Therapeutic combinations, compositions, and methods for designing and generating entactogenic states of mind

Abstract

Therapeutic combinations for inducing entactogenic states of mind, such as through the use of compositions comprising imidazoline receptor agents, cannabinoid receptor agents, and / or serotonin receptor agents, are disclosed. Also disclosed are certain selective receptor agents, pharmaceutical compositions thereof, and methods of their use for treating mental health conditions, improving mental health and mental function, and designing and creating entactogenic states of mind or mood.

Description

[Technical Field]

[0001] Thomas S. Ray, Mindstate Design Labs cross reference Priority is claimed under PCT Article 8(1) and Rule 4.10 of U.S. Provisional Patent Application No. 63 / 318,369, filed March 9, 2022, and incorporated by reference for all purposes as if fully set forth herein.

[0002] FIELD OF THE INVENTION The present disclosure relates to the creation of an entactogenic mental state through the use of therapeutic combinations, such as compositions of imidazoline receptor agents, cannabinoid receptor agents, and / or serotonin receptor agents. [Background technology]

[0003] 3,4-Methylenedioxymethamphetamine (MDMA) is a member of a class of drugs called empathogens or entactogens, which are promising treatment options for mental health disorders such as PTSD (Mitchell, 2021). Clinical studies have demonstrated that MDMA has rapid and long-lasting therapeutic effects when taken in combination with psychotherapy.

[0004] MDMA is also known to have numerous adverse physiological effects, making its use contraindicated in certain populations (Oeri, 2020). MDMA and its metabolites may also pose safety risks related to toxicity (Kalant, 2001). Furthermore, MDMA has a tolerance-inducing effect that causes many individuals to suffer a partial or complete loss of its entactogenic effects ("disenchantment") and prevents repeated use.

[0005] Thus, there is a need for treatment options that provide the entactogenic effects of MDMA upon administration and lasting therapeutic benefits without the adverse effects and health risks associated with MDMA and other entactogens. Such treatment options are needed for mental health conditions, for improving health and function generally, and more broadly for human flourishing. Disclosed herein are therapeutic combinations, pharmaceutical compositions, and methods of use thereof for meeting these needs, with other advantages as will become apparent from the disclosure below.

[0006] Incorporation by Reference Each patent, publication, and non-patent document cited or listed in the "References" section is incorporated by reference in its entirety as if individually incorporated by reference and fully set forth herein. However, when such reference is made, whether to a patent, publication, non-patent document, or other source, it is for the general purpose of providing a context for discussing the features of the disclosed invention. Accordingly, it should not be construed as an admission that any document or information is prior art or forms part of the general knowledge in the art in any jurisdiction. Summary of the Invention

[0007] The following presents a simplified summary of some embodiments of the present invention in order to provide a basic understanding of the invention. It is not an exhaustive overview of the disclosure and is not intended to identify key or critical elements of the disclosure or to delineate the scope thereof. Its sole purpose is to present some embodiments in simplified form as a prelude to the more detailed description that is presented later.

[0008] In a first aspect, a therapeutic combination for inducing an entactogenic state is provided, comprising an imidazoline-1 (I1) agent and a 5-HT7 agent.

[0009] In some embodiments, the I1 agent is an I1 agonist. In some embodiments, the I1 agent has a selectivity for the I1 receptor compared to the alpha-2 (α2) adrenergic receptor of at least about 30:1 (or greater). In some embodiments, the I1 agent is agmatine, BDBM50091347, clonidine, guanfacine, mCPP, memantine, moxonidine, naphazoline, oxymetazoline, rilmenidine, tetrizoline, tizanidine, or tolonidine, or a pharmaceutically acceptable salt thereof. In some embodiments, the I1 agent is clonidine, moxonidine, or rilmenidine, or a pharmaceutically acceptable salt thereof. In some embodiments, the I1 agent is clonidine or a pharmaceutically acceptable salt thereof. In some embodiments, the I1 agent is moxonidine or a pharmaceutically acceptable salt thereof. In some embodiments, the I1 agent is rilmenidine or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the 5-HT7 agent is a 5-HT7 agonist. In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K activity of less than 10 nM. i In some embodiments, the 5-HT7 agent is tryptamine. In some embodiments, the 5-HT7 agent is 5-MeO-DMT or 5-MeO-MiPT, or a pharmaceutically acceptable salt thereof. In some embodiments, the 5-HT7 agent is 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is 5-MeO-MiPT or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the therapeutic combination comprises clonidine or a pharmaceutically acceptable salt thereof and 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic combination comprises moxonidine or a pharmaceutically acceptable salt thereof and 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic combination comprises rilmenidine or a pharmaceutically acceptable salt thereof and 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the therapeutic combination comprises clonidine, or a pharmaceutically acceptable salt thereof, and 5-MeO-MiPT, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic combination comprises moxonidine, or a pharmaceutically acceptable salt thereof, and 5-MeO-MiPT, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic combination comprises rilmenidine, or a pharmaceutically acceptable salt thereof, and 5-MeO-MiPT, or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the therapeutic combination further comprises a 5-HT2 agent, a CB1 agent, an additional I1 agent, or an additional 5-HT7 agent.

[0014] In some embodiments, the therapeutic combination further comprises a 5-HT2 agent. In some embodiments, the 5-HT2 agent is a 5-HT2 agonist. In some embodiments, the 5-HT2 agonist is 1-methylpsilocin, 2C-B-FLY, 5-MeO-AMT, AL-37350A, CP 809101, DALT, DOB, DOET, DOHx, MEM, CPP, NBOH-2C-CN, TCB-2, or WAY 161503, or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the therapeutic combination further comprises a CB1 agent. In some embodiments, the CB1 agent is a cannabinoid. In some embodiments, the CB1 agent is 2-AGE, A-834,735, ACEA, AZ-11713908, AZD-1940, CBN, CP-47497, CP55940, HU-210, JWH-007, JWH-051, JWH-146, JWH-176, JWH-200, JWH-398, Org 28611, rimonabant, THC, WIN 55,212-2, XLR11, or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the therapeutic combination further comprises an additional I1 agent. In some embodiments, the additional I1 agent is an I1 agonist. In some embodiments, the additional I1 agent has a selectivity for the I1 receptor compared to the alpha-2 (α2) adrenergic receptor of at least about 30:1 (or greater). In some embodiments, the additional I1 agent is agmatine, BDBM50091347, clonidine, guanfacine, mCPP, MDMA, memantine, moxonidine, naphazoline, oxymetazoline, rilmenidine, tetrizoline, tizanidine, or tolonidine, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional I1 agent is clonidine, moxonidine, or rilmenidine, or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the therapeutic combination further comprises an additional 5-HT7 agent. In embodiments, the additional 5-HT7 agent is a 5-HT7 agonist. In embodiments, the additional 5-HT7 agent has a 5-HT7 receptor K agonist activity of less than 10 nM. i In embodiments, the additional 5-HT7 agent is DMT, 6-F-DMT, 5-MeO-MiPT, LSD, 5-MeO-DMT, 5-MeO-TMT, cis-2a, DPT, 5-MeO-DiPT, psilocin, RR-2b, EMDT, lisuride, DiPT, SS-2c, TMA, 2C-B, 2C-E, or MDA, or a pharmaceutically acceptable salt thereof. In embodiments, the additional 5-HT7 agent is 5-MeO-DMT or 5-MeO-MiPT, or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the therapeutic combination further comprises (a) a 5-HT2 agent and a CB1 agent; (b) a 5-HT2 agent and an additional I1 agent; (c) a 5-HT2 agent and an additional 5-HT7 agent; (d) a 5-HT2 agent and an additional 5-HT2 agent; (e) a CB1 agent and an additional I1 agent; (f) a CB1 agent and an additional 5-HT7 agent; or (g) a CB1 agent and an additional CB1 agent.

[0019] In some embodiments, where the therapeutic combination further comprises (a) a 5-HT2 agent and a CB1 agent; (b) a 5-HT2 agent and an additional I1 agent; (c) a 5-HT2 agent and an additional 5-HT7 agent; or (d) a 5-HT2 agent and an additional 5-HT2 agent, the 5-HT2 agent is a 5-HT2 agonist. In embodiments, the 5-HT2 agonist is 1-methylpsilocin, 2C-B-FLY, 5-MeO-AMT, AL-37350A, CP 809101, DALT, DOB, DOET, DOHx, MEM, CPP, NBOH-2C-CN, TCB-2, or WAY 161503, or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the therapeutic combination further comprises (e) a CB1 agent and an additional I1 agent; (f) a CB1 agent and an additional 5-HT7 agent; or (g) a CB1 agent and an additional CB1 agent, and the CB1 agent is a cannabinoid.In some embodiments, the CB1 agent is 2-AGE, A-834,735, ACEA, AZ-11713908, AZD-1940, CBN, CP-47497, CP55940, HU-210, JWH-007, JWH-051, JWH-146, JWH-176, JWH-200, JWH-398, Org 28611, rimonabant, THC, WIN 55,212-2, XLR11, or a pharmaceutically acceptable salt thereof.In some embodiments, the additional CB1 agent is a cannabinoid. In some embodiments, the additional CB1 agent is 2-AGE, A-834,735, ACEA, AZ-11713908, AZD-1940, CBN, CP-47497, CP55940, HU-210, JWH-007, JWH-051, JWH-146, JWH-176, JWH-200, JWH-398, Org 28611, rimonabant, THC, WIN 55,212-2, XLR11, or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, where the therapeutic combination further comprises (b) a 5-HT2 agent and an additional I1 agent or (e) a CB1 agent and an additional I1 agent, the additional I1 agent is an I1 agonist. In embodiments, the additional I1 agent has a selectivity for the I1 receptor compared to the alpha-2 (α2) adrenergic receptor of at least about 30:1 (or greater). In embodiments, the additional I1 agent is agmatine, BDBM50091347, clonidine, guanfacine, mCPP, memantine, moxonidine, naphazoline, oxymetazoline, rilmenidine, tetrizoline, tizanidine, or tolonidine, or a pharmaceutically acceptable salt thereof. In embodiments, the additional I1 agent is clonidine, moxonidine, or rilmenidine, or a pharmaceutically acceptable salt thereof. In embodiments, the additional I1 agent is clonidine or a pharmaceutically acceptable salt thereof. In embodiments, the additional I1 agent is moxonidine or a pharmaceutically acceptable salt thereof. In embodiments, the additional I1 agent is rilmenidine or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, where the therapeutic combination further comprises (c) a 5-HT2 agent and an additional 5-HT7 agent or (f) a CB1 agent and an additional 5-HT7 agent, the additional 5-HT7 agent has an activity against the 5-HT7 receptor K i In some embodiments, the additional 5-HT7 agent is DMT, 6-F-DMT, 5-MeO-MiPT, LSD, 5-MeO-DMT, 5-MeO-TMT, cis-2a, DPT, 5-MeO-DiPT, psilocin, RR-2b, EMDT, lisuride, DiPT, SS-2c, TMA, 2C-B, 2C-E, or MDA, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional 5-HT7 agent is 5-MeO-DMT or 5-MeO-MiPT, or a pharmaceutically acceptable salt thereof.

[0023] In another aspect, a pharmaceutical composition is provided comprising a therapeutic combination of the present disclosure and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the composition is suitable for oral, buccal, sublingual, intranasal, ocular, injectable, subcutaneous, intravenous, or transdermal administration. In some embodiments, the composition is provided in a unit dosage form. In some embodiments, the unit dosage form is an immediate release formulation, a controlled release formulation, a sustained release formulation, an extended release formulation, or a modified release formulation.

[0024] In another aspect, there is provided a method of inducing an entactogenic state of mind in a subject, comprising administering to the subject a therapeutic combination or pharmaceutical composition of any of the preceding embodiments.

[0025] In some embodiments, the agents of the therapeutic combination or pharmaceutical composition are administered simultaneously, separately, or sequentially. In some embodiments, the agents are administered simultaneously. In some embodiments, the agents are administered separately. In some embodiments, the agents are administered sequentially. In some embodiments, the I1 agent is administered before the 5-HT7 agent. In embodiments where the therapeutic combination or composition includes a CB1 agent, the CB1 agent is administered before the 5-HT7 agent. In embodiments where the therapeutic combination or composition includes a CB1 agent, the CB1 agent is administered after the I1 agent.

[0026] In some embodiments, the I1 agent is administered orally. In some embodiments, the 5-HT7 agent is administered orally, sublingually, intranasally, or by inhalation. In some embodiments, the therapeutic combination or composition includes a CB1 agent, the CB1 agent is administered orally, sublingually, or by inhalation.

[0027] In some embodiments, the I1 agent is administered at a dose of about 0.1 mg to 1.0 mg.

[0028] In embodiments, the 5-HT7 agent is administered in a dose of about 2 mg to 20 mg.

[0029] In some embodiments, the method further comprises administering a therapeutically effective amount of an additional active agent, hi some embodiments, the additional therapeutic agent is an amino acid, antioxidant, anti-inflammatory agent, analgesic, anti-neuropathic or anti-nociceptive agent, anti-migraine agent, anti-anxiety agent, antidepressant, antipsychotic agent, anti-PTSD agent, cannabinoid, dissociative agent, immunostimulant, anti-cancer agent, antiemetic agent, appetite stimulant, antiulcer agent, antihistamine, antihypertensive agent, anticonvulsant, anti-epileptic agent, bronchodilator, neuroprotective agent, entactogen or empathogen, entheogen, psychedelic agent, monoamine oxidase inhibitor, tryptamine, terpene, phenethylamine, sedative, serotonergic agent, stimulant, vitamin, SSRI, SNRI, NDRI, TCA, or benzodiazepine.

[0030] In some embodiments, the entactogen state is an entactogen state similar to MDMA or another known entactogen, and the entactogen state is determined by brain imaging or by measuring the level of one or more neurotransmitters in the subject. In some embodiments, the entactogen state is a greater entactogen state than MDMA or another known entactogen, and the entactogen state is determined by brain imaging or by measuring the level of one or more neurotransmitters in the subject. In some embodiments, the greater entactogen state is an expanded or enhanced entactogen state compared to MDMA or another known entactogen, and the entactogen state is determined by brain imaging or by measuring the level of one or more neurotransmitters in the subject. In some embodiments, the neurotransmitter is one or more of serotonin, dopamine, norepinephrine, oxytocin, or cortisol.

[0031] In some embodiments, the method does not result in or reduces the adverse effects of MDMA or another known entactogen. In some embodiments, the adverse effects are neurotoxic effects. In some embodiments, the absence or reduction of neurotoxic effects is determined by in silico, in vitro, or in vivo tests and procedures. In some embodiments, the absence or reduction of neurotoxic effects is determined by measuring one or more of: a) at least one toxic metabolite of MDMA or at least one toxic metabolite of another entactogen; b) oxidative stress and dopamine system quinones; c) mitochondrial dysfunction; and d) glial cell activation. In some embodiments, the reduction of neurotoxic effects is at least 5%, 10%, 25%, 50%, 75%, 100%, 150%, or 200% compared to one or more controls.

[0032] Also provided is a method for regulating neurotransmission in a mammal, comprising administering any of the therapeutic combinations or pharmaceutical compositions of the above embodiments to the mammal.In some embodiments, the neurotransmission is mediated by I1 receptor, 5-HT2 receptor, 5-HT7 receptor, or CB1 receptor.In some embodiments, the mammal is a human.

[0033] In another aspect, there is provided a method of treating a medical condition in a human in need thereof, comprising administering to the human a therapeutic combination or pharmaceutical composition of any of the preceding embodiments.

[0034] In some embodiments, the medical condition is a disorder associated with dysregulation or insufficient function of neurotransmission. In some embodiments, the disorder is associated with dysregulation or insufficient function of neurotransmission mediated by I1 receptor, 5-HT2 receptor, 5-HT7 receptor, or CB1 receptor.

[0035] In some embodiments, the medical condition is a CNS disorder. In some embodiments, the CNS disorder is any of post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, a phobic disorder, binge eating disorder, body dysmorphic disorder, alcohol or drug abuse or dependence disorder, substance-related disorder, substance-induced mood disorder, mood disorder associated with another health condition, disruptive behavior disorder, eating disorder, impulse control disorder, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorder, attachment disorder, dissociative disorder, Alzheimer's disease, ataxia, Huntington's disease, Parkinson's disease, motor neuron disease, multiple system atrophy, progressive supranuclear palsy, migraine, cluster headache, short-lasting unilateral neuralgiform headache, fibromyalgia, traumatic brain injury, and mild traumatic brain injury (mTBI). In some embodiments, CNS disorder is the disorder associated with inflexible thinking.In some embodiments, the disorder associated with inflexible thinking is anxiety, depression, addiction, eating disorder, alcohol or drug abuse or dependence disorder, OCD or PTSD.In some embodiments, depression is MDD or TRD.In some embodiments, anxiety is GAD.

[0036] In another aspect, a method of improving mental health or mental function in a human, comprising identifying a human in need of said improvement and administering to the human a therapeutic combination or pharmaceutical composition of any of the preceding embodiments. In some embodiments, the improvement in mental health or mental function is a decrease in neuroticism or psychological defensiveness, an increase in creativity or openness to experience, an increase in decision-making ability, an increase in the ability to fall asleep or stay asleep, an increase in wellness or satisfaction, an increase in the ability to forgive oneself or others, an increase in the ability to experience or reflect on pain, including psychological pain, or an increase in the ability to "touch within," including during and between daily life and activities. In some embodiments, the increase in creativity is an increase in intentional cognitive creativity, intentional emotional creativity, spontaneous cognitive creativity, or spontaneous emotional creativity.

[0037] In another aspect, provided is a method of reducing symptoms of a CNS disorder in a human, the method comprising identifying a human in need thereof and administering to the human a therapeutic combination or pharmaceutical composition of the present disclosure.

[0038] In another aspect, a pharmaceutical composition is provided comprising any one of the therapeutic combinations of the preceding embodiments and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the composition is suitable for oral, buccal, sublingual, intranasal, ocular, injectable, subcutaneous, intravenous, or transdermal administration. In some embodiments, the composition is provided in a unit dosage form. In embodiments, the unit dosage form is an immediate-release formulation, a controlled-release formulation, a sustained-release formulation, an extended-release formulation, or a modified-release formulation.

[0039] In another aspect, there is provided a method of inducing an entactogenic state in a subject, the method comprising administering to the subject a therapeutic combination or pharmaceutical composition of the present disclosure.

[0040] In another aspect, a method of modulating neurotransmission in a mammal is provided, comprising administering to the mammal a therapeutic combination or pharmaceutical composition of the present disclosure.

[0041] In another aspect, there is provided a method of treating a medical condition in a human in need thereof, the method comprising administering to the human a therapeutic combination or pharmaceutical composition of the present disclosure.

[0042] In another aspect, there is provided a method of improving mental health or mental function in a human, the method comprising identifying a human in need of said improvement and administering to the human a therapeutic combination or pharmaceutical composition of the present disclosure.

[0043] In another aspect, provided is a method of reducing symptoms of a CNS disorder in a human, the method comprising identifying a human in need thereof and administering to the human a therapeutic combination or pharmaceutical composition of the present disclosure.

[0044] In another aspect, there is provided a therapeutic combination for inducing an entactogenic state of mind, comprising: (a) a therapeutic combination described in any one of claims 1 to 53; or (b) an I1 agent and one or more of a 5-HT2 agent, a 5-HT7 agent, and a CB1 agent.

[0045] Also provided in further aspects are methods of any of the preceding embodiments, wherein the pharmaceutical composition or therapeutic combination is administered in conjunction with psychotherapy. Also provided are methods of any of the preceding embodiments, wherein the pharmaceutical composition or therapeutic combination is administered in conjunction with psychological support. Also provided are methods of any of the preceding embodiments, wherein the pharmaceutical composition or therapeutic combination is administered in conjunction with patient monitoring. Also provided are methods of any of the preceding embodiments, wherein the pharmaceutical composition or therapeutic combination is administered in conjunction with the patient's performance of a therapeutically beneficial activity. Also provided are methods of any of the preceding embodiments, wherein the pharmaceutical composition or therapeutic combination is administered without psychotherapy or psychological support.

[0046] The foregoing has outlined in broad summary form certain pertinent features of the present disclosure so that the detailed description of the invention that follows may be better understood, and so that the contribution to the art may be more fully appreciated. The foregoing should be considered a brief, general summary of only some of the disclosed aspects and embodiments, and is merely for the benefit and convenience of the reader. It is not intended to limit in any way the scope or equivalents to which the claims are entitled. Additional features of the present invention are described below. It will be understood by those skilled in the art that all disclosed specific compositions and methods are illustrative only and may be readily utilized as a basis for modifying or designing other compositions and methods for carrying out the same purposes. Such equivalent compositions and methods will also be understood to be within the scope and spirit of the present disclosure as recited in the claims. It will be understood that the headings within this document are utilized solely to facilitate review. They should not be construed as limiting the invention in any way. DETAILED DESCRIPTION OF THE INVENTION

[0047] While certain aspects and embodiments have been summarized above, the following description sets forth several exemplary embodiments in further detail to enable those skilled in the art to implement such embodiments and to make and use the full scope of the invention as claimed. The described examples are provided for illustrative purposes and are not intended to limit the scope of the invention or its application. It will be understood that many modifications, substitutions, changes, and variations in the described examples, embodiments, applications, and details of the invention shown herein may be made by those skilled in the art without departing from the spirit of the invention or the scope of the invention as set forth in the appended claims. It will also be understood that the headings within this document are utilized solely to facilitate reader review. They should not be construed as limiting the invention in any way.

[0048] MDMA and other known entactogens are known to be “messy” drugs from a pharmacological perspective, with a wide range of distinct and independent mechanisms ( Ray, 2016 ; Sessa, 2017 ).

[0049] For example, MDMA promotes increased levels of serotonin (5-HT), dopamine (DA), and norepinephrine (NE), and 5-HT 1A and 5-HT 1B It is believed to exert its effects by increasing activity at receptors (Graeff et al., 1996), acting at 5-HT2 receptors in common with "classical" psychedelics (Liechti and Vollenweider, 2001), at alpha-2 receptors (Bexis and Docherty, 2005; Giovannitti et al., 2015), and by promoting oxytocin release (Thompson et al., 2007; Kirsch et al., 2005; Domes et al., 2007). Previous studies by the present inventors have demonstrated that MDMA activates at least imidazoline-1 receptors; serotonin-2B receptors; alpha-2A, alpha-2B, and alpha-2C adrenergic receptors; muscarinic-3, muscarinic-4, and muscarinic-5 acetylcholine receptors; and Ca receptors. 2+ It has been demonstrated to act on the ATP channel (Ray, 2010). A recent study reported the binding affinity profile of MDMA across most of the receptorome (Dunlap, 2018, Table 5 and accompanying text).

[0050] The broader class of phenylalkylamine and tryptamine entactogens generally includes potent releasers and / or reuptake inhibitors of presynaptic 5-HT, DA, and NE, whose actions result from interactions with membrane transporters (e.g., SERT, DAT, NET, VMAT) involved in neurotransmitter reuptake and vesicular storage systems (de la Torre 2004); 1A , 5-HT 1D , 5-HT 1E , 5-HT 2A , 5-HT5A It has direct effects on various receptors, including 5-HT6, 5-HT7, D1, D2, D3, D4, D5, NMDA, and imidazoline-1 (Ray 2010; Vegting 2016); Ca 2+ These include compounds known to be 5-HT releasers by neuroleptic-independent mechanisms. They can also inhibit 5-HT reuptake and inhibit monoamine oxidase (MAO), both of which can result in increased amounts of extracellular 5-HT (Leonardi 1994; Simmler 2018).

[0051] This "messy" pharmacology is believed to be responsible for the adverse effects of entactogens. However, agents with more selective activity, and consequently lacking one or more adverse effects, also may not provide the full complement of entactogenic effects necessary to produce the entactogenic state of mind, and consequently may not provide lasting therapeutic benefit. It has not been possible to separate the many adverse effects of entactogens from their "entactogenic" effect; that is, until the present inventors' work.

[0052] In aspects of the present disclosure, distinct receptor systems are independently targeted, allowing for the creation of combinations or compositions with specific effect profiles, where such effect profiles are desirable psychological states, particularly entactogenic psychological states. In one example, the entactogenic effect of MDMA is replicated by the disclosed combinations or compositions, which provide the same (or in some preferred embodiments, greater) therapeutic benefits as MDMA, without the inherent drawbacks of MDMA.

[0053] In some embodiments, the disclosed combinations and compositions may be used in entactogen-assisted therapy (EAP), including individual, couples, and group EAP, without one or more adverse effects or complications seen with prior art entactogens such as MDMA.

[0054] In some embodiments, when MDMA itself is used in a disclosed combination or composition, the combination substantially reduces the dose of MDMA required to induce an entactogenic state, thus reducing the risk of adverse side effects compared to administration of MDMA alone.

[0055] In some aspects, the entactogenic effect of MDMA or another entactogen is achieved through selective and simultaneous, separate, or sequential activation of specific receptor systems by co-administration (including simultaneous, separate, or sequential administration) of a "primer" and a "probe." In some embodiments, the primer is selective for serotonin (5-HT) receptors. In some embodiments, the primer selectively activates 5-HT receptors. In some embodiments, the primer is a selective 5-HT receptor agonist, e.g., a 5-HT2 agonist or a 5-HT7 agonist. In some embodiments, the probe is selective for imidazoline receptors. In some embodiments, the probe selectively activates imidazoline receptors. In some embodiments, the probe is an imidazoline receptor agonist, e.g., an imidazoline-1 agonist. In some embodiments, entactogen compositions are disclosed that can selectively activate the imidazoline-1 (I1) receptor in combination with the serotonin-2 (5-HT2) receptor, the serotonin-7 (5-HT7) receptor, and / or the cannabinoid-1 (CB1) receptor. By administering a therapeutically effective amount of such a composition, for example, an I1 agent in combination with any of a 5-HT2 agent, a 5-HT7 agent, and / or a CB1 agent, the entactogen effects of an agent such as MDMA can be produced without the adverse effects.

[0056] Thus, in some embodiments, one or more of the entactogenic effects of MDMA and other known entactogens are provided. Also, in some embodiments, one or more of the adverse effects of MDMA and other known entactogens are reduced or eliminated. Furthermore, in some embodiments, an expanded and enhanced entactogenic effect is provided compared to MDMA and other known entactogens. Still other embodiments include combinations, compositions, and methods for treating CNS disorders, mental health conditions and psychiatric disorders, such as psychiatric and neuropsychiatric disorders, and neurological conditions, including neurodevelopmental and neurodegenerative disorders. Other embodiments include combinations, compositions, and methods for improving mental health and mental function.

[0057] Some disclosed embodiments include the therapeutic use of an I1 agent in combination with a 5-HT2 agent, a 5-HT7 agent, and / or a CB1 agent. Some embodiments include a pharmaceutical composition comprising an I1 agent in combination with a 5-HT2 agent, a 5-HT7 agent, and / or a CB1 agent, and a pharmaceutically acceptable carrier, diluent, or excipient. The term "an I1 agent in combination with a 5-HT2 agent, a 5-HT7 agent, and / or a CB1 agent" and similar combinations are intended to encompass all possible combinations, such as an I1 agent in combination with a CB1 agent; an I1 agent in combination with a 5-HT2 agent; an I1 agent in combination with a 5-HT7 agent; an I1 agent in combination with a CB1 agent and a 5-HT2 agent; an I1 agent in combination with a CB1 agent and a 5-HT7 agent; an I1 agent in combination with a 5-HT2 agent and a 5-HT7 agent; an I1 agent in combination with a 5-HT2 agent, a CB1 agent, and a 5-HT7 agent, and the same applies hereinafter to any similar combinations discussed herein.

[0058] A. General Definitions and Terminology As used in this disclosure and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" includes a reference to a combination of one or more active agents, and reference to "an excipient" includes a reference to a combination of one or more excipients. While the term "one or more" may be used, its absence (or its replacement with the singular) simply highlights the possibility of multiple agents or ingredients in a particular embodiment, rather than meaning only the singular.

[0059] The terms "comprising," "including," "such as," and "having" are intended to be inclusive and not exclusive (i.e., other elements may be present in addition to the listed elements). Accordingly, "including" means, and is used interchangeably with, the phrase "including but not limited to." The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless the context clearly dictates otherwise.

[0060] When ranges are given herein, the invention includes embodiments in which the endpoints are included, embodiments in which both endpoints are excluded, and embodiments in which one endpoint is included and the other is excluded. Unless otherwise indicated, both endpoints should be assumed to be inclusive. Furthermore, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, it should be understood that values ​​expressed as ranges may, in different embodiments, assume any specific value or subrange within the stated range, down to the tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise. When a series of numerical values ​​is described herein, it is also understood that the invention includes embodiments relating to any intervening value or range defined by any two values ​​in the series, with the lowest value being the minimum and the highest value being the maximum. Numerical values ​​used herein include values ​​expressed as percentages. For any embodiment in which a numerical value is preceded by "about" or "approximately," the invention includes embodiments in which the exact value is recited. For any embodiment in which a numerical value is not preceded by "about" or "approximately," the invention includes embodiments in which the value is preceded by "about" or "approximately." "Approximately" or "about," unless otherwise specified or clear from context, is intended to encompass numbers that fall within ±10% of the number, in some embodiments within ±5% of the number, in some embodiments within ±1% of the number, in some embodiments within ±0.5% of the number, and in some embodiments within ±0.1% of the number (except where such numbers impermissibly exceed 100% of possible values). In some embodiments, the numerical parameters set forth in the specification and appended claims are approximations that can vary (and will be understood by those of skill in the art) depending upon the desired properties sought to be obtained by a particular embodiment.

[0061] In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as practicable. In some embodiments, the numerical values ​​presented may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0062] Throughout this disclosure, various aspects are presented as ranges. 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 claimed subject matter. Accordingly, the description of a range should be considered to specifically disclose all possible subranges and individual numerical values ​​within that range. For example, when a range of values ​​is provided, it is understood that each intervening value between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is encompassed within the claimed subject matter. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the claimed subject matter, subject to any specifically excluded limits in the stated ranges. When a stated range includes one or both of the limits, ranges excluding one or both of those included limits are also encompassed within the claimed subject matter. This applies regardless of the width of the range.

[0063] A list of abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry. This list is typically presented in a table entitled "Standard List of Abbreviations." The list as of the date of this application is incorporated by reference as if fully set forth herein.

[0064] Unless otherwise defined, all technical and scientific terms herein have the meanings commonly understood by those skilled in the art to which this invention belongs, who may simply be referred to as "one of skill" as a shorthand. Further definitions that may aid the reader in understanding the disclosed embodiments are as follows. However, it will be understood that such definitions are not intended to limit the scope of the invention, but should be properly interpreted and understood by reference to the complete specification (as well as any clear meaning known to those skilled in the relevant art) in light of the language used in the appended claims. The terms used herein are merely for the purpose of describing particular embodiments and are not intended to be limiting.

[0065] Generally, the nomenclature and terminology used herein, and the procedures performed, are those known in the art relevant to one or more of the disclosed embodiments, such as those of biology, pharmacology, neuroscience, organic chemistry, synthetic chemistry, medicinal chemistry, and / or pharmaceutical science, and are well-known and commonly used in one or more of such fields. Standard techniques and procedures are generally performed according to conventional methods in the art.

[0066] As used herein, "in an embodiment" is used as shorthand for, and may be equivalent to, "in some embodiments."

[0067] As used herein, an "entactogenic mindstate" may refer to a state of consciousness characterized by connection with the self. In some embodiments, an entactogenic mindstate promotes or enhances feelings of ecstasy, empathy, openness, compassion, serenity, acceptance, healing, generous kindness, love, unity, and compassion. In some embodiments, an entactogenic mindstate promotes or enhances forgiveness of both others (truly letting go of internal anger and resentment) and oneself (truly letting go of internal guilt and shame). In some embodiments, an entactogenic mindstate promotes the ability to safely experience and contemplate pain, such as psychic pain. In some embodiments, the entactogenic state of mind may refer to the process or feeling of "touching one's inner self," as described (in a non-drug context) in Brown 2021: "Often, when we feel lost and adrift in life, our first instinct is to look into the distance to find the nearest shore. But that shore, that solid foundation, lies within us. The anchor we seek is connection, and it is internal. To form meaningful connections with others, we must first connect with ourselves, but to do either, we must first establish a language of emotion and a shared understanding of human experience." David Nichols, professor of pharmacology and medicinal chemistry at Purdue University, coined the term "entactogenic" in 1986 to convey this meaning—"touching one's inner self" (Holland 2001, p. 182, no. 2). The term entactogen was adopted following the original term "empathogen" (meaning "generating an empathic state"), which was independently suggested in 1983-1984 by David Nichols and psychologist and psychopharmacologist Ralph Metzner (id.), and is described in further detail herein.

[0068] As used herein, "agent" can refer to a compound that modulates the activity of a target, such as a receptor. In some embodiments, the agent is a ligand for a receptor and modulates the activity of the receptor. In some embodiments, the agent binds to, blocks, activates, inhibits, or affects activity at a given receptor system (e.g., via an allosteric reaction). Among various aspects of the present invention is the therapeutic use of an I1 agent in combination with any of a 5-HT2 agent, a 5-HT7 agent, and / or a CB1 agent. In some embodiments, any of the I1 agent, a 5-HT2 agent, a 5-HT7 agent, and / or a CB1 agent can be a receptor modulator, i.e., can modulate activity at the I1 receptor, the 5-HT2 receptor, the 5-HT7 receptor, and / or the CB1 receptor, respectively.

[0069] As used herein, "modulate" can refer to a direct or indirect interaction with a target to alter the activity of the target. In some embodiments, the target is a receptor. Non-limiting examples of altering the activity of a target, such as a receptor, are provided herein.

[0070] As used herein, "modulator" and "receptor modulator" may refer to a receptor ligand that regulates or modifies the function of a receptor. In some embodiments, the modification is mediated directly or indirectly by interaction with the receptor. By way of example only, modulating the activity of a receptor may enhance, inhibit, limit, or prolong the activity of the receptor. In some embodiments, the change in activity is dose-dependent. In some embodiments, activation or inhibition of receptor activity may include, but is not limited to, activation of a signal transduction pathway. In some embodiments, any of the I1 agent, 5-HT2 agent, 5-HT7 agent, and / or CB1 agent may be a receptor modulator, i.e., an I1 receptor modulator, a 5-HT2 receptor modulator, a 5-HT7 receptor modulator, and / or a CB1 receptor modulator, respectively.

