [73] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. [74] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For WSGR Docket No.60906-708601 example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. [75] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof. [76] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of” can include determining the amount of something present in addition to determining whether it is present or absent depending on the context. [77] The terms “subject,” “individual,” or “patient” are often used interchangeably herein. A “subject” can be a biological entity containing expressed genetic materials. The biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. The subject can be tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro. The subject can be a mammal. The mammal can be a human. The subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease. [78] As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value. [79] As used herein, the terms “treatment” or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For WSGR Docket No.60906-708601 prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made. [80] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Examples [81] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. Example 1: Intravenous (IV) MDMA self -administration (SA) [82] Sprague-Dawley (SD) rats were used on a cocaine intravenous (IV) self- administration (SA). A small group of these cocaine-experienced animals were then tested with MDMA SA followed by a within subject test of naloxone (10 mg/kg). [83] Protocol of cocaine-experienced animals: (i) 10-14 days of 0.5mg/kg cocaine IV SA followed by 8-10 days of cocaine extinction and (ii)1 day memory-reconsolidation test, 1 day cue reinstatement testing, 14 days of withdrawal, 1 day long-term cue reinstatement, and 1 day conditioned reinforcement (CR) test. [84] Test Protocol: In 24 hrs after the above CR test, animals were placed on sessions with 0.25mg/kg of MDMA-IV-SA. These were 2hr sessions over a period of approximately 3 weeks to generate stable MDMA-IV-SA. There were only 4 animals that showed stable responding that were ultimately tested with the naloxone/naltrexone. [85] The results in these 4 animals for this study suggest that a 10mg/kg dose of Naloxone (1hr prior the SA session) reduce MDMA SA (FIG.1 & FIG.2). Note that baseline is number of infusions over the last few days of the SA period. Animals then received a saline test session, followed by a Naloxone test session. The animals were re-stabilized on MDMS SA and tested again but this time with a 10mg/kg dose of Naltrexone. A similar reduction in MDMA SA was observed. [86] A small study will be repeated with the above design but with a drug-naïve “clean” group on a either the 0.25 or a higher dose of MDMA (1mg/kg) to determine if stable SA of MDMA can be obtained. Alternatively, cocaine-experienced animals can be used before testing with MDMA and naloxone/naltrexone but in “clean” animals that did not undergo the varied testing protocols used in our pilot study. [87] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now WSGR Docket No.60906-708601 occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Docket No.60906-708601 CLAIMS What is claimed is: 1. A pharmaceutical composition comprising an opioid receptor modulator and an agent, wherein the agent comprises a 3,4-Methylenedioxymethamphetamine (MDMA), 3,4- methylenedioxyamphetamine (MDA), N-ethyl-3,4-methylenedioxyamphetamine (MDEA), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha-ethyl-N- methylphenethylamine (MBDB), 1-Benzofuran-5-ylpropan-2-amine (5-APB), 1- (benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB), 6-(2-aminopropyl)benzofuran (6- APB), 1-(benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N- methylcathinone (methylone), 4-methylmethcathinone (mephedrone), gamma- Hydroxybutyric acid (GHB), α-Methyltryptamine (αMT), α-Ethyltryptamine (αET), or 5,6- methylenedioxy-2-aminoindane (MDAI), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 2. The pharmaceutical composition of claim 1, wherein the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta- opioid receptor modulator. 