Therapeutic combinations, compositions and methods for designing and producing enhanced human intimacy mental status

Abstract

Disclosed are therapeutic combinations for eliciting an enhanced human intimacy mental state, such as by using a composition comprising an imidazoline receptor agent, a cannabinoid receptor agent and / or a serotonin receptor agent. Also disclosed are certain selective receptor agents, pharmaceutical compositions thereof, and methods for their use in treating mental health conditions, improving mental health and mental function, and designing and generating mental states or mental states enhancing human intimacy.

Description

[0001] Thomas S. Ray, Mindstate Design Labs

[0002] Cross-references

[0003] Priority is claimed under PCT Section 8(1) and Rule 4.10 to U.S. Provisional Application No. 63 / 318,369, filed on March 9, 2022, and is incorporated by reference for all purposes as if fully set forth herein. Technical Field

[0004] The present disclosure relates to producing a psychological state that enhances interpersonal intimacy through the use of therapeutic combinations, such as a combination of imidazoline receptor agents, cannabinoid receptor agents, and / or serotonin receptor agents. Background Art

[0005] 3,4-Methylenedioxymethamphetamine (MDMA), a member of a class of drugs known as empathy enhancers or interpersonal bonding enhancers, is a promising treatment option for mental health conditions such as PTSD (Mitchell, 2021). Clinical studies have shown that MDMA has rapid and long-lasting therapeutic effects when combined with psychotherapy.

[0006] MDMA is also known to have multiple adverse physiological effects, making it contraindicated in certain populations (Oeri, 2020). MDMA and its metabolites may also pose safety risks related to toxicity (Kalant, 2001). Furthermore, MDMA has tolerance-inducing properties, resulting in a partial or complete loss of its interpersonal bonding effects ("loss of the mojo") in many people, hindering repeat use.

[0007] Therefore, there is a need for a treatment option that provides the bonding effects of MDMA and the long-lasting therapeutic benefits upon administration without the adverse effects and health risks associated with MDMA and other bonding agents. There is a need for such treatment options for mental health conditions to generally improve health and function and, more broadly, promote human flourishing. Disclosed herein are therapeutic combinations, pharmaceutical compositions, and methods for their use that address these needs, with additional advantages that will become apparent from the disclosure below.

[0008] Incorporated by Reference

[0009] Each patent, publication, and non-patent document cited or listed in the "References" section is incorporated herein by reference in its entirety as if individually cited and fully set forth herein. However, when such references are made, and whether to patents, publications, non-patent documents, or other sources of information, their general purpose is to provide a context for discussing the features of the disclosed invention. Accordingly, they should not be construed as an admission that the documents or information are prior art in any jurisdiction or form part of the common general knowledge in the art. Summary of the Invention

[0010] The following presents a brief summary of some embodiments of the present invention to provide a basic understanding thereof. This is not a comprehensive overview of the disclosure, nor is it intended to identify key or important elements of the disclosure or to describe the scope thereof. Its sole purpose is to present some embodiments in a simplified form as a prelude to the more detailed description that is provided later.

[0011] In a first aspect, a therapeutic combination for inducing a state of mind that enhances interpersonal intimacy is provided, comprising an imidazoline-1 (I1) agent and a 5-HT7 agent.

[0012] In some embodiments, the I1 agent is an I1 agonist. In some embodiments, the I1 agent has a selectivity for I1 receptors compared to its selectivity for α2 (alpha-2) adrenergic receptors of at least about 30:1. In some embodiments, the I1 agent is agmatine, BDBM50091347, clonidine, guanfacine, mCPP, memantine, moxonidine, naphazoline, oxymetazoline, rilmenidine, tetryzoline, 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.

[0013] 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 iLess than 10 nM. In some embodiments, the 5-HT7 agent is a 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.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] 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-methylpsilocybin, 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.

[0018] 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.