[0071] As used herein, "activation" can refer to the binding of either a receptor modulator, agent, or agonist to a receptor, resulting in the physiological or pharmacological response characteristic of the receptor.

[0072] As used herein, "inhibition" can refer to the binding of either a receptor modulator, agent, or antagonist to a receptor, which completely or partially blocks, attenuates, reduces, prevents, or delays the physiological or pharmacological response characteristic of that receptor.

[0073] As used herein, "agonist" may refer to a compound that induces or elicits an observable positive response from the receptor to which it binds. In some embodiments, an agonist may refer to a chemical species that interacts with a receptor, activates the receptor, or increases or enhances the activity of one or more receptors, such as the 5-HT2, 5-HT7, CB1, or I1 family of receptors, thereby initiating a physiological or pharmacological response characteristic of that receptor. In some embodiments, an agonist may activate multiple receptors, non-limiting examples of which include activation of 5-HT2, 5-HT7, CB1, I1, or a combination thereof. In some embodiments, any of the I1, 5-HT2, 5-HT7, and / or CB1 agents may be agonists, i.e., I1 agonists, 5-HT2 agonists, 5-HT7 agonists, and / or CB1 agonists.

[0074] As used herein, a "partial agonist" may refer to any compound that increases the activity of a receptor to which it binds, but with a maximum efficacy that is less than 100%. In some embodiments, a "partial agonist" may refer to any compound that has lower intrinsic activity than an agonist that can reach 100% efficacy. In practice, a "partial agonist" produces a partial or incomplete functional effect in a given functional assay. Due to these properties, a partial agonist may also function as a competitive antagonist when competing with an agonist that has the ability to reach 100% efficacy at a given receptor. Partial agonists may have reduced biological effects, which may result in significantly reduced side effects and receptor desensitization when utilizing partial agonists in treatment. In some embodiments, partial agonists may be administered for longer periods of time to achieve a longer-lasting response.

[0075] As used herein, an "inverse agonist" can refer to a compound that induces a conformational change in the receptor to which it binds, rendering the receptor "inactive." Functionally, "inactive" or "inactivity" can refer to a state in which less signaling associated with a receptor is generated than under basal conditions, i.e., in the absence of an agonist ("constitutive activity") or when an antagonist binds to the receptor. Thus, in the presence of an inverse agonist, the signaling pathway associated with the receptor is effectively blocked (Stahl, 2013). In other words, agonists have "intrinsic efficacy," while inverse agonists have "negative" intrinsic efficacy.

[0076] Non-limiting examples of agonists useful in the disclosed embodiments are discussed, among others, in the Imidazoline-1 (11), Cannabinoid-1 (CB1), Serotonin-2 (5-HT2), and Serotonin-7 (5-HT7) sections herein.

[0077] As used herein, "antagonist" can refer to a compound that binds to a given receptor and partially or completely blocks, attenuates, i.e., "inhibits" or "attenuates," prevents, or delays the biological response characteristic of that receptor. Antagonists can prevent agonists from binding to the receptor and increasing receptor activity. Without being bound by theory, antagonists can accomplish this by binding to either the active site, which directly regulates receptor activation; an allosteric site or a site other than the active site; or a site not normally involved in the biological regulation of receptor activity (Hopkins and Groom, 2002).

[0078] In some embodiments, the antagonist may be an "indirect antagonist" or "physiological antagonist," used interchangeably herein, which partially or completely blocks, attenuates, i.e., "inhibits" or "attenuates," prevents, or delays the biological response of a receptor without binding to the receptor.

[0079] As used herein, "selective" and "selectively binds" may refer to the ability of an agent to bind to a target receptor with higher affinity than it binds to a non-target receptor. In some embodiments, the target receptor is any one of the I1 receptor, the 5-HT2 receptor, the 5-HT7 receptor, and the CB1 receptor. In some embodiments, any of the agonists and antagonists provided herein may be described as selective.

[0080] Although any materials and methods similar or equivalent to those described herein can be used in embodiments of the present disclosure, certain exemplary materials and methods are now described.

[0081] B. Imidazoline 1 (I1) In embodiments, the therapeutic combination will include an imidazoline-1 agent. As used herein, "therapeutic combination" can refer to two or more active agents administered in combination to achieve a therapeutic effect. "In combination" includes active agents administered as part of "combination drugs" or "combination therapy," as those terms are used herein and understood in the art, as well as other embodiments as will become apparent in light of this disclosure and the general knowledge in the art.

[0082] In some embodiments, an "imidazoline-1 agent" (or "I1 agent") may refer to a compound that modulates activity at the imidazoline-1 (I1) receptor. In embodiments, an I1 agent binds to, blocks, activates, inhibits, or affects activity at the I1 receptor (e.g., via an allosteric reaction). In embodiments, an I1 agent acts as a receptor modulator, where the I1 agent alters the function of the receptor to which it binds, and the alteration includes activating the activity of the receptor, inhibiting the activity of the receptor, and either activating or inhibiting the activity of the receptor, depending on the dose administered. In some embodiments, an I1 agent is a "selective agent," which may refer to an agent that selectively binds to the I1 receptor system over receptors that are not part of the I1 receptor system. In some embodiments, such selectivity (which may also be referred to herein as "specificity") is expressed as a ratio greater than 1.0. In some embodiments, an I1 agent exhibits a (Ki The selectivity (as measured via I1 receptor selectivity) is at least 1.1:1, 1.5:1, 2:1, 5:1, 10:1, 15:1, 25:1, 30:1, 50:1, 100:1, etc., compared to receptors that are not part of the I1 receptor system.

[0083] In some embodiments, the I receptor system (K i The selectivity (as measured via K) for the I1 receptor system is about 1.1:1 compared to receptors that are not part of the I1 receptor system. i The selectivity (as measured via K) for the I1 receptor system is about 1.5:1 compared to receptors that are not part of the I1 receptor system. i The selectivity (as measured via K) for the I1 receptor system is about 2:1 compared to receptors that are not part of the I1 receptor system. i The selectivity (as measured via K) for the I1 receptor system is about 5:1 compared to receptors that are not part of the I1 receptor system. i Selectivity (as measured via K) for the I1 receptor system is at least about 10:1 compared to receptors that are not part of the I1 receptor system. For example, in some embodiments, i In some preferred embodiments, the selectivity (as measured via K) for the I1 receptor system is about 10:1 compared to receptors that are not part of the I1 receptor system. i In another preferred embodiment, the selectivity (as measured via K) for the I1 receptor system is about 25:1 compared to receptors that are not part of the I1 receptor system. i In another preferred embodiment, the selectivity (as measured via K) for the I1 receptor system is about 30:1 compared to receptors that are not part of the I1 receptor system. i In some embodiments, the selectivity (as measured via K) for the I1 receptor system is at least about 30:1 compared to receptors that are not part of the I1 receptor system. iThe selectivity (as measured via K) for the I1 receptor system is about 50:1 compared to receptors that are not part of the I1 receptor system. i The selectivity (as measured via ) is at least about 100:1 compared to receptors that are not part of the I1 receptor system.

[0084] In some embodiments, the I receptor system (K i The selectivity (as measured via K) for the I1 receptor system is about 1.1:1 compared to receptors of the alpha-2 (α2) adrenergic receptor system. i The selectivity (as measured via K) for the I1 receptor system is about 1.5:1 compared to the α2 adrenergic receptor. i The selectivity (as measured via K) for the I1 receptor system is about 2:1 compared to the α2 adrenergic receptor. i The selectivity (as measured via K) for the I1 receptor system is about 5:1 compared to the α2 adrenergic receptor. i For example, in some embodiments, the selectivity (as measured via K) for the I1 receptor system is at least about 10:1 compared to the α2 adrenergic receptor. i In some preferred embodiments, the selectivity for the I1 receptor system (as measured via K i In another preferred embodiment, the selectivity for the I1 receptor system (as measured via K i In another preferred embodiment, the selectivity for the I1 receptor system (as measured via K i In some embodiments, the selectivity (as measured via K) for the I1 receptor system is at least about 30:1 compared to the α2 adrenergic receptor. i The selectivity (as measured via K) for the I1 receptor system is about 50:1 compared to the α2 adrenergic receptor.i The selectivity (as measured via α2 adrenergic receptors) is at least about 100:1 compared to α2 adrenergic receptors.

[0085] In some embodiments, the I1 agent is an imidazoline-1 receptor agonist. Generally, an "imidazoline-1 receptor agonist" (or "imidazoline-1 agonist," "I1 receptor agonist," or "I1 agonist") is a compound that initiates a biological response upon binding to the I1 receptor. In some embodiments, the I1 agonist has high specificity for the I1 receptor. In some embodiments, the I1 agonist has low specificity for receptors that are not part of the imidazoline-1 receptor system. Herein, in embodiments, modifiers such as "high" and "low" are used comparatively, and "high" specificity simply means higher than "low" specificity, unless the terms are specifically defined or intended to have a different meaning necessary to provide a technical effect.

[0086] In embodiments, the I1 agonist binds to both alpha-2 adrenergic (α2 adrenergic) receptors and imidazoline-1 receptors, but has lower specificity for α2 adrenergic receptors than for imidazoline-1 receptors, resulting in a higher selectivity of the agent for imidazoline-1 receptors than for α2 adrenergic receptors.

[0087] In some embodiments, the I1 agent is an imidazoline-1 receptor antagonist. Generally, an "imidazoline-1 receptor antagonist" (or "imidazoline-1 antagonist", "I1 receptor antagonist", or "I1 antagonist") is a compound that inhibits a biological response upon binding to the I1 receptor.

[0088] In embodiments, the I1 antagonist has low specificity for receptors that are not part of the imidazoline-1 receptor system. In embodiments, the I1 antagonist binds to both alpha-2 (α2) adrenergic receptors and imidazoline-1 receptors, but has lower specificity for α2 adrenergic receptors than for imidazoline-1 receptors, resulting in a higher selectivity of the agent for imidazoline-1 than for α2 adrenergic receptors.

[0089] In some embodiments, the selective agent will have 100-fold or greater selectivity for its target receptor over all other receptors, while in many embodiments, the selective agent will have less than 100-fold selectivity. Thus, in some embodiments, the I1-selective agent will have 100-fold or greater selectivity for the I1 receptor over all other receptors, while in other embodiments, the I1-selective agent will have less than 100-fold selectivity. For example, in some such embodiments, the I1-selective agent will have about 30-fold or greater selectivity for the I1 receptor over all other receptors. In some embodiments, the I1-selective agent will have any degree of selectivity for the I1 receptor over all other receptors, with the degree of selectivity being as further described herein. In some embodiments, the I1-selective agent will have about 30-fold or greater selectivity for the I1 receptor over the α2-adrenergic receptor. In some embodiments, the I1-selective agent is moxonidine or rilmenidine. In some embodiments, the selective agent will have selectivity for its target receptor over one or more other types of receptors, but not over all other receptors.

[0090] In some embodiments, the imidazoline agent will have greater than about 30-fold selectivity for I1 over α2 receptors. For example, the imidazoline agents moxonidine and rilmenidine have been shown to be about 33- and 30-fold selective for I1 over α2 receptors, respectively (Ziegler, 1996): [Table 1]

[0091] In some embodiments, the I1 agent is an inverse agonist. In some embodiments, the I1 inverse agonist has high specificity for the I1 receptor. In some embodiments, the I1 inverse agonist has low specificity for receptors that are not part of the imidazoline-1 receptor system. In some embodiments, the I1 inverse agonist binds to both alpha-2 adrenergic (α2 adrenergic) receptors and imidazoline-1 receptors, but has lower specificity for α2 adrenergic receptors than for imidazoline-1 receptors, resulting in a higher selectivity of the agent for imidazoline-1 than for α2 adrenergic receptors.

[0092] Additional I agonists that have no detectable affinity or activity for α2-adrenergic receptors are currently known and may be used in some embodiments herein, non-limiting examples of which include LNP599 [3-chloro-2-methyl-phenyl)-(4-methyl-4,5-dihydro-3H-pyrrol-2-yl)-amine], which, in addition to its inactivity at α2, also has nanomolar affinity for I; LNP509 [dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine], LNP630 [(2,6-dichloro-phenyl)-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)-amine], LNP911 [2-(2-chloro-4-iodo-phenylamino)-5-methyl-pyrroline], and LNP906 [2-(5-azido-2-chloro-4-iodo-phenyl-amino)-5-methyl-pyrroline], the last of which has been shown to antagonize the I1 receptor system and possess photoaffinity properties (Urosevic et al., 2004).

[0093] In some embodiments, clonidine is used in a therapeutic combination or pharmaceutical composition, and when administered in a therapeutically effective amount, can induce an entactogenic state according to the present invention. In some embodiments, clonidine or other I1 agonists that exhibit affinity for α2-adrenergic receptors will be used. In some embodiments, the I1 agent is clonidine. In other embodiments, the I1 agent is rilmenidine or moxonidine, or another selective I1 agonist.

[0094] In embodiments, an I1 agent is used in therapeutic combination with one or more of a 5-HT2 agent, a 5-HT7 agent, and / or a CB1 agent, which induces the entactogenic effects of the I1 receptor system, while exhibiting the undesirable adverse effects associated with MDMA and other known entactogens.

[0095] a. Exemplary I1 Agents Useful in Embodiments of the Invention In some embodiments, non-limiting examples of I1 agents useful in the therapeutic combination include 1-(4-aminobutyl)guanidine (agmatine), 2-(1-phenylpropan-2-yl)-4,5-dihydro-1H-imidazole (BDBM50091347), N-(2,6-dichlorophenyl)-4,5-1H-imidazol-2-amine (clonidine), N-(diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide (guanfacine), 1-(3-chlorophenoxyethanol), 1-(4-aminopropyl)-2-(2,6-dichlorophenyl ... (RS)-1-(1,3-benzodioxol-5-yl)-N-methylpropan-2-amine (MDMA), 3,5-dimethyladamantan-1-amine (memantine), 4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methylpyrimidin-5-amine (moxonidine), 2-(naphthalen-1-ylmethyl)-4,5-dihydro-1H-imidazole (naphazoline), 3-(4,5-dihydro-1H- Imidazol-2-ylmethyl)-2,4-dimethyl-6-tert-butyl-phenol (oxymetazoline), N-(dicyclopropylmethyl)-4,5-dihydro-1,3-oxazol-2-amine (rilmenidine), (RS)-2-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydro-1H-imidazole (also known as tetrizoline, tetrahydrozoline), 5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)benzo[c [1,2,5]thiadiazol-4-amine (tizanidine), N-(2-chloro-4-methylphenyl)-4,5-dihydro-1H-imidazol-2-amine (tronidine), and the following additional compounds: and any salts, isomers (including structural isomers and stereoisomers, e.g., enantiomers), precursors, prodrugs, metabolites, derivatives, analogs, isotopically substituted or variants thereof, or combinations thereof (see, e.g., Nikolic et al., 2012). Certain other exemplary I1 agents useful in the disclosed embodiments include idazoxan, p-aminoclonidine, benazolin, BDF 6143, and p-iodoclonidine.

[0096] Those skilled in the art will appreciate the ability to determine which other compounds are useful agents in the practice of the disclosed embodiments by reference to the teachings herein in combination with general knowledge in the art, such as by reference to DrugCentral, DrugBank, and other compendia of drug data.

[0097] C. Cannabinoid-1 (CB1) Agents In some embodiments, the therapeutic combination will include a cannabinoid-1 agent. In some embodiments, a "cannabinoid-1 agent" (or "CB1 agent") may refer to a compound that modulates the cannabinoid-1 (CB1) receptor. In some embodiments, a CB1 agent binds to, blocks, activates, inhibits, or affects activity at the CB1 receptor (e.g., via an allosteric reaction). In some embodiments, a CB1 agent acts as a receptor modulator, altering the function of the receptor to which it binds, the alteration including activating the activity of the receptor, inhibiting the activity of the receptor, and either activating or inhibiting the activity of the receptor, depending on the dose administered.

[0098] In some embodiments, the CB1 agent is a "selective agent," which may refer to an agent that binds to the CB1 receptor system preferentially over receptors that are not part of the CB1 receptor system. In some embodiments, such selectivity (also referred to herein as "specificity") is expressed as a ratio greater than 1.0. In some embodiments, the K i The selectivity (as measured via CB1 receptor selectivity) is at least 1.1:1, 1.5:1, 2:1, 5:1, 10:1, 15:1, 25:1, 50:1, 100:1, etc., compared to receptors that are not part of the CB1 receptor system.

[0099] It will be readily understood here (as well as elsewhere herein for other receptor systems) that selectivity for a single receptor system (such as the CB1 receptor system) does not necessarily require selectivity over all other receptor systems, nor does it require testing of a compound at all possible receptor systems to determine whether such a compound is in fact "selective"; rather, the term may be used and given a meaning understood by those skilled in the art (e.g., Ray 2010) in light of the other receptor systems disclosed herein.

[0100] In some embodiments, the CB1 agent is a CB1 receptor agonist. Generally, a "CB1 receptor agonist" (or "cannabinoid-1 agonist," "CB1 receptor agonist," or "CB1 agonist") is a compound that initiates a biological response upon binding to a CB1 receptor. In some embodiments, the CB1 agonist has high specificity for the CB1 receptor. In embodiments, the CB1 agonist has low specificity for receptors that are not part of the endocannabinoid system.

[0101] In some embodiments, the CB1 agent is a CB1 receptor antagonist. Generally, a "CB1 receptor antagonist" (or "cannabinoid-1 antagonist," "CB1 receptor antagonist," or "CB1 antagonist") is a compound that inhibits a biological response upon binding to a CB1 receptor. In some embodiments, the CB1 antagonist has high specificity for the CB1 receptor. In some embodiments, the CB1 antagonist has low specificity for receptors that are not part of the endocannabinoid system.

[0102] In some embodiments, the CB1 agent is an inverse agonist. In some embodiments, the CB1 inverse agonist has high specificity for the CB1 receptor. In some embodiments, the CB1 inverse agonist has low specificity for receptors that are not part of the endocannabinoid system.

[0103] Functionally, the CB1 receptor is activated by (-)-trans-Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), and Δ 9 -mediates most of the CNS effects of THC (Zimmer et al., 1999). 9 -THC is the most widely known cannabinoid derived from cannabis, particularly for its intoxicating effects, resulting in the "high" associated with cannabis use.

[0104] THC and other cannabinoids can be ingested via inhalation of burned Cannabis flower, such as marijuana packed into a pipe (tear bowl), in a marijuana cigarette (joint), in a hollow cigar (blunt) filled with marijuana, in a bong, including those using water; as a vaporized extract, isolate, distillate, or concentrate (e.g., as wax, shatter, budder, crumble, live resin, various oils, and others, including dabs), or from a pen or vape pen containing cartridges; or via edibles infused with or incorporated with Cannabis or its extracts, including gummies, chocolates, pills, sweets, brownies, cookies, cakes, candies, etc. Because each method of administration has a fundamentally different absorption mechanism, the duration of effect and the time elapsed until the effect is felt may vary, but such knowledge is within the ordinary skill of the art. For example, administration by inhalation is felt almost immediately by the subject, whereas ingestion of an edible can take 30 minutes to an hour or more to take effect (depending on age, weight, height, metabolism, etc.) There are a variety of methods for administering Cannabis and cannabinoids, too numerous to list exhaustively here, but would be readily appreciated by one of skill in the art.

[0105] The predominant THC isomer Δ 9 In addition to -THC, Δ 8 There are numerous isomers of THC, such as Δ-THC. Other naturally occurring, synthetic (including bioengineered) isomers, metabolites (e.g., THC-COOH (11-nor-9-carboxy-THC)), salts, derivatives, analogs, or variants of THC will be recognized or known to those skilled in the art, or could be created by the practice of those skilled in the art. Thus, in embodiments, "THC" refers to Δ 3 -THC, Δ 8 -THC, Δ 9 -THC, Δ 10-THC, THCV, THCO, THCP, and THCB, or (at least in certain embodiments) their equivalents. In embodiments, "THC" refers to Δ 9 -THC and its isomers. In embodiments, where the context permits, "THC" refers to a single compound, e.g., Δ 3 -THC, Δ 8 -THC, Δ 9 -THC, Δ 10 -May refer to any of THC, THCV, THCO, THCP, and THCB.

[0106] In embodiments, the CB1 agent is a cannabinoid. "Cannabinoid" may refer to one of a class of structurally or functionally related compounds. Cannabinoids bind to CB1 receptors, CB2 receptors, and GPR receptors. 55 Ligands for these receptors are functionally related in that they each act on one or more of the receptors. In general, the ligands for these receptors include what may be referred to as "endocannabinoids" (i.e., cannabinoids produced endogenously in the body by humans and other mammals), "phytocannabinoids" (i.e., cannabinoids derived from Cannabis or other plants), and "synthetic cannabinoids" (i.e., synthetic analogs of natural cannabinoids).

[0107] In some embodiments, the CB1 agent is an endocannabinoid. In some embodiments, the endocannabinoid is any of anandamide, oleamide, 2-arachidonoylglycerol (2-AG), N-arachidonoylethanolamide (AEA), N-arachidonoylglycine (NAGly), N-arachidonoyldopamine (NADA), 2-arachidonoyl-glyceryl ether (2-AGE), and 9-octadecenoamide (oleamide). In embodiments, the endocannabinoid is the same as that produced endogenously, but is administered exogenously.

[0108] In some embodiments, the CB1 agent is a phytocannabinoid. In some embodiments, the CB1 agent is a natural phytocannabinoid, and "natural phytocannabinoid" may refer to a cannabinoid that occurs in nature and is produced by plants (e.g., Cannabis plants). In some embodiments, the phytocannabinoid is any of tetrahydrocannabinol (THC), cannabidiol (CBD), cannabichromene (CBC), cannabidinodiol (also known as cannabinodil) (CBND, CBDL), cannabielsoin (CBE), cannabicyclol (CBL), cannabicitran (CBTC), cannabiditriol (CBT), cannabivarin (CBV), cannabigerol monomethyl ether (CBGM), cannabidiphorol (CBDP), tetrahydrocannabiphorol (THCP), and iso-tetrahydrocannabinol (iso-THC).

[0109] In embodiments, the CB1 agent will be a phytocannabinoid derived from the Cannabis plant. Generally, "cannabis" can refer to any plant belonging to the Cannabaceae family, including Cannabis sativa, Cannabis indica, and Cannabis ruderalis plants, their cultivars and chemovarietals, as well as any plant parts or tissues (e.g., preferably female inflorescences and top leaves, but including stalks, stems, roots, etc.), and preparations made therefrom (e.g., extracts and ingestibles or consumables).

[0110] In embodiments, the phytocannabinoid (including from Cannabis) is any of CBD, CBDV, CBND, CBDL, CBE, CBL, CBTC, CBT, CBV, CBG, CBGV, CBGM, CBDP, THC (e.g., further including THCP and THCV), and iso-THC, and their acidic forms, their propyl, methyl, and ethyl homologs, and the acidic forms of their homologs (i.e., their acidic propyl, methyl, and ethyl homolog forms).

[0111] In embodiments, the cannabinoid may be any one or more of those set forth and described by Radwan et al., Cannabinoids, Phenolics, Terpenes and Alkaloids of Cannabis, Molecules, 26(9), 2774 (2021), which is incorporated by reference as if fully set forth herein. Generally, without being bound by theory, cannabinoids according to this classification are classified into 11 cannabinoid subclasses: cannabichromene (CBC) type, cannabidiol (CBD) type, cannabielsoin (CBE) type, cannabigerol (CBG) type, cannabicyclol (CBL) type, cannabinol (CBN) type, cannabinodiol (CBND) type, cannabiditriol (CBT) type, (-)-Δ8 -trans-tetrahydrocannabinol (Δ 8 -THC) type, (-)Δ 9 -trans-tetrahydrocannabinol (Δ 9 These include compounds having the characteristic C21 terpenophenolic skeleton that are part of one of the (-THC)-type and miscellaneous types of cannabinoids. Non-limiting examples of such cannabinoids, all of which are understood to be useful in the practice of the present invention, are known from the disclosure of Radwan 2021 and references below. For example, in embodiments, a CB1 agent is a Δ 9 -THC-C5, Δ 9 -THCAA-C5, Δ 9 -THCAB-C5, Δ 9 -THC-C4, Δ 9 -THCAA-C4, Δ 9 -THCV, Δ 9 -THCVAA, Δ 9 -THCO, Δ 9 -THCOAA, Δ 9 -THC-aldehyde, β-fenchyl (-)-Δ9-trans-tetrahydro-cannabinolate, α-fenchyl (-)-Δ9-trans-tetrahydro-cannabinolate, epi-bornyl (-)-Δ9-trans-tetrahydro-cannabinolate, bornyl (-)-Δ9-trans-tetrahydrocannabinolate, α-terpenyl (-)-Δ9-trans-tetrahydrocannabinolate, 4-terpenyl (-)-Δ9-trans-tetrahydrocannabinolate, α-cadinyl (-)-Δ9-trans-tetrahydrocannabinolate, γ-eudesmyl one or more "Δ" hydroxybenzoates, including (-)-Δ9-trans-tetrahydrocannabinolate, 8α-hydroxy-(-)-Δ9-trans-tetrahydrocannabinol, 8β-hydroxy-(-)-Δ9-trans-tetrahydrocannabinol, 11-acetoxy-(-)-Δ9-trans-tetrahydrocannabinolic acid A, 8-oxo-(-)-Δ9-trans-tetrahydrocannabinol, cannabisol, (-)-Δ9-trans-tetrahydrocannabiphorol, and (-)-Δ9-trans-tetrahydrocannabihexol;9 -THC-type cannabinoids (Δ 9 -THC-type cannabinoids).

[0112] In embodiments, the CB1 agent is a Δ 8 -THC, Δ 8 -THCA, 10α-OH-Δ 8 -THC, 10β-OH-Δ 8 -THC, and one or more "Δ8-THC" 8 -THC-type cannabinoids (Δ 8 -THC-type cannabinoids).

[0113] In embodiments, the CB1 agent is one or more "CBG-type cannabinoids," including (£)CBG, (£)CBGA, (£)CBGG, (£)CBGAM, (£)CBGV, (£)CBGVA, (Z)CBGA, 5-acetyl-4-hydroxy-cannabigerol, (±)-6,7-trans-epoxycannabigerolic acid, (±)-6,7-cis-epoxy-cannabigerolic acid, (±)-6,7-cis-epoxycannabigerol, (±)-6,7-trans-epoxycannabigerol, camagerol, and sesquicannabigerol.

[0114] In embodiments, the CB1 agent is one or more of "CBD, CBND, CBE, and CBL-type cannabinoids," including CBD-C5, CBDA-C5, CBDM-C5, CBD-C4, CBDV, CBDVA, CBD-C1, CBDH, CBDP, CBDD, CBND-C3, CBND-C5, CBE-C5, CBEAA-C5, CBEAB-C5, CBE-C3, CBEAB-C3, CBL, CBLA, and CBLV.

[0115] In embodiments, the CB1 agent is one or more "CBC and CBN-type cannabinoids," including CBC, CBCA, ±CBCV, +CBCV, CBCVA, 4-acetoxy-CBC, (±)-3"-hydroxy-Δ4"-cannabichromene, (-)-7-hydroxy-cannabichroman, CBC-C3, CBN-C5, CBNA-C5, CBN-C4, CBN-C3, CBN-C2, CBN-C1, CBNM-C5, 8-OH-CBN, 8-OH-CBNA, 1'S-OH-CBN, and 4-terpenyl-cannabinolate.

[0116] In embodiments, the CB1 agent is one or more "CBT-type cannabinoids," including (-)-trans-CBT-C5, (+)-trans-CBT-C5, (±)-cis-CBT-C5, (±)-trans-CBT-C3, CBT-C3-homologues, (-)-trans-CBT-OEt-C5, (-)-trans-CBT-OEt-C3, 8,9-di-OH-CBT-C5, and CBDA-C5, and 9-OH-CBT-C5 esters.

[0117] In embodiments, the CB1 agent is DCBF-C5, CBF-C5, OH-iso-HHCV-C3OTHC, cannabiditran, cis-Δ 9 -THC, CBCON-C5, CBR, CBTT, CBCN-C5, CBCN-C3, cis-iso-Δ 7 -THCV, trans-iso-Δ 7 -THCV, trans-iso-Δ 7 -THC, CBCNB, CBCNC, CBCND, (-)-(7R)-cannabicoumarononic acid, 4-acetoxy-2-geranyl-5-hydroxy-3-n-pentylphenol, 2-geranyl-5-hydroxy-3-n-pentyl-1,4-benzoquinone, 5-acetoxy-6-geranyl-3-n-pentyl-1,4-benzoquinone, CBM, CBX, 10α-hydroxy-Δ 9,11-Hexahydrocannabinol, 9β,10β-epoxyhexahydrocannabinol, 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexahydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10αR-hydroxyhexahydrocannabinol, and 9α-hydroxy-10-oxo-Δ 6a,10a -One or more "miscellaneous-type cannabinoids," including THC.

[0118] In embodiments, the CB1 agent, cannabinoid, phytocannabinoid, or phytocannabinoid derived from Cannabis is a hydrogenated derivative. For example, the hydrogenated derivative of THC is hexahydrocannabinol (HHC), which is a naturally occurring phytocannabinoid identified as a minor component in certain Cannabis and can be and has been synthetically produced by hydrogenating Cannabis extracts, and has also been synthesized from citronellal and olivetol as both (+)-HHC isomer and (-)-HHC isomer. As with other cannabinoids discussed herein, HHC can be administered by a suitable vaporizer, such as a disposable vape, or by any other suitable administration means described herein. Other structurally related hydrogenated derivatives that are also within the scope of the present disclosure and useful as CB1 agents, cannabinoids, phytocannabinoids, or Cannabis-derived phytocannabinoids include cannabilipsol, 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexahydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10αR-hydroxyhexahydrocannabinol and 1′S-hydroxycannabinol, 10α-hydroxy-Δ(9,11)-hexahydrocannabinol, and 9β,10β-epoxyhexahydrocannabinol. Other related compounds, sometimes referred to as "HHC," are also available, including, by way of example, 9-nor-9β-hydroxyhexahydrocannabinol (9-nor-9beta-HHC), 9-hydroxyhexahydrocannabinol (9-OH-HHC), 11-hydroxyhexahydrocannabinol (11-OH-HHC and 7-OH-HHC).

[0119] In some embodiments, the CB1 agent is cannabidiol (CBD). Unlike THC, CBD does not produce intoxicating effects in humans and can actually antagonize the effects of THC. CBD is an inverse agonist of the CB2 receptor and acts as an indirect antagonist of CB1 and CB2 cannabinoid receptor agonists (i.e., as an antagonist of other ligands at the CB1 and CB2 receptors). While THC directly activates the CB1 and CB2 receptors, CBD does not bind to either but instead affects them indirectly. Thus, the pharmacology of CBD is more enigmatic and involves interactions with multiple neurochemical systems, including the serotonergic and adenosinergic systems. Possible mechanisms related to CBD's action include activation of TRPV1 channels, inhibition of the uptake and metabolism of the endocannabinoid anandamide (partially via FAAH inhibition), inhibition of adenosine uptake, and inhibition of GPR. 55 CBD has been shown to inhibit serotonergic 5-HT 1A It can act as an agonist of the receptor.

[0120] Thus, it will be understood that in some embodiments, an "agent" need not be an "agonist" (e.g., a CB1 agent need not be a CB1 agonist but may instead be an antagonist, inverse agonist, receptor modulator, etc.), and that neither an "agent" nor an "agonist" need be limited to activity at a particular receptor or receptor system, but may have activity across multiple such systems and may have multiple mechanisms of action (although in some embodiments, including certain preferred embodiments herein, an agent or agonist at one receptor or receptor system will be selective for it and will have minimal or no activity at other sites).

[0121] It will be appreciated that in fresh Cannabis plant material, cannabinoids are found almost exclusively in their "acidic" forms (e.g., THCA, CBDA, CBCA) (and may have isomers, e.g., THCA-A and THCA-B), rather than their "neutral" forms (e.g., THC, CBD, CBC). In embodiments, the CB1 agent will be a decarboxylated cannabinoid, including, for example, a fully decarboxylated cannabinoid, a substantially decarboxylated cannabinoid, a partially decarboxylated cannabinoid, or a relatively decarboxylated cannabinoid. In embodiments, the CB1 agent will be an acidic cannabinoid (a non-decarboxylated cannabinoid).

[0122] In some embodiments, the CB1 agent is a naturally occurring phytocannabinoid derived from the Cannabis plant and is any one or more of CBD, CBDV, CBND, CBDL, CBE, CBL, CBTC, CBT, CBV, CBG, CBGV, CBGM, CBDP, THC (e.g., further including THCP and THCV), and iso-THC.

[0123] Cannabinoids may also occur in their propyl homolog forms, such as cannabichromevarin (CBCV), cannabigerovarin (CBGV), etc. Cannabinoids may also be found in acidic versions of these homolog forms (e.g., acidic propyl homolog forms, acidic methyl homolog forms, and acidic ethyl homolog forms). In some embodiments, the CB1 agent is an acidic propyl homolog, an acidic methyl homolog, or an acidic ethyl homolog.

[0124] In embodiments, the CB1 agent is a synthetic cannabinoid. In embodiments, the synthetic cannabinoid is a synthetic classical cannabinoid, a synthetic non-classical cannabimimetic compound, a hybrid cannabinoid, an aminoalkyl indole, and / or an eicosanoid, such as AKB48, CP55940, CP-47497, CP-47497 C8, JWH-015, WIN55212-2, JWH-018, AM-2201, JWH-122, JWH-073, JWH-081, JWH-200, JWH-210, UR-144, XLR11. In embodiments, the synthetic cannabinoid is a cannabinoid glycoside (“cannaboside”) or an acetylated cannabinoid, such as those described in U.S. Patent Applications 16 / 110,728 and 16 / 110,954.