3. The pharmaceutical composition of claim 1, wherein the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist. 4. The pharmaceutical composition of claim 1, wherein the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, naltrindole, UPHIT ((1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N- methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide), DIPPA (2-(3,4- dichlorophenyl)- N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1- pyrrolidinyl)ethyl]acetamide), JDTic ((3R)-7-Hydroxy-N-[(2S)-1-[(3R,4R)-4-(3- hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl]-1,2,3,4- tetrahydroisoquinoline-3-carboxamide), Nor-BNI (Norbinaltorphimine), GNTI (5’- Guanidinonaltrindole), CERC-501 (4-(4-{[(2S)-2-(3,5-Dimethylphenyl)-1- pyrrolidinyl]methyl}phenoxy)-3-fluorobenzamide), PF-4455242 (2-methylN-((2′- (pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine), AZ-MTAB (3- [[(3-endo)- 8-[(5-methyl-2-thienyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]oxy]-benzamide), Arodyn (Ac[Phe1,2,3,Arg4, D-Ala8]dynorphin A-(1–11) amide), Zyklophin (N-Benzyl-L- tyrosylglycylglycyl-N-[(3S,6S,9S,12S)-6-[(2S)-2-butanyl]-3-({(2S)-5-carbamimidamido-1- [(2S)-2-{[(2S)-1,6-diamino-1-oxo-2-hexanyl]carbamoyl}-1-pyrrolidinyl]-1-oxo-2- pentanyl}carbamoyl)-9-(3-carbamimidamidopropyl)-5,8,11,14-tetraoxo-1,4,7,10- WSGR Docket No.60906-708601 tetraazacyclotetradecan-12-yl]-L-phenylalaninamide), Buprenorphine ((2S)-2- [(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6- methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol), CYX-5, eluxadoline, D24M, FBNTI, BOM (benzylideneoxymorphone), naldemedine, ICI-174,864, naltriben, NCGC00485585- 01, NCGC00114968-02, NCGC00485288-01, NCGC00106344-01, NCGC00386726-01, cyclopropylsulfonamide 9f (17-(Cyclopropylsulfonyl)-6,7-didehydro-4,5α- epoxyindolo[2′,3′:6,7]morphinan-3,14β-diol, SYK-839), phenethylsulfonamide 9e (6,7- Didehydro-4,5α-epoxy-17-((2-phenylethyl)sulfonyl)indolo[2′,3′:6,7]morphinan-3,14β-diol, SYK-901), Methylnaltrexone (Relistor), Naloxegol (Movantik), and any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 5. The pharmaceutical composition of any one of claims 1-4, wherein the agent comprises 3,4- Methylenedioxymethamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 6. The pharmaceutical composition of any one of claims 1-4, wherein the agent comprises 3,4- methylenedioxyamphetamine (MDA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 7. The pharmaceutical composition of any one of claims 1-4, wherein the agent comprises N- ethyl-3,4-methylenedioxyamphetamine (MDEA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 8. The pharmaceutical composition of any one of claims 1-7, wherein the opioid receptor modulator is present in an amount of about 1-150 mg. 9. The pharmaceutical composition of any one of claims 1-7, wherein the opioid receptor modulator is present in an amount of about 5-50 mg. 10. The pharmaceutical composition of any one of claims 1-7, wherein the opioid receptor modulator is present in an amount of about 5-30 mg. 11. The pharmaceutical composition of any one of claims 1-7, wherein the opioid receptor modulator is present in an amount of about 5-20 mg. 12. The pharmaceutical composition of any one of claims 1-10, wherein the agent is present in an amount of about 0.1-200 mg. 13. The pharmaceutical composition of any one of claims 1-10, wherein the agent is present in an amount of about 0.2-100 mg. 14. The pharmaceutical composition of any one of claims 1-10, wherein the agent is present in an amount of about 0.2-10 mg. WSGR Docket No.60906-708601 15. The pharmaceutical composition of any one of claims 1-10, wherein the agent is present in an amount of about 0.2-1 mg. 16. A method for treating, ameliorating or preventing a disease or disorder in a subject in need thereof comprising administering the pharmaceutical composition of any one of claims 1-15 to the subject. 