[0019] In some embodiments, the therapeutic combination further comprises an additional I agent. In some embodiments, the additional I agent is an I agonist. In some embodiments, the additional I agent has a selectivity for I receptors compared to its selectivity for α2 (alpha-2) adrenergic receptors of at least about 30:1. In some embodiments, the additional I agent is agmatine, BDBM50091347, clonidine, guanfacine, mCPP, MDMA, memantine, moxonidine, naphazoline, oxymetazoline, rilmenidine, tetrahydrozoline, tizanidine, or tolonidine, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional I agent is clonidine, moxonidine, or rilmenidine, or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the therapeutic combination further comprises an additional 5-HT7 agent. In some embodiments, the additional 5-HT7 agent is a 5-HT7 agonist. In some embodiments, the 5-HT7 receptor K of the additional 5-HT7 agent is i Less than 10 nM. 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, psilocybin, 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.

[0021] 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.

[0022] In some embodiments wherein 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-methylpsilocybin, 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.

[0023] In some embodiments wherein 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, 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, Org28611, 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.

[0024] In some embodiments wherein 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 I1 receptors compared to its selectivity for α2 (alpha-2) adrenergic receptors of at least about 30:1. In embodiments, the additional I1 agent is agmatine, BDBM50091347, clonidine, guanfacine, mCPP, memantine, moxonidine, naphazoline, oxymetazoline, rilmenidine, tetrahydrozoline, 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.

[0025] In some embodiments wherein 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 5-HT7 receptor K i Less than 10 nM. 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, psilocybin, RR-2b, EMDT, lisuride, DiPT, SS-2c, TMA, 2C-B, 2C-E, or MDA, or a pharmaceutically acceptable salt thereof. In an embodiment, the additional 5-HT7 agent is 5-MeO-DMT or 5-MeO-MiPT, or a pharmaceutically acceptable salt thereof.

[0026] In another aspect, a pharmaceutical composition is provided, comprising the 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, controlled release, sustained release, extended release, or modified release formulation.

[0027] In another aspect, provided is a method of inducing a state of mind in a subject that enhances interpersonal intimacy, the method comprising administering to the subject the therapeutic combination or pharmaceutical composition according to any one of the preceding embodiments.

[0028] 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.

[0029] 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 wherein the therapeutic combination or composition comprises a CB1 agent, the CB1 agent is administered orally, sublingually, or by inhalation.

[0030] In some embodiments, the I1 agent is administered at a dose of about 0.1 mg to 1.0 mg.

[0031] In embodiments, the 5-HT7 agent is administered at a dose of about 2 mg to 20 mg.

[0032] In some embodiments, the method further comprises administering a therapeutically effective amount of an additional active agent. In some embodiments, the additional therapeutic agent is an amino acid, an antioxidant, an anti-inflammatory agent, an analgesic, an anti-neuropathy or anti-nociceptive agent, an anti-migraine agent, an anxiolytic agent, an anti-depressant, an antipsychotic agent, an anti-PTSD agent, a cannabinoid, a dissociative agent, an immunostimulant, an anti-cancer agent, an antiemetic, an appetite-inducing agent, an anti-ulcer agent, an antihistamine, an antihypertensive agent, an anticonvulsant, an anti-epileptic agent, a bronchodilator, a neuroprotective agent, an interpersonal bonding agent or empathy enhancer, a religious hallucinogen, a hallucinogen, a monoamine oxidase inhibitor, a tryptamine, a terpene, a phenylethylamine, a sedative, a serotonergic agent, a stimulant, a vitamin, an SSRI, a SNRI, an NDRI, a TCA, or a benzodiazepine.

[0033] In some embodiments, the interpersonal intimacy-enhancing state of mind is a similar interpersonal intimacy-enhancing state of mind to that of MDMA or another known interpersonal intimacy-enhancing agent, wherein the interpersonal intimacy-enhancing state of mind is determined by brain imaging or by measuring the levels of one or more neurotransmitters in the subject. In some embodiments, the interpersonal intimacy-enhancing state of mind is a better interpersonal intimacy-enhancing state of mind than that of MDMA or another known interpersonal intimacy-enhancing agent, wherein the interpersonal intimacy-enhancing state of mind is determined by brain imaging or by measuring the levels of one or more neurotransmitters in the subject. In some embodiments, the better interpersonal intimacy-enhancing state of mind is an extended interpersonal intimacy-enhancing state of mind or an enhanced interpersonal intimacy-enhancing state of mind when compared to MDMA or another known interpersonal intimacy-enhancing agent, wherein the interpersonal intimacy-enhancing state of mind is determined by brain imaging or by measuring the levels of one or more neurotransmitters in the subject. In some embodiments, the neurotransmitter is one or more of: serotonin, dopamine, norepinephrine, oxytocin, or cortisol.