[0125] In some embodiments, synthetic cannabimimetic compounds include those that generally act as CB1 receptor agonists as described herein, such as adamantoylindole or indazole carboxamides (e.g., 5F-AKB-48, APICA, STS-135); benzimidazoles (e.g., AZ-11713908, AZD-1940); phenylacetylindoles (e.g., JWH-250, RCS-8); cyclohexylphenols (e.g., CP-47,947, CP-55,940); dibenzopyrans (e.g., JWH-051, JWH-056); eicosanoids (e.g., AM-883, AM-1346, O-585, O-689); naphthylindenes (e.g., JWH-171, JWH-176); indazole carboxamides (e.g., AB-PINACA, AB-FUBINACA); indazole-3-carboxamides (e.g., AB-CHMINACA, AB-FUBINACA, PX-2, PX-3); indole-3-carboxamides (e.g., CUMYL-BICA, CUMYL-CBMICA, Organ 28312, Org 28611); indole-3-carboxylate or aryloxycarbonyl indole (e.g., FDU-PB-22, FUB-PB-22); naphthoylindazole (e.g., THJ-018, THJ-2201); naphthoylindole (e.g., JWH-007, JWH-018); naphthoylindole (e.g., JWH-398, AM-1221); naphthoylindole (e.g., AM-2201, WIN-55,212-2); naphthoylindole (e.g., JWH-073, JWH-200); phenylacetylindole (e.g., JWH-167, JWH-203); pyrazolecarboxamide (e.g., 5F-AB-FUPPYCA, AB-CHFUPYCA); pyrrolobenzoxazine or naphthoylindole (e.g., WIN 55,212-2); quinolinyl ester or aryloxycarbonyl indole (e.g., PB-22, 5F-PB-22); tetramethylcyclopropylcarbonyl indole (e.g., A-796,260, A-834,735, XLR-11, XLR-12); tetramethylcyclopropylcarbonyl indazole (e.g., FAB-144);and tetramethylcyclopropylcarbonylindoles (e.g., UR-144, XLR-11) from a number of structural classes.

[0126] In embodiments, the CB1 agent will be a cannabinoid that is structurally related in that it has a similar structure to any one or more of the above compounds, is a direct modification of any such compound, or is a salt, isomer (including structural or stereoisomer, e.g., enantiomer), precursor, prodrug, metabolite, derivative, analog, isotopic substitute, or variant (including combinations thereof) thereof. Compounds are described, for example, in U.S. Pat. Nos. 5,532,237; 5,605,906; 5,631,297; 6,410,588; 6,610,737; 6,630,507 at columns 3:36-6:66; 6,274,635 at columns 8:63-20:11; and 8,071,641 at columns 5:38-6:26; and the references cited therein; Silva et al., 2020, and numerous other cannabinoids will be recognized or known to those skilled in the art, or may be created by the practice of those skilled in the art.

[0127] In embodiments, the therapeutic combination includes an I1 agent in combination with a CB1 agent, such as any of the disclosed CB1 agents, and optionally a 5-HT2 agent and / or a 5-HT7 agent. In some embodiments, the therapeutic combination includes an I1 agent in combination with an exemplary CB1 agent, such as those listed below. In embodiments, administration of a therapeutic combination including a CB1 agent provides a therapeutic effect, such as a therapeutic effect that produces one or more entactogenic effects or entactogenic states.

[0128] a. Exemplary CB1 Agents Useful in Embodiments of the Invention In some embodiments, the CB1 agent is 2-{[(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraen-1-yl]oxy}propane-1,3-diol (2-AGE), {1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-indol-3-yl}-(2,2,3,3-tetramethylcyclopropyl)methanone (A-834,735), arachidonyl-2′-chloroethylamide (ACEA) N-(1-(cyclohexylmethyl)-2-((5-ethoxypyridin-2-yl)methyl)-1H-benzo[d]imidazol-5-yl)-N-methylthiophene-2-sulfonamide (AZ-11713908), N-{1-[(4,4-difluorocyclohexyl)methyl]-2-(1,1-dimethylethyl)-1H-benzimidazol-5-yl}ethanesulfonamide (AZD-1940 ), 6,6,9-trimethyl-3-pentyl-benzo[c]chromen-1-ol (cannabinol; CBN), 5-(1,1-dimethylheptyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol (CP-47497), 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP-5594 0), (6aR,10aR)-9-(hydroxymethyl)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6H,6aH,7H,10H,10aH-benzo[c]isochromen-1-ol (HU-210), 1-pentyl-2-methyl-3-(1-naphthoyl)indole (JWH-007), ((6aR,10aR)-6,6-dimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromen-9-yl)methanol (JWH-051), (1-heptyl-5-phenyl-1H-pyrrol-3-yl)-1-naphthalenyl-methanone (JWH-146), 1-([(1E)-3-pentylidene-1-ylidine]methyl)naphthalene (JWH-176), (1-(2-morpholin-4-ylethyl)indol-3-yl)-naphthalen-1-ylmethanone (JWH-200), 1-pentyl-3-(4-chloro-1-naphthoyl)indole (JWH-398), [1-(cyclohexylmethyl)-7-methoxyindol-3-yl]-[(3S)-3,4-dimethylpiperazin-1-yl]methanone (Organic 28611), 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (rimonabant), tetrahydrocannabinol (THC), (11R)-2-methyl-11-[(morpholin-4-yl)methyl]-3-(naphthalene-1-carbonyl)-9-oxa-1-azatricyclo[6.3.1.04,12]dodeca-2,4(12 ), 5,7-tetraene (WIN55212-2), (1-(5-fluoropentyl)-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone (XLR11), and any salts, isomers (including structural isomers and stereoisomers, e.g., enantiomers), precursors, prodrugs, metabolites, derivatives, analogs, isotopically substituted or variants thereof, or any combination thereof.

[0129] Those skilled in the art will appreciate the ability to determine which other compounds are useful agents in the practice of the disclosed embodiments by reference to the teachings herein in combination with general knowledge in the art, such as by reference to DrugCentral, DrugBank, and other compendia of drug data.

[0130] D. Serotonin-2 (5-HT2) agents In some embodiments, the therapeutic combination will include a serotonin-2 agent. In some embodiments, "serotonin-2 agent" can refer to a compound that modulates the activity of the serotonin-2 (5-HT2) receptor. In some embodiments, the 5-HT2 agent binds to, blocks, activates, inhibits, or affects activity at the serotonin-2 (5-HT2) receptor (e.g., via an allosteric reaction). In some embodiments, the 5-HT2 agent acts as a receptor modulator, altering the function of the receptor to which it binds, and the alteration includes activating the activity of the receptor, inhibiting the activity of the receptor, and either activating or inhibiting the activity of the receptor, depending on the dose administered.

[0131] Many compounds that have affinity for a certain serotonin receptor subfamily can also bind to serotonin receptors of other subfamilies, or can have affinity for receptors of the serotonin receptor system as a whole. Thus, in some embodiments, the 5-HT2 agent is a compound that also has affinity for another serotonin receptor. In embodiments, the 5-HT2 agent is a phenethylamine or tryptamine disclosed herein as a serotonin receptor agent, and may also have affinity for other serotonin receptor subfamilies in addition to the 5-HT2 receptor. However, a 5-HT2 agent can be selected based on, for example, its potency at the 5-HT2 receptor (e.g., K i their selectivity for the 5-HT2 receptor subfamily or specific 5-HT2 receptor subtypes (e.g., K to calculate selectivity compared to a given receptor) according to their selectivity for a given receptor, or for a given 5-HT2 receptor subfamily or specific 5-HT2 receptor subtype (e.g., K) compared to another receptor system or compared to another serotonin receptor subfamily (e.g., 5-HT7). i It can also be distinguished from other serotonin receptor agents by the agonist activity (determined by comparing the agonist activity values).

[0132] In some embodiments, the 5-HT2 agent is a "selective agent," which may refer to an agent that binds to the 5-HT2 receptor system preferentially over receptors that are not part of the 5-HT2 receptor system. In some embodiments, such selectivity (also referred to herein as "specificity") is expressed as a ratio greater than 1.0. ... i In embodiments, the selectivity (as measured via K) for the 5-HT7 receptor system is at least 1.1:1, 1.5:1, 2:1, 5:1, 10:1, 15:1, 25:1, 50:1, 100:1, etc., compared to receptors that are not part of the 5-HT2 receptor system. i In embodiments, the selectivity (as K) for the 5-HT7 receptor system is greater than 1.0, for example, but not limited to, 1.1:1, 1.5:1, 2:1, 5:1, 10:1, 15:1, 25:1, 50:1, 100:1, etc., relative to the 5-HT1 receptor. i The selectivity (as a function of the 5-HT7 receptor) is greater than 1.0, for example, but not limited to, 1.1:1, 1.5:1, 2:1, 5:1, 10:1, 15:1, 25:1, 50:1, 100:1, etc., compared to the 5-HT7 receptor.

[0133] In embodiments, the serotonin-2 agent is an agonist. Generally, a "serotonin-2 receptor agonist" (or "serotonin-2 agonist," "5-HT2 receptor agonist," or "5-HT2 agonist") is a compound that initiates a biological response upon binding to a serotonin-2 receptor. A "serotonin-2 receptor" may include serotonin-2A receptors, serotonin-2B receptors, and serotonin-2C receptors. In embodiments, a 5-HT2 agonist has high specificity for the 5-HT2 receptor. In embodiments, a 5-HT2 agonist has low specificity for receptors that are not part of the serotonin-2 receptor system.

[0134] In some embodiments, the serotonin-2 agent is an antagonist. Generally, a "serotonin-2 receptor antagonist" (or "serotonin-2 antagonist," "5-HT2 receptor antagonist," or "5-HT2 antagonist") is a compound that inhibits a biological response upon binding to a serotonin-2 receptor. A "serotonin-2 receptor" may include a serotonin-2A receptor, a serotonin-2B receptor, and a serotonin-2C receptor. In some embodiments, the 5-HT2 antagonist has high specificity for the 5-HT2 receptor. In some embodiments, the 5-HT2 antagonist has low specificity for receptors that are not part of the serotonin-2 receptor system.

[0135] In some embodiments, the 5-HT2 agent is an inverse agonist. Generally, a "5-HT2 receptor inverse agonist" (or "5-HT2 inverse agonist," "5-HT2 receptor inverse agonist," or "5-HT2 inverse agonist") is a compound that, upon binding to a 5-HT2 receptor, reduces the constitutive activity of the 5-HT2 receptor to a level below its basal state. A "5-HT2 receptor" may include a serotonin-2A receptor, a serotonin-2B receptor, and a serotonin-2C receptor. In embodiments, a 5-HT2 inverse agonist has high specificity for the 5-HT2 receptor. In embodiments, the 5-HT2 inverse agonist has low specificity for receptors that are not part of the 5-HT2 receptor system.

[0136] In some embodiments, a "5-HT2 agonist" refers to a 5-HT 2B Compared to 5-HT 2A or 5-HT 2C In some embodiments, the 5-HT2 agonist is selective for 5-HT 2B Compared to 5-HT 2A and 5-HT 2C In some embodiments, the 5-HT2 agonist is selective for 5-HT 2B or 5-HT 2C Compared to 5-HT 2A In some embodiments, the 5-HT2 agonist is selective for 5-HT 2B and 5-HT 2C Compared to 5-HT 2A In some embodiments, the 5-HT2 agonist is selective for 5-HT 2A or 5-HT 2B Compared to 5-HT 2C In some embodiments, the 5-HT2 agonist is selective for 5-HT 2A and 5-HT 2B Compared to 5-HT 2C In some embodiments, the 5-HT2 agonist is selective for 5-HT 2A or 5-HT 2C Compared to 5-HT 2B In some embodiments, the 5-HT2 agonist is selective for 5-HT 2A and 5-HT 2C Compared to 5-HT 2B In some embodiments, the 5-HT2 agonist is selective for 5-HT relative to 5-HT7. 2A , 5-HT 2B , and 5-HT 2C In some embodiments, the 5-HT2 agonist is selective for any one or more of 5-HT compared to 5-HT7. 2A , 5-HT 2B , and 5-HT 2CIn some embodiments, the 5-HT2 agonist is selective for all of 5-HT compared to 5-HT7. 2A It is selective for

[0137] In some embodiments, the disclosed 5-HT 2A Agonists and other 5-HT 2A The disclosed 5-HT agents will not produce psychedelic effects when administered as part of the disclosed entactogen combinations and pharmaceutical compositions. 2A Agonists and other 5-HT 2A An agent, when administered as part of the disclosed entactogen combinations and pharmaceutical compositions, will not produce a psychedelic effect when administered in an amount or manner that would produce a psychedelic effect if such agent were administered alone.

[0138] Serotonin receptor agents generally include tryptamine and phenethylamine. In embodiments, an exemplary 5-HT2 agent is tryptamine. In embodiments, an exemplary 5-HT2 agent is phenethylamine.

[0139] "Tryptamine" is readily understood by those skilled in the art, and examples of tryptamines useful in the practice of the present invention include, but are not limited to, baeocystin, norbaeocystin, tryptamine, 4-hydroxytryptamine (or, as an abbreviation, "4-hydroxyT" where the final "T" represents "tryptamine"), N-methyl T, N-ethyl T, N-propyl T, N-isopropyl T, N-allyl T, N,N-dimethyl T, N,N-diethyl T, N,N-dipropyl T, N,N-diisopropyl T, N,N-diallyl T, N-methyl -N-Ethyl Tetroxide, N-Methyl-N-Propyl Tetroxide, N-Methyl-N-Isopropyl Tetroxide, N-Methyl-N-Allyl Tetroxide, N-Ethyl-N-Propyl Tetroxide, N-Ethyl-N-Isopropyl Tetroxide, N-Ethyl-N-Allyl Tetroxide, N-Propyl-N-Isopropyl Tetroxide, N-Propyl-N-Allyl Tetroxide, N-Isopropyl-N-Allyl Tetroxide, 4-Hydroxy-Tetroxide, 4-Hydroxy-N-Methyl Tetroxide, 4-Hydroxy-N-Ethyl Tetroxide, 4-Hydroxy-N-Propyl Tetroxide, 4-Hydroxy-N-Isopropyl Tetroxide, 4-Hydroxy-N-Allyl Tetroxide, 4-Hydroxy-N,N- Dimethyl T, 4-hydroxy-N,N-diethyl T, 4-hydroxy-N,N-dipropyl T, 4-hydroxy-N,N-diisopropyl T, 4-hydroxy-N,N-diallyl T, 4-hydroxy-N-methyl-N-ethyl T, 4-hydroxy-N-methyl-N-propyl T, 4-hydroxy-N-methyl-N-isopropyl T, 4-hydroxy-N-methyl-N-allyl T, 4-hydroxy-N-ethyl-N-propyl T, 4-hydroxy-N-ethyl-N-isopropyl T, 4-hydroxy-N-ethyl-N-allyl T, 4-hydroxy-N-ethyl-N-allyl T, 4-hydroxy Hydroxy-N-propyl-N-isopropyl T, 4-hydroxy-N-propyl-N-allyl T, 4-hydroxy-N-isopropyl-N-allyl T, 5-hydroxy-N, 5-hydroxy-N-methyl T, 5-hydroxy-N-ethyl T, 5-hydroxy-N-propyl T, 5-hydroxy-N-isopropyl T, 5-hydroxy-N-allyl T, 5-hydroxy-N,N-dimethyl T, 5-hydroxy-N,N-diethyl T, 5-hydroxy-N,N-dipropyl T, 5-hydroxy-N,N-diisopropyl T, 5-hydroxy-N,N-Diallyl T, 5-Hydroxy-N-methyl-N-ethyl T, 5-Hydroxy-N-methyl-N-propyl-T, 5-Hydroxy-N-methyl-N-isopropyl T, 5-Hydroxy-N-methyl-N-allyl T, 5-Hydroxy-N-ethyl-N-propyl T, 5-Hydroxy-N-ethyl-N-isopropyl-T, 5-Hydroxy-N-ethyl-N-ethyl T, 5-Hydroxy-N-propyl-N-isopropyl T, 5-Hydroxy -N-Propyl-N-allyl T, 5-hydroxy-N-isopropyl-N-allyl T, 4-Methoxy-T, 4-Methoxy-N-methyl T, 4-Methoxy-N-ethyl T, 4-Methoxy-N-propyl T, 4-Methoxy-N-isopropyl T, 4-Methoxy-N-allyl T, 4-Methoxy-N,N-dimethyl T, 4-Methoxy-N,N-diethyl T, 4-Methoxy-N,N-dipropyl-T, 4-Methoxy-N,N-diisopropyl T, 4- Methoxy-N,N-diallyl T, 4-methoxy-N-methyl-N-ethyl T, 4-methoxy-N-methyl-N-propyl T, 4-methoxy-N-methyl-N-isopropyl T, 4-methoxy-N-methyl-N-allyl T, 4-methoxy-N-ethyl-N-propyl T, 4-methoxy-N-ethyl-N-isopropyl T, 4-methoxy-N-ethyl-N-allyl T, 4-methoxy-N-propyl-N-isopropyl T, 4-methoxy-N-propyl N-propyl-N-allyl T, 4-methoxy-N-isopropyl-N-allyl T, 5-methoxy-N, 5-methoxy-N-methyl T, 5-methoxy-N-ethyl T, 5-methoxy-N-propyl T, 5-methoxy-N-isopropyl T, 5-methoxy-N-allyl T, 5-methoxy-N,N-dimethyl T, 5-methoxy-N,N-diethyl T, 5-methoxy-N,N-dipropyl T, 5-methoxy-N,N-diisopropyl T, 5-methoxy-N,N-Diallyl T, 5-Methoxy-N-methyl-N-ethyl T, 5-Methoxy-N-methyl-N-propyl T, 5-Methoxy-N-methyl-N-isopropyl-T, 5-Methoxy-N-methyl-N-allyl T, 5-Methoxy-N-ethyl-N-propyl T, 5-Methoxy-N-ethyl-N-isopropyl T, 5-Methoxy-N-ethyl-N-allyl T, 5-Methoxy-N-propyl-N-isopropyl T, 5-Methoxy-N-propyl-N-allyl T, 5 -Methoxy-N-isopropyl-N-allyl T, 4-acetoxy-T, 4-acetoxy-N-methyl T, 4-acetoxy-N-ethyl T, 4-acetoxy-N-propyl T, 4-acetoxy-N-isopropyl T, 4-acetoxy-N-allyl T, 4-acetoxy-N,N-dimethyl T, 4-acetoxy-N,N-diethyl T, 4-acetoxy-N,N-dipropyl T, 4-acetoxy-N,N-diisopropyl T, 4-acetoxy-N,N-diallyl T T, 4-acetoxy-N-methyl-N-ethyl T, 4-acetoxy-N-methyl-N-propyl T, 4-acetoxy-N-methyl-N-isopropyl-T, 4-acetoxy-N-methyl-N-allyl-T, 4-acetoxy-N-ethyl-N-propyl T, 4-acetoxy-N-ethyl-N-isopropyl-T, 4-acetoxy-N-ethyl-N-allyl T, 4-acetoxy-N-propyl-N-isopropyl T, 4-acetoxy-N-propyl-N-allyl T, 4-acetoxy-N-propyl-N-isopropyl T, 4-acetoxy-N-propyl-N-allyl Allyl T, 4-acetoxy-N-isopropyl-N-allyl T, 5-acetoxy-T, 5-acetoxy-N-methyl T, 5-acetoxy-N-ethyl T, 5-acetoxy-N-propyl T, 5-acetoxy-N-isopropyl T, 5-acetoxy-N-allyl T, 5-acetoxy-N,N-dimethyl T, 5-acetoxy-N,N-diethyl T, 5-acetoxy-N,N-dipropyl T, 5-acetoxy-N,N-diisopropyl T, 5-acetoxy-N,N-Diallyl T, 5-Acetoxy-N-methyl-N-ethyl T, 5-Acetoxy-N-methyl-N-propyl T, 5-Acetoxy-N-methyl-N-isopropyl-T, 5-Acetoxy-N-methyl-N-allyl T, 5-Acetoxy-N-ethyl-N-propyl T, 5-Acetoxy-N-ethyl-N-isopropyl T, 5-Acetoxy-N-ethyl-N-allyl T, 5-Acetoxy-N-propyl-N-isopropyl T, 5-Acetoxy-N-propyl-N-allyl T, 5-Acetoxy-N-isopropyl-N-allyl T Psilocylic Acid, α-methyl T, N-ethyl-N-isopropyl T, N-methyl-N-butyl T, 2,α-dimethyl T, α-N-dimethyl T, α-methyl-N,N-dimethyl T, α-ethyl T, 2-methyl-N,N-dimethyl T, 2-methyl-N,N-diethyl T, 1-methylpsilocin, 5-methoxy-α-methyl T, ibogaine, harmaline, 7-methoxy-1-methyl-1,2,3,4-tetrahydro-b-carboline (tetrahydroharmine), N,N-diethyl-D-lysergamide (LSD), 6-allyl-N, N-diethyl-norlysergic acid (6-allyl-N,N-diethyl-norlysergic acid), 9,10-didehydro-N,N,6-triethylergoline-8b-carboxamide (6,N,N-triethyl-norlysergic acid), 9,10-didehydro-6-propyl-N,N-diethylergoline-8b-carboxamide (6-propyl-norlysergic acid), 4-OH-DALT, 5-Br-DALT, 5-MeO-DALT, 4-AcO-DALT, 5-F-DALT, 5-F-2-Me-DALT, 7-Et-DALT, DALT, 2-Ph-DALT, 5-MeO-2-Me-DALT, other tryptamine compounds, or their pharmaceutically acceptable salts, hydrates, solvates, precursors, prodrugs, metabolites, derivatives, analogs, isotopically substituted variants, mutants, tautomers, isomers, or stereoisomers (including pure or substantially pure individual enantiomers and enantiomerically enriched mixtures having any enantiomeric excess greater than 0%), or combinations thereof (including all amorphous and polymorphic forms).

[0140] In embodiments, when the compound is tryptamine, its ring-substituted derivatives known in the art are also useful in the practice of the present invention. For example, when the compound is DALT, ring-substituted derivatives (including other known derivatives) include, for example, its 2-phenyl-, 4-acetoxy-, 4-hydroxy-, 5-methoxy-, 5-methoxy-2-methyl-, 5-fluoro-, 5-fluoro-2-methyl-, 5-bromo-, and 7-ethyl-derivatives (Klein, 2018). When the compound is another tryptamine, similar ring-substituted derivatives such as those described above (and others) will be readily apparent to those skilled in the art.

[0141] Those skilled in the art will readily understand how to determine whether a compound is, for example, a 5-HT2 and / or 5-HT7 agent, agonist and / or antagonist, and their selectivity for one or more receptor systems. For example, using the data available in Klein 2018, the above derivatives ranked in order of relative affinity to 5-HT7 are 4-OH-DALT, 5-Br-DALT, 5-MeO-DALT, 4-AcO-DALT, 5-F-DALT, and 5-F-2-Me-DALT. In order of relative affinity to 5-HT2, they are 7-Et-DALT, DALT, 2-Ph-DALT, and 5-MeO-2-Me-DALT. Those skilled in the art will understand how to perform such analysis and ranking of any compound taught or suggested herein based on already published data or data that can be generated based on the teachings herein and the general skills of those skilled in the art.

[0142] Still other psychotropic tryptamines contemplated for use in the practice of the present invention include 6-allyl-N,N-diethyl-norlysergamid (AL-LAD), N,N-dibutyltryptamine ("N,N-dibutyltrypT"; DBT, using the abbreviation described elsewhere), α,N-dimethyl T (α,N-DMT), 6,N,N-triethylnorlysergamid (ETH-LAD), 3,4-dihydro-7-methoxy-1-methylcarboline (harmaline), 7-methoxy-1-methylcarboline (harmine), N,N-dibutyl-4-hydroxy T (4-HO-DBT), N,N-diethyl-4-hydroxytetrahydrofuran (4-HO-DET), N,N-diisopropyl-4-hydroxytetrahydrofuran (4-HO-DiPT), N,N-dimethyl-4-hydroxytetrahydrofuran (4-HO-DMT), N,N-dimethyl-5-hydroxytetrahydrofuran (5-HO-DMT, bufotenin), N,N-dipropyl-4-hydroxytetrahydrofuran (4-HO-DPT), N-ethyl-4-hydroxy-N-methyltetrahydrofuran (4-HO-MET), 4-hydroxy-N-isopropyl-N-methyltetrahydrofuran (4-HO-MiPT), 4-hydroxy-N,N-tetramethylene- T (4-HO-pyr-T), 12-methoxyibogamine (ibogaine), N-butyl-N-methyl T (MBT), N,N-diisopropyl-4,5-methylenedioxy T (4,5-MDO-DiPT), N,N-diisopropyl-5,6-methylenedioxy T (5,6-MDO-DiPT), N,N-dimethyl-4,5-methylenedioxy T (4,5-MDO-DMT), N,N-dimethyl-5,6-methylenedioxy T (5,6-MDO-DMT), N-isopropyl-N-methyl-5,6-methylenedioxy T (5,6-MDO-MiPT), N , N-diethyl-2-methyl T4 (2-Me-DET), 2,N,N-trimethyl T4 (2-Me-DMT), N-acetyl-5-methoxy T4 (melatonin), N,N-diethyl-5-methoxy T4 (5-MeO-DET), N,N-diisopropyl-5-methoxy T4 (5-MeO-DiPT), N-isopropyl-4-methoxy-N-methyl T4 (4-MeO-MiPT), N-isopropyl-5-methoxy-N-methyl T4 (5-MeO-MiPT), 5,6-dimethoxy-N-isopropyl-N-methyl T4 (5,6-MeO-MiPT), 5-methoxy-N,Included are N-tetramethylene T4 (5-MeO-pyr-T4), 6-methoxy-1-methyl-1,2,3,4-tetrahydrocarboline (6-MeO-THH), 5-methoxy-2,N,N-trimethyl T4 (5-MeO-TMT), N,N-dimethyl-5-methylthio T4 (5-MeS-DMT), N-isopropyl-N-methyl-T4 (MiPT), 6-propylnorlysergamide (PRO-LAD), N,N-tetramethylene T4 (pyr-T4), tryptamine (T4), 7-methoxy-1-methyl-1,2,3,4-tetrahydrocarboline (tetrahydroharmine), or α,N-dimethyl-5-methoxy T4 (α,N,O-TMS), or a pharmaceutically acceptable isomer, salt, ester, hydrate, solvate, polymorph, prodrug, isotopic substitution, or metabolite thereof, or a combination thereof. See Shulgin and Shulgin, TIHKAL: The Continuation, Transform Press (1997), which is incorporated herein by reference in its entirety. Additional examples of psychedelic tryptamines can be found in numerous references known to those skilled in the art (e.g., Araujo 2015).

[0143] While some psychotropic tryptamines of the present invention can be obtained from fungal sources, it will be readily understood that other disclosed tryptamine compounds can be obtained from numerous other plants and plant sources. For example, N,N-DMT can be extracted from species of the genera Phalaris, Delosperma, Acacia, Desmodium, Mimosa, Virola, and Psychotria, among other sources.

[0144] In embodiments, tryptamine has the following structure: N1 , R N2 , R α , R β , R 2 , R 4 , R 5 , R 6 , and R 7as taught herein and as commonly understood in the art): [ka] The tryptamine may be a substituted tryptamine having the formula:

[0145] For example, in some embodiments, R N1 , R N2 , R α , R β , R 2 , R 4 , R 5 , R 6 , and R 7 are independently hydrogen, deuterium, halogen, hydroxy, methoxy, phosphoryloxy, C1-C5 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl (independently or ring closed by nitrogen), C3-C8 cycloalkenyl (independently or ring closed by nitrogen), aryl, or heterocyclyl, any of which are optionally substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, —O—P(O)(OH), —O—C(O)H, —O—S—O—H, —O—S—O—H, and —O—S—H. Additionally, tryptamines useful in the practice of the present invention also necessarily include any salts, isomers (including structural isomers and stereoisomers, e.g., enantiomers), precursors, prodrugs, metabolites, derivatives, analogs, isotopic substitutions, or variants thereof, or combinations thereof.

[0146] In embodiments, the tryptamine is an N-substituted tryptamine with either a methyl, ethyl, propyl, isopropyl, or allyl group, and in embodiments, tryptamine, N-methyltryptamine, N-ethyltryptamine, N-propyltryptamine, N-isopropyltryptamine, N-allyltryptamine, N,N-dimethyltryptamine, N,N-diethyltryptamine, N,N-dipropyltryptamine, N,N-diiso ... N-methyl-N-allyltryptamine, N-methyl-N-ethyltryptamine, N-methyl-N-propyltryptamine, N-methyl-N-isopropyltryptamine, N-methyl-N-allyltryptamine, N-ethyl-N-propyltryptamine, N-ethyl-N-isopropyltryptamine, N-ethyl-N-allyltryptamine, N-propyl-N-isopropyltryptamine, N-propyl-N-allyltryptamine, and N-isopropyl-N-allyltryptamine.

[0147] In some embodiments, the tryptamines of the present invention are "complex tryptamines" or other indoleamines, including, but not limited to, ergolines and ergoline alkaloids (including ergoline derivatives such as lysergamides, ergopeptines or ergopeptides, and clavines; including synthetic ergoline derivatives such as cabergoline, pergolide, and lisuride) (chemical classes commonly known in the art and including at least such exemplary compounds as generally known in the art, and analogs and derivatives thereof), natural and synthetic ibogaine alkaloids, and other plant alkaloids including harmine, harmane, norharmine, harmaline, perlolidine, harmol, and other beta-carbolines, e.g., from Banisteriopsis caapi and Peganum harmala, or other monoamine oxidase inhibitors (MAOIs) that enhance the pharmaceutical effectiveness of tryptamines when used in combination with tryptamines in the practice of the present invention. Thus, in some embodiments where tryptamine or conjugated tryptamines are taken orally, and in some preferred embodiments (particularly where such tryptamines are not orally active), an MAOI is an additional active agent in the composition or therapeutic combination in a dosage to provide oral activity of the tryptamine or conjugated tryptamine, as known to those skilled in the art.