17. A kit comprising an opioid receptor modulator and an agent, wherein the agent comprises a 3,4-Methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), N-ethyl-3,4-methylenedioxyamphetamine (MDEA), 3,4-methylenedioxy-N- hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha-ethyl-N-methylphenethylamine (MBDB), 1-Benzofuran-5-ylpropan-2-amine (5-APB), 1-(benzofuran-5-yl)-N- methylpropan-2-amine (5-MAPB), 6-(2-aminopropyl)benzofuran (6-APB), 1-(benzofuran-6- yl)-N-methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N-methylcathinone (methylone), 4-methylmethcathinone (mephedrone), gamma-Hydroxybutyric acid (GHB), α- Methyltryptamine (αMT), α-Ethyltryptamine (αET), or 5,6-methylenedioxy-2-aminoindane (MDAI), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 18. The kit of claim 17, wherein the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta-opioid receptor modulator. 19. The kit of claim 17, wherein the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist. 20. The kit of claim 17, wherein the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, naltrindole, UPHIT ((1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide), DIPPA (2-(3,4-dichlorophenyl)- N-methyl-N- [(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide), JDTic ((3R)-7- Hydroxy-N-[(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3- methylbutan-2-yl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide), Nor-BNI (Norbinaltorphimine), GNTI (5’-Guanidinonaltrindole), CERC-501 (4-(4-{[(2S)-2-(3,5- Dimethylphenyl)-1-pyrrolidinyl]methyl}phenoxy)-3-fluorobenzamide), PF-4455242 (2- methylN-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine), AZ-MTAB (3- [[(3-endo)-8-[(5-methyl-2-thienyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]oxy]-benzamide), Arodyn (Ac[Phe1,2,3,Arg4, D-Ala8]dynorphin A-(1–11) amide), Zyklophin (N-Benzyl-L- tyrosylglycylglycyl-N-[(3S,6S,9S,12S)-6-[(2S)-2-butanyl]-3-({(2S)-5-carbamimidamido-1- [(2S)-2-{[(2S)-1,6-diamino-1-oxo-2-hexanyl]carbamoyl}-1-pyrrolidinyl]-1-oxo-2- WSGR Docket No.60906-708601 pentanyl}carbamoyl)-9-(3-carbamimidamidopropyl)-5,8,11,14-tetraoxo-1,4,7,10- tetraazacyclotetradecan-12-yl]-L-phenylalaninamide), Buprenorphine ((2S)-2- [(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6- methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol), CYX-5, eluxadoline, D24M, FBNTI, BOM (benzylideneoxymorphone), naldemedine, ICI-174,864, naltriben, NCGC00485585- 01, NCGC00114968-02, NCGC00485288-01, NCGC00106344-01, NCGC00386726-01, cyclopropylsulfonamide 9f (17-(Cyclopropylsulfonyl)-6,7-didehydro-4,5α- epoxyindolo[2′,3′:6,7]morphinan-3,14β-diol, SYK-839), phenethylsulfonamide 9e (6,7- Didehydro-4,5α-epoxy-17-((2-phenylethyl)sulfonyl)indolo[2′,3′:6,7]morphinan-3,14β-diol, SYK-901), Methylnaltrexone (Relistor), Naloxegol (Movantik), and any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 21. The kit of any one of claims 17-20, wherein the agent comprises 3,4-Methylenedioxy methamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 22. The kit of any one of claims 17-20, wherein the agent comprises 3,4- methylenedioxyamphetamine (MDA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 23. The kit of any one of claims 17-20, wherein the agent comprises N-ethyl-3,4- methylenedioxyamphetamine (MDEA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 24. The kit of any one of claims 17-23, wherein the opioid receptor modulator is present in an amount of about 1-150 mg. 25. The kit of any one of claims 17-23, wherein the opioid receptor modulator is present in an amount of about 5-50 mg. 26. The kit of any one of claims 17-23, wherein the opioid receptor modulator is present in an amount of about 5-30 mg. 27. The kit of any one of claims 17-23, wherein the opioid receptor modulator is present in an amount of about 5-20 mg. 28. The kit of any one of claims 17-27, wherein the agent is present in an amount of about 0.1- 10 mg. 29. The kit of any one of claims 17-27, wherein the agent is present in an amount of about 0.2-5 mg. 30. The kit of any one of claims 17-27, wherein the agent is present in an amount of about 0.2- 200 mg. WSGR Docket No.60906-708601 31. The kit of any one of claims 17-27, wherein