[0034] In some embodiments, the methods produce no adverse effects of MDMA or another known intimacy enhancer, or produce reduced adverse effects of MDMA or another known intimacy enhancer. In some embodiments, the adverse effect is a neurotoxic effect. In some embodiments, the absence or reduction of neurotoxic effects is determined by computer simulations, 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 the following: a) at least one toxic metabolite of MDMA or at least one toxic metabolite of another intimacy enhancer; b) oxidative stress and dopamine-based quinones; c) mitochondrial dysfunction; and d) glial cell activation. In some embodiments, the reduction in neurotoxic effects is at least 5%, 10%, 25%, 50%, 75%, 100%, 150%, or 200% relative to one or more comparators.

[0035] Also provided is a method for modulating neurotransmission in a mammal, the method comprising administering to the mammal a therapeutic combination or pharmaceutical composition according to any of the preceding embodiments. In some embodiments, the neurotransmission is mediated by an I1 receptor, a 5-HT2 receptor, a 5-HT7 receptor, or a CB1 receptor. In some embodiments, the mammal is a human.

[0036] In another aspect, there is provided a method of treating a medical condition in a human in need of such treatment, said method comprising administering to said human a therapeutic combination or pharmaceutical composition according to any one of the preceding embodiments.

[0037] In some embodiments, the medical condition is a disorder associated with dysregulation or insufficiency of neurotransmission. In some embodiments, the disorder is associated with dysregulation or insufficiency of neurotransmission mediated by: an I1 receptor, a 5-HT2 receptor, a 5-HT7 receptor, or a CB1 receptor.

[0038] In some embodiments, the medical condition is a CNS disorder. In some embodiments, the CNS disorder is any one 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 disorder, phobia, indulgence 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, In some embodiments, the CNS disorder is a disorder associated with a rigid thought pattern. In some embodiments, the disorder associated with a rigid thought pattern is an anxiety disorder, 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, the anxiety disorder is GAD.

[0039] In another aspect, a method of improving a person's mental health or functioning comprises identifying a person in need of such improvement and administering to the person a therapeutic combination or pharmaceutical composition according to any of the preceding embodiments. In some embodiments, the improvement in mental health or functioning is a decrease in neuroticism or psychological defensiveness, an increase in creativity or openness to experience, an improvement in decision-making ability, an improvement in the ability to fall asleep or stay asleep, an increase in well-being or contentment, an improvement in the ability to forgive oneself or others, an improvement in the ability to experience or consider pain, including mental pain, or an improvement in the ability to "get in touch with the inside," including in and during daily life and activities. In some embodiments, the improvement in creativity is an increase in intentional cognitive creativity, intentional emotional creativity, spontaneous cognitive creativity, or spontaneous emotional creativity.

[0040] In another aspect, there is provided a method of reducing symptoms of a CNS disorder in a human, the method comprising identifying a human in need of such reduction, and administering to the human a therapeutic combination or pharmaceutical composition of the present disclosure.

[0041] In another aspect, a pharmaceutical composition is provided, comprising the therapeutic combination according to any one 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, controlled release, sustained release, extended release, or modified release formulation.

[0042] In another aspect, provided is a method of inducing a state of mind in a subject that enhances interpersonal intimacy, the method comprising administering to the subject a therapeutic combination or pharmaceutical composition of the present disclosure.

[0043] In another aspect, there is provided a method for modulating neurotransmission in a mammal, the method comprising administering to the mammal a therapeutic combination or pharmaceutical composition of the present disclosure.

[0044] In another aspect, there is provided a method of treating a medical condition in a human in need of such treatment, the method comprising administering to the human a therapeutic combination or pharmaceutical composition of the present disclosure.