[0148] Non-limiting examples of "phenethylamines" that will be readily apparent to one of ordinary skill in the art include α-ethyl-3,4,5-trimethoxyphenethylamine (or for shorthand, "α-ethyl-3,4,5-trimethoxy PEA"; AEM), where "PEA" refers to "phenethylamine"); 4-allyloxy-3,5-dimethoxy PEA (AL); 2,5-dimethoxy-4-methyl-thioamphetamine (or for shorthand, "2,5-dimethoxy-4-methyl-thio A"; ALEPH), where "A" refers to "amphetamine"; ), 2,5-dimethoxy-4-ethylthio A (ALEPH-2), 2,5-dimethoxy-4-isopropylthio A (ALEPH-4), 2,5-dimethoxy-4-phenylthio A (ALEPH-6), 2,5-dimethoxy-4-propylthio A (ALEPH-7), 2,5-dimethoxy-α-ethyl-4-methyl PEA (ARIADNE), 3,4-diethoxy-5-methoxy PEA (ASB), 4-butoxy-3,5-dimethoxy-PEA (B), 2,5-dimethoxy-4,N-dimethyl A (BEATRICE), 2,5-bismethylthio-4-methyl A (BIS-TOM), 4-bromo-2,5,β-trimethoxy PEA (BOB), 2,5,β-trimethoxy-4-methyl PEA (BOD), β-methoxy-3,4-methylenedioxy PEA (BOH), 2,5-dimethoxy-β-hydroxy-4-methyl PEA (BOHD), 3,4,5,β-tetramethoxy PEA (BOM), 4-bromo-3,5-dimethoxy A (4-Br-3,5-DMA), 2-bromo-4,5-methylenedioxy A (2-Br-4,5-MDA), 4-bromo-2,5-dimethoxy-PEA (2C-B), 2-(4-bromo-2 ,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran-8-yl)ethanamine (2C-B-FLY), 4-benzyloxy-3,5-dimethoxy PEA (3C-BZ), 4-chloro-2,5-dimethoxy-PEA (2C-C), 2,5-dimethoxy-4-methyl-PEA (2C-D), 2,5-dimethoxy-4-ethyl-PEA (2C-E), 3,5-dimethoxy-4-ethoxy PEA (3C-E), 2,5-dimethoxy-4-fluoro PEA (2C-F), 2,5-dimethoxy-3,4-dimethyl PEA (2C-G), 2,5-dimethoxy-3,4-trimethylene PEA (2C-G-3), 2,5-dimethoxy-3,4-tetramethylene-PEA (2C-G-4), 3,4-norbornyl-2,5-dimethoxy PEA (2C-G-5), 1,4-dimethoxynaphthyl-2-ethylamine (2C-GN), 2,5-dimethoxy PEA (2C-H), 4-iodo-2,5-dimethoxy PEA (2C-I), 2,5-dimethoxy-4-nitro-PEA (2C-N), 2,5-dimethoxy-4-isopropoxy PEA (2C-O-4), 2,5-dimethoxy-4-propyl PEA (2C-P), 4- Cyclopropylmethoxy-3,5-dimethoxy PEA (CPM), 2,5-dimethoxy-4-methylseleno PEA (2C-SE), 2,5-dimethoxy-4-methylthio PEA (2C-T), 2,5-dimethoxy-4-ethylthio PEA (2C-T-2), 2,5-dimethoxy-4-isopropylthio PEA (2C-T-4), 2,6-dimethoxy-4-isopropylthio PEA (psi-2C-T-4), 2,5-dimethoxy-4-propylthio PEA (2C-T-7), 4-cyclopropylmethylthio-2,5-dimethoxy PEA (2C-T- 8), 4-(t)-butylthio-2,5-dimethoxy-PEA (2C-T-9), 2,5-dimethoxy-4-(2-methoxyethylthio)PEA (2C-T-13), 4-cyclopropylthio-2,5-dimethoxyPEA (2C-T-15), 4-(s)-butylthio-2,5-dimethoxyPEA (2C-T-17), 2,5-dimethoxy-4-(2-fluoroethylthio)PEA (2C-T-21), 3,5-dimethoxy-4-trideuteromethylPEA (4-D), β,β-dideutero-3,4,5-trimethoxyPEA (β-D), 3 ,5-Dimethoxy-4-methyl-PEA (DESOXY), 2,4-Dimethoxy A (2,4-DMA), 2,5-Dimethoxy A (2,5-DMA), 3,4-Dimethoxy A (3,4-DMA), 2-(2,5-Dimethoxy-4-methylphenyl)cyclopropylamine (DMCPA), 3,4-Dimethoxy-β-hydroxyPEA (DME), 2,5-Dimethoxy-3,4-methylenedioxy A (DMMDA), 2,3-Dimethoxy-4,5-methylenedioxy A (DMMDA-2), 3,4-Dimethoxy PEA (DMPEA), 4-amyl-2,5-Dimethoxy A (DOAM), 4-bromo-2,5-dimethoxy A (DOB), 4-butyl-2,5-dimethoxy A (DOBU), 4-chloro-2,5-dimethoxy A (DOC), 2,5-dimethoxy-4-(2-fluoroethyl) A (DOEF), 2,5-dimethoxy-4-ethyl A (DOET), 4-iodo-2,5-dimethoxy A (DOI), 2,5-dimethoxy-4-methyl A (DOM(STP)), 2,6-dimethoxy-4-methyl A (psi-DOM), 2,5-dimethoxy-4-nitro A (DON), 2,5-dimethoxy-4 -propyl A (DOPR), 3,5-dimethoxy-4-ethoxy PEA (E), 2,4,5-triethoxy A (EEE), 2,4-diethoxy-5-methoxy A (EEM), 2,5-diethoxy-4-methoxy A (EME), 4,5-dimethoxy-2-ethoxy A (EMM), 2-ethylamino-1-(3,4-methylenedioxyphenyl)butane (ETHYL-J), 2-ethylamino-1-(3,4-methylenedioxyphenyl)pentane (ETHYL-K), 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydro Benzofuran (F-2), 6-(2-aminopropyl)-2,2-dimethyl-5-methoxy-2,3-dihydrobenzofuran (F-22), N-hydroxy-N-methyl-3,4-methylenedioxy A (FLEA), 2,5-dimethoxy-3,4-(trimethylene) A (G-3), 2,5-dimethoxy-3,4-(tetramethylene) A (G-4), 3,6-dimethoxy-4-(2-aminopropyl)benzonorbornane (G-5), 2,5-dimethoxy-3,4-dimethyl A (GANESHA), 1,4-dimethoxynaphthyl-2-isopropyl Amine (GN), 2,5-dimethoxy-4-ethylthio-N-hydroxy PEA (HOT-2), 2,5-dimethoxy-N-hydroxy-4-(n)-propylthio PEA (HOT-7), 4-(s)-butylthio-2,5-dimethoxy-N-hydroxy PEA (HOT-17), 2,5-dimethoxy-N,N-dimethyl-4-iodo PEA (IDNNA), 2,3,4-trimethoxy PEA (IM), 3,5-dimethoxy-4-isopropoxy PEA (IP), 5-ethoxy-2-methoxy-4-methyl PEA (IRIS), 2-amino-1-(3,4-methylene-dioxyphenyl)butane (J, BDB), 3-methoxy-4,5-methylenedioxy PEA (LOPHOPHINE), 3,4,5-trimethoxy PEA (M), 4-methoxy A (4-MA, PMA), 2,N-dimethyl-4,5-methylenedioxy A (MADAM-6), 3,5-dimethoxy-4-methallyloxy PEA (MAL), 3,4-methylenedioxy A (MDA), N-allyl-3,4-methylenedioxy A (MDAL), N-butyl-3,4-methylenedioxy A (MDBU), N-benzyl-3,4-methylenedioxy A (MDBZ), N-cyclopropylmethyl-3,4-methylenedioxy A (MDCPM), N,N-dimethyl-3,4-methylenedioxy A (MDDM), N-ethyl-3,4-methylenedioxy A (MDE), N-(2-hydroxyethyl)-3,4-methylenedioxy A (MDHOET), N-isopropyl-3,4-methylenedioxy A (MDIP), N-methyl-3,4-methylenedioxy A (MDMA), 3,4-ethylenedioxy-N-methyl A (MDMC), N-methoxy-3,4-methylenedioxy A (MDMEO), N-(2-methoxy)-3,4-methylenedioxy A (MDMEO), Ethyl)-3,4-methylenedioxy A (MDMEOET), 3,4-methylenedioxy-α,α,N-trimethyl PEA (MDMP), N-hydroxy-3,4-methylenedioxy A (MDOH), 3,4-methylenedioxy PEA (MDPEA), α,α-dimethyl-3,4-methylenedioxy PEA (MDPH), 3,4-methylenedioxy-N-propargyl A (MDPL), 3,4-methylenedioxy-N-propyl-A (MDPR), 3,4-dimethoxy-5-ethoxy PEA (ME), 4,5-ethylenedioxy-3-methoxy A (MEDA) ), 4,5-diethoxy-2-methoxy A (MEE), 2,5-dimethoxy-4-ethoxy A (MEM), 4-ethoxy-3-methoxy PEA (MEPEA), 5-bromo-2,4-dimethoxy A (META-DOB), 2,4-dimethoxy-5-methylthio A (META-DOT), 2,5-dimethoxy-N-methyl A (METHYL-DMA), 4-bromo-2,5-dimethoxy-N-methyl A (METHYL-DOB), 2-methylamino-1-(3,4-methylenedioxyphenyl)butane (METHYL-J, MBDB), 2-methylamino-1-(3,4-methylenedioxyphenyl)pentane (METHYL-K), 4-methoxy-N-methyl A (METHYL-MA, PMMA), 2-methoxy-N-methyl-4,5-methylenedioxy A (METHYL-MMDA-2), 3-methoxy-4,5-methylenedioxy A (MMDA), 2-methoxy-4,5-methylenedioxy A (MMDA-2), 2-methoxy-3,4-methylenedioxy A (MMDA-3a), 4-methoxy-2,3-methylenedioxy A (MMDA-3b), 2,4-dimethoxy-5- Ethoxy A (MME), 3,4-dimethoxy-5-(n)-propoxy PEA (MP), 2,5-dimethoxy-4-(n)-propoxy A (MPM), 4,5-dimethoxy-2-methylthio A (ORTHO-DOT), 3,5-dimethoxy-4-propoxy PEA (P), 3,5-dimethoxy-4-phenethyloxy PEA (PE), PEA (PEA), 3,5-dimethoxy-4-(2-propynyloxy) PEA (PROPYNYL), 3,5-diethoxy-4-methoxy PEA (SB), 2,3,4,5-tetraethoxy Trimethoxy PEA (TA), 4-ethoxy-3-ethylthio-5-methoxy PEA (3-TASB), 3-ethoxy-4-ethylthio-5-methoxy PEA (4-TASB), 3,4-diethoxy-5-methylthio PEA (5-TASB), 4-(n)-butylthio-3,5-dimethoxy PEA (TB), 4-ethoxy-5-methoxy-3-methylthio PEA (3-TE), 3,5-dimethoxy-4-ethylthio PEA (TE, 4-TE), 3,4-dimethoxy-2-methylthio PEA (2-TIM), 2,4-di Methoxy-3-methylthio PEA (3-TIM), 2,3-dimethoxy-4-methylthio PEA (4-TIM), 3,4-dimethoxy-5-methylthio PEA (3-TM), 3,5-dimethoxy-4-methylthio PEA (4-TM), 3,4,5-trimethoxy A (TMA), 2,4,5-trimethoxy A (TMA-2), 2,3,4-trimethoxy A (TMA-3), 2,3,5-trimethoxy A (TMA-4), 2,3,6-trimethoxy A (TMA-5), 2,4,6-trimethoxy A (TMA-6), 4,5-Dimethoxy-3-ethylthio PEA (3-TME), 3-ethoxy-5-methoxy-4-methylthio PEA (4-TME), 3-ethoxy-4-methoxy-5-methylthio PEA (5-TME), 3,4-methylenedioxy-2-methylthio A (2T-MMDA-3a), 2-methoxy-4,5-methylene-thiooxy A (4T-MMDA-2), 2,4,5-trimethoxy PEA (TMPEA), 4-ethyl-5-methoxy-2-methylthio A (2-TOET), 4-ethyl-2-methoxy-5-methylthio A (5-T, OET), 5-methoxy-4-methyl-2-methylthio A (2-TOM), 2-methoxy-4-methyl-5-methylthio A (5-TOM), 2-methoxy-4-methyl-5-methylsulfinyl A (TOMSO), 3,5-dimethoxy-4-propylthio PEA (TP), 3,4,5-triethoxy PEA (TRIS), 3-ethoxy-5-ethylthio-4-methoxy PEA (3-TSB), 3,5-diethoxy-4 4-methylthio PEA (4-TSB), 3,4-diethoxy-5-ethylthio PEA (3-T-TRIS), 3,5-diethoxy-4-ethylthio PEA (4-T-TRIS), (R)-2,5-dimethoxy-4-iodo A (R-DOI), or a pharmaceutically acceptable isomer, salt, ester, hydrate, polymorph, solvate, prodrug, isotopic substitution, or metabolite thereof, or a combination thereof. See Shulgin and Shulgin, PIHKAL: A Chemical Love Story, Transform Press (1994), the entirety of which is incorporated herein by reference.

[0149] In some embodiments, the phenethylamines useful in the practice of the present invention will be substituted phenethylamines derived from the "2C" or "2C-x" family known as "NBOMe," "25-NB," or "25x-NBx" compounds. Such compounds are useful, for example, for the treatment of highly potent and relatively selective 5-HT 2AThey can act as agonists. Without being bound by theory and recognizing that exceptions exist, some examples are listed below. NBOMe compounds are generally N-benzylphenethylamines (although the phenyl ring of the N-benzyl group may be replaced by other heterocycles such as thiophene, pyridine, furan, tetrahydrofuran, benzodioxole, or naphthalene, among others) that have methoxy groups at the 2- and 5-positions of the phenyl ring, substitutions such as halogen or alkyl groups at the 4-position of the phenyl ring, and methoxy or other substitutions (e.g., hydroxyl, fluoro) at the 2-position of the N-benzyl ring. Other substitution patterns may also exist (e.g., NBOMe-mescaline, 25G-NBOMe, 2CBFly-NBOMe, and 25C-NB3OMe). NBOMe compounds generally differ from the 2C series by the presence of the N-benzyl moiety. In some compounds, an alpha-methyl group is present (making the compound N-benzylamphetamine), which typically results in reduced potency and activity. In some compounds, the side chain methyl group is cyclized back into the ring (e.g., 2CBCB-NBOMe) or links the two alpha positions (e.g., DMBMPP) to form 5-HT 2A Selectivity for receptor subtypes may be improved.

[0150] Non-limiting examples of "NBOMe compounds" useful in the practice of the present invention include N-benzyl-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NB), N-benzyl-1-(2,5-dimethoxy-4-chlorophenyl)-2-aminoethane (25C-NB), N-benzyl-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NB), N-[(thiophen-2-yl)methyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NMeTh), N-[(pyridine-2 N-[(furan-2-yl)methyl]-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NMePyr), N-[(furan-2-yl)methyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NMeFur), N-[(tetrahydrofuran-2-yl)methyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NMeTHF), N-(2-fluorobenzyl)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NBF) , N-(2-hydroxybenzyl)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NBOH), N-(2-methoxybenzyl)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NBOMe), N-(2,3-dimethoxybenzyl)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NB23DM), N-(2,5-dimethoxybenzyl)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NB25 DM), N-[(benzofuran-7-yl)methyl]-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NMe7BF), N-[(2,3-dihydrobenzofuran-7-yl)methyl]-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NMe7DHBF), N-[(benzothiophen-7-yl)methyl]-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NMe7BT), N-[(benzoxazol-7-yl)methyl]-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NMe7Box), N-[(indol-7-yl)methyl]-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NMe7Ind), N-[(indazol-7-yl)methyl]-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NMe7Indz), N-[(benzimidazol-7-yl)methyl]-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NMe7Bim), N- [(2-fluoroethoxy)benzyl]-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (FECIMBI-36), N-(2-methoxybenzyl)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (DOB-NBOMe), N-(3-methoxybenzyl)-1-(2,5-dimethoxy-4-chlorophenyl)-2-aminoethane (25C-NB3OMe), N-(4-methoxybenzyl)-1-(2,5-dimethoxy-4-chlorophenyl)-2-aminoethane (25C-NB4OMe), N-(3, 4,5-trimethoxybenzyl)-1-(2,5-dimethoxy-4-chlorophenyl)-2-aminoethane (C30-NBOMe), N-(2-fluorobenzyl)-1-(2,5-dimethoxy-4-chlorophenyl)-2-aminoethane (25C-NBF), N-(2-chlorobenzyl)-1-(2,5-dimethoxy-4-chlorophenyl)-2-aminoethane (25C-NBCl), N-(2-hydroxybenzyl)-1-(2,5-dimethoxy-4-chlorophenyl)-2-aminoethane (25C-NBOH), N-(2-methoxybenzyl) -1-(2,5-dimethoxy-4-chlorophenyl)-2-aminoethane (25C-NBOMe), N-(2-ethoxybenzyl)-1-(2,5-dimethoxy-4-chlorophenyl)-2-aminoethane (25C-NBOEt), N-(2-isopropoxybenzyl)-1-(2,5-dimethoxy-4-chlorophenyl)-2-aminoethane (25C-NBOiPr), N-(2-methoxybenzyl)-1-(2,5-dimethoxy-4-fluorophenyl)-2-aminoethane (25F-NBOMe), N-(2-hydroxybenzyl)-1-(2,5-Dimethoxy-4-cyanophenyl)-2-aminoethane (25CN-NBOH), N-(2-methoxybenzyl)-1-(2,5-dimethoxy-4-cyanophenyl)-2-aminoethane (25CN-NBOMe), N-(2-methoxybenzyl)-1-(2,5-dimethoxy-4-methylphenyl)-2-aminoethane (25D-NBOMe), N-(2-hydroxybenzyl)-1-(2,5-dimethoxy-4-methylphenyl)-2-aminoethane (25D-NBOH), N-(2-methoxybenzyl)-1-(2,5-dimethoxy-4-methylphenyl)-2-aminoethane N-(2-hydroxybenzyl)-1-(2,5-dimethoxy-4-ethylphenyl)-2-aminoethane (25E-NBOH), N-(2-methoxybenzyl)-1-(2,5-dimethoxy-3,4-dimethylphenyl)-2-aminoethane (25G-NBOMe), N-(2-methoxybenzyl)-1-(2,5-dimethoxyphenyl)-2-aminoethane (25H-NBOMe), N-(3,4-methylene-dioxybenzyl)-1-(2,5-dimethoxy- N-(3-methoxybenzyl)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NB34MD), N-(3-methoxybenzyl)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NB3OMe), N-(4-methoxybenzyl)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NB4OMe), N-(2-fluorobenzyl)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NBF), N-(2-bromobenzyl)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NBF), N-(2,3-methylenedioxybenzyl)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NBBr), N-[2-(trifluoromethyl)benzyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NBTFM), N-(2,3-methylenedioxybenzyl)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NBMD), N-(2,3-methylenedioxybenzyl)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25B-NBMD), N-(2,3-methylenedioxybenzyl)-1-(2,5-dimethoxy-4-chlorophenyl)-2-aminoethane (25C-NBMD), N-(2,3-methylenedioxybenzyl)-1-(2,5-dimethoxy-4-methylphenyl)-2-aminoethane (25D-NBMD), N-(2-hydroxybenzyl)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NBOH), N-(2-methoxybenzyl)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NBOMe), N-(2-methoxybenzyl)-1-(2, 5-Dimethoxy-4-iodophenyl)-2-aminoethane (DOI-NBOMe), N-[2-(hydroxymethyl)benzyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NBMeOH), N-[2-(carbamoyl)benzyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NBAm), N-[(2,3-dihydrobenzofuran-7-yl)methyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NMe7DHB F), N-[(1-hydroxynaphthalen-2-yl)methyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-N2Nap1OH), N-[(3-methoxythiophen-2-yl)methyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-N3MT2M), N-[(4-methoxythiophen-3-yl)methyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-N4MT3M), N-(2-methoxybenzyl)-1-(2,5 -dimethoxy-4-isopropylphenyl)-2-aminoethane (25iP-NBOMe), N-(2-methoxybenzyl)-1-(2,5-dimethoxy-4-nitrophenyl)-2-aminoethane (25N-NBOMe), N-(2-methoxybenzyl)-1-(2,5-dimethoxy-4-propylphenyl)-2-aminoethane (25P-NBOMe), N-(2-hydroxybenzyl)-1-(2,5-dimethoxy-4-propylphenyl)-2-aminoethane (25P-NBOH), N-(2-methoxybenzyl)-1-[2,5-dimethoxy-4-(trifluoromethyl)phenyl]-2-aminoethane (25TFM-NBOMe), N-(2-methoxybenzyl)-1-[2,5-dimethoxy-4-(methylthio)phenyl]-2-aminoethane (25T-NBOMe), N-(2-methoxybenzyl)-1-[2,5-dimethoxy-4-(ethylthio)phenyl]-2-aminoethane (25T2-NBOMe), N-(2-methoxybenzyl)-1-[2,5-dimethoxy-4-(isopropylthio)phenyl]-2-aminoethane (25T4-NBOMe), N-(2- N-(2-hydroxybenzyl)-1-[2,5-dimethoxy-4-(propylthio)phenyl]-2-aminoethane (25T7-NBOH), N-(2-methoxybenzyl)-1-(3,4,5-trimethoxyphenyl)-2-aminoethane (NBOMe-mescaline), N-(2-methoxybenzyl)-1-(3,5-dimethoxy-4-ethoxyphenyl)-2-aminoethane (NBOMe-escaline), N-( 2-Methoxybenzyl)-1-(3,4-methylenedioxyphenyl)-2-aminoethane (MDPEA-NBOMe), N-benzyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDBZ), N-(2-chlorobenzyl)-1-phenyl-2-aminopropane (clobenzorex), N-(2-methoxybenzyl)-1-(4-ethylphenyl)-2-aminopropane (4-EA-NBOMe), N-(2-methoxybenzyl)-1-(benzofuran-5-yl)-2-aminopropane (5-APB-NBOMe), N- [1-(2-methoxyphenyl)ethyl]-2,5-dimethoxy-4-bromo-PEA (25B-N1POMe), 2-phenyl-2-[2-(2,5-dimethoxy-4-bromophenyl)ethylamino]acetonitrile (2C-B-AN), N-[(3-bromo-2,5-dimethoxy-bicyclo[4,2,0]octa-1,3,5-trien-7-yl)methyl]-1-(2-methoxyphenyl)methanamine (2CBCB-NBOMe), N-(2-methoxybenzyl)-1-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminoethane (2CBFly-NBOMe), N-(2-hydroxybenzyl)-1-(8-bromobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminoethane (2C-B-DragonFLY-NBOH), N-(2-ethoxy-5-chlorobenzyl)-1-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminoethane (2C-B-, FLY-NB2EtO5Cl), (S,S)-2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine (DMBMPP), 2-{[2-(4-bromo-2,5-dimethoxyphenyl)ethyl]amino}-1-(piperidin-1-yl)ethanone (25B-NAcPip), 1,3-dimethyl-7-{2-[1-(2,5-dimethoxy-4-chlorophenyl)propan-2-ylamino]ethyl}purine-2,6-dione (ZDCM-04), 3-[2-(2-methoxy-benzylamino)ethyl]-1H-quinazoline-2,4-dione N-[(4-methoxy-thiophen-3-yl)methyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-N4MT3M), and N-(2-methoxybenzyl)-1-(2,5-dimethoxy-4-isopropylphenyl)-2-aminoethane (25iP-NBOMe).

[0151] In some embodiments, the phenethylamines useful in the practice of the present invention will be α-methyl-substituted phenethylamines of the 4-substituted-2,5-dimethoxyamphetamine or "DOx" class of compounds, i.e., substituted amphetamines. Without being bound by theory, DOx compounds generally have methoxy groups at the 2- and 5-positions of the phenyl ring and a substituent, such as an alkyl or halogen, at the 4-position of the phenyl ring. Such compounds are known to produce highly selective 5-HT 2A , 5-HT2B and / or 5-HT 2CNon-limiting examples of "DOx compounds" useful in the practice of the present invention include 2,5-dimethoxy-4-amylamphetamine (or for shorthand, "2,5-dimethoxy-4-amyl A" where "A" represents "amphetamine"; DOAM), 2,5-dimethoxy-4-bromo A (DOB), 2,5-dimethoxy-4-butyl A (DOBU), 2,5-dimethoxy-4-chloro A (DOC), 2,5-dimethoxy-4-ethoxy A (MEM), 2,5-dimethoxy-4-(methoxymethyl) A (DOMOM), 2,5-dimethoxy-4-(ethoxymethyl) A (DOMOM), 2,5-dimethoxy-4-(ethoxymethyl) A (DOMOM), 2,5-dimethoxy-4-bromo A (DOB), 2,5-dimethoxy-4-butyl A (DOBU), 2,5-dimethoxy-4-chloro A (DOC), 2,5-dimethoxy-4-ethoxy A (MEM), 2,5-dimethoxy-4-(methoxymethyl) A (DOMOM), 2,5-dimethoxy-4-(ethoxymethyl) A (DOMOM), 2,5-dimethoxy-4-bromo A (DOB), 2,5-dimethoxy-4-butyl A (DOBU), 2,5-dimethoxy-4-chloro A (DOC), 2,5-dimethoxy-4-ethoxy A (MEM), 2,5-dimethoxy-4-(ethoxymethyl) A (DOMOM), 2,5-dimethoxy-4-bromo A (DOB ...bromo A (DOB), 2,5-dimethoxy-4-butyl A (DOBU), 2, 2,5-Dimethoxymethyl) A (DOMOE), 2,5-Dimethoxy-4-ethyl A (DOET), 2,5-Dimethoxy-4-ethyl-thio A (Aleph-2), 2,5-Dimethoxy-4-fluoro A (DOF), 2,5-Dimethoxy-4-(2-fluoroethyl) A (DOEF), 2,5-Dimethoxy-4-(3-fluoropropyl) A (DOPF), 2,5-Dimethoxy-4-iodo A (DOI), 2,5-Dimethoxy-4-isopropylthio A (Aleph-4), 2,5-Dimethoxy-4-methyl A (DOM), 2,5-Dimethoxy 2,5-Dimethoxy-4-methylthio A (Aleph-1), 2,5-dimethoxy-4-nitro A (DON), 2,5-dimethoxy-4-phenylthio-A (Aleph-6), 2,5-dimethoxy-4-benzyl A (DOBZ), 2,5-dimethoxy-4-(3-methoxybenzyl) A (DO3MeOBZ), 2,5-dimethoxy-4-[(tetrahydrofuran-2-yl)methyl] A (DOTHFM), 2,5-dimethoxy-4-propyl A (DOPR), 2,5-dimethoxy-4-isopropyl A (DOiP), 2,5-dimethoxy -4-Propylthio A (Aleph-7), 2,5-dimethoxy-4-(difluoromethyl) A (DODFM), 2,5-dimethoxy-4-trifluoromethyl A (DOTFM), 2,5-dimethoxy-4-(2,2,2-trifluoroethyl) A (DOTFE), 2,5-dimethoxy-4-cyano A (DOCN), 2,5-dimethoxy-4-ethynyl-A (DOYN), dimoxamine (“Ariadne”) (4C-D), 1-(2,5-dimethoxy-4-ethyl-phenyl)butan-2-amine (4C-E), 1-(2,5-Dimethoxy-4-(n-propyl)phenyl)butan-2-amine (4C-P), 1-(2,5-dimethoxy-4-bromophenyl)butan-2-amine (4C-B), 1-(2,5-dimethoxy-4-chlorophenyl)butan-2-amine (4C-C), 1-(2,5-dimethoxy-4-iodophenyl)butan-2-amine (4C-I), 1-(2,5-dimethoxy-4-nitrophenyl)butan-2-amine (4C-N), 1-[2,5-dimethoxy-4-(ethylthio)phenyl]butan-2-amine (4C-T-2), DimethoxymethA ("Beatr"). "ice") (N-methyl-DOM), 2,5-dimethoxy-3,4-methylenedioxy A (DMMDA), 2,5-dimethoxy-3,4-dimethyl A ("Ganesha") (3-methyl-DOM), 2,5-dimethoxy-3,4-trimethylenyl A (G-3), 2,5-dimethoxy-3,4-tetramethylenyl A (G-4), 2,5-dimethoxy-3,4-norbornyl A (G-5), 1-(5,8-dimethoxy-3,4-dihydro-1H-isochromen-7-yl)propan-2-amine (GO), 2,5-dimethoxy-3,4-dichloro A (DODC), IDNNA (IDNNA), methyl-DOB (, 2A N-methyl-DOB), 2,3,4,5-tetramethoxy A (2,3,4,5-tetramethoxy A), 1-(4-bromo-2,3,6,7-tetrahydrofuro[2,3-f][1]benzofuran-8-yl)propan-2-amine (DOB-FLY), and bromo-DragonFLY (DOB-DFLY).

[0152] In some embodiments, the phenethylamine has the following structure: N , R α , R β , and R 2 ~R 6 as taught herein and as commonly understood in the art): [ka] The substituted phenethylamine may have the formula:

[0153] For example, in some embodiments, R N , R α , R β , and R 2~6 are independently hydrogen, deuterium, halogen, C1-C5 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl (independently or R N , a ring closed with nitrogen), C3-C8 cycloalkenyl (independently or R N (in the case of R, the ring is closed with nitrogen), aryl, or heterocyclyl; 3 and R 4 may be taken together to form dioxole (similar to MDMA), furan, tetrahydrofuran, thiophene, pyrrole, pyridine, pyrrolidine, ethylene oxide, ethyleneimine, trimethylene oxide, pyran, piperidine, imidazole, thiazole, dioxane, morpholine, pyrimidine, or may produce a benzene heterocycle; any of which are optionally substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH), -OC(O)H, -OSOOH, -OC(O)NH, and -SONH. In some embodiments, the psychedelic phenethylamine may be provided with an additional R N are independently defined above, with all other substituents as defined above. Furthermore, phenethylamines useful in the practice of this invention also necessarily include any salts, isomers (including structural isomers and stereoisomers, e.g., enantiomers), precursors, prodrugs, metabolites, derivatives, analogs, isotopic substitutions, or variants thereof, or combinations thereof.

[0154] Other phenethylamines and tryptamines useful in the disclosed embodiments will be known in the art (see, e.g., Grob and Grigsby 2021; Luethi and Liechti 2020; Nichols 2016; Glennon 1999). For example, over 300 "novel psychoactive substances" (NPSs) have been increasingly synthesized since the beginning of the 21st century. These substances belong to multiple chemical classes, such as tryptamines, phenethylamines, cathinones, cannabinoids, and piperazines (EMCDDA, 2014). While almost all contemporary research is dominated by a small number of compounds, "classic" psychedelics, such as NPSs (e.g., Winter, 2009), may also have clinical utility when used in the inventive combinations, compositions, and methods according to the present disclosure.

[0155] a. Exemplary 5-HT2 Agents Useful in Embodiments of the Invention In some exemplary embodiments, the 5-HT2 agent is 3-[2-(dimethylamino)ethyl]-1-methylindol-4-ol (1-methylpsilocin), 1-(5-methoxy-1H-indol-3-yl)propan-2-amine (5-MeO-aMTb), 2-(4-bromo-2,3,6,7-tetra-hydrofuro[2,3-f][1]benzofuran-8-yl)ethanamine (2C-B-FLY), (S)-(+)-1-(2-aminopropyl)-8,9-dihydropyrano[3,2-e]indole (AL-37350A), 2-[(3-chlorophenyl)methoxy]-6-(1-piperazinyl)pyrazine (CP 809101), N-allyl-N-[2-(1H-indol-3-yl)ethyl]prop-2-en-1-amine (DALT), 4-bromo-2,5-dimethoxyamphetamine (DOB), 2,5-dimethoxy-4-ethylamphetamine (DOET), 1-(4-hexyl-2,5-dimethoxy-phenyl)propan-2-amine (DOHx), 2,5-dimethoxy-4-ethoxyamphetamine (MEM), 6-chloro- 2-(1-piperazinyl)pyrazine (CPP; MK-212), 4-[2-[[(2-hydroxyphenyl)methyl]amino]ethyl]-2,5-dimethoxybenzonitrile (NBOH-2C-CN), (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine (TCB-2), 8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one (WAY 161503), and any pharmaceutically acceptable salts (e.g., hydrochloride, hydrobromide, fumarate), hydrates, solvates, precursors, prodrugs, metabolites, derivatives, analogs, isotopic substitutes, variants, tautomers, isomers, or stereoisomers thereof (including pure or substantially pure individual enantiomers and enantiomerically enriched mixtures having any enantiomeric excess greater than 0%), or combinations thereof (including all amorphous and polymorphic forms).

[0156] Those skilled in the art will appreciate the ability to determine which other compounds are useful agents in the practice of the disclosed embodiments by reference to the teachings herein in combination with general knowledge in the art, such as by reference to DrugCentral, DrugBank, and other compendia of drug data.

[0157] E. Serotonin 7 (5-HT7) agents In some embodiments, the therapeutic combination will include a serotonin-7 agent. In some embodiments, a "serotonin-7 agent" may refer to a compound that binds to, blocks, activates, inhibits, or affects activity at the serotonin-7 (5-HT7) receptor (e.g., via an allosteric reaction). As used herein, the terms "serotonin-7 receptor" and "5-HT7 receptor" refer to compounds that bind to the 5-HT7 receptor subtype (i.e., HT 7(a) , H.T. 7(b)、 HT 7(d) ), or the 5-HT7 receptor system as a whole. In some embodiments, a 5-HT7 agent acts as a receptor modulator, which alters the function of the receptor to which it binds, and the alteration includes activating the activity of the receptor, inhibiting the activity of the receptor, and either activating or inhibiting the activity of the receptor, depending on the dose administered.

[0158] Many compounds that have affinity for one serotonin receptor subfamily can also bind to serotonin receptors of other subfamilies, or can have affinity for receptors of the serotonin receptor system as a whole. Thus, in some embodiments, the 5-HT7 agent is a compound that also has affinity for another serotonin receptor. In embodiments, the 5-HT7 agent is a phenethylamine or tryptamine disclosed herein as a serotonin receptor agent, and may also have affinity for other serotonin receptor subfamilies in addition to the 5-HT7 receptor. However, the 5-HT7 agent can be selected based on, for example, its potency at the 5-HT7 receptor (e.g., K i or their selectivity for the 5-HT7 receptor subfamily or specific 5-HT7 receptor subtypes (e.g., K to calculate selectivity compared to a given receptor) compared to another receptor system or compared to another serotonin receptor subfamily (e.g., 5-HT2). i It can also be distinguished from other serotonin receptor agents by the agonist activity (determined by comparing the agonist activity values).

[0159] In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K activity of less than 5 nM, less than 10 nM, less than 15 nM, less than 20 nM, less than 25 nM, less than 50 nM, less than 100 nM, or less than 1 μM. i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K activity of less than 50 nM. i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor Ki In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K activity of about 1-5 nM, 5-10 nM, 5-15 nM, 5-20 nM, 5-25 nM, 5-50 nM, 5-100 nM, and 5 nM-1 μM. i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i It has.

[0160] In some embodiments, the 5-HT7 agent is a "selective agent," which may refer to an agent that binds to the 5-HT7 receptor system preferentially over receptors that are not part of the 5-HT7 receptor system. In some embodiments, such selectivity (also referred to herein as "specificity") is expressed as a ratio greater than 1.0. ... i The selectivity (as measured via K) for the 5-HT7 receptor system is greater than 1.0, for example, but not limited to, about 1.1:1, 1.5:1, 2:1, 5:1, 10:1, 15:1, 25:1, 50:1, 100:1, etc., compared to a receptor that is not part of the 5-HT7 receptor system. iSelectivity for 5-HT2 receptors, e.g., 5-HT 2A , 5-HT 2B , and / or 5-HT 2C In embodiments, the K for the 5-HT7 receptor system is greater than 1.0, for example, but not limited to, about 1.1:1, 1.5:1, 2:1, 5:1, 10:1, 15:1, 25:1, 50:1, 100:1, etc. i The selectivity (as K) for the 5-HT1 receptor system is greater than 1.0, for example, but not limited to, about 1.1:1, 1.5:1, 2:1, 5:1, 10:1, 15:1, 25:1, 50:1, 100:1, etc., compared to the 5-HT1 receptor. i The selectivity (as K) relative to the 5-HT2 receptor is greater than 1.0, for example, but not limited to, about 1.1:1, 1.5:1, 2:1, 5:1, 10:1, 15:1, 25:1, 50:1, 100:1, etc. In some embodiments, such selectivity (also referred to herein as "specificity") is expressed as a ratio less than 1.0. In some embodiments, the selectivity (as K) relative to the 5-HT7 receptor system is greater than 1.0, for example, but not limited to, about 1.1:1, 1.5:1, 2:1, 5:1, 10:1, 15:1, 25:1, 50:1, 100:1, etc. In some embodiments, such selectivity (also referred to herein as "specificity") is expressed as a ratio less than 1.0. i The selectivity (as a function of the 5-HT7 receptor system) is less than 1.0, for example, but not limited to, about 0.9:1, 0.8:1, 0.7:1, 0.6:1, 0.5:1, 0.4:1, 0.3:1, 0.2:1, 0.1:1, etc., compared to a receptor that is not part of the 5-HT7 receptor system.

[0161] In some embodiments, the 5-HT7 receptor system (K i The selectivity (as K) for the 5-HT7 receptor system is about 0.5:1 to 500:1 compared to receptors that are not part of the 5-HT7 receptor system. i The selectivity (as K) for the 5-HT7 receptor system is about 0.5:1 to 1:1 compared to receptors that are not part of the 5-HT7 receptor system. i The selectivity (as K) for the 5-HT7 receptor system is about 0.6:1 compared to receptors that are not part of the 5-HT7 receptor system. iThe selectivity (as K) for the 5-HT7 receptor system is about 50:1 to 500:1 compared to receptors that are not part of the 5-HT7 receptor system. i The selectivity (as K) for the 5-HT7 receptor system is about 100:1 to 500:1 compared to receptors that are not part of the 5-HT7 receptor system. i The selectivity (as K) for the 5-HT7 receptor system is about 100:1 to 300:1 compared to receptors that are not part of the 5-HT7 receptor system. i In embodiments, the selectivity (as K) for the 5-HT7 receptor system is about 150:1 to 250:1 compared to receptors that are not part of the 5-HT7 receptor system. i The selectivity (as a 5-HT7 receptor) is approximately 200:1 compared to receptors that are not part of the 5-HT7 receptor system.