the agent is present in an amount of about 0.2- 10 mg. 32. A method for treating, ameliorating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject an opioid receptor modulator and an agent, wherein the agent comprises a 3,4-Methylenedioxymethamphetamine (MDMA), 3,4- methylenedioxyamphetamine (MDA), N-ethyl-3,4-methylenedioxyamphetamine (MDEA), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 3,4-methylenedioxy-alpha-ethyl-N- methylphenethylamine (MBDB), 1-Benzofuran-5-ylpropan-2-amine (5-APB), 1- (benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB), 6-(2-aminopropyl)benzofuran (6- APB), 1-(benzofuran-6-yl)-N-methylpropan-2-amine (6-MAPB), 3,4-methylenedioxy-N- methylcathinone (methylone), 4-methylmethcathinone (mephedrone), gamma- Hydroxybutyric acid (GHB), α-Methyltryptamine (αMT), α-Ethyltryptamine (αET), or 5,6- methylenedioxy-2-aminoindane (MDAI), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 33. The method of claim 32, wherein the opioid receptor modulator and the agent are administered concurrently. 34. The method of claim 32, wherein the opioid receptor modulator and the agent are administered separately. 35. The method of claim 32, wherein the opioid receptor modulator and the agent are administered sequentially. 36. The method of any one of claims 32-35, wherein the opioid receptor modulator is administered once per day, twice per day, or three times per day. 37. The method of any one of claims 32-35, wherein the opioid receptor modulator is administered once per week, twice per week, or three times per week. 38. The method of any one of claims 32-35, wherein the opioid receptor modulator is administered once per month, twice per month, or three times per month. 39. The method of any one of claims 32-38, wherein the agent is administered once per day, twice per day, or three times per day. 40. The method of any one of claims 32-38, wherein the agent is administered once per week, twice per week, or three times per week. 41. The method of any one of claims 32-38, wherein the agent is administered once per month, twice per month, or three times per month. 42. The method of any one of claims 32-41, wherein the opioid receptor modulator is administered to the subject by a route selected from the group consisting of intranasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, WSGR Docket No.60906-708601 subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous. 43. The method of any one of claims 32-42, wherein the agent is administered to the subject by a route selected from the group consisting of intranasal, inhalational, topical, oral, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, intrathecal, and intravenous. 44. The method of any one of claims 32-43, wherein administration of the opioid receptor modulator prevents, ameliorates, or minimizes abuse of the agent by the subject, wherein the abuse is contributed by a behavioral effect of the agent including agent liking, agent craving, or agent seeking. 45. The method of any one of claims 32-44, wherein the disease or disorder is selected from the group consisting of major depressive disorder, major depressive disorder, major depressive episode in bipolar disorder (bipolar depression), bipolar I disorder, bipolar II disorder, persistent depressive disorder (dysthymia), disruptive mood dysregulation disorder, major depressive disorder (including major depressive episode), resistant depressive disorder, partially responsive depressive disorder, substance use disorder (with or without anxiety or depressive disorder), alcohol use disorder, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, unspecified depressive disorder, anxiety disorder, generalized anxiety disorder, social anxiety disorder (social phobia), specific phobia, panic disorder, agoraphobia, separation anxiety disorder, selective mutism, substance-induced anxiety disorder, medication-induced anxiety disorder, anxiety disorder due to another medical condition, borderline personality disorder, treatment-resistant depression, unspecified anxiety disorder, obsessive compulsive disorder, bulimia nervosa, anorexia nervosa, binge eating disorder, and posttraumatic stress disorder. 