[0045] In another aspect, a method of improving the mental health or functioning of a human is provided, the method comprising identifying a human in need of such improvement, and administering to the human a therapeutic combination or pharmaceutical composition of the present disclosure.

[0046] In another aspect, there is provided a method of reducing symptoms of a CNS disorder in a human, the method comprising identifying a human in need of such reduction, and administering to the human a therapeutic combination or pharmaceutical composition of the present disclosure.

[0047] In another aspect, a therapeutic combination for inducing a state of mind that enhances interpersonal intimacy is provided, comprising: (a) the therapeutic combination of 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.

[0048] In additional aspects, the method of any of the preceding embodiments is provided, wherein the pharmaceutical composition or therapeutic combination is administered with psychotherapy. The method of any of the preceding embodiments is provided, wherein the pharmaceutical composition or therapeutic combination is administered with psychological support. The method of any of the preceding embodiments is provided, wherein the pharmaceutical composition or therapeutic combination is administered with patient monitoring. The method of any of the preceding embodiments is provided, wherein the pharmaceutical composition or therapeutic combination is administered with the patient's performance of therapeutically beneficial activities. The method of any of the preceding embodiments is provided, wherein the pharmaceutical composition or therapeutic combination is administered without psychotherapy or psychological support.

[0049] The above has broadly outlined certain relevant features of the present disclosure so that the following detailed description of the invention can be better understood and so that the contribution of the present invention to the art can be more fully understood. It will be regarded as only a brief overview of some aspects of the disclosed aspects and embodiments, only for the benefit and convenience of the reader, and is not intended to limit the scope of the claims or the scope of equivalents in any way. Additional features of the present invention are described below. Those skilled in the art will understand that all specific compositions and methods disclosed are merely exemplary and can be easily used as the basis for modifying or designing other compositions and methods for achieving the same purpose. Such equivalent compositions and methods will also be understood to be within the scope and spirit of the present disclosure listed in the claims. It should be understood that the titles within this document are only used to speed up its review speed. It should not be interpreted as limiting the present invention in any way. DETAILED DESCRIPTION

[0050] Although certain aspects and embodiments have been summarized above, the following description shows several exemplary embodiments in more detail to enable those skilled in the art to practice such embodiments and to formulate and use the full scope of the claimed invention. The described examples are provided for illustrative purposes and are not intended to limit the scope of the invention or its applications. It should be understood that those skilled in the art may make many modifications, substitutions, changes and variations to the examples, embodiments, applications and details described in the invention shown herein without departing from the spirit of the invention or the scope of the invention as described in the appended claims. It should also be understood that the titles within this document are only used to speed up the reader's review of them. It should not be interpreted as limiting the present invention in any way.

[0051] From a pharmacological perspective, MDMA and other known interpersonal bonding enhancers are considered “promiscuous” drugs, with a wide range of separate and independent mechanisms (Ray, 2016; Sessa, 2017).

[0052] For example, MDMA is thought to increase serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels, thereby increasing 5-HT 1A and 5-HT 1B MDMA has been shown to have a synergistic effect on the activity of 5-HT2 receptors (Graeff et al., 1996), acting at 5-HT2 receptors, and, like “classic” hallucinogens (Liechti and Vollenweider, 2001), at α2 receptors (Bexis and Docherty, 2005; Giovannitti et al., 2015), and promotes the release of oxytocin (Thompson et al., 2007; Kirsch et al., 2005; Domes et al., 2007). Previous work by the present inventors has shown that MDMA acts at least at the imidazoline-1 receptor; the serotonin-2B receptor; the α-2A, α-2B, and α-2C adrenergic receptors; the muscarinic-3, muscarinic-4, and muscarinic-5 acetylcholine receptors; and the Ca 2+ Channel (Ray, 2010). Recent studies have reported binding affinity profiles for MDMA at a number of receptor particles (see Table 5 and accompanying text in Dunlap, 2018).