[0162] In some embodiments, the 5-HT7 receptor system (K i In some embodiments, the selectivity (as K) for the 5-HT7 receptor system is about 0.5:1 to 500:1 compared to the 5-HT2 receptor. i In some embodiments, the selectivity (as K) for the 5-HT7 receptor system is about 0.5:1 to 1:1 compared to the 5-HT2 receptor. i The selectivity (as K) for the 5-HT7 receptor system is about 0.6:1 compared to the 5-HT2 receptor. i In some embodiments, the selectivity (as K) for the 5-HT7 receptor system is about 50:1 to 500:1 compared to the 5-HT2 receptor. i In some embodiments, the selectivity (as K) for the 5-HT7 receptor system is about 100:1 to 500:1 compared to the 5-HT2 receptor. i In some embodiments, the selectivity (as K) for the 5-HT7 receptor system is about 100:1 to 300:1 compared to the 5-HT2 receptor. i In some embodiments, the selectivity (as K) for the 5-HT7 receptor system is about 150:1 to 250:1 compared to the 5-HT2 receptor.i The selectivity (as a agonist) over the 5-HT2 receptor is approximately 200:1.

[0163] In some embodiments, the serotonin-7 agent is an agonist. Generally, a "serotonin-7 receptor agonist" (or "serotonin-7 agonist," "5-HT7 receptor agonist," or "5-HT7 agonist") is a compound that initiates a biological response upon binding to a serotonin-7 receptor. In some embodiments, the 5-HT7 agonist has high specificity for the 5-HT7 receptor. In some embodiments, the 5-HT7 agonist has low specificity for receptors that are not part of the serotonin-7 receptor system.

[0164] In some embodiments, the serotonin-7 agent is an antagonist. Generally, a "serotonin-7 receptor antagonist" (or "serotonin-7 antagonist," "5-HT7 receptor antagonist," or "5-HT7 antagonist") is a compound that inhibits a biological response upon binding to a serotonin-7 receptor. In some embodiments, the 5-HT7 antagonist has high specificity for the 5-HT7 receptor. In some embodiments, the 5-HT7 antagonist has low specificity for receptors that are not part of the serotonin-7 receptor system.

[0165] In some embodiments, the serotonin-7 agent is an inverse agonist. Generally, a "serotonin-7 receptor inverse agonist" (or "serotonin-7 inverse agonist," "5-HT7 receptor inverse agonist," or "5-HT7 inverse agonist") is a compound that, upon binding to a serotonin-7 receptor, reduces the constitutive activity of the serotonin-7 receptor to a level below its basal state. In some embodiments, the 5-HT7 inverse agonist has high specificity for the 5-HT7 receptor. In some embodiments, the 5-HT7 inverse agonist has low specificity for receptors that are not part of the serotonin-7 receptor system.

[0166] Exemplary 5-HT agents include, but are not limited to, tryptamines (including ergolines and other complex tryptamines), phenylalkylamines, and phenethylamines, such as, but not limited to, 5-HT 2A In certain embodiments, tryptamines (including complex tryptamines such as ergolines) (generally and generally as a chemical class) have a higher relative affinity for 5-HT7 than phenethylamines and other phenylalkylamines (generally and generally as a chemical class), and it will be understood that such a determination can be readily made by one skilled in the art in light of the teachings herein and the general knowledge of those skilled in the art (see, e.g., Ray 2010).

[0167] In some embodiments, exemplary 5-HT7 agents would include (in some embodiments, in order of decreasing preference based on decreasing relative affinity for 5-HT7): tryptamines DMT, 6-F-DMT, 5-MeO-MiPT, LSD, 5-MeO-DMT, 5-MeO-TMT, cis-2a, DPT, 5-MeO-DiPT, psilocin, RR-2b, EMDT, lisuride, DiPT, SS-2c; and phenylalkylamines TMA, 2C-B, 2C-E, and MDA (see also, e.g., Ray 2010).

[0168] a. Exemplary 5-HT7 Agents Useful in Embodiments of the Invention In some embodiments, the 5-HT7 agent is 5-carboxamidotryptamine (5-CT), N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N-(prop-2-en-1-yl)prop-2-en-1-amine (5-MeO-DALT), 5-methoxy-N,N-dimethyl-tryptamine (5-MeO-DMT); other exemplary 5-HT7 agents include N-isopropyl-5-methoxy-N-methyltryptamine (5-MeO-MiPT) (“Moxy”), 3-(3-ethylimidazole- 4-yl)-5-iodo-1H-indole (AGH-107), 3-(3-ethylimidazol-4-yl)-4-fluoro-5-iodo-1H-indole (AGH-192), 1-(1H-indol-3-yl)propan-2-amine (AMT), 7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one (aripiprazole), (2S)-N,N-dimethyl-5-(1,3,5-trimethyl-pyrazol-4-yl)-1,2,3,4 -Tetrahydronaphthalen-2-amine (AS-19), N,N-dimethyl-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenethylamine (E-55888), N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211), (4-[2-(methylthio)phenyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-1-piperazinehexanamide) (LP-44), (6aR,9R)-N,N-diethyl-7-methyl-4,6,6 a,7,8,9-Hexahydroindolo[4,3-fg]quinoline-9-carboxamide (LSD), or a pharmaceutically acceptable salt, hydrate, solvate, precursor, prodrug, metabolite, derivative, analog, isotopically substituted variant, tautomer, isomer, or stereoisomer thereof (including pure or substantially pure individual enantiomers and enantiomerically enriched mixtures having any enantiomeric excess greater than 0%), or combinations thereof (including all amorphous and polymorphic forms).

[0169] In embodiments, the 5-HT7 agent is DMT or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is 6-F-DMT or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is 5-MeO-MiPT or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is LSD or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is 5-MeO-TMT or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is cis-2a or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is 5-MeO-DiPT or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is psilocin or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is RR-2b or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is EMDT or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is lisuride or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is DiPT or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is SS-2c or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is TMA or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is 2C-B or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is 2C-E or a pharmaceutically acceptable salt thereof. In embodiments, the 5-HT7 agent is MDA or a pharmaceutically acceptable salt thereof.

[0170] In embodiments, including some preferred embodiments, the 5-HT7 agent is 5-MeO-DMT or 5-MeO-MiPT, or a pharmaceutically acceptable salt thereof.

[0171] Those skilled in the art will appreciate the ability to determine which other compounds are useful agents in the practice of the disclosed embodiments by reference to the teachings herein in combination with general knowledge in the art, such as by reference to DrugCentral, DrugBank, and other compendia of drug data.

[0172] F. Receptor Selectivity and Modulatory Activity Combinations of agents are provided that exhibit selectivity for receptors that contribute to entactogenic states of mind. In embodiments, imidazoline-1 (I1), 5-HT2, 5-HT7, and CB1 are among the receptors that contribute to the induction of entactogenic states of mind. In embodiments, the agents provided herein are selective for one or more of the I1 receptor, 5-HT2 receptor, 5-HT7 receptor, and CB1 receptor. In embodiments, the combinations provided herein exhibit selectivity for the I1 receptor and one or more of the 5-HT2 receptor, 5-HT7 receptor, and CB1 receptor. In embodiments, the agents provided herein modulate activity at one or more of the I1 receptor, 5-HT2 receptor, 5-HT7 receptor, and CB1 receptor. In embodiments, the combinations provided herein modulate activity at the I1 receptor and one or more of the 5-HT2 receptor, 5-HT7 receptor, and CB1 receptor. In embodiments, the agents provided herein selectively modulate the activity of one or more of the I1 receptor, 5-HT2 receptor, 5-HT7 receptor, and CB1 receptor. In embodiments, the combinations provided herein selectively modulate the activity of one or more of the I1 receptor and the 5-HT2 receptor, 5-HT7 receptor, and CB1 receptor. In some embodiments, the combinations provided herein are therapeutic combinations that induce an entactogenic state of mind.

[0173] Selectivity The therapeutic combinations provided herein may include one or more agents that are selective for one or more targets. The selectivity of an agent for a target, such as a receptor, can be defined in different contexts. In some embodiments, an agent is selective for a receptor if it exhibits the highest relative affinity for said receptor. In some embodiments, an agent is selective for a receptor if it acts exclusively at said receptor. In some embodiments, a selective agent does not exhibit its highest affinity or act exclusively at a target receptor, but instead exhibits relatively greater affinity for one receptor compared to another receptor. In particular, the selectivity of a compound is determined in the context of the assayed target and receptor. In some embodiments, the selectivity of a ligand for its target, such as a receptor, can be expressed as a measure of binding strength called binding affinity. In some embodiments, selectivity is measured using measures of binding available to those skilled in the art, such as the dissociation constant (K D ), coupling constant (K A ), and the inhibition constant (K i In some embodiments, the target receptor is I1, 5-HT2, 5-HT7, or CB1. In some embodiments, the provided therapeutic combinations including an agent, e.g., a selection agent, induce an entactogenic state.

[0174] In some embodiments, selectivity can be assessed by determining the binding affinity, such as the binding affinity, between a ligand, e.g., an agent described herein, and a target, e.g., a receptor, described herein. Methods for determining binding affinity are known to those skilled in the art and include radioligand binding assays (Maguire, 2012; Roth, 2018). Radioligand binding experiments represent a sensitive and quantitative technique for determining affinity, such as the binding affinity, between a compound and a receptor.

[0175] In some embodiments, selectivity can be assessed by determining the inhibition constant of an agent provided herein with a receptor system (e.g., I1, 5-HT2, 5-HT7, or CB1). i) can be written as the concentration at which 50% of a radiolabeled ligand, such as an agonist, is displaced by the test ligand. Thus, the observed IC, as shown in the Cheng-Prusoff equation, is 50 Using K i can be determined: Ki = IC50 / (1 + [R] / Kd) (where IC 50 is the concentration of competitive inhibitor that results in 50% inhibition, R is the concentration of radioligand used in the competitive binding assay, and Kd is the equilibrium dissociation constant of the radioligand in the assay).

[0176] Competitive binding assays or radioligand displacement assays may also be performed according to methods known in the art. i (Toro-Sazo, 2019). In some cases, the substituted radioligand acts as an antagonist, e.g., 5-HT 2A About [ 3 H]ketanserin, 5-HT 2C About [ 3 In some instances, the displaced radioligand can be an agonist, such as 5-HT 2B About [ 3 3H]LSD.

[0177] K i Another example of determining K i Before determining the K, one or more agents are first screened against various receptor systems to determine activity at a given receptor. As described by Glennon et al., compounds are first assayed at 10 μM against each receptor, transporter, or ion channel. Those that induce greater than 50% inhibition are then assayed at 1 nM, 10 nM, 100 nM, 1,000 nM, and 10,000 nM to determine the K. i Then, for each K i Values ​​are calculated from at least three replicate assays (Glennon, 2000).

[0178] In some embodiments, such measures as described herein and other measures known to those of skill in the art are compared to determine relative affinity. A or K D Relative affinities are determined by comparing measures of binding affinity, such as: A indicates weaker binding affinity and a higher K A In some cases, a relatively high K D indicates weaker binding affinity and a lower K D indicates a stronger binding affinity. In some embodiments, the equilibrium inhibition constant (K i ) to determine relative affinity. In some cases, a relatively high K i indicates weaker affinity and a lower K i indicates a stronger affinity.

[0179] In some cases, K values ​​are distributed over several orders of magnitude. i Values ​​can be log-transformed as described by Ray et al. to facilitate comparison, e.g., by calculating pK = -log(K). In such instances, the higher pK i A higher value indicates a higher affinity. In some cases, the log-transformed values ​​can then be normalized. Such normalization of values, including excluding potency so that agents of different potencies can be directly compared, provides the advantage of facilitating comparison. In one example, values ​​are normalized by adjusting the highest pKi value of each drug to a value of 4, and all K values ​​reported as greater than 10,000 are normalized. i Values ​​were set to a value of 0 (Ray, 2010). In some embodiments, relative affinity may be determined by comparing transformed and / or normalized measures described herein. Only values ​​that have undergone the same transformation will be compared when determining relative affinity.

[0180] In embodiments, selective affinity is measured using the "NIMH Psychotropic Drug Screening Program (PDSP)" K, a public domain resource that provides information on the ability of drugs to interact with different molecular targets. iThis can be measured by known methods, including using the PDSP K database (available at the time of application at https: / / pdsp.unc.edu / databases / kidb.php). i The database contains published and internally derived pK values ​​for a large number of drugs and drug candidates in an increasing number of G protein-coupled receptors, ion channels, transporters, and enzymes. i The PDSP internet site also serves as a data warehouse for affinity data, e.g., for different 5-HT receptors, and for such other receptor systems discussed herein. i Commonly used protocols and assays for measuring values ​​are provided.

[0181] In some embodiments, the affinity of an agent for a certain receptor is compared with the affinity of the same agent for a different receptor to determine relative affinity.In some embodiments, the agent provided herein exhibits a relative affinity for one or more target receptors that is at least 1.1 times, for example, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 20 times, at least 30 times, at least 50 times, at least 100 times, at least 200 times, at least 500 times, and values ​​therebetween, when compared with non-target receptors.In some embodiments, the target receptor is I1 receptor, 5-HT2 receptor, 5-HT7 receptor, or CB1 receptor.In some embodiments, an agent that exhibits relatively high selectivity for I1 receptor, 5-HT2 receptor, 5-HT7 receptor, or CB1 receptor is selected for use in the therapeutic combinations described herein.

[0182] In embodiments, the affinity of an agent for a receptor is compared with the affinity of a different agent for the same receptor to determine relative affinity.In embodiments, the agent provided herein exhibits a relative affinity for one or more target receptors that is at least 1.1 times, for example, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 20 times, at least 30 times, at least 50 times, at least 100 times, at least 200 times, at least 500 times, and values ​​therebetween.In embodiments, the target receptor is I1 receptor, 5-HT2 receptor, 5-HT7 receptor, or CB1 receptor (i.e., receptors of I1 receptor system, 5-HT2 receptor system, 5-HT7 receptor system, or CB1 receptor system). In embodiments, agents that exhibit relatively high selectivity for the I1 receptor, the 5-HT2 receptor, the 5-HT7 receptor, or the CB1 receptor (i.e., agents selective for either the I1 receptor system, the 5-HT2 receptor system, the 5-HT7 receptor system, or the CB1 receptor system) are selected for use in the therapeutic combinations described herein.

[0183] In some embodiments, the disclosed entactogenic combinations include agents that are selective or relatively highly selective for one or more of the I1 receptor, 5-HT2 receptor, 5-HT7 receptor, and CB1 receptor (i.e., one or more of the I1 receptor system, 5-HT2 receptor system, 5-HT7 receptor system, and CB1 receptor system). In some embodiments, an agent selective for one or more receptors (or, unless the context indicates otherwise, "receptor system," as similarly described and used interchangeably elsewhere) modulates activity at the receptor (i.e., receptor system). In some embodiments, a therapeutic combination including a selective agent modulates activity at one or more of the receptors, such as the I1 receptor and one or more of the 5-HT2 receptor, 5-HT7 receptor, and CB1 receptor. In some embodiments, affinity measures can be determined by binding assays, such as radioligand binding assays, or binding assays incorporating functional activity, such as measuring the functional response of the system to a drug in the presence of an antagonist, as known to those skilled in the art.

[0184] b. Regulatory activity Provided is a combination of agents that modulate certain receptors to produce therapeutic effects, such as entactogenic mood.In some embodiments, I1, 5-HT2, 5-HT7 and CB1 are one of the receptors that are modulated to produce entactogenic mood.Also provided is the selectivity and efficacy profile of the agents described herein.

[0185] In some embodiments, the agents of the disclosed entactogen combinations modulate the activity of the imidazoline-1 (I1) receptor (I1 receptor system). In some embodiments, the agents of the disclosed entactogen combinations modulate the activity of the cannabinoid-1 (CB1) receptor (CB1 receptor system). In some embodiments, the agents of the disclosed entactogen combinations modulate the activity of the serotonin-2 (5-HT2) receptor and its subtypes (5-HT2 receptor system). In embodiments, the agents of the therapeutic combinations modulate the activity of the serotonin-7 (5-HT7) receptor (5-HT7 receptor system).

[0186] In some embodiments, the agents of the disclosed entactogen combinations modulate the activity of the 5-HT2 receptor and the 5-HT7 receptor. In some embodiments, the agents of the disclosed entactogen combinations modulate the activity of the I1 receptor and the CB1 receptor. In some embodiments, the agents of the disclosed entactogen combinations modulate the activity of the I1 receptor and the 5-HT2 receptor. In some embodiments, the agents of the disclosed entactogen combinations modulate the activity of the I1 receptor and the 5-HT7 receptor. In some embodiments, the agents of the disclosed entactogen combinations modulate the activity of the I1 receptor, the 5-HT2 receptor, and the 5-HT7 receptor. In some embodiments, the agents of the disclosed entactogen combinations modulate the activity of the CB1 receptor and the 5-HT2 receptor. In some embodiments, the agents of the disclosed entactogen combinations modulate the activity of the CB1 receptor and the 5-HT7 receptor. In some embodiments, the agents of the disclosed entactogen combinations modulate the activity of the CB1 receptor, the 5-HT2 receptor, and the 5-HT7 receptor. In some embodiments, the agents of the disclosed entactogenic combinations modulate the activity of the I1 receptor, the CB1 receptor, and the 5-HT2 receptor. In some embodiments, the agents of the disclosed entactogenic combinations modulate the activity of the I1 receptor, the CB1 receptor, and the 5-HT7 receptor. In embodiments, the agents of the therapeutic combinations modulate the activity of the I1 receptor, the CB1 receptor, the 5-HT2 receptor, and the 5-HT7 receptor.

[0187] i. Agonism In some embodiments, modulation comprises agonist activity. In embodiments, modulation comprises partial agonism. In embodiments, modulation comprises inverse agonism. In embodiments, agonism is determined using in vitro techniques such as ligand binding assays, the Furchgott receptor inactivation method, which involves analyzing the concentration-response curves for an agonist before and after partial inactivation of the receptor with an irreversible antagonist; or a comparison method in a functional assay that compares the concentration-response curves of a full agonist and a partial agonist (Strange, 2008).

[0188] In some embodiments, agonists are measured by their "efficacy." As used herein, "efficacy" may refer to the ability of a substance to exert an effect on a receptor and its associated signaling system. The imidazoline-1 receptor may contribute to the regulation of sympathetic activity. In one example, the I1 receptor agonist moxonidine activates I1 receptors in the rostral ventrolateral medulla (RVLM) and reduces sympathetic nervous system activity (Ziegler, 1996). In some examples, imidazoline-1 activity can be determined from electrophysiological recordings of brain cells (Hayar and Guyenet, 2000). The efficacy of the imidazoline-1 agonist monoxide has been described in a norepinephrine release assay (Schafer, 2002). Such efficacy measures are merely exemplary and should not be construed as limiting.

[0189] In some embodiments, receptor activation and efficacy can be determined by evaluating the interaction of components of GPCR (Harrison, 2003). In one example, 5-HT2 receptor activation and GPCR subunit interaction are evaluated using bioluminescence resonance energy transfer (BRET) and compared with serotonin as a benchmark (International Publication No. 2021179091, citing McCorvey, 2020). In another example, CB1-induced [(35)S] GTPγS binding is used to determine the efficacy of different compounds (DeLuca, 2015). Such efficacy measures are illustrative and should not be construed as limiting.

[0190] In embodiments, the efficacy measure may be, for example, a comparison of baseline and a maximum threshold E as the maximal effect of the agonist. max EC as the concentration of agent that induces a response intermediate between 50 K as the ratio of the agonist dissociation constant to the agonist concentration that produces a half-maximal effect in a functional assay obs / EC 50 (K obs refers to the measurement of agonist affinity using ligation binding); and E as a combination parameter max K obs / EC 50 (Strange, 2008). In embodiments, efficacy is assessed by determining activity in a suitable receptor-linked assay system using a range of concentrations of the test substance to generate a concentration / response experiment (Strange, 2008).

[0191] In some embodiments, the agonist, upon binding to the target receptor system, reduces the agonist activity by at least 2.5%, at least 5%, at least 7.5%, at least 10%, at least 12.5%, at least 15%, at least 17.5%, at least 20%, at least 22.5%, at least 25%, at least 27.5%, at least 30%, at least 32.5%, at least 35%, at least 37.5%, at least 40%, at least 42.5%, at least 45%, at least 47.5%, at least 50.5%, at least 52.5%, at least 55%, In some embodiments, the receptor is I1, CB1, 5-HT2, 5-HT7, or a combination thereof, and the maximum efficacy is greater than 0%, including 57.5%, at least 60%, at least 62.5%, at least 65%, at least 67.5%, at least 70%, at least 72.5%, at least 75%, at least 77.5%, at least 80%, at least 82.5%, at least 85%, at least 87.5%, at least 90%, at least 92.5%, at least 95%, at least 97.5%, at least 98%, at least 98.5%, at least 99%, at least 99.5%, at least 99.9%, 100%, and values ​​therebetween. In some embodiments, the receptor is I1, CB1, 5-HT2, 5-HT7, or a combination thereof.

[0192] In some embodiments, the imidazoline-1 agonist, cannabinoid-1 agonist, serotonin-2 agonist, serotonin-7 agonist, or combination thereof, upon binding to the I1 receptor system, the CB1 receptor system, the 5-HT2 receptor system, the 5-HT7 receptor system, or combinations thereof, exhibits an agonistic effect of at least 2.5%, at least 5%, at least 7.5%, at least 10%, at least 12.5%, at least 15%, at least 17.5%, at least 20%, at least 22.5%, at least 25%, at least 27.5%, at least 30%, at least 32.5%, at least 35%, at least 37.5%, at least 40%, at least 42.5%, at least 44%, at least 48%, at least 50%, at least 52%, at least 54%, at least 56%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 82%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 100%, at least 101%, at least 10 refers to a compound having a maximum efficacy of greater than 0%, including 5%, at least 47.5%, at least 50.5%, at least 52.5%, at least 55%, at least 57.5%, at least 60%, at least 62.5%, at least 65%, at least 67.5%, at least 70%, at least 72.5%, at least 75%, at least 77.5%, at least 80%, at least 82.5%, at least 85%, at least 87.5%, at least 90%, at least 92.5%, at least 95%, at least 97.5%, at least 98%, at least 98.5%, at least 99%, at least 99.5%, at least 99.9%, 100%, and values ​​therebetween.

[0193] In embodiments, one or more of the provided agents are partial agonists. In some embodiments, any of the I1 agent, 5-HT2 agent, 5-HT7 agent, and / or CB1 agent can be a partial agonist, i.e., an I1 partial agonist, a 5-HT2 partial agonist, a 5-HT7 partial agonist, and / or a CB1 partial agonist. Unless the context indicates otherwise, "agonist" includes "partial agonist," and therefore, unless expressly or implicitly specified otherwise, an I1 agonist includes an I1 partial agonist, a 5-HT2 agonist includes a 5-HT2 partial agonist, a 5-HT7 agonist includes a 5-HT7 partial agonist, and a CB1 agonist includes a CB1 partial agonist.

[0194] In some embodiments, the disclosed agents are partial agonists, which compounds have an efficacy of less than 99.9%, less than 99.5%, less than 99%, less than 97.5%, less than 95%, less than 92.5%, less than 90%, less than 87.5%, less than 85%, less than 82.5%, less than 80%, less than 77.5%, less than 75%, less than 72.5%, less than 70%, less than 67.5%, less than 65%, less than 62.5%, compared to an agonist with the ability to reach 100% efficacy, such as serotonin as a reference agonist for a serotonin receptor or serotonin receptor system. binds to and activates a given receptor with less than 100% maximum efficacy, including less than 65%, less than 62.5%, less than 60%, less than 57.5%, less than 55%, less than 52.5%, less than 50%, less than 47.5%, less than 45%, less than 42.5%, less than 40%, less than 37.5%, less than 35%, less than 32.5%, less than 30%, less than 27.5%, less than 25%, less than 22.5%, less than 20%, less than 17.5%, less than 15%, less than 12.5%, less than 10%, less than 7.5%, less than 5%, less than 2.5%, or any value in between the recited numbers.

[0195] In some embodiments, the disclosed agents are partial agonists for imidazoline-1, that is, compounds that activate imidazoline-1 with less than 100% maximal efficacy at the I1 receptor.

[0196] In some embodiments, the disclosed agents are partial agonists for cannabinoid-1, that is, the compounds activate cannabinoid-1 with less than 100% maximal efficacy at the CB1 receptor.

[0197] In some embodiments, the disclosed agents are partial agonists for serotonin-2, that is, the compounds activate serotonin-2 with less than 100% maximal efficacy at the 5-HT2 receptor.

[0198] In some embodiments, the disclosed agents are partial agonists for serotonin-7, that is, the compounds activate serotonin-7 with less than 100% maximal efficacy at the 5-HT7 receptor.

[0199] In some embodiments, the disclosed agents are partial agonists for imidazoline-1 and cannabinoid-1, where the compounds activate imidazoline-1 and cannabinoid-1 with less than 100% maximal efficacy at the I1 and CB1 receptors.

[0200] In some embodiments, the disclosed agents are partial agonists for imidazoline-1 and serotonin-2, where the compounds activate imidazoline-1 and serotonin-2 with less than 100% maximal efficacy at the I1 and 5-HT2 receptors.

[0201] In some embodiments, the disclosed agents are partial agonists for imidazoline-1 and serotonin-7, where the compounds activate imidazoline-1 and serotonin-7 with less than 100% maximal efficacy at the I1 receptor and the 5-HT7 receptor.

[0202] In some embodiments, the disclosed agents are partial agonists for cannabinoid-1 and serotonin-2, where the compounds activate cannabinoid-1 and serotonin-2 with less than 100% maximal efficacy at the CB1 receptor and the 5-HT2 receptor.

[0203] In some embodiments, the disclosed agents are partial agonists for cannabinoid-1 and serotonin-7, where the compounds activate cannabinoid-1 and serotonin-7 with less than 100% maximal efficacy at the CB1 receptor and the 5-HT7 receptor.

[0204] In some embodiments, the disclosed agents are partial agonists for serotonin-2 and serotonin-7, where the compounds activate serotonin-2 and serotonin-7 with less than 100% maximal efficacy at 5-HT2 and 5-HT7 receptors.

[0205] In some embodiments, the disclosed agents are partial agonists for imidazoline-1, cannabinoid-1, and serotonin-2, which bind to the I1 receptor, the CB1 receptor, and the 5-HT2 receptor and activate imidazoline-1, cannabinoid-1, and serotonin-2 at these receptors with less than 100% maximal efficacy.

[0206] In some embodiments, the disclosed agents are partial agonists for imidazoline-1, cannabinoid-1, and serotonin-7, which bind to the I1 receptor, the CB1 receptor, and the 5-HT7 receptor and activate imidazoline-1, cannabinoid-1, and serotonin-7 at these receptors with less than 100% maximal efficacy.

[0207] In some embodiments, the disclosed agents are partial agonists for imidazoline-1, serotonin-2, and serotonin-7, which bind to the I1 receptor, the 5-HT2 receptor, and the 5-HT7 receptor and activate imidazoline-1, serotonin-2, and serotonin-7 at these receptors with less than 100% maximal efficacy.

[0208] In some embodiments, the disclosed agents are partial agonists for cannabinoid-1, serotonin-2, and serotonin-7, where the compounds bind to CB1 receptors, 5-HT2 receptors, and 5-HT7 receptors and activate cannabinoid-1, serotonin-2, and serotonin-7 at these receptors with less than 100% maximal efficacy.

[0209] In embodiments, the disclosed agents are partial agonists for imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7, which bind to the I1 receptor, CB1 receptor, 5-HT2 receptor, and 5-HT7 receptor and activate imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7 at these receptors with less than 100% maximal efficacy.

[0210] In some embodiments, one or more of the agents provided herein are inverse agonists.In some embodiments, any of I1 agents, 5-HT2 agents, 5-HT7 agents, and / or CB1 agents can be inverse agonists, i.e., I1 inverse agonists, 5-HT2 inverse agonists, 5-HT7 inverse agonists, and / or CB1 inverse agonists.Unless the context indicates otherwise, "agonist" includes "inverse agonist", and therefore, unless expressly or implicitly specified otherwise, I1 agonists include I1 inverse agonists, 5-HT2 agonists include 5-HT2 inverse agonists, 5-HT7 agonists include 5-HT7 inverse agonists, and CB1 agonists include CB1 inverse agonists.

[0211] In some embodiments, the disclosed agents are inverse agonists for imidazoline-1, which compounds bind to the I1 receptor system and reduce its constitutive activity below its basal activity.

[0212] In some embodiments, the disclosed agents are inverse agonists for cannabinoid-1, which compounds bind to the CB1 receptor system and reduce its constitutive activity below its basal activity.

[0213] In embodiments, the disclosed agents are inverse agonists for serotonin-2, which compounds bind to the 5-HT2 receptor system and reduce its constitutive activity below its basal activity.

[0214] In embodiments, the disclosed agents are inverse agonists for serotonin-7, which compounds bind to the 5-HT7 receptor system and reduce its constitutive activity below its basal activity.

[0215] In some embodiments, the disclosed agents are inverse agonists for imidazoline-1 and cannabinoid-1, which bind to either the I1 and CB1 receptor systems and reduce their constitutive activity below their basal activity.

[0216] In some embodiments, the disclosed agents are inverse agonists for imidazoline-1 and serotonin-2, which bind to either the I1 and 5-HT2 receptor systems and reduce their constitutive activity below their basal activity.

[0217] In some embodiments, the disclosed agents are inverse agonists for imidazoline-1 and serotonin-7, which bind to either the I1 and 5-HT7 receptor systems and reduce their constitutive activity below their basal activity.

[0218] In some embodiments, the disclosed agents are inverse agonists for cannabinoid-1 and serotonin-2, which bind to either the CB1 and 5-HT2 receptor systems and reduce their constitutive activity below their basal activity.

[0219] In some embodiments, the disclosed agents are inverse agonists for cannabinoid-1 and serotonin-7, which bind to either the CB1 and 5-HT7 receptor systems and reduce their constitutive activity below their basal activity.

[0220] In some embodiments, the disclosed agents are inverse agonists for serotonin-2 and serotonin-7, which bind to either the 5-HT2 or 5-HT7 receptor systems and reduce their constitutive activity below their basal activity.

[0221] In some embodiments, the disclosed agents are inverse agonists for imidazoline-1, cannabinoid-1, and serotonin-2, which bind to any of the I1, CB1, and 5-HT2 receptor systems and reduce their constitutive activity below their basal activity.

[0222] In some embodiments, the disclosed agents are inverse agonists for imidazoline-1, cannabinoid-1, and serotonin-7, which bind to any of the I1, CB1, and 5-HT7 receptor systems and reduce their constitutive activity below their basal activity.

[0223] In some embodiments, the disclosed agents are inverse agonists for imidazoline-1, serotonin-2, and serotonin-7, which bind to any of the I1, 5-HT2, and 5-HT7 receptor systems and reduce their constitutive activity below their basal activity.

[0224] In some embodiments, the disclosed agents are inverse agonists for cannabinoid-1, serotonin-2, and serotonin-7, which bind to and reduce the constitutive activity of any of the CB1, 5-HT2, and 5-HT7 receptor systems below their basal activity.

[0225] In some embodiments, the disclosed agents are inverse agonists for imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7, which bind to and reduce the constitutive activity of any of the I1, CB1, 5-HT2, and 5-HT7 receptor systems below their basal activity.

[0226] In some embodiments, the disclosed agents are inverse agonists, which are compounds that bind to a given receptor and reduce its constitutive activity below its basal activity, including reducing its constitutive activity by up to 99.9%, up to 99.5%, up to 99%, up to 97.5%, up to 95%, up to 92.5%, up to 90%, up to 87.5%, up to 85%, up to 82.5%, up to 80%, up to 77.5%, up to 75%, up to 72.5%, up to 70%, up to 67.5%, up to 65%, up to 62.5%, up to This includes decreases of up to 100%, including a large decrease of 65%, up to 62.5%, up to 60%, up to 57.5%, up to 55%, up to 52.5%, up to 50%, up to 47.5%, up to 45%, up to 42.5%, up to 40%, up to 37.5%, up to 35%, up to 32.5%, up to 30%, up to 27.5%, up to 25%, up to 22.5%, up to 20%, up to 17.5%, up to 15%, up to 12.5%, up to 10%, up to 7.5%, up to 5%, up to 2.5%, or any value therebetween.

[0227] In some embodiments, agonists can be distinguished by their selectivity for a given receptor or set of receptors. In such embodiments, the compound is an agonist for at least one desired receptor (i.e., either the I1 receptor, the 5-HT2 receptor, the 5-HT7 receptor, or the CB1 receptor, or a combination thereof) and has a selectivity for at least one desired receptor greater than a ratio of 1.0. That is, a (K i The selectivity ratio of the compound (as measured via) is greater than 1.1:1, greater than 1.5:1, greater than 2:1, greater than 5:1, greater than 10:1, greater than 15:1, greater than 25:1, greater than 50:1, greater than 100:1, etc., compared to a receptor that is not part of at least one desired receptor system.

[0228] ii. Antagonism In some embodiments, one or more of the provided agents are antagonists. The antagonist activity of the disclosed agents can be either reversible or irreversible, and competitive or non-competitive, depending on the mechanism by which the antagonist binds. In some embodiments, an "antagonist" has an IC50 of 50 micromolar or less, 40 micromolar or less, 30 micromolar or less, 20 micromolar or less, 10 micromolar or less, 5 micromolar or less, 2 micromolar or less, 1 micromolar or less, 500 nanomolar or less, 200 nanomolar or less, 100 nanomolar or less, 10 nanomolar or less, and values ​​therebetween. 50 It can also refer to a substance that inhibits receptor binding at

[0229] In some embodiments, an "antagonist" is at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, or more than 100-fold (including values ​​therebetween) selective for the target receptor compared to a receptor that is not part of the target receptor system (as measured by functional or competitive binding assays).

[0230] In some embodiments, any of the I1 agent, 5-HT2 agent, 5-HT7 agent, and / or CB1 agent can be an antagonist, ie, an I1 antagonist, a 5-HT2 antagonist, a 5-HT7 antagonist, and / or a CB1 antagonist.

[0231] In some embodiments, one or more of the agents provided herein are indirect antagonists or physiological antagonists. In some embodiments, an indirect antagonist or physiological antagonist may refer to an agent that produces a biological effect at a receptor and partially or completely blocks, attenuates, i.e., "inhibits" or "attenuates," prevents, or delays the biological effect caused by an agonist bound to a different receptor system. Without being bound by theory, one non-limiting example of such an effect is epinephrine, which increases arterial pressure through vasoconstriction mediated by alpha 1-adrenergic receptor activation. Thus, epinephrine exhibits antihistamine properties and is a physiological antagonist of histamine without physically binding to or "antagonizing" histamine receptors.