46. The method of any one of claims 32-45, wherein the opioid receptor modulator comprises a mu-opioid receptor modulator, a kappa-opioid receptor modulator, or a delta-opioid receptor modulator. 47. The method of any one of claims 32-45, wherein the opioid receptor modulator is selected from the group consisting of an opioid receptor antagonist, an opioid receptor negative allosteric modulator, and an opioid receptor partial agonist. 48. The method of any one of claims 32-45, wherein the opioid receptor modulator comprises a compound selected from the group consisting of naltrexone, naloxone, nalmefene, nalodeine, naltrindole, UPHIT ((1S,2S)-trans-2-Isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1- pyrrolidinyl)cyclohexyl]benzeneacetamide), DIPPA (2-(3,4-dichlorophenyl)- N-methyl-N- WSGR Docket No.60906-708601 [(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide), JDTic ((3R)-7- Hydroxy-N-[(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3- methylbutan-2-yl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide), Nor-BNI (Norbinaltorphimine), GNTI (5’-Guanidinonaltrindole), CERC-501 (4-(4-{[(2S)-2-(3,5- Dimethylphenyl)-1-pyrrolidinyl]methyl}phenoxy)-3-fluorobenzamide), PF-4455242 (2- methylN-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine), AZ-MTAB (3- [[(3-endo)-8-[(5-methyl-2-thienyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]oxy]-benzamide), Arodyn (Ac[Phe1,2,3,Arg4, D-Ala8]dynorphin A-(1–11) amide), Zyklophin (N-Benzyl-L- tyrosylglycylglycyl-N-[(3S,6S,9S,12S)-6-[(2S)-2-butanyl]-3-({(2S)-5-carbamimidamido-1- [(2S)-2-{[(2S)-1,6-diamino-1-oxo-2-hexanyl]carbamoyl}-1-pyrrolidinyl]-1-oxo-2- pentanyl}carbamoyl)-9-(3-carbamimidamidopropyl)-5,8,11,14-tetraoxo-1,4,7,10- tetraazacyclotetradecan-12-yl]-L-phenylalaninamide), Buprenorphine ((2S)-2- [(5R,6R,7R,14S)-9α-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6- methoxymorphinan-7-yl]-3,3-dimethylbutan-2-ol), CYX-5, eluxadoline, D24M, FBNTI, BOM (benzylideneoxymorphone), naldemedine, ICI-174,864, naltriben, NCGC00485585- 01, NCGC00114968-02, NCGC00485288-01, NCGC00106344-01, NCGC00386726-01, cyclopropylsulfonamide 9f (17-(Cyclopropylsulfonyl)-6,7-didehydro-4,5α- epoxyindolo[2′,3′:6,7]morphinan-3,14β-diol, SYK-839), phenethylsulfonamide 9e (6,7- Didehydro-4,5α-epoxy-17-((2-phenylethyl)sulfonyl)indolo[2′,3′:6,7]morphinan-3,14β-diol, SYK-901), Methylnaltrexone (Relistor), Naloxegol (Movantik), and any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 49. The method of any one of claims 32-48, wherein the agent comprises 3,4-Methylenedioxy methamphetamine (MDMA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 50. The method of any one of claims 32-48, wherein the agent comprises 3,4- methylenedioxyamphetamine (MDA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 51. The method of any one of claims 32-48, wherein the agent comprises N-ethyl-3,4- methylenedioxyamphetamine (MDEA), any salt, solvate, enantiomer, tautomer, stereoisomer, or geometric isomer thereof, or any combination thereof. 52. The method of any one of claims 32-51, wherein the opioid receptor modulator is present in an amount of about 1-200 mg. 53. The method of any one of claims 32-51, wherein the opioid receptor modulator is present in an amount of about 5-50 mg. WSGR Docket No.60906-708601 54. The method of any one of claims 32-51, wherein the opioid receptor modulator is present in an amount of about 5-30 mg. 55. The method of any one of claims 32-51, wherein the opioid receptor modulator is present in an amount of about 5-20 mg. 56. The method of any one of claims 32-55, wherein the agent is present in an amount of about 0.1-200 mg. 57. The method of any one of claims 32-55, wherein the agent is present in an amount of about 0.2-50 mg. 58. The method of any one of claims 32-55, wherein the agent is present in an amount of about 0.2-10 mg. 59. The method of any one of claims 32-55, wherein the agent is present in an amount of about 0.2-1 mg.
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