[0053] The broader class of phenylalkylamine and tryptamine interpersonal bonding agents generally includes compounds known to be potent releasers and / or reuptake inhibitors of presynaptic 5-HT, DA, and NE, actions resulting from their interactions with membrane transporters involved in neurotransmitter reuptake and vesicular storage systems (e.g., SERT, DAT, NET, VMAT) (de la Torre 2004); compounds known to have direct effects on a variety of receptors, including (among others) 5-HT 1A , 5-HT 1D , 5-HT 1E , 5-HT 2A , 5-HT 5A , 5-HT6, 5-HT7, D1, D2, D3, D4, D5, NMDA, and imidazoline-1 (Ray 2010; Vegting 2016); and is known to be activated by Ca 2+ Its independent mechanism is to act as a 5-HT releaser. It can also inhibit 5-HT reuptake and inhibit monoamine oxidase (MAO), both of which can increase the amount of extracellular 5-HT (Leonardi 1994; Simmler 2018).

[0054] This "confused" pharmacology is believed to be responsible for the adverse effects of intimacy-enhancing agents. However, agents with more selective activity, and therefore lacking one or more adverse effects, also cannot provide the full complement of intimacy-enhancing effects required to provide an intimacy-enhancing state of mind, nor can they therefore provide a lasting therapeutic benefit. It has not yet been possible to decouple the many adverse effects of intimacy-enhancing agents from their "intimacy-enhancing" effects. That is, until the work of the present inventors.

[0055] In aspects of the present disclosure, separate receptor systems are independently targeted, thereby enabling the creation of combinations or compositions with specific action profiles, wherein such action profiles are desirable mental states, particularly those that enhance interpersonal intimacy. In one example, the interpersonal intimacy-enhancing effects of MDMA are reproduced by the disclosed combinations or compositions, which provide the same (or, in some preferred embodiments, greater) therapeutic benefits as MDMA without its inherent disadvantages.

[0056] In some embodiments, the disclosed combinations and compositions can be used in intimacy-enhancing agent-assisted therapy (EAP), including individual, couples, and group EAPs, without one or more adverse effects or complications of prior art intimacy-enhancing agents such as MDMA.

[0057] In some embodiments, when MDMA itself is used in the disclosed combinations or compositions, the combination results in a significantly reduced dose of MDMA required to induce a mind state that enhances interpersonal intimacy, thereby reducing the risk of adverse side effects compared to administration of MDMA alone.

[0058] In some aspects, the interpersonal intimacy-enhancing effect of MDMA or another interpersonal intimacy-enhancing agent is achieved by selectively and simultaneously, individually or sequentially activating a specific receptor system through the 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, such as a 5-HT2 or 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 a selective imidazoline receptor agonist, such as an imidazoline-1 agonist. In some embodiments, a composition for enhancing interpersonal intimacy is disclosed that can selectively activate imidazoline-1 (I1) receptors and serotonin-2 (5-HT2), serotonin-7 (5-HT7) and / or cannabinoid-1 (CB1) receptors together. By administering a therapeutically effective amount of such a composition (e.g., an I1 agent together with any of 5-HT2, 5-HT7, and / or CB1 agents), the interpersonal bonding effects of agents such as MDMA can be produced without their negative effects.

[0059] Therefore, in some aspects, one or more interpersonal intimacy-enhancing effects of MDMA and other known interpersonal intimacy-enhancing agents are provided. And, in some aspects, one or more adverse effects of MDMA and other known interpersonal intimacy-enhancing agents are reduced or eliminated. Additionally, in some aspects, compared with MDMA and other known interpersonal intimacy-enhancing agents, an expanded and enhanced interpersonal intimacy-enhancing effect is provided. Other aspects include combinations, compositions and methods for the treatment of CNS disorders, mental health conditions and mental disorders (such as mental and neuropsychiatric disorders) and neurological conditions (including neurodevelopmental and neurodegenerative disorders). Other aspects include combinations, compositions and methods for improving mental health and psychological function.