[0232] In some embodiments, the disclosed agents are physiological antagonists, which compounds bind to and modulate receptors in a manner that antagonizes the effects of agonists bound to receptor systems useful in the practice of the present invention.

[0233] In some embodiments, the disclosed agents are physiological antagonists of imidazoline-1, which bind to and modulate the receptor in a manner that antagonizes the effects of agonists bound to the I1 receptor system.

[0234] In some embodiments, the disclosed agents are physiological antagonists of cannabinoid-1, which compounds bind to and modulate the receptor in a manner that antagonizes the effects of agonists bound to the CB1 receptor system.

[0235] In some embodiments, the disclosed agents are physiological antagonists of serotonin-2, which compounds bind to and modulate the receptor in a manner that antagonizes the effects of agonists bound to the 5-HT2 receptor system.

[0236] In some embodiments, the disclosed agents are physiological antagonists of serotonin-7, which compounds bind to and modulate the receptor in a manner that antagonizes the effects of agonists bound to the 5-HT7 receptor system.

[0237] In some embodiments, the disclosed agents are physiological antagonists of imidazoline-1 and cannabinoid-1, which bind to and modulate the receptors in a manner that antagonizes the effects of agonists bound to either the I1 and CB1 receptor systems.

[0238] In some embodiments, the disclosed agents are physiological antagonists of imidazoline-1 and serotonin-2, which bind to and modulate the receptors in a manner that antagonizes the effects of agonists bound to either the I1 and 5-HT2 receptor systems.

[0239] In some embodiments, the disclosed agents are physiological antagonists of imidazoline-1 and serotonin-7, which bind to and modulate the receptors in a manner that antagonizes the effects of agonists bound to either the I1 and 5-HT7 receptor systems.

[0240] In some embodiments, the disclosed agents are physiological antagonists of cannabinoid-1 and serotonin-2, which bind to and modulate the receptors in a manner that antagonizes the effects of agonists bound to either the CB1 and 5-HT2 receptor systems.

[0241] In some embodiments, the disclosed agents are physiological antagonists of cannabinoid-1 and serotonin-7, which bind to and modulate the receptors in a manner that antagonizes the effects of agonists bound to either the CB1 and 5-HT7 receptor systems.

[0242] In some embodiments, the disclosed agents are physiological antagonists of serotonin-2 and serotonin-7, which bind to and modulate the receptors in a manner that antagonizes the effects of agonists bound to either the 5-HT2 and 5-HT7 receptor systems.

[0243] In some embodiments, the disclosed agents are physiological antagonists of imidazoline-1, cannabinoid-1, and serotonin-2, which bind to and modulate the receptors in a manner that antagonizes the effects of agonists bound to either the I1, CB1, and 5-HT2 receptor systems.

[0244] In some embodiments, the disclosed agents are physiological antagonists of imidazoline-1, cannabinoid-1, and serotonin-7, which bind to and modulate the receptors in a manner that antagonizes the effects of agonists bound to either the I1, CB1, and 5-HT7 receptor systems.

[0245] In some embodiments, the disclosed agents are physiological antagonists of imidazoline-1, serotonin-2, and serotonin-7, which bind to and modulate the receptors in a manner that antagonizes the effects of agonists bound to either the I1, 5-HT2, and 5-HT7 receptor systems.

[0246] In some embodiments, the disclosed agents are physiological antagonists of cannabinoid-1, serotonin-2, and serotonin-7, which bind to and modulate the receptors in a manner that antagonizes the effects of agonists bound to either the CB1 receptor system, the 5-HT2 receptor system, and the 5-HT7 receptor system.

[0247] In embodiments, the disclosed agents are physiological antagonists of imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7, which bind to and modulate the receptors in a manner that antagonizes the effects of agonists bound to any of the I1, CB1, 5-HT2, and 5-HT7 receptor systems.

[0248] In some embodiments, antagonists can be distinguished by their selectivity for a given receptor or set of receptors. In such embodiments, the compound is an antagonist of at least one desired receptor (i.e., either the I1 receptor, the 5-HT2 receptor, the 5-HT7 receptor, or the CB1 receptor, or a combination thereof) and has a selectivity for at least one desired receptor greater than a ratio of 1.0. That is, a (K i The selectivity ratio of the compound (as measured via) is greater than 1.1:1, greater than 1.5:1, greater than 2:1, greater than 5:1, greater than 10:1, greater than 15:1, greater than 25:1, greater than 50:1, greater than 100:1, etc., compared to a receptor that is not part of at least one desired receptor system.

[0249] iii. Selective agonism In some embodiments, whether a compound is a selective agonist can be determined, for example, in some embodiments, activity or potency (e.g., EC 50 as a selective agonist), and a compound that selectively binds to one receptor and not another may be considered a selective agonist in that respect.

[0250] In some embodiments, the compounds suitable for the invention herein may be selective agonists for at least one of I1, CB1, 5-HT2, and 5-HT7, and the compounds have an EC2 for at least one of I1, CB1, 5-HT2, and 5-HT7 that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween, greater than a receptor that is not part of the I1, CB1, 5-HT2, and 5-HT7 receptor systems, as measured by a binding assay or a functional assay. 50 It has.

[0251] In embodiments, the disclosed agents are selective agonists for I1, and the compounds have an EC50 for I1 as measured by binding or functional assays that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween that are greater than receptors that are not part of the I1 receptor system. 50 It has.

[0252] In embodiments, the disclosed agents are selective agonists for CB1, and the compounds have an EC agonist activity for CB1 as measured by binding or functional assays that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween, that is at least 2-fold, at least 30-fold, at least 500-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween that are greater than receptors that are not part of the CB1 receptor system. 50 It has.

[0253] In embodiments, the disclosed agents are selective agonists for 5-HT2, and the compounds have an EC50 for 5-HT2 as measured by binding or functional assays that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween that are greater than receptors that are not part of the 5-HT2 receptor system. 50 It has.

[0254] In embodiments, the disclosed agents are selective agonists for 5-HT7, and the compounds have an EC50 for 5-HT7 as measured by binding or functional assays that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween that are greater than receptors that are not part of the 5-HT7 receptor system. 50 It has.

[0255] In embodiments, the disclosed agents are selective agonists for imidazoline-1 and cannabinoid-1, and the compounds have an EC50 for imidazoline-1 and cannabinoid-1 that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween that are at least 2-fold, at least 30-fold, at least 50 ... 50 It has.

[0256] In embodiments, the disclosed agents are selective agonists for imidazoline-1 and serotonin-2, and the compounds have an EC50 for imidazoline-1 and serotonin-2 that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween, greater than receptors that are not part of the I1 or 5-HT2 receptor systems, as measured by binding or functional assays. 50 It has.

[0257] In embodiments, the disclosed agents are selective agonists for imidazoline-1 and serotonin-7, and the compounds have an EC50 for imidazoline-1 and serotonin-7 that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween that are at least 2-fold, at least 30-fold, at least 50 ... 50 It has.

[0258] In embodiments, the disclosed agents are selective agonists for cannabinoid-1 and serotonin-2, and the compounds have an EC 2 for cannabinoid-1 and serotonin-2 that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween that are at least 2-fold, at least 30-fold, at least 50 ... 50 It has.

[0259] In embodiments, the disclosed agents are selective agonists for cannabinoid-1 and serotonin-7, and the compounds have an EC 2 O 3 for cannabinoid-1 and serotonin-7 that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween that are at least 2-fold, at least 30-fold, at least 50 ... 50 It has.

[0260] In embodiments, the disclosed agents are selective agonists for serotonin-2 and serotonin-7, and the compounds have an EC50 for serotonin-2 and serotonin-7 as measured by binding or functional assays that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween that are greater than receptors that are not part of the 5-HT2 or 5-HT7 receptor systems. 50 It has.

[0261] In embodiments, the disclosed agents are selective agonists for imidazoline-1, cannabinoid-1, and serotonin-2, and the compounds have an EC50 for imidazoline-1, cannabinoid-1, and serotonin-2 that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween, greater than for receptors that are not part of the I1 receptor system, the CB1 receptor system, or the 5-HT2 receptor system, as measured by binding or functional assays. 50 It has.

[0262] In embodiments, the disclosed agents are selective agonists for imidazoline-1, cannabinoid-1, and serotonin-7, and the compounds have an EC50 for imidazoline-1, cannabinoid-1, and serotonin-7 that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween that are at least 2-fold, at least 30-fold, at least 50 ... 50 It has.

[0263] In embodiments, the disclosed agents are selective agonists for imidazoline-1, serotonin-2, and serotonin-7, and the compounds have affinity for imidazoline-1, serotonin-2, and serotonin-7 as measured by binding or functional assays that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween, greater than for receptors that are not part of the I1, 5-HT2, or 5-HT7 receptor systems.

[0264] In embodiments, the disclosed agents are selective agonists for cannabinoid-1, serotonin-2, and serotonin-7, and the compounds have affinity for cannabinoid-1, serotonin-2, and serotonin-7 as measured by binding or functional assays that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween, greater than for receptors that are not part of the CB1, 5-HT2, or 5-HT7 receptor systems.

[0265] In embodiments, the disclosed agents are selective agonists for imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7, and the compounds have affinity for imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7 as measured by binding or functional assays that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 500-fold, and values ​​therebetween, greater than for receptors that are not part of the I1, CB1, 5-HT2, or 5-HT7 receptor systems.

[0266] In some preferred embodiments, the disclosed agents are selective agonists for imidazoline-1 over alpha-2, and the compounds have an affinity for imidazoline-1 that is at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) greater than for alpha-2 adrenergic receptors. In such embodiments, the I1 agonist may also be selective for at least one of the 5-HT2 receptor system, the 5-HT7 receptor system, and the CB1 receptor system.

[0267] In some preferred embodiments, the disclosed agents are selective agonists for serotonin-2A and serotonin-2C over serotonin-2B, and the compounds have at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) greater affinity for serotonin-2A and serotonin-2C than for serotonin-2B receptors. In such embodiments, the 5-HT2 agonist may also be selective for at least one of the I1, 5-HT7, and CB1 receptor systems.

[0268] iv.Selective antagonism In embodiments, the agents provided herein are selective antagonists. In embodiments, selective antagonists are selective antagonists that inhibit IC2 activity against receptors other than the target receptor. 50 IC at the target receptor at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0269] In embodiments, a compound suitable for the invention herein may be a selective antagonist for at least one of imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7, which compound has an IC for at least one of imidazoline-1, cannabinoid-1, serotonin-2, or serotonin-7 that is at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) greater than a receptor that is not part of the I1, CB1, 5-HT2, and 5-HT7 receptor systems, as measured by a binding assay or a functional assay. 50 It has.

[0270] In embodiments, the disclosed agents are selective antagonists for imidazoline-1, and the compounds have IC 50 IC for imidazoline-1 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0271] In embodiments, the disclosed agents are selective antagonists for serotonin-2, and the compounds have IC 50 IC for serotonin-2 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0272] In embodiments, the disclosed agents are selective antagonists for serotonin-7, and the compounds have IC50 activity against receptors that are not part of the 5-HT7 receptor system. 50IC for serotonin-7 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0273] In embodiments, the disclosed agents are selective antagonists for serotonin-2 and serotonin-7, and the compounds have IC50 activity against receptors that are not part of the 5-HT2 or 5-HT7 receptor systems. 50 IC for serotonin-7 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0274] In embodiments, the disclosed agents are selective antagonists for CB1, and the compounds have IC 50 IC for cannabinoid-1 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0275] In embodiments, the disclosed agents are selective antagonists for I1 and CB1, and the compounds have IC1 activity against receptors that are not part of the I1 or CB1 receptor systems. 50 IC for I1 and CB1 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0276] In embodiments, the disclosed agents are selective antagonists for I1 and 5-HT2, and the compounds have IC2 activity against receptors that are not part of the I1 or 5-HT2 receptor systems.50 IC for I1 and 5-HT2 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0277] In embodiments, the disclosed agents are selective antagonists for I1 and 5-HT7, and the compounds have IC50 activity against receptors that are not part of the I1 or 5-HT7 receptor systems. 50 IC for I1 and 5-HT7 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0278] In embodiments, the disclosed agents are selective antagonists for imidazoline-1, serotonin-2, and serotonin-7, and the compounds have IC50 activity for receptors that are not part of the I1 receptor system, the 5-HT2 receptor system, or the 5-HT7 receptor system. 50 IC for imidazoline-1, serotonin-2, and serotonin-7 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0279] In embodiments, the disclosed agents are selective antagonists of imidazoline-1, cannabinoid-1, and serotonin-2, and the compounds have IC50 activity against receptors that are not part of the I1, CB1, or 5-HT2 receptor systems. 50 IC for imidazoline-1, cannabinoid-1, and serotonin-2 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0280] In embodiments, the disclosed agents are selective antagonists of imidazoline-1, cannabinoid-1, and serotonin-7, and the compounds have IC50 activity against receptors that are not part of the I1 receptor system, the CB1 receptor system, or the 5-HT7 receptor system. 50 IC for imidazoline-1, cannabinoid-1, and serotonin-7 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0281] In embodiments, the disclosed agents are selective antagonists of imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7, and the compounds have IC50 activity for receptors that are not part of the I1 receptor system, the CB1 receptor system, the 5-HT2 receptor system, or the 5-HT7 receptor system. 50 IC for imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0282] In embodiments, the disclosed agents are selective antagonists for CB1 and 5-HT2, and the compounds have IC50 activity against receptors that are not part of the CB1 or 5-HT2 receptor systems. 50 IC for CB1 and 5-HT2 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0283] In embodiments, the disclosed agents are selective antagonists for CB1 and 5-HT7, and the compounds have IC50 activity against receptors that are not part of the CB1 or 5-HT7 receptor systems. 50 IC for CB1 and 5-HT7 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0284] In embodiments, the disclosed agents are selective antagonists of cannabinoid-1, serotonin-2, and serotonin-7, and the compounds have IC50 activity against receptors that are not part of the CB1 receptor system, the 5-HT2 receptor system, or the 5-HT7 receptor system. 50 IC for cannabinoid-1, serotonin-2, and serotonin-7 at least 2-fold (including 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, and values ​​therebetween) lower than 50 It has.

[0285] G. Exemplary Therapeutic Combinations In embodiments, the therapeutic combination of the present invention comprises an I1 agent and a CB1 agent. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist and a CB1 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist and a CB1 antagonist. In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist and a CB1 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist and a CB1 antagonist.

[0286] In embodiments, the therapeutic combination of the present invention comprises an I1 agent and a 5-HT2 agent. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist and a 5-HT2 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist and a 5-HT2 antagonist. In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist and a 5-HT2 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist and a 5-HT2 antagonist.

[0287] In embodiments, the therapeutic combination of the present invention comprises an I1 agent and a 5-HT7 agent. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist and a 5-HT7 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist and a 5-HT7 antagonist. In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist and a 5-HT7 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist and a 5-HT7 antagonist.

[0288] In embodiments, therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, and a 5-HT2 agent. In embodiments, therapeutic combinations of the present invention comprise an I1 agonist, a CB1 agonist, and a 5-HT2 agonist. In embodiments, therapeutic combinations of the present invention comprise an I1 agonist, a CB1 agonist, and a 5-HT2 antagonist. In embodiments, therapeutic combinations of the present invention comprise an I1 agonist, a CB1 antagonist, and a 5-HT2 agonist. In embodiments, therapeutic combinations of the present invention comprise an I1 agonist, a CB1 antagonist, and a 5-HT2 antagonist. In embodiments, therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, and a 5-HT2 agent. In embodiments, therapeutic combinations of the present invention comprise an I1 antagonist, a CB1 agonist, and a 5-HT2 agonist. In an embodiment, a therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, and a 5-HT2 antagonist. In an embodiment, a therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, and a 5-HT2 agonist. In an embodiment, a therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, and a 5-HT2 antagonist.

[0289] In embodiments, therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, and a 5-HT7 agent. In embodiments, therapeutic combinations of the present invention comprise an I1 agonist, a CB1 agonist, and a 5-HT7 agonist. In embodiments, therapeutic combinations of the present invention comprise an I1 agonist, a CB1 agonist, and a 5-HT7 antagonist. In embodiments, therapeutic combinations of the present invention comprise an I1 agonist, a CB1 antagonist, and a 5-HT7 agonist. In embodiments, therapeutic combinations of the present invention comprise an I1 agonist, a CB1 antagonist, and a 5-HT7 antagonist. In embodiments, therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, and a 5-HT7 agent. In embodiments, therapeutic combinations of the present invention comprise an I1 antagonist, a CB1 agonist, and a 5-HT7 agonist. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, and a 5-HT7 antagonist. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, and a 5-HT7 agonist. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, and a 5-HT7 antagonist.

[0290] In embodiments, the therapeutic combination of the present invention comprises an I1 agent, a 5-HT2 agent, and a 5-HT7 agent. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist, a 5-HT2 agonist, and a 5-HT7 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist, a 5-HT2 agonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist, a 5-HT2 antagonist, and a 5-HT7 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist, a 5-HT2 antagonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combination of the present invention comprises an I1 agent, a 5-HT2 agent, and a 5-HT7 agent. In an embodiment, a therapeutic combination of the present invention comprises an I1 antagonist, a 5-HT2 agonist, and a 5-HT7 agonist. In an embodiment, a therapeutic combination of the present invention comprises an I1 antagonist, a 5-HT2 agonist, and a 5-HT7 antagonist. In an embodiment, a therapeutic combination of the present invention comprises an I1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist. In an embodiment, a therapeutic combination of the present invention comprises an I1 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist.

[0291] In embodiments, the therapeutic combination of the present invention comprises an I1 agent, a CB1 agent, a 5-HT2 agent, and a 5-HT7 agent. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 agonist, a 5-HT2 agonist, and a 5-HT7 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 agonist, a 5-HT2 agonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 antagonist, a 5-HT2 agonist, and a 5-HT7 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 antagonist, a 5-HT2 agonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, a 5-HT2 agonist, and a 5-HT7 agonist. In an embodiment, a therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, a 5-HT2 agonist, and a 5-HT7 antagonist. In an embodiment, a therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 agonist. In an embodiment, a therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 antagonist. In an embodiment, a therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, a 5-HT2 agonist, and a 5-HT7 agonist.In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, a 5-HT2 agonist, and a 5-HT7 antagonist. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist.

[0292] In embodiments, the therapeutic combinations of the present invention include an I1 agent and a CB1 agent that are administered together but are not formulated as part of a single pharmaceutical composition. In other embodiments, the therapeutic combinations of the present invention include an I1 agent and a CB1 agent, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention include an I1 agonist and a CB1 agonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention include an I1 agonist and a CB1 antagonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention include an I1 antagonist and a CB1 agonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, a therapeutic combination of the present invention comprises an I1 antagonist and a CB1 antagonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

[0293] In embodiments, the therapeutic combinations of the present invention include an I1 agent and a 5-HT2 agent that are administered together but are not formulated as part of a single pharmaceutical composition. In other embodiments, the therapeutic combinations of the present invention include an I1 agent and a 5-HT2 agent, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention include an I1 agonist and a 5-HT2 agonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention include an I1 agonist and a 5-HT2 antagonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention include an I1 antagonist and a 5-HT2 agonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist and a 5-HT2 antagonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

[0294] In embodiments, the therapeutic combinations of the present invention include an I1 agent and a 5-HT7 agent that are administered together but are not formulated as part of a single pharmaceutical composition. In other embodiments, the therapeutic combinations of the present invention include an I1 agent and a 5-HT7 agent, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention include an I1 agonist and a 5-HT7 agonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention include an I1 agonist and a 5-HT7 antagonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention include an I1 antagonist and a 5-HT7 agonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist and a 5-HT7 antagonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

[0295] In embodiments, the therapeutic combinations of the present invention include an I1 agent, a CB1 agent, and a 5-HT2 agent that are administered together but are not formulated as part of a single pharmaceutical composition. In other embodiments, the therapeutic combinations of the present invention include an I1 agent, a CB1 agent, and a 5-HT2 agent, where the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention include an I1 agonist, a CB1 agonist, and a 5-HT2 agonist, where the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention include an I1 agonist, a CB1 agonist, and a 5-HT2 antagonist, where the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 antagonist, and a 5-HT2 agonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 antagonist, and a 5-HT2 antagonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, and a 5-HT2 agonist, and the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, and a 5-HT2 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, and a 5-HT2 agonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient.In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, and a 5-HT2 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

[0296] In some embodiments, the therapeutic combinations of the present invention include an I1 agent, a CB1 agent, and a 5-HT7 agent that are administered together but are not formulated as part of a single pharmaceutical composition. In other embodiments, the therapeutic combinations of the present invention include an I1 agent, a CB1 agent, and a 5-HT7 agent, where the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the therapeutic combinations of the present invention include an I1 agonist, a CB1 agonist, and a 5-HT7 agonist, where the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the therapeutic combinations of the present invention include an I1 agonist, a CB1 agonist, and a 5-HT7 antagonist, where the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 antagonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 antagonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient.In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

[0297] In embodiments, the therapeutic combinations of the present invention include an I1 agent, a 5-HT2 agent, and a 5-HT7 agent that are administered together but are not formulated as part of a single pharmaceutical composition. In other embodiments, the therapeutic combinations of the present invention include an I1 agent, a 5-HT2 agent, and a 5-HT7 agent, where the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention include an I1 agonist, a 5-HT2 agonist, and a 5-HT7 agonist, where the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention include an I1 agonist, a 5-HT2 agonist, and a 5-HT7 antagonist, where the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 agonist, a 5-HT2 antagonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 agonist, a 5-HT2 antagonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a 5-HT2 agonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a 5-HT2 agonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient.In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

[0298] In embodiments, the therapeutic combinations of the present invention include an I1 agent, a CB1 agent, a 5-HT2 agent, and a 5-HT7 agent that are administered together but are not formulated as part of a single pharmaceutical composition. In other embodiments, the therapeutic combinations of the present invention include an I1 agent, a CB1 agent, a 5-HT2 agent, and a 5-HT7 agent, where the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention include an I1 agonist, a CB1 agonist, a 5-HT2 agonist, and a 5-HT7 agonist, where the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 agonist, a 5-HT2 agonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 antagonist, a 5-HT2 agonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 antagonist, a 5-HT2 agonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient.In an embodiment, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 agonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, a 5-HT2 agonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, a 5-HT2 agonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, a 5-HT2 agonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, a 5-HT2 agonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient.In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

[0299] H. Exemplary Synergistic Combinations In embodiments, "synergistic," "synergistic effects," or "synergy" may refer to a pharmaceutical composition or combination therapy (comprising at least two agents) that, when administered to a subject, results in an effect (either mental, physical, physiological, or a combination thereof) that the patient does not experience when taking one of the at least two agents alone. In embodiments, the effect may be an effect of an entactogenic experience or "mindstate," as defined herein.

[0300] In embodiments, "synergistic" can refer to a pharmaceutical composition or combination therapy that is more effective than the additive effects of any two or more single agents. For example, synergy allows for the effective treatment of a disease using lower amounts (doses) of the individual therapies. This includes lower doses of a first or second pharmaceutical agent ("apparent one-way synergy"), or lower doses of both pharmaceutical agents ("two-way synergy") than would normally be required if either drug were used alone. In effect, lower doses result in reduced toxicity without reduced efficacy. Synergistic effects can further result in improved efficacy, including improved disease avoidance or reduction compared to any single therapy.

[0301] "Synergistic effects" will also be understood to include an increase in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect (including one or more additional therapeutic effects) that is greater than the additive contribution of the components acting alone and / or greater than the contribution of the isolated compounds themselves.

[0302] Numerous methods known to those skilled in the art exist for determining whether there is synergy with respect to a particular effect, i.e., whether the effect of two or more ingredients when mixed together is greater than the sum of the effects of the individual ingredients applied alone, thereby resulting in "1 + 1 > 2." Suitable methods include isobologram (or contour) analysis (Huang et al. 2019) or the Loewe additivity equation (Loewe and Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326). Synergistic effects can also be calculated using methods such as the sigmoid-Emax equation (Holford and Scheiner, 1981, Clin. Pharmacokinet. 6:429-453) and the median effect equation (Chou and Talalay, 1984, Adv. Enzyme Regul. 22:27-55). The corresponding graphs associated with the above-mentioned equations are the concentration-effect curve and the combination index curve, respectively. Each of the equations referenced above can be applied to experimental data to generate corresponding graphs to aid in assessing the effects of drug combinations.

[0303] In embodiments, therapeutic combinations comprising an I1 agent and a CB1 agent will be synergistic or will provide a synergistic effect. That is, in embodiments, the therapeutic combinations will also be "synergistic combinations." In embodiments, therapeutic combinations of the invention comprising an I1 agonist and a CB1 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the invention comprising an I1 agonist and a CB1 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the invention comprising an I1 antagonist and a CB1 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the invention comprising an I1 antagonist and a CB1 antagonist will be synergistic or will provide a synergistic effect.

[0304] In embodiments, therapeutic combinations of the present invention comprising an I1 agent and a 5-HT2 agent will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist and a 5-HT2 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist and a 5-HT2 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist and a 5-HT2 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist and a 5-HT2 antagonist will be synergistic or will provide a synergistic effect.

[0305] In embodiments, therapeutic combinations of the present invention comprising an I1 agent and a 5-HT7 agent will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect.

[0306] In embodiments, therapeutic combinations of the present invention comprising an I1 agent, a CB1 agent, and a 5-HT2 agent will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 agonist, and a 5-HT2 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 agonist, and a 5-HT2 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 antagonist, and a 5-HT2 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 antagonist, and a 5-HT2 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 agonist, and a 5-HT2 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 agonist, and a 5-HT2 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 antagonist, and a 5-HT2 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 antagonist, and a 5-HT2 antagonist will be synergistic or will provide a synergistic effect.

[0307] In embodiments, therapeutic combinations of the present invention comprising an I1 agent, a CB1 agent, and a 5-HT7 agent will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 agonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 agonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 antagonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 antagonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 agonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 agonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 antagonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 antagonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect.

[0308] In embodiments, therapeutic combinations of the present invention comprising an I1 agent, a 5-HT2 agent, and a 5-HT7 agent will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a 5-HT2 agonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a 5-HT2 agonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a 5-HT2 antagonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a 5-HT2 antagonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a 5-HT2 agonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a 5-HT2 agonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect.

[0309] In embodiments, therapeutic combinations of the present invention comprising an I1 agent, a CB1 agent, a 5-HT2 agent, and a 5-HT7 agent will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 agonist, a 5-HT2 agonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 agonist, a 5-HT2 agonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 antagonist, a 5-HT2 agonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 antagonist, a 5-HT2 agonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 agonist, a 5-HT2 agonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect.In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 agonist, a 5-HT2 agonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 antagonist, a 5-HT2 agonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 antagonist, a 5-HT2 agonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist will be synergistic or will provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist will be synergistic or will provide a synergistic effect.

[0310] In embodiments in which MDMA is utilized as an I1 agent, it may be combined with at least one of a CB1 agent, a 5-HT2 agent, and a 5-HT7 agent, and the combination exhibits a synergistic effect. In such embodiments, substantially smaller doses of MDMA may be required to induce the entactogenic state characterized by MDMA, reducing the likelihood of adverse reactions or reducing or delaying the likelihood of loss of therapeutic or entactogenic effect ("loss of magic").

[0311] I. Illustrative Embodiments of the Invention Although many embodiments will be understood by those skilled in the art upon review of the description and claims, several illustrative and non-limiting embodiments are disclosed. In some such exemplary embodiments, "combination" may refer to a "therapeutic combination" in which two or more compounds are administered together, simultaneously, sequentially, or separately. In some such exemplary embodiments, "combination" may refer to a pharmaceutical composition in which two or more compounds are administered together in a single formulation, along with a pharmaceutically acceptable carrier, diluent, or excipient. In some such exemplary embodiments, "combination" may refer to a therapeutic combination or pharmaceutical composition in which any two or more compounds in the combination exhibit synergistic or additive effects. In some such exemplary embodiments, the "combination" may be used in a method of the invention, such as any method disclosed or claimed herein. In some such exemplary embodiments, the "combination" will induce an entactogenic state. Exemplary such embodiments, each of which may be used in other disclosed embodiments of the invention, are as follows:

[0312] In embodiments, the combination includes agmatine and 2-AGE. In embodiments, the combination includes agmatine and A-834,735. In embodiments, the combination includes agmatine and ACEA. In embodiments, the combination includes agmatine and AZ-11713908. In embodiments, the combination includes agmatine and AZD-1940. In embodiments, the combination includes agmatine and CBN. In embodiments, the combination includes agmatine and CP-47497. In embodiments, the combination includes agmatine and CP55940. In embodiments, the combination includes agmatine and HU-210. In embodiments, the combination includes agmatine and JWH-007. In embodiments, the combination includes agmatine and JWH-051. In embodiments, the combination includes agmatine and JWH-146. In embodiments, the combination includes agmatine and JWH-176. In embodiments, the combination includes agmatine and JWH-200. In embodiments, the combination includes agmatine and JWH-398. In embodiments, the combination includes agmatine and Org 28611. In embodiments, the combination includes agmatine and rimonabant. In embodiments, the combination includes agmatine and THC. In embodiments, the combination includes agmatine and WIN 55,212-2. In embodiments, the combination includes agmatine and XLR11. In embodiments, the combination includes agmatine and 1-methylpsilocine. In embodiments, the combination includes agmatine and 2C-B-FLY. In embodiments, the combination includes agmatine and 5-MeO-AMT. In embodiments, the combination includes agmatine and AL-37350A. In embodiments, the combination comprises agmatine and CP 809101. In embodiments, the combination comprises agmatine and DALT. In embodiments, the combination comprises agmatine and DOB. In embodiments, the combination comprises agmatine and DOET. In embodiments, the combination comprises agmatine and DOHx. In embodiments, the combination comprises agmatine and MEM. In embodiments, the combination comprises agmatine and CPP.In embodiments, the combination comprises agmatine and NBOH-2C-CN. In embodiments, the combination comprises agmatine and TCB-2. In embodiments, the combination comprises agmatine and WAY 161503. In embodiments, the combination comprises agmatine and 5-CT. In embodiments, the combination comprises agmatine and 5-MeO-DALT. In embodiments, the combination comprises agmatine and 5-MeO-DMT. In embodiments, the combination comprises agmatine and 5-MeO-MiPT. In embodiments, the combination comprises agmatine and AGH-192. In embodiments, the combination comprises agmatine and AGH-107. In embodiments, the combination comprises agmatine and AMT. In embodiments, the combination comprises agmatine and aripiprazole. In embodiments, the combination comprises agmatine and AS-19. In embodiments, the combination comprises agmatine and E-55888. In embodiments, the combination comprises agmatine and LSD. In embodiments, the combination comprises agmatine and LP-211. In embodiments, the combination comprises agmatine and LP-44.

[0313] In embodiments, the combination includes BDBM50091347 and 2-AGE. In embodiments, the combination includes BDBM50091347 and A-834,735. In embodiments, the combination includes BDBM50091347 and ACEA. In embodiments, the combination includes BDBM50091347 and AZ-11713908. In embodiments, the combination includes BDBM50091347 and AZD-1940. In embodiments, the combination includes BDBM50091347 and CBN. In embodiments, the combination includes BDBM50091347 and CP-47497. In embodiments, the combination includes BDBM50091347 and CP55940. In embodiments, the combination includes BDBM50091347 and HU-210. In embodiments, the combination comprises BDBM50091347 and JWH-007. In embodiments, the combination comprises BDBM50091347 and JWH-051. In embodiments, the combination comprises BDBM50091347 and JWH-146. In embodiments, the combination comprises BDBM50091347 and JWH-176. In embodiments, the combination comprises BDBM50091347 and JWH-200. In embodiments, the combination comprises BDBM50091347 and JWH-398. In embodiments, the combination comprises BDBM50091347 and Org 28611. In embodiments, the combination comprises BDBM50091347 and rimonabant. In embodiments, the combination comprises BDBM50091347 and THC. In embodiments, the combination comprises BDBM50091347 and WIN 55,212-2. In embodiments, the combination comprises BDBM50091347 and XLR11. In embodiments, the combination comprises BDBM50091347 and 1-methylpsilocin. In embodiments, the combination comprises BDBM50091347 and 2C-B-FLY. In embodiments, the combination comprises BDBM50091347 and 5-MeO-AMT. In embodiments, the combination comprises BDBM50091347 and AL-37350A. In embodiments, the combination comprises BDBM50091347 and CP 809101.In embodiments, the combination comprises BDBM50091347 and DALT. In embodiments, the combination comprises BDBM50091347 and DOB. In embodiments, the combination comprises BDBM50091347 and DOET. In embodiments, the combination comprises BDBM50091347 and DOHx. In embodiments, the combination comprises BDBM50091347 and MEM. In embodiments, the combination comprises BDBM50091347 and CPP. In embodiments, the combination comprises BDBM50091347 and NBOH-2C-CN. In embodiments, the combination comprises BDBM50091347 and TCB-2. In embodiments, the combination comprises BDBM50091347 and WAY 161503. In embodiments, the combination comprises BDBM50091347 and 5-CT. In embodiments, the combination comprises BDBM50091347 and 5-MeO-DALT. In embodiments, the combination comprises BDBM50091347 and 5-MeO-DMT. In embodiments, the combination comprises BDBM50091347 and 5-MeO-MiPT. In embodiments, the combination comprises BDBM50091347 and AGH-192. In embodiments, the combination comprises BDBM50091347 and AGH-107. In embodiments, the combination comprises BDBM50091347 and AMT. In embodiments, the combination comprises BDBM50091347 and aripiprazole. In embodiments, the combination comprises BDBM50091347 and AS-19. In embodiments, the combination comprises BDBM50091347 and E-55888. In embodiments, the combination comprises BDBM50091347 and LSD. In embodiments, the combination comprises BDBM50091347 and LP-211. In embodiments, the combination comprises BDBM50091347 and LP-44.

[0314] In embodiments, the combination comprises clonidine and 2-AGE. In embodiments, the combination comprises clonidine and A-834,735. In embodiments, the combination comprises clonidine and ACEA. In embodiments, the combination comprises clonidine and AZ-11713908. In embodiments, the combination comprises clonidine and AZD-1940. In embodiments, the combination comprises clonidine and CBN. In embodiments, the combination comprises clonidine and CP-47497. In embodiments, the combination comprises clonidine and CP55940. In embodiments, the combination comprises clonidine and HU-210. In embodiments, the combination comprises clonidine and JWH-007. In embodiments, the combination comprises clonidine and JWH-051. In embodiments, the combination comprises clonidine and JWH-146. In embodiments, the combination comprises clonidine and JWH-176. In embodiments, the combination comprises clonidine and JWH-200. In embodiments, the combination comprises clonidine and JWH-398. In embodiments, the combination comprises clonidine and Org 28611. In embodiments, the combination comprises clonidine and rimonabant. In embodiments, the combination comprises clonidine and THC. In embodiments, the combination comprises clonidine and WIN 55,212-2. In embodiments, the combination comprises clonidine and XLR11. In embodiments, the combination comprises clonidine and 1-methylpsilocin. In embodiments, the combination comprises clonidine and 2C-B-FLY. In embodiments, the combination comprises clonidine and 5-MeO-AMT. In embodiments, the combination comprises clonidine and AL-37350A. In embodiments, the combination comprises clonidine and CP 809101. In an embodiment, the combination comprises clonidine and DALT. In an embodiment, the combination comprises clonidine and DOB. In an embodiment, the combination comprises clonidine and DOET. In an embodiment, the combination comprises clonidine and DOHx. In an embodiment, the combination comprises clonidine and MEM. In an embodiment, the combination comprises clonidine and CPP.In embodiments, the combination comprises clonidine and NBOH-2C-CN. In embodiments, the combination comprises clonidine and TCB-2. In embodiments, the combination comprises clonidine and WAY 161503. In embodiments, the combination comprises clonidine and 5-CT. In embodiments, the combination comprises clonidine and 5-MeO-DALT. In embodiments, the combination comprises clonidine and 5-MeO-DMT. In embodiments, the combination comprises clonidine and 5-MeO-MiPT. In embodiments, the combination comprises clonidine and AGH-192. In embodiments, the combination comprises clonidine and AGH-107. In embodiments, the combination comprises clonidine and AMT. In embodiments, the combination comprises clonidine and aripiprazole. In embodiments, the combination comprises clonidine and AS-19. In embodiments, the combination comprises clonidine and E-55888. In an embodiment, the combination comprises clonidine and LSD. In an embodiment, the combination comprises clonidine and LP-211. In an embodiment, the combination comprises clonidine and LP-44.

[0315] In embodiments, the combination comprises guanfacine and 2-AGE. In embodiments, the combination comprises guanfacine and A-834,735. In embodiments, the combination comprises guanfacine and ACEA. In embodiments, the combination comprises guanfacine and AZ-11713908. In embodiments, the combination comprises guanfacine and AZD-1940. In embodiments, the combination comprises guanfacine and CBN. In embodiments, the combination comprises guanfacine and CP-47497. In embodiments, the combination comprises guanfacine and CP55940. In embodiments, the combination comprises guanfacine and HU-210. In embodiments, the combination comprises guanfacine and JWH-007. In embodiments, the combination comprises guanfacine and JWH-051. In embodiments, the combination comprises guanfacine and JWH-146. In embodiments, the combination comprises guanfacine and JWH-176. In embodiments, the combination comprises guanfacine and JWH-200. In embodiments, the combination comprises guanfacine and JWH-398. In embodiments, the combination comprises guanfacine and Org 28611. In embodiments, the combination comprises guanfacine and rimonabant. In embodiments, the combination comprises guanfacine and THC. In embodiments, the combination comprises guanfacine and WIN 55,212-2. In embodiments, the combination comprises guanfacine and XLR11. In embodiments, the combination comprises guanfacine and 1-methylpsilocin. In embodiments, the combination comprises guanfacine and 2C-B-FLY. In embodiments, the combination comprises guanfacine and 5-MeO-AMT. In embodiments, the combination comprises guanfacine and AL-37350A. In an embodiment, the combination comprises guanfacine and CP 809101. In an embodiment, the combination comprises guanfacine and DALT. In an embodiment, the combination comprises guanfacine and DOB. In an embodiment, the combination comprises guanfacine and DOET. In an embodiment, the combination comprises guanfacine and DOHx.In embodiments, the combination comprises guanfacine and MEM. In embodiments, the combination comprises guanfacine and CPP. In embodiments, the combination comprises guanfacine and NBOH-2C-CN. In embodiments, the combination comprises guanfacine and TCB-2. In embodiments, the combination comprises guanfacine and WAY 161503. In embodiments, the combination comprises guanfacine and 5-CT. In embodiments, the combination comprises guanfacine and 5-MeO-DALT. In embodiments, the combination comprises guanfacine and 5-MeO-DMT. In embodiments, the combination comprises guanfacine and 5-MeO-MiPT. In embodiments, the combination comprises guanfacine and AGH-192. In embodiments, the combination comprises guanfacine and AGH-107. In embodiments, the combination comprises guanfacine and AMT. In embodiments, the combination comprises guanfacine and aripiprazole. In embodiments, the combination comprises guanfacine and AS-19. In embodiments, the combination comprises guanfacine and E-55888. In embodiments, the combination comprises guanfacine and LSD. In embodiments, the combination comprises guanfacine and LP-211. In embodiments, the combination comprises guanfacine and LP-44.

[0316] In embodiments, the combination includes mCPP and 2-AGE. In embodiments, the combination includes mCPP and A-834,735. In embodiments, the combination includes mCPP and ACEA. In embodiments, the combination includes mCPP and AZ-11713908. In embodiments, the combination includes mCPP and AZD-1940. In embodiments, the combination includes mCPP and CBN. In embodiments, the combination includes mCPP and CP-47497. In embodiments, the combination includes mCPP and CP55940. In embodiments, the combination includes mCPP and HU-210. In embodiments, the combination includes mCPP and JWH-007. In embodiments, the combination includes mCPP and JWH-051. In embodiments, the combination includes mCPP and JWH-146. In embodiments, the combination includes mCPP and JWH-176. In embodiments, the combination includes mCPP and JWH-200. In embodiments, the combination includes mCPP and JWH-398. In embodiments, the combination includes mCPP and Org 28611. In embodiments, the combination includes mCPP and rimonabant. In embodiments, the combination includes mCPP and THC. In embodiments, the combination includes mCPP and WIN 55,212-2. In embodiments, the combination includes mCPP and XLR11. In embodiments, the combination includes mCPP and 1-methylpsilocin. In embodiments, the combination includes mCPP and 2C-B-FLY. In embodiments, the combination includes mCPP and 5-MeO-AMT. In embodiments, the combination includes mCPP and AL-37350A. In embodiments, the combination includes mCPP and CP 809101. In embodiments, the combination comprises mCPP and DALT. In embodiments, the combination comprises mCPP and DOB. In embodiments, the combination comprises mCPP and DOET. In embodiments, the combination comprises mCPP and DOHx. In embodiments, the combination comprises mCPP and MEM. In embodiments, the combination comprises mCPP and CPP. In embodiments, the combination comprises mCPP and NBOH-2C-CN.In embodiments, the combination includes mCPP and TCB-2. In embodiments, the combination includes mCPP and WAY 161503. In embodiments, the combination includes mCPP and 5-CT. In embodiments, the combination includes mCPP and 5-MeO-DALT. In embodiments, the combination includes mCPP and 5-MeO-DMT. In embodiments, the combination includes mCPP and 5-MeO-MiPT. In embodiments, the combination includes mCPP and AGH-192. In embodiments, the combination includes mCPP and AGH-107. In embodiments, the combination includes mCPP and AMT. In embodiments, the combination includes mCPP and aripiprazole. In embodiments, the combination includes mCPP and AS-19. In embodiments, the combination includes mCPP and E-55888. In embodiments, the combination includes mCPP and LSD. In embodiments, the combination comprises mCPP and LP-211. In embodiments, the combination comprises mCPP and LP-44.

[0317] In embodiments, the combination includes MDMA and 2-AGE. In embodiments, the combination includes MDMA and A-834,735. In embodiments, the combination includes MDMA and ACEA. In embodiments, the combination includes MDMA and AZ-11713908. In embodiments, the combination includes MDMA and AZD-1940. In embodiments, the combination includes MDMA and CBN. In embodiments, the combination includes MDMA and CP-47497. In embodiments, the combination includes MDMA and CP55940. In embodiments, the combination includes MDMA and HU-210. In embodiments, the combination includes MDMA and JWH-007. In embodiments, the combination includes MDMA and JWH-051. In embodiments, the combination includes MDMA and JWH-146. In embodiments, the combination includes MDMA and JWH-176. In embodiments, the combination includes MDMA and JWH-200. In embodiments, the combination includes MDMA and JWH-398. In embodiments, the combination includes MDMA and Org 28611. In embodiments, the combination includes MDMA and rimonabant. In embodiments, the combination includes MDMA and THC. In embodiments, the combination includes MDMA and WIN 55,212-2. In embodiments, the combination includes MDMA and XLR11. In embodiments, the combination includes MDMA and 1-methylpsilocin. In embodiments, the combination includes MDMA and 2C-B-FLY. In embodiments, the combination includes MDMA and 5-MeO-AMT. In embodiments, the combination includes MDMA and AL-37350A. In embodiments, the combination includes MDMA and CP 809101. In embodiments, the combination includes MDMA and DALT. In embodiments, the combination comprises MDMA and DOB. In embodiments, the combination comprises MDMA and DOET. In embodiments, the combination comprises MDMA and DOHx. In embodiments, the combination comprises MDMA and MEM. In embodiments, the combination comprises MDMA and CPP. In embodiments, the combination comprises MDMA and NBOH-2C-CN.In embodiments, the combination includes MDMA and TCB-2. In embodiments, the combination includes MDMA and WAY 161503. In embodiments, the combination includes MDMA and 5-CT. In embodiments, the combination includes MDMA and 5-MeO-DALT. In embodiments, the combination includes MDMA and 5-MeO-DMT. In embodiments, the combination includes MDMA and 5-MeO-MiPT. In embodiments, the combination includes MDMA and AGH-192. In embodiments, the combination includes MDMA and AGH-107. In embodiments, the combination includes MDMA and AMT. In embodiments, the combination includes MDMA and aripiprazole. In embodiments, the combination includes MDMA and AS-19. In embodiments, the combination includes MDMA and E-55888. In embodiments, the combination includes MDMA and LSD. In embodiments, the combination includes MDMA and LP-211. In an embodiment, the combination comprises MDMA and LP-44.

[0318] In embodiments, the combination includes memantine and 2-AGE. In embodiments, the combination includes memantine and A-834,735. In embodiments, the combination includes memantine and ACEA. In embodiments, the combination includes memantine and AZ-11713908. In embodiments, the combination includes memantine and AZD-1940. In embodiments, the combination includes memantine and CBN. In embodiments, the combination includes memantine and CP-47497. In embodiments, the combination includes memantine and CP55940. In embodiments, the combination includes memantine and HU-210. In embodiments, the combination includes memantine and JWH-007. In embodiments, the combination includes memantine and JWH-051. In embodiments, the combination includes memantine and JWH-146. In embodiments, the combination includes memantine and JWH-176. In embodiments, the combination comprises memantine and JWH-200. In embodiments, the combination comprises memantine and JWH-398. In embodiments, the combination comprises memantine and Org 28611. In embodiments, the combination comprises memantine and rimonabant. In embodiments, the combination comprises memantine and THC. In embodiments, the combination comprises memantine and WIN 55,212-2. In embodiments, the combination comprises memantine and XLR11. In embodiments, the combination comprises memantine and 1-methylpsilocin. In embodiments, the combination comprises memantine and 2C-B-FLY. In embodiments, the combination comprises memantine and 5-MeO-AMT. In embodiments, the combination comprises memantine and AL-37350A. In embodiments, the combination comprises memantine and CP 809101. In embodiments, the combination comprises memantine and DALT. In embodiments, the combination comprises memantine and DOB. In embodiments, the combination comprises memantine and DOET. In embodiments, the combination comprises memantine and DOHx. In embodiments, the combination comprises memantine and MEM. In embodiments, the combination comprises memantine and CPP.In embodiments, the combination comprises memantine and NBOH-2C—CN. In embodiments, the combination comprises memantine and TCB-2. In embodiments, the combination comprises memantine and WAY 161503. In embodiments, the combination comprises memantine and 5-CT. In embodiments, the combination comprises memantine and 5-MeO-DALT. In embodiments, the combination comprises memantine and 5-MeO-DMT. In embodiments, the combination comprises memantine and 5-MeO-MiPT. In embodiments, the combination comprises memantine and AGH-192. In embodiments, the combination comprises memantine and AGH-107. In embodiments, the combination comprises memantine and AMT. In embodiments, the combination comprises memantine and aripiprazole. In embodiments, the combination comprises memantine and AS-19. In embodiments, the combination comprises memantine and E-55888. In embodiments, the combination comprises memantine and LSD. In embodiments, the combination comprises memantine and LP-211. In embodiments, the combination comprises memantine and LP-44.

[0319] In embodiments, the combination comprises moxonidine and 2-AGE. In embodiments, the combination comprises moxonidine and A-834,735. In embodiments, the combination comprises moxonidine and ACEA. In embodiments, the combination comprises moxonidine and AZ-11713908. In embodiments, the combination comprises moxonidine and AZD-1940. In embodiments, the combination comprises moxonidine and CBN. In embodiments, the combination comprises moxonidine and CP-47497. In embodiments, the combination comprises moxonidine and CP55940. In embodiments, the combination comprises moxonidine and HU-210. In embodiments, the combination comprises moxonidine and JWH-007. In embodiments, the combination comprises moxonidine and JWH-051. In embodiments, the combination comprises moxonidine and JWH-146. In embodiments, the combination comprises moxonidine and JWH-176. In embodiments, the combination comprises moxonidine and JWH-200. In embodiments, the combination comprises moxonidine and JWH-398. In embodiments, the combination comprises moxonidine and Org 28611. In embodiments, the combination comprises moxonidine and rimonabant. In embodiments, the combination comprises moxonidine and THC. In embodiments, the combination comprises moxonidine and WIN 55,212-2. In embodiments, the combination comprises moxonidine and XLR11. In embodiments, the combination comprises moxonidine and 1-methylpsilocin. In embodiments, the combination comprises moxonidine and 2C-B-FLY. In embodiments, the combination comprises moxonidine and 5-MeO-AMT. In embodiments, the combination comprises moxonidine and AL-37350A. In embodiments, the combination comprises moxonidine and CP 809101. In embodiments, the combination comprises moxonidine and DALT. In embodiments, the combination comprises moxonidine and DOB. In embodiments, the combination comprises moxonidine and DOET. In embodiments, the combination comprises moxonidine and DOHx. In embodiments, the combination comprises moxonidine and MEM.In an embodiment, the combination comprises moxonidine and CPP. In an embodiment, the combination comprises moxonidine and NBOH-2C-CN. In an embodiment, the combination comprises moxonidine and TCB-2. In an embodiment, the combination comprises moxonidine and WAY 161503. In an embodiment, the combination comprises moxonidine and 5-CT. In an embodiment, the combination comprises moxonidine and 5-MeO-DALT. In an embodiment, the combination comprises moxonidine and 5-MeO-DMT. In an embodiment, the combination comprises moxonidine and 5-MeO-MiPT. In an embodiment, the combination comprises moxonidine and AGH-192. In an embodiment, the combination comprises moxonidine and AGH-107. In an embodiment, the combination comprises moxonidine and AMT. In an embodiment, the combination comprises moxonidine and aripiprazole. In an embodiment, the combination comprises moxonidine and AS-19. In an embodiment, the combination comprises moxonidine and E-55888. In an embodiment, the combination comprises moxonidine and LSD. In an embodiment, the combination comprises moxonidine and LP-211. In an embodiment, the combination comprises moxonidine and LP-44.

[0320] In embodiments, the combination includes naphazoline and 2-AGE. In embodiments, the combination includes naphazoline and A-834,735. In embodiments, the combination includes naphazoline and ACEA. In embodiments, the combination includes naphazoline and AZ-11713908. In embodiments, the combination includes naphazoline and AZD-1940. In embodiments, the combination includes naphazoline and CBN. In embodiments, the combination includes naphazoline and CP-47497. In embodiments, the combination includes naphazoline and CP55940. In embodiments, the combination includes naphazoline and HU-210. In embodiments, the combination includes naphazoline and JWH-007. In embodiments, the combination includes naphazoline and JWH-051. In embodiments, the combination includes naphazoline and JWH-146. In embodiments, the combination includes naphazoline and JWH-176. In embodiments, the combination includes naphazoline and JWH-200. In embodiments, the combination includes naphazoline and JWH-398. In embodiments, the combination includes naphazoline and Org 28611. In embodiments, the combination includes naphazoline and rimonabant. In embodiments, the combination includes naphazoline and THC. In embodiments, the combination includes naphazoline and WIN 55,212-2. In embodiments, the combination includes naphazoline and XLR11. In embodiments, the combination includes naphazoline and 1-methylpsilocin. In embodiments, the combination includes naphazoline and 2C-B-FLY. In embodiments, the combination includes naphazoline and 5-MeO-AMT. In embodiments, the combination includes naphazoline and AL-37350A. In embodiments, the combination comprises naphazoline and CP 809101. In embodiments, the combination comprises naphazoline and DALT. In embodiments, the combination comprises naphazoline and DOB. In embodiments, the combination comprises naphazoline and DOET. In embodiments, the combination comprises naphazoline and DOHx. In embodiments, the combination comprises naphazoline and MEM.In embodiments, the combination includes naphazoline and CPP. In embodiments, the combination includes naphazoline and NBOH-2C-CN. In embodiments, the combination includes naphazoline and TCB-2. In embodiments, the combination includes naphazoline and WAY 161503. In embodiments, the combination includes naphazoline and 5-CT. In embodiments, the combination includes naphazoline and 5-MeO-DALT. In embodiments, the combination includes naphazoline and 5-MeO-DMT. In embodiments, the combination includes naphazoline and 5-MeO-MiPT. In embodiments, the combination includes naphazoline and AGH-192. In embodiments, the combination includes naphazoline and AGH-107. In embodiments, the combination includes naphazoline and AMT. In embodiments, the combination includes naphazoline and aripiprazole. In embodiments, the combination includes naphazoline and AS-19. In embodiments, the combination includes naphazoline and E-55888. In embodiments, the combination includes naphazoline and LSD. In embodiments, the combination includes naphazoline and LP-211. In embodiments, the combination includes naphazoline and LP-44.

[0321] In embodiments, the combination includes oxymetazoline and 2-AGE. In embodiments, the combination includes oxymetazoline and A-834,735. In embodiments, the combination includes oxymetazoline and ACEA. In embodiments, the combination includes oxymetazoline and AZ-11713908. In embodiments, the combination includes oxymetazoline and AZD-1940. In embodiments, the combination includes oxymetazoline and CBN. In embodiments, the combination includes oxymetazoline and CP-47497. In embodiments, the combination includes oxymetazoline and CP55940. In embodiments, the combination includes oxymetazoline and HU-210. In embodiments, the combination includes oxymetazoline and JWH-007. In embodiments, the combination includes oxymetazoline and JWH-051. In embodiments, the combination includes oxymetazoline and JWH-146. In embodiments, the combination includes oxymetazoline and JWH-176. In embodiments, the combination includes oxymetazoline and JWH-200. In embodiments, the combination includes oxymetazoline and JWH-398. In embodiments, the combination includes oxymetazoline and Org 28611. In embodiments, the combination includes oxymetazoline and rimonabant. In embodiments, the combination includes oxymetazoline and THC. In embodiments, the combination includes oxymetazoline and WIN 55,212-2. In embodiments, the combination includes oxymetazoline and XLR11. In embodiments, the combination includes oxymetazoline and 1-methylpsilocin. In embodiments, the combination includes oxymetazoline and 2C-B-FLY. In embodiments, the combination includes oxymetazoline and 5-MeO-AMT. In embodiments, the combination includes oxymetazoline and AL-37350A. In embodiments, the combination comprises oxymetazoline and CP 809101. In embodiments, the combination comprises oxymetazoline and DALT. In embodiments, the combination comprises oxymetazoline and DOB. In embodiments, the combination comprises oxymetazoline and DOET.In embodiments, the combination includes oxymetazoline and DOHx. In embodiments, the combination includes oxymetazoline and MEM. In embodiments, the combination includes oxymetazoline and CPP. In embodiments, the combination includes oxymetazoline and NBOH-2C-CN. In embodiments, the combination includes oxymetazoline and TCB-2. In embodiments, the combination includes oxymetazoline and WAY 161503. In embodiments, the combination includes oxymetazoline and 5-CT. In embodiments, the combination includes oxymetazoline and 5-MeO-DALT. In embodiments, the combination includes oxymetazoline and 5-MeO-DMT. In embodiments, the combination includes oxymetazoline and 5-MeO-MiPT. In embodiments, the combination includes oxymetazoline and AGH-192. In embodiments, the combination includes oxymetazoline and AGH-107. In embodiments, the combination includes oxymetazoline and AMT. In embodiments, the combination comprises oxymetazoline and aripiprazole. In embodiments, the combination comprises oxymetazoline and AS-19. In embodiments, the combination comprises oxymetazoline and E-55888. In embodiments, the combination comprises oxymetazoline and LSD. In embodiments, the combination comprises oxymetazoline and LP-211. In embodiments, the combination comprises oxymetazoline and LP-44.

[0322] In embodiments, the combination comprises rilmenidine and 2-AGE. In embodiments, the combination comprises rilmenidine and A-834,735. In embodiments, the combination comprises rilmenidine and ACEA. In embodiments, the combination comprises rilmenidine and AZ-11713908. In embodiments, the combination comprises rilmenidine and AZD-1940. In embodiments, the combination comprises rilmenidine and CBN. In embodiments, the combination comprises rilmenidine and CP-47497. In embodiments, the combination comprises rilmenidine and CP55940. In embodiments, the combination comprises rilmenidine and HU-210. In embodiments, the combination comprises rilmenidine and JWH-007. In embodiments, the combination comprises rilmenidine and JWH-051. In embodiments, the combination comprises rilmenidine and JWH-146. In embodiments, the combination comprises rilmenidine and JWH-176. In embodiments, the combination comprises rilmenidine and JWH-200. In embodiments, the combination comprises rilmenidine and JWH-398. In embodiments, the combination comprises rilmenidine and Org 28611. In embodiments, the combination comprises rilmenidine and rimonabant. In embodiments, the combination comprises rilmenidine and THC. In embodiments, the combination comprises rilmenidine and WIN 55,212-2. In embodiments, the combination comprises rilmenidine and XLR11. In embodiments, the combination comprises rilmenidine and 1-methylpsilocin. In embodiments, the combination comprises rilmenidine and 2C-B-FLY. In embodiments, the combination comprises rilmenidine and 5-MeO-AMT. In embodiments, the combination comprises rilmenidine and 37350A. In an embodiment, the combination comprises rilmenidine and CP 809101. In an embodiment, the combination comprises rilmenidine and DALT. In an embodiment, the combination comprises rilmenidine and DOB. In an embodiment, the combination comprises rilmenidine and DOET. In an embodiment, the combination comprises rilmenidine and DOHx. In an embodiment, the combination comprises rilmenidine and MEM.In an embodiment, the combination comprises rilmenidine and CPP. In an embodiment, the combination comprises rilmenidine and NBOH-2C-CN. In an embodiment, the combination comprises rilmenidine and TCB-2. In an embodiment, the combination comprises rilmenidine and WAY 161503. In an embodiment, the combination comprises rilmenidine and 5-CT. In an embodiment, the combination comprises rilmenidine and 5-MeO-DALT. In an embodiment, the combination comprises rilmenidine and 5-MeO-DMT. In an embodiment, the combination comprises rilmenidine and 5-MeO-MiPT. In an embodiment, the combination comprises rilmenidine and AGH-192. In an embodiment, the combination comprises rilmenidine and AGH-107. In an embodiment, the combination comprises rilmenidine and AMT. In an embodiment, the combination comprises rilmenidine and aripiprazole. In an embodiment, the combination comprises rilmenidine and AS-19. In an embodiment, the combination comprises rilmenidine and E-55888. In an embodiment, the combination comprises rilmenidine and LSD. In an embodiment, the combination comprises rilmenidine and LP-211. In an embodiment, the combination comprises rilmenidine and LP-44.

[0323] In embodiments, the combination includes tetrizoline and 2-AGE. In embodiments, the combination includes tetrizoline and A-834,735. In embodiments, the combination includes tetrizoline and ACEA. In embodiments, the combination includes tetrizoline and AZ-11713908. In embodiments, the combination includes tetrizoline and AZD-1940. In embodiments, the combination includes tetrizoline and CBN. In embodiments, the combination includes tetrizoline and CP-47497. In embodiments, the combination includes tetrizoline and CP55940. In embodiments, the combination includes tetrizoline and HU-210. In embodiments, the combination includes tetrizoline and JWH-007. In embodiments, the combination includes tetrizoline and JWH-051. In embodiments, the combination includes tetrizoline and JWH-146. In embodiments, the combination includes tetrizoline and JWH-176. In embodiments, the combination includes tetrizoline and JWH-200. In embodiments, the combination includes tetrizoline and JWH-398. In embodiments, the combination includes tetrizoline and Org 28611. In embodiments, the combination includes tetrizoline and rimonabant. In embodiments, the combination includes tetrizoline and THC. In embodiments, the combination includes tetrizoline and WIN 55,212-2. In embodiments, the combination includes tetrizoline and XLR11. In embodiments, the combination includes tetrizoline and 1-methylpsilocin. In embodiments, the combination includes tetrizoline and 2C-B-FLY. In embodiments, the combination includes tetrizoline and 5-MeO-AMT. In embodiments, the combination includes tetrizoline and AL-37350A. In embodiments, the combination comprises tetrizoline and CP 809101. In embodiments, the combination comprises tetrizoline and DALT. In embodiments, the combination comprises tetrizoline and DOB. In embodiments, the combination comprises tetrizoline and DOET. In embodiments, the combination comprises tetrizoline and DOHx. In embodiments, the combination comprises tetrizoline and MEM.In embodiments, the combination includes tetrizoline and CPP. In embodiments, the combination includes tetrizoline and NBOH-2C-CN. In embodiments, the combination includes tetrizoline and TCB-2. In embodiments, the combination includes tetrizoline and WAY 161503. In embodiments, the combination includes tetrizoline and 5-CT. In embodiments, the combination includes tetrizoline and 5-MeO-DALT. In embodiments, the combination includes tetrizoline and 5-MeO-DMT. In embodiments, the combination includes tetrizoline and 5-MeO-MiPT. In embodiments, the combination includes tetrizoline and AGH-192. In embodiments, the combination includes tetrizoline and AGH-107. In embodiments, the combination includes tetrizoline and AMT. In embodiments, the combination includes tetrizoline and aripiprazole. In embodiments, the combination includes tetrizoline and AS-19. In embodiments, the combination includes tetrizoline and E-55888. In embodiments, the combination includes tetrizoline and LSD. In embodiments, the combination includes tetrizoline and LP-211. In embodiments, the combination includes tetrizoline and LP-44.

[0324] In embodiments, the combination includes tizanidine and 2-AGE. In embodiments, the combination includes tizanidine and A-834,735. In embodiments, the combination includes tizanidine and ACEA. In embodiments, the combination includes tizanidine and AZ-11713908. In embodiments, the combination includes tizanidine and AZD-1940. In embodiments, the combination includes tizanidine and CBN. In embodiments, the combination includes tizanidine and CP-47497. In embodiments, the combination includes tizanidine and CP55940. In embodiments, the combination includes tizanidine and HU-210. In embodiments, the combination includes tizanidine and JWH-007. In embodiments, the combination includes tizanidine and JWH-051. In embodiments, the combination includes tizanidine and JWH-146. In embodiments, the combination includes tizanidine and JWH-176. In embodiments, the combination includes tizanidine and JWH-200. In embodiments, the combination includes tizanidine and JWH-398. In embodiments, the combination includes tizanidine and Org 28611. In embodiments, the combination includes tizanidine and rimonabant. In embodiments, the combination includes tizanidine and THC. In embodiments, the combination includes tizanidine and WIN 55,212-2. In embodiments, the combination includes tizanidine and XLR11. In embodiments, the combination includes tizanidine and 1-methylpsilocin. In embodiments, the combination includes tizanidine and 2C-B-FLY. In embodiments, the combination includes tizanidine and 5-MeO-AMT. In embodiments, the combination includes tizanidine and AL-37350A. In embodiments, the combination comprises tizanidine and CP 809101. In embodiments, the combination comprises tizanidine and DALT. In embodiments, the combination comprises tizanidine and DOB. In embodiments, the combination comprises tizanidine and DOET. In embodiments, the combination comprises tizanidine and DOHx. In embodiments, the combination comprises tizanidine and MEM. In embodiments, the combination comprises tizanidine and CPP.In embodiments, the combination comprises tizanidine and NBOH-2C-CN. In embodiments, the combination comprises tizanidine and TCB-2. In embodiments, the combination comprises tizanidine and WAY 161503. In embodiments, the combination comprises tizanidine and 5-CT. In embodiments, the combination comprises tizanidine and 5-MeO-DALT. In embodiments, the combination comprises tizanidine and 5-MeO-DMT. In embodiments, the combination comprises tizanidine and 5-MeO-MiPT. In embodiments, the combination comprises tizanidine and AGH-192. In embodiments, the combination comprises tizanidine and AGH-107. In embodiments, the combination comprises tizanidine and AMT. In embodiments, the combination comprises tizanidine and aripiprazole. In embodiments, the combination comprises tizanidine and AS-19. In embodiments, the combination comprises tizanidine and E-55888. In embodiments, the combination comprises tizanidine and LSD. In embodiments, the combination comprises tizanidine and LP-211. In embodiments, the combination comprises tizanidine and LP-44.

[0325] In embodiments, the combination comprises tronidine and 2-AGE. In embodiments, the combination comprises tronidine and A-834,735. In embodiments, the combination comprises tronidine and ACEA. In embodiments, the combination comprises tronidine and AZ-11713908. In embodiments, the combination comprises tronidine and AZD-1940. In embodiments, the combination comprises tronidine and CBN. In embodiments, the combination comprises tronidine and CP-47497. In embodiments, the combination comprises tronidine and CP55940. In embodiments, the combination comprises tronidine and HU-210. In embodiments, the combination comprises tronidine and JWH-007. In embodiments, the combination comprises tronidine and JWH-051. In embodiments, the combination comprises tronidine and JWH-146. In embodiments, the combination comprises tronidine and JWH-176. In embodiments, the combination comprises toronidine and JWH-200. In embodiments, the combination comprises toronidine and JWH-398. In embodiments, the combination comprises toronidine and Org 28611. In embodiments, the combination comprises toronidine and rimonabant. In embodiments, the combination comprises toronidine and THC. In embodiments, the combination comprises toronidine and WIN 55,212-2. In embodiments, the combination comprises toronidine and XLR11. In embodiments, the combination comprises toronidine and 1-methylpsilocin. In embodiments, the combination comprises toronidine and 2C-B-FLY. In embodiments, the combination comprises toronidine and 5-MeO-AMT. In embodiments, the combination comprises toronidine and AL-37350A. In embodiments, the combination comprises toronidine and CP 809101. In an embodiment, the combination comprises tronidine and DALT. In an embodiment, the combination comprises tronidine and DOB. In an embodiment, the combination comprises tronidine and DOET. In an embodiment, the combination comprises tronidine and DOHx. In an embodiment, the combination comprises tronidine and MEM. In an embodiment, the combination comprises tronidine and CPP.In an embodiment, the combination comprises tronidine and NBOH-2C-CN. In an embodiment, the combination comprises tronidine and TCB-2. In an embodiment, the combination comprises tronidine and WAY 161503. In an embodiment, the combination comprises tronidine and 5-CT. In an embodiment, the combination comprises tronidine and 5-MeO-DALT. In an embodiment, the combination comprises tronidine and 5-MeO-DMT. In an embodiment, the combination comprises tronidine and 5-MeO-MiPT. In an embodiment, the combination comprises tronidine and AGH-192. In an embodiment, the combination comprises tronidine and AGH-107. In an embodiment, the combination comprises tronidine and AMT. In an embodiment, the combination comprises tronidine and aripiprazole. In an embodiment, the combination comprises tronidine and AS-19. In an embodiment, the combination comprises tronidine and E-55888. In an embodiment, the combination comprises tronidine and LSD. In an embodiment, the combination comprises tronidine and LP-211. In an embodiment, the combination comprises tronidine and LP-44.

[0326] In embodiments, the combination includes agmatine, a CB1 agent, and 1-methylpsilocin. In embodiments, the combination includes agmatine, a CB1 agent, and 2C-B-FLY. In embodiments, the combination includes agmatine, a CB1 agent, and 5-MeO-AMT. In embodiments, the combination includes agmatine, a CB1 agent, and AL-37350A. In embodiments, the combination includes agmatine, a CB1 agent, and CP 809101. In embodiments, the combination includes agmatine, a CB1 agent, and DALT. In embodiments, the combination includes agmatine, a CB1 agent, and DOB. In embodiments, the combination includes agmatine, a CB1 agent, and DOET. In embodiments, the combination includes agmatine, a CB1 agent, and DOHx. In embodiments, the combination includes agmatine, a CB1 agent, and MEM. In embodiments, the combination includes agmatine, a CB1 agent, and a CPP. In embodiments, the combination includes agmatine, a CB1 agent, and NBOH-2C-CN. In embodiments, the combination includes agmatine, a CB1 agent, and TCB-2. In embodiments, the combination includes agmatine, a CB1 agent, and WAY 161503. In embodiments, the combination includes agmatine, a CB1 agent, and 5-CT. In embodiments, the combination includes agmatine, a CB1 agent, and 5-MeO-DALT. In embodiments, the combination includes agmatine, a CB1 agent, and 5-MeO-DMT. In embodiments, the combination includes agmatine, a CB1 agent, and 5-MeO-MiPT. In embodiments, the combination includes agmatine, a CB1 agent, and AGH-192. In embodiments, the combination includes agmatine, a CB1 agent, and AGH-107. In embodiments, the combination includes agmatine, a CB1 agent, and AMT. In embodiments, the combination includes agmatine, a CB1 agent, and aripiprazole. In embodiments, the combination includes agmatine, a CB1 agent, and AS-19. In embodiments, the combination includes agmatine, a CB1 agent, and E-55888. In embodiments, the combination includes agmatine, a CB1 agent, and LSD.In embodiments, the combination comprises agmatine, a CB1 agent, and LP-211. In embodiments, the combination comprises agmatine, a CB1 agent, and LP-44.

[0327] In embodiments, the combination includes BDBM50091347, a CB1 agent, and 1-methylpsilocin. In embodiments, the combination includes BDBM50091347, a CB1 agent, and 2C-B-FLY. In embodiments, the combination includes BDBM50091347, a CB1 agent, and 5-MeO-AMT. In embodiments, the combination includes BDBM50091347, a CB1 agent, and AL-37350A. In embodiments, the combination includes BDBM50091347, a CB1 agent, and CP 809101. In embodiments, the combination includes BDBM50091347, a CB1 agent, and DALT. In embodiments, the combination includes BDBM50091347, a CB1 agent, and DOB. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and DOET. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and DOHx. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and MEM. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and CPP. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and NBOH-2C-CN. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and TCB-2. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and WAY 161503. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and 5-CT. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and 5-MeO-DALT. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and 5-MeO-DMT. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and 5-MeO-MiPT. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and AGH-192. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and AGH-107. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and AMT.In embodiments, the combination includes BDBM50091347, a CB1 agent, and aripiprazole. In embodiments, the combination includes BDBM50091347, a CB1 agent, and AS-19. In embodiments, the combination includes BDBM50091347, a CB1 agent, and E-55888. In embodiments, the combination includes BDBM50091347, a CB1 agent, and LSD. In embodiments, the combination includes BDBM50091347, a CB1 agent, and LP-211. In embodiments, the combination includes BDBM50091347, a CB1 agent, and LP-44.

[0328] In embodiments, the combination comprises clonidine, a CB1 agent, and 1-methylpsilocin. In embodiments, the combination comprises clonidine, a CB1 agent, and 2C-B-FLY. In embodiments, the combination comprises clonidine, a CB1 agent, and 5-MeO-AMT. In embodiments, the combination comprises clonidine, a CB1 agent, and AL-37350A. In embodiments, the combination comprises clonidine, a CB1 agent, and CP 809101. In embodiments, the combination comprises clonidine, a CB1 agent, and DALT. In embodiments, the combination comprises clonidine, a CB1 agent, and DOB. In embodiments, the combination comprises clonidine, a CB1 agent, and DOET. In embodiments, the combination comprises clonidine, a CB1 agent, and DOHx. In embodiments, the combination comprises clonidine, a CB1 agent, and MEM. In embodiments, the combination includes clonidine, a CB1 agent, and a CPP. In embodiments, the combination includes clonidine, a CB1 agent, and NBOH-2C-CN. In embodiments, the combination includes clonidine, a CB1 agent, and TCB-2. In embodiments, the combination includes clonidine, a CB1 agent, and WAY 161503. In embodiments, the combination includes clonidine, a CB1 agent, and 5-CT. In embodiments, the combination includes clonidine, a CB1 agent, and 5-MeO-DALT. In embodiments, the combination includes clonidine, a CB1 agent, and 5-MeO-DMT. In embodiments, the combination includes clonidine, a CB1 agent, and 5-MeO-MiPT. In embodiments, the combination includes clonidine, a CB1 agent, and AGH-192. In embodiments, the combination comprises clonidine, a CB1 agent, and AGH-107. In embodiments, the combination comprises clonidine, a CB1 agent, and AMT. In embodiments, the combination comprises clonidine, a CB1 agent, and aripiprazole. In embodiments, the combination comprises clonidine, a CB1 agent, and AS-19. In embodiments, the combination comprises clonidine, a CB1 agent, and E-55888. In embodiments, the combination comprises clonidine, a CB1 agent, and LSD.In embodiments, the combination comprises clonidine, a CB1 agent, and LP-211.In embodiments, the combination comprises clonidine, a CB1 agent, and LP-44.

[0329] In embodiments, the combination includes guanfacine, a CB1 agent, and 1-methylpsilocin. In embodiments, the combination includes guanfacine, a CB1 agent, and 2C-B-FLY. In embodiments, the combination includes guanfacine, a CB1 agent, and 5-MeO-AMT. In embodiments, the combination includes guanfacine, a CB1 agent, and AL-37350A. In embodiments, the combination includes guanfacine, a CB1 agent, and CP 809101. In embodiments, the combination includes guanfacine, a CB1 agent, and DALT. In embodiments, the combination includes guanfacine, a CB1 agent, and DOB. In embodiments, the combination includes guanfacine, a CB1 agent, and DOET. In embodiments, the combination includes guanfacine, a CB1 agent, and DOHx. In embodiments, the combination includes guanfacine, a CB1 agent, and MEM. In embodiments, the combination includes guanfacine, a CB1 agent, and a CPP. In embodiments, the combination includes guanfacine, a CB1 agent, and NBOH-2C—CN. In embodiments, the combination includes guanfacine, a CB1 agent, and TCB-2. In embodiments, the combination includes guanfacine, a CB1 agent, and WAY 161503. In embodiments, the combination includes guanfacine, a CB1 agent, and 5-CT. In embodiments, the combination includes guanfacine, a CB1 agent, and 5-MeO-DALT. In embodiments, the combination includes guanfacine, a CB1 agent, and 5-MeO-DMT. In embodiments, the combination includes guanfacine, a CB1 agent, and 5-MeO-MiPT. In embodiments, the combination includes guanfacine, a CB1 agent, and AGH-192. In embodiments, the combination includes guanfacine, a CB1 agent, and AGH-107. In embodiments, the combination includes guanfacine, a CB1 agent, and AMT. In embodiments, the combination includes guanfacine, a CB1 agent, and aripiprazole. In embodiments, the combination includes guanfacine, a CB1 agent, and AS-19. In embodiments, the combination includes guanfacine, a CB1 agent, and E-55888.In embodiments, the combination includes guanfacine, a CB1 agent, and LSD. In embodiments, the combination includes guanfacine, a CB1 agent, and LP-211. In embodiments, the combination includes guanfacine, a CB1 agent, and LP-44.

[0330] In embodiments, the combination includes mCPP, a CB1 agent, and 1-methylpsilocin. In embodiments, the combination includes mCPP, a CB1 agent, and 2C-B-FLY. In embodiments, the combination includes mCPP, a CB1 agent, and 5-MeO-AMT. In embodiments, the combination includes mCPP, a CB1 agent, and AL-37350A. In embodiments, the combination includes mCPP, a CB1 agent, and CP 809101. In embodiments, the combination includes mCPP, a CB1 agent, and DALT. In embodiments, the combination includes mCPP, a CB1 agent, and DOB. In embodiments, the combination includes mCPP, a CB1 agent, and DOET. In embodiments, the combination includes mCPP, a CB1 agent, and DOHx. In embodiments, the combination includes mCPP, a CB1 agent, and MEM. In embodiments, the combination includes mCPP, a CB1 agent, and a CPP. In embodiments, the combination includes mCPP, a CB1 agent, and NBOH-2C-CN. In embodiments, the combination includes mCPP, a CB1 agent, and TCB-2. In embodiments, the combination includes mCPP, a CB1 agent, and WAY 161503. In embodiments, the combination includes mCPP, a CB1 agent, and 5-CT. In embodiments, the combination includes mCPP, a CB1 agent, and 5-MeO-DALT. In embodiments, the combination includes mCPP, a CB1 agent, and 5-MeO-DMT. In embodiments, the combination includes mCPP, a CB1 agent, and 5-MeO-MiPT. In embodiments, the combination includes mCPP, a CB1 agent, and AGH-192. In embodiments, the combination includes mCPP, a CB1 agent, and AGH-107. In embodiments, the combination includes mCPP, a CB1 agent, and AMT. In embodiments, the combination includes mCPP, a CB1 agent, and aripiprazole. In embodiments, the combination includes mCPP, a CB1 agent, and AS-19. In embodiments, the combination includes mCPP, a CB1 agent, and E-55888. In embodiments, the combination includes mCPP, a CB1 agent, and LSD. In embodiments, the combination includes mCPP, a CB1 agent, and LP-211.In embodiments, the combination comprises mCPP, a CB1 agent, and LP-44.

[0331] In embodiments, the combination includes MDMA, a CB1 agent, and 1-methylpsilocin. In embodiments, the combination includes MDMA, a CB1 agent, and 2C-B-FLY. In embodiments, the combination includes MDMA, a CB1 agent, and 5-MeO-AMT. In embodiments, the combination includes MDMA, a CB1 agent, and AL-37350A. In embodiments, the combination includes MDMA, a CB1 agent, and CP 809101. In embodiments, the combination includes MDMA, a CB1 agent, and DALT. In embodiments, the combination includes MDMA, a CB1 agent, and DOB. In embodiments, the combination includes MDMA, a CB1 agent, and DOET. In embodiments, the combination includes MDMA, a CB1 agent, and DOHx. In embodiments, the combination includes MDMA, a CB1 agent, and MEM. In embodiments, the combination includes MDMA, a CB1 agent, and CPP. In embodiments, the combination includes MDMA, a CB1 agent, and NBOH-2C—CN. In embodiments, the combination includes MDMA, a CB1 agent, and TCB-2. In embodiments, the combination includes MDMA, a CB1 agent, and WAY 161503. In embodiments, the combination includes MDMA, a CB1 agent, and 5-CT. In embodiments, the combination includes MDMA, a CB1 agent, and 5-MeO-DALT. In embodiments, the combination includes MDMA, a CB1 agent, and 5-MeO-DMT. In embodiments, the combination includes MDMA, a CB1 agent, and 5-MeO-MiPT. In embodiments, the combination includes MDMA, a CB1 agent, and AGH-192. In embodiments, the combination includes MDMA, a CB1 agent, and AGH-107. In embodiments, the combination includes MDMA, a CB1 agent, and AMT. In embodiments, the combination includes MDMA, a CB1 agent, and aripiprazole. In embodiments, the combination includes MDMA, a CB1 agent, and AS-19. In embodiments, the combination includes MDMA, a CB1 agent, and E-55888. In embodiments, the combination includes MDMA, a CB1 agent, and LSD. In embodiments, the combination includes MDMA, a CB1 agent, and LP-211.In an embodiment, the combination comprises MDMA, a CB1 agent, and LP-44.

[0332] In embodiments, the combination includes memantine, a CB1 agent, and 1-methylpsilocin. In embodiments, the combination includes memantine, a CB1 agent, and 2C-B-FLY. In embodiments, the combination includes memantine, a CB1 agent, and 5-MeO-AMT. In embodiments, the combination includes memantine, a CB1 agent, and AL-37350A. In embodiments, the combination includes memantine, a CB1 agent, and CP 809101. In embodiments, the combination includes memantine, a CB1 agent, and DALT. In embodiments, the combination includes memantine, a CB1 agent, and DOB. In embodiments, the combination includes memantine, a CB1 agent, and DOET. In embodiments, the combination includes memantine, a CB1 agent, and DOHx. In embodiments, the combination includes memantine, a CB1 agent, and MEM. In embodiments, the combination includes memantine, a CB1 agent, and a CPP. In embodiments, the combination includes memantine, a CB1 agent, and NBOH-2C—CN. In embodiments, the combination includes memantine, a CB1 agent, and TCB-2. In embodiments, the combination includes memantine, a CB1 agent, and WAY 161503. In embodiments, the combination includes memantine, a CB1 agent, and 5-CT. In embodiments, the combination includes memantine, a CB1 agent, and 5-MeO-DALT. In embodiments, the combination includes memantine, a CB1 agent, and 5-MeO-DMT. In embodiments, the combination includes memantine, a CB1 agent, and 5-MeO-MiPT. In embodiments, the combination includes memantine, a CB1 agent, and AGH-192. In embodiments, the combination includes memantine, a CB1 agent, and AGH-107. In embodiments, the combination includes memantine, a CB1 agent, and AMT. In embodiments, the combination includes memantine, a CB1 agent, and aripiprazole. In embodiments, the combination includes memantine, a CB1 agent, and AS-19. In embodiments, the combination includes memantine, a CB1 agent, and E-55888. In embodiments, the combination includes memantine, a CB1 agent, and LSD.In embodiments, the combination comprises memantine, a CB1 agent, and LP-211. In embodiments, the combination comprises memantine, a CB1 agent, and LP-44.

[0333] In embodiments, the combination includes moxonidine, a CB1 agent, and 1-methylpsilocin. In embodiments, the combination includes moxonidine, a CB1 agent, and 2C-B-FLY. In embodiments, the combination includes moxonidine, a CB1 agent, and 5-MeO-AMT. In embodiments, the combination includes moxonidine, a CB1 agent, and AL-37350A. In embodiments, the combination includes moxonidine, a CB1 agent, and CP 809101. In embodiments, the combination includes moxonidine, a CB1 agent, and DALT. In embodiments, the combination includes moxonidine, a CB1 agent, and DOB. In embodiments, the combination includes moxonidine, a CB1 agent, and DOET. In embodiments, the combination includes moxonidine, a CB1 agent, and DOHx. In embodiments, the combination includes moxonidine, a CB1 agent, and MEM. In embodiments, the combination includes moxonidine, a CB1 agent, and CPP. In embodiments, the combination includes moxonidine, a CB1 agent, and NBOH-2C-CN. In embodiments, the combinat...

Claims

1. Imidazoline-1(I １ ) drugs and 5-HT ７ A therapeutic combination for inducing an entactogenic state of mind comprising:

2. I １ The agent is I １ The therapeutic combination of claim 1 which is an agonist.

3. I １ The agent has an I receptor relative to alpha-2 (α2) adrenergic receptors of at least about 30:

1. １ The therapeutic combination of claim 1 having selectivity for the receptor.

4. I １ 2. The therapeutic combination of claim 1, wherein the agent is agmatine, BDBM50091347, clonidine, guanfacine, mCPP, memantine, moxonidine, naphazoline, oxymetazoline, rilmenidine, tetrizoline, tizanidine, or tolonidine, or a pharma- ceutically acceptable salt thereof.

5. I １ 5. The therapeutic combination of claim 4, wherein the agent is clonidine, moxonidine, or rilmenidine, or a pharma- ceutically acceptable salt thereof.

6. I １ 6. The therapeutic combination of claim 5, wherein the agent is clonidine or a pharma- ceutically acceptable salt thereof.

7. I １ 6. The therapeutic combination of claim 5, wherein the agent is moxonidine or a pharma- ceutically acceptable salt thereof.

8. I １ 6. The therapeutic combination of claim 5, wherein the agent is rilmenidine or a pharma- ceutically acceptable salt thereof.

9. The 5-HT ７ The drug is 5-HT ７ The therapeutic combination of claim 1 which is an agonist.

10. The 5-HT ７ The agent has a 5-HT antagonist activity of less than 10 nM. ７ Receptor K ｉ 2. The therapeutic combination of claim 1, having the formula:

11. The 5-HT ７ The therapeutic combination of claim 1 , wherein the agent is a tryptamine.

12. The 5-HT ７ 12. The therapeutic combination of claim 11, wherein the agent is 5-MeO-DMT or 5-MeO-MiPT, or a pharma- ceutically acceptable salt thereof.

13. The 5-HT ７ 13. The therapeutic combination of claim 12, wherein the agent is 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

14. The 5-HT ７ 13. The therapeutic combination of claim 12, wherein the agent is 5-MeO-MiPT or a pharma- ceutically acceptable salt thereof.

15. 2. The therapeutic combination of claim 1 comprising clonidine, or a pharma- ceutically acceptable salt thereof, and 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

16. 2. The therapeutic combination of claim 1 comprising moxonidine, or a pharma- ceutically acceptable salt thereof, and 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

17. 2. The therapeutic combination of claim 1 comprising rilmenidine, or a pharma- ceutically acceptable salt thereof, and 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

18. 2. The therapeutic combination of claim 1 comprising clonidine, or a pharma- ceutically acceptable salt thereof, and 5-MeO-MiPT, or a pharma- ceutically acceptable salt thereof.

19. 2. The therapeutic combination of claim 1, comprising moxonidine, or a pharma- ceutically acceptable salt thereof, and 5-MeO-MiPT, or a pharma- ceutically acceptable salt thereof.

20. 2. The therapeutic combination of claim 1 comprising rilmenidine, or a pharma- ceutically acceptable salt thereof, and 5-MeO-MiPT, or a pharma- ceutically acceptable salt thereof.

21. 5-HT ２ Agent, CB １ Agent, additional I １ agents, or additional 5-HT ７ 21. The therapeutic combination of any one of claims 1 to 20, further comprising an agent.

22. 5-HT ２ 21. The therapeutic combination of any one of claims 1 to 20, further comprising an agent.

23. The 5-HT ２ The drug is 5-HT ２ 23. The therapeutic combination of claim 22 which is an agonist.

24. The 5-HT ２ 24. The therapeutic combination of claim 23, wherein the agonist is 1-methylpsilocin, 2C-B-FLY, 5-MeO-AMT, AL-37350A, CP 809101, DALT, DOB, DOET, DOHx, MEM, CPP, NBOH-2C-CN, TCB-2, or WAY 161503, or a pharma-ceutically acceptable salt thereof.

25. C.B. １ 21. The therapeutic combination of any one of claims 1 to 20, further comprising an agent.

26. Said CB １ 26. The therapeutic combination of claim 25, wherein the agent is a cannabinoid.

27. Said CB １ 26. The therapeutic combination of claim 25, wherein the agent is 2-AGE, A-834,735, ACEA, AZ-11713908, AZD-1940, CBN, CP-47497, CP55940, HU-210, JWH-007, JWH-051, JWH-146, JWH-176, JWH-200, JWH-398, Org 28611, rimonabant, THC, WIN 55,212-2, XLR11, or a pharma- ceutically acceptable salt thereof.

28. Additional I １ 21. The therapeutic combination of any one of claims 1 to 20, further comprising an agent.

29. The additional I １ The agent is I １ 29. The therapeutic combination of claim 28 which is an agonist.

30. The additional I １ The agent has an I receptor relative to alpha-2 (α2) adrenergic receptors of at least about 30:

1. １ 29. The therapeutic combination of claim 28, which has selectivity for the receptor.

31. The additional I １ 29. The therapeutic combination of claim 28, wherein the agent is agmatine, BDBM50091347, clonidine, guanfacine, mCPP, MDMA, memantine, moxonidine, naphazoline, oxymetazoline, rilmenidine, tetrizoline, tizanidine, or tolonidine, or a pharma- ceutically acceptable salt thereof.

32. The additional I １ 32. The therapeutic combination of claim 31, wherein the agent is clonidine, moxonidine, or rilmenidine, or a pharma- ceutically acceptable salt thereof.

33. Additional 5-HT ７ 21. The therapeutic combination of any one of claims 1 to 20, further comprising an agent.

34. The additional 5-HT ７ The drug is 5-HT ７ 34. The therapeutic combination of claim 33 which is an agonist.

35. The additional 5-HT ７ The agent has a 5-HT antagonist activity of less than 10 nM. ７ Receptor K ｉ 34. The therapeutic combination of claim 33, comprising:

36. The additional 5-HT ７ 34. The therapeutic combination of claim 33, wherein the agent is DMT, 6-F-DMT, 5-MeO-MiPT, LSD, 5-MeO-DMT, 5-MeO-TMT, cis-2a, DPT, 5-MeO-DiPT, psilocin, RR-2b, EMDT, lisuride, DiPT, SS-2c, TMA, 2C-B, 2C-E, or MDA, or a pharma- ceutically acceptable salt thereof.

37. The additional 5-HT ７ 37. The therapeutic combination of claim 36, wherein the agent is 5-MeO-DMT or 5-MeO-MiPT, or a pharma- ceutically acceptable salt thereof.

38. a. 5-HT ２ Agents and CB １ Agent; b. 5-HT ２ Agent and additional I １ Agent; c. 5-HT ２ Agents and additional 5-HT ７ Agent; d. 5-HT ２ Agents and additional 5-HT ２ Agent; e. CB １ Agent and additional I １ Agent; f. CB １ Agents and additional 5-HT ７ agent; or g. CB １ Agents and additional CB １ Agent 21. The therapeutic combination of any one of claims 1 to 20, further comprising:

39. The 5-HT ２ The drug is 5-HT ２ 39. The therapeutic combination of claim 38 which is an agonist.

40. The 5-HT ２ 41. The therapeutic combination of claim 40, wherein the agonist is 1-methylpsilocin, 2C-B-FLY, 5-MeO-AMT, AL-37350A, CP 809101, DALT, DOB, DOET, DOHx, MEM, CPP, NBOH-2C-CN, TCB-2, or WAY 161503, or a pharma- ceutically acceptable salt thereof.

41. The additional 5-HT ２ The drug is 5-HT ２ 39. The therapeutic combination of claim 38 which is an agonist.

42. The additional 5-HT ２ 42. The therapeutic combination of claim 41, wherein the agonist is 1-methylpsilocin, 2C-B-FLY, 5-MeO-AMT, AL-37350A, CP 809101, DALT, DOB, DOET, DOHx, MEM, CPP, NBOH-2C-CN, TCB-2, or WAY 161503, or a pharma- ceutically acceptable salt thereof.

43. Said CB １ 39. The therapeutic combination of claim 38, wherein the agent is a cannabinoid.

44. Said CB １ 39. The therapeutic combination of claim 38, wherein the agent is 2-AGE, A-834,735, ACEA, AZ-11713908, AZD-1940, CBN, CP-47497, CP55940, HU-210, JWH-007, JWH-051, JWH-146, JWH-176, JWH-200, JWH-398, Org 28611, rimonabant, THC, WIN 55,212-2, XLR11, or a pharma- ceutically acceptable salt thereof.

45. The additional CB １ 39. The therapeutic combination of claim 38, wherein the agent is a cannabinoid.

46. The additional CB １ 39. The therapeutic combination of claim 38, wherein the agent is 2-AGE, A-834,735, ACEA, AZ-11713908, AZD-1940, CBN, CP-47497, CP55940, HU-210, JWH-007, JWH-051, JWH-146, JWH-176, JWH-200, JWH-398, Org 28611, rimonabant, THC, WIN 55,212-2, XLR11, or a pharma- ceutically acceptable salt thereof.

47. The additional I １ The agent is I １ 39. The therapeutic combination of claim 38 which is an agonist.

48. The additional I １ The agent has an I receptor relative to alpha-2 (α2) adrenergic receptors of at least about 30:

1. １ 39. The therapeutic combination of claim 38, which has selectivity for the receptor.

49. The additional I １ 39. The therapeutic combination of claim 38, wherein the agent is agmatine, BDBM50091347, clonidine, guanfacine, mCPP, MDMA, memantine, moxonidine, naphazoline, oxymetazoline, rilmenidine, tetrizoline, tizanidine, or tolonidine, or a pharma- ceutically acceptable salt thereof.

50. The additional I １ 80. The therapeutic combination of claim 79, wherein the agent is clonidine, moxonidine, or rilmenidine, or a pharma- ceutically acceptable salt thereof.

51. The additional 5-HT ７ The agent has a 5-HT antagonist activity of less than 10 nM. ７ Receptor K ｉ 39. The therapeutic combination of claim 38, having the formula:

52. The additional 5-HT ７ 39. The therapeutic combination of claim 38, wherein the agent is DMT, 6-F-DMT, 5-MeO-MiPT, LSD, 5-MeO-DMT, 5-MeO-TMT, cis-2a, DPT, 5-MeO-DiPT, psilocin, RR-2b, EMDT, lisuride, DiPT, SS-2c, TMA, 2C-B, 2C-E, or MDA, or a pharma- ceutically acceptable salt thereof.

53. The additional 5-HT ７ 53. The therapeutic combination of claim 52, wherein the agent is 5-MeO-DMT or 5-MeO-MiPT, or a pharma- ceutically acceptable salt thereof.

54. 21. A pharmaceutical composition comprising a therapeutic combination according to any one of claims 1 to 20 and a pharma- ceutically acceptable carrier, diluent, or excipient.

55. 55. The pharmaceutical composition of claim 54, suitable for oral, buccal, sublingual, intranasal, ocular, injectable, subcutaneous, intravenous, or transdermal administration.

56. 55. The pharmaceutical composition of claim 54 provided in unit dosage form.

57. 57. The pharmaceutical composition of claim 56, wherein the unit dosage form is an immediate release formulation, a controlled release formulation, a sustained release formulation, an extended release formulation, or a modified release formulation.

58. 54. A method for inducing an entactogenic state in a subject, comprising administering to the subject a therapeutic combination described in any one of claims 1 to 20 or a pharmaceutical composition described in claim 54.

59. 59. The method of claim 58, wherein the agents of the therapeutic combination of any one of claims 1 to 20 or the pharmaceutical composition of claim 54 are administered simultaneously, separately or sequentially.

60. 60. The method of claim 59, wherein the agents are administered simultaneously.

61. 59. The method of claim 58, wherein the agents are administered separately.

62. 60. The method of claim 58, wherein the agents are administered sequentially.

63. I １ The agent is a 5-HT ７ 63. The method of claim 62, wherein the agent is administered prior to the administration of the agent.

64. The therapeutic combination or composition is １ When the agent is included, the CB １ The agent is a 5-HT ７ 63. The method of claim 62, wherein the agent is administered prior to the administration of the agent.

65. The therapeutic combination or composition is １ When the agent is included, the CB １ The agent is １ 63. The method of claim 62, wherein the agent is administered after the

66. I １ 59. The method of claim 58, wherein the agent is administered orally.

67. The 5-HT ７ 59. The method of claim 58, wherein the agent is administered orally, sublingually, intranasally, or by inhalation.

68. The therapeutic combination or composition is １ When the agent is included, the CB １ 59. The method of claim 58, wherein the agent is administered orally, sublingually, or by inhalation.

69. I １ 59. The method of claim 58, wherein the agent is administered in a dosage of about 0.1 mg to 1.0 mg.

70. The 5-HT ７ 59. The method of claim 58, wherein the agent is administered in a dosage of about 2 mg to 20 mg.

71. 60. The method of claim 58, further comprising administering a therapeutically effective amount of an additional active agent.

72. 72. The method of claim 71, wherein the additional therapeutic agent is an amino acid, an antioxidant, an anti-inflammatory agent, an analgesic, an anti-neuropathic or anti-nociceptive agent, an anti-migraine drug, an anxiolytic, an antidepressant, an antipsychotic, an anti-PTSD drug, a cannabinoid, a dissociative drug, an immunostimulant, an anti-cancer drug, an antiemetic drug, an appetite stimulant, an antiulcer drug, an antihistamine, an antihypertensive drug, an anticonvulsant, an antiepileptic drug, a bronchodilator, a neuroprotectant, an entactogen or empathogen, an entheogen, a psychedelic drug, a monoamine oxidase inhibitor, a tryptamine, a terpene, a phenethylamine, a sedative, a serotonergic drug, a stimulant, a vitamin, an SSRI, an SNRI, an NDRI, a TCA, or a benzodiazepine.

73. The method of claim 58, wherein the entactogen state is an entactogen state similar to MDMA or another known entactogen, and the entactogen state is determined by brain imaging or by measuring levels of one or more neurotransmitters in the subject.

74. The method of claim 58, wherein the entactogen state is a greater entactogen state than MDMA or another known entactogen, and the entactogen state is determined by brain imaging or by measuring levels of one or more neurotransmitters in the subject.

75. The method of claim 58, wherein the greater entactogen state is an expanded or enhanced entactogen state compared to MDMA or another known entactogen, and the entactogen state is determined by brain imaging or by measuring levels of one or more neurotransmitters in the subject.

76. 76. The method of any one of claims 72 to 75, wherein the neurotransmitters are one or more of serotonin, dopamine, norepinephrine, oxytocin, or cortisol.

77. 59. The method of claim 58, which does not produce or reduces the adverse effects of MDMA or another known entactogen.

78. 78. The method of claim 77, wherein the adverse effect is a neurotoxic effect.

79. 79. The method of claim 78, wherein the absence or reduction of neurotoxic effects is determined by in silico, in vitro, or in vivo tests and procedures.

80. 80. The method of claim 79, wherein the absence or reduction of neurotoxic effects is determined by measuring one or more of: a) at least one toxic metabolite of MDMA or at least one toxic metabolite of another entactogen; b) oxidative stress and dopamine system quinones; c) mitochondrial dysfunction; and d) glial cell activation.

81. 81. The method of claim 80, wherein the reduction in neurotoxic effects is at least 5%, 10%, 25%, 50%, 75%, 100%, 150%, or 200% as compared to one or more comparison controls.

82. 55. A method of regulating neurotransmission in a mammal comprising administering to said mammal a therapeutic combination described in any one of claims 1 to 20 or a pharmaceutical composition described in claim 54.

83. The neurotransmission is １ Receptor, 5-HT ２ Receptor, 5-HT ７ Receptor, or CB １ 83. The method of claim 82, which is receptor mediated.

84. 84. The method of claim 83, wherein the mammal is a human.

85. 54. A method of treating a medical condition in a human in need thereof, comprising administering to said human a therapeutic combination according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 54.

86. 86. The method of claim 85, wherein the medical condition is a disorder associated with dysregulation or insufficient functioning of neurotransmission.

87. The disorder is １ Receptor, 5-HT ２ Receptor, 5-HT ７ Receptor, or CB １ 87. The method of claim 86, which is associated with dysregulation or insufficient function of receptor-mediated neurotransmission.

88. 86. The method of claim 85, wherein the medical condition is a CNS disorder.

89. 89. The method of claim 88, wherein the CNS disorder is any of post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, phobic disorder, binge eating disorder, body dysmorphic disorder, alcohol or drug abuse or dependence disorder, substance-related disorder, substance-induced mood disorder, mood disorder associated with another health condition, disruptive behavior disorder, eating disorder, impulse control disorder, obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorder, attachment disorder, dissociative disorder, Alzheimer's disease, ataxia, Huntington's disease, Parkinson's disease, motor neuron disease, multiple system atrophy, progressive supranuclear palsy, migraine, cluster headache, short-lasting unilateral neuralgiform headache, fibromyalgia, traumatic brain injury, and mild traumatic brain injury (mTBI).

90. 89. The method of claim 88, wherein the CNS disorder is a disorder associated with inflexible thinking patterns.

91. 91. The method of claim 90, wherein the disorder associated with inflexible thinking patterns is anxiety, depression, an addiction, an eating disorder, an alcohol or drug abuse or dependence disorder, OCD, or PTSD.

92. 92. The method of claim 89 or 91, wherein the depression is MDD or TRD.

93. 92. The method of claim 89 or 91, wherein the anxiety is GAD.

94. 54. A method for improving mental health or function in a human, comprising identifying a human in need of said improvement and administering to said human a therapeutic combination of any one of claims 1 to 20 or a pharmaceutical composition of claim 54.

95. 95. The method of claim 94, wherein said improvement in mental health or mental function is a decrease in neuroticism or psychological defensiveness, an increase in creativity or openness to experience, an increase in decision-making ability, an increase in the ability to fall asleep or stay asleep, an increase in wellness or satisfaction, an increase in the ability to forgive oneself or others, an increase in the ability to experience or contemplate pain, including psychological pain, or an increase in the ability to "get in touch with oneself", including during and during daily life and activities.

96. 96. The method of claim 95, wherein the increase in creativity is an increase in deliberate cognitive creativity, deliberate emotional creativity, spontaneous cognitive creativity, or spontaneous emotional creativity.

97. 54. A method of reducing symptoms of a CNS disorder in a human, comprising identifying a human in need of said reduction and administering to said human a therapeutic combination of any one of claims 1 to 20 or a pharmaceutical composition of claim 54.

98. 1. A therapeutic combination for inducing an entactogenic state, comprising: a. a therapeutic combination according to any one of claims 1 to 53; or b.I １ Agents, as well as 5-HT ２ Agents, 5-HT ７ Agents, and CB １ One or more of the agents A therapeutic combination comprising:

99. 99. A pharmaceutical composition comprising a therapeutic combination according to any one of claims 1 to 53 and 98, and a pharma- ceutically acceptable carrier, diluent, or excipient.

100. 100. The pharmaceutical composition of claim 99, suitable for oral, buccal, sublingual, intranasal, ocular, injectable, subcutaneous, intravenous, or transdermal administration.

101. 101. The pharmaceutical composition of claim 99 or 100 provided in unit dosage form.

102. 102. The pharmaceutical composition of claim 101, wherein the unit dosage form is an immediate release formulation, a controlled release formulation, a sustained release formulation, an extended release formulation, or a modified release formulation.

103. A method for inducing an entactogenic state in a subject, comprising administering to the subject a therapeutic combination or pharmaceutical composition described in any one of claims 1 to 57 and 98 to 102.

104. 103. A method of modulating neurotransmission in a mammal comprising administering to said mammal a therapeutic combination or a pharmaceutical composition according to any one of claims 1 to 57 and 98 to 102.

105. 103. A method of treating a medical condition in a human in need thereof, comprising administering to said human a therapeutic combination or pharmaceutical composition according to any one of claims 1 to 57 and 98 to 102.

106. A method for improving mental health or function in a human, comprising identifying a human in need of said improvement and administering to said human a therapeutic combination or pharmaceutical composition described in any one of claims 1-57 and 98-102.

107. A method of reducing symptoms of a CNS disorder in a human, comprising identifying a human in need of said reduction and administering to said human a therapeutic combination or pharmaceutical composition described in any one of claims 1-57 and 98-102.

108. 108. The method of any one of claims 58-97 and 103-107, wherein the pharmaceutical composition or therapeutic combination is administered in conjunction with psychotherapy.

109. 109. The method of any one of claims 58-97 and 103-108, wherein the pharmaceutical composition or therapeutic combination is administered in conjunction with psychological support.

110. 110. The method of any one of claims 58-97 and 103-109, wherein the pharmaceutical composition or therapeutic combination is administered in conjunction with patient monitoring.

111. 111. The method of any one of claims 58-97 and 103-110, wherein the pharmaceutical composition or therapeutic combination is administered in conjunction with the performance of a therapeutically beneficial activity by the patient.

112. 112. The method of any one of claims 58-97 and 103-111, wherein the pharmaceutical composition or therapeutic combination is administered without psychotherapy or psychological support.

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