[0060] In some disclosed aspects, the therapeutic use of an I1 agent together with any of a 5-HT2, 5-HT7, and / or CB1 agent. In some aspects, the pharmaceutical composition comprises an I1 agent together with any of a 5-HT2, 5-HT7, and / or CB1 agent, and a pharmaceutically acceptable carrier, diluent, or excipient. By the term "I1 agent together with any of a 5-HT2, 5-HT7 and / or CB1 agent" and similar combination terms, it should be understood that all possible combinations are meant to be encompassed, for example, any of the following: an I1 agent together with a CB1 agent; an I1 agent together with a 5-HT2 agent; an I1 agent together with a 5-HT7 agent; an I1 agent together with a CB1 agent and a 5-HT2 agent; an I1 agent together with a CB1 agent and a 5-HT7 agent; an I1 agent together with a 5-HT2 agent and a 5-HT7 agent; an I1 agent together with a 5-HT2 agent, a CB1 agent, and a 5-HT7 agent; and so forth for any similar combinations discussed herein.

[0061] A. General Definitions and Terminology

[0062] 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 reference to a combination of one or more active agents, and reference to an "excipient" includes reference to a combination of one or more excipients. Although the term "one or more" may be used, its absence (or replacement with the singular) does not imply singularity, but rather emphasizes the possibility of multiple agents or ingredients in a particular embodiment.

[0063] The terms "comprising," "including," "such as," and "having" are intended to be inclusive rather than exclusive (i.e., there may be additional elements in addition to the listed elements). Thus, "including" is intended to mean, and is used interchangeably with, the phrase "including, but not limited to." Unless the context clearly dictates otherwise, the term "or" is used herein to mean, and is used interchangeably with, the term "and / or."

[0064] In the case of providing a range herein, the present invention includes embodiments including endpoints, embodiments excluding two endpoints, and embodiments including one endpoint and excluding another endpoint. Unless otherwise stated, it should be assumed that two endpoints are included. In addition, it should be understood that, unless otherwise specified or otherwise become apparent according to the context and the understanding of those of ordinary skill, the value expressed as a range can assume that any specific value or sub-range within the range described in different embodiments is one-tenth of the lower limit unit of the range (unless otherwise clearly indicated in the context). It should also be understood that, in the case of stating a series of numerical values ​​herein, the present invention includes embodiments similarly related to any intermediate value or range defined by any two values ​​in the series, and the lowest value can be taken as the minimum value and the highest value can be taken as the maximum value. As used herein, numerical values ​​include values ​​expressed as percentages. For any embodiment wherein numerical values ​​begin with "about" or "approximately", the present invention includes embodiments wherein the exact value is listed. For any embodiment of the present invention wherein numerical values ​​do not begin with "about" or "approximately", the present invention includes embodiments wherein the value begins with "about" or "approximately". "About" or "about" is intended to encompass numbers that fall within ±10% of a number, in some embodiments, within ±5% of a number, in some embodiments, within ±1% of a number, in some embodiments, within ±0.5% of a number, and in some embodiments, within ±0.1% of a number, unless otherwise specified or apparent from the context (unless such numbers do not allow for more than 100% of the possible values). In some embodiments, the numerical parameters set forth in the written description and appended claims are approximate values ​​that may vary depending upon the desired properties sought to be obtained by a particular embodiment (and as understood by those skilled in the art).

[0065] In some embodiments, numerical parameters should be interpreted in light of the number of reported significant figures and by applying conventional rounding techniques. Although the numerical ranges and parameters setting forth the broad scope of some embodiments are approximate, the numerical values ​​set forth in the specific examples are reported as precisely as possible. The numerical values ​​presented in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0066] Throughout this disclosure, various aspects are presented as ranges. It should be understood that the description in range form is merely for convenience and brevity, and should not be construed as an inflexible limitation on the scope of the claimed subject matter. Therefore, the description of a range should be considered to have clearly disclosed all possible sub-ranges and individual numerical values ​​within the range. For example, where a range of values ​​is provided, it should be understood that each intermediate value between the upper and lower limits of the range and any other specified values ​​or intermediate values ​​within the specified range are encompassed within the claimed subject matter. The upper and lower limits of these smaller ranges may be independently included in the smaller range and are also encompassed within the claimed subject matter, subject to any specifically excluded limits within the stated range. Where the stated range includes one or both of the limitations, the claimed subject matter also includes a range that excludes one or both of the included limitations. This applies regardless of how broad the range.

[0067] A list of abbreviations used 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 usually presented in table form entitled "Standard List of Abbreviations"; the list as of the date of this filing is incorporated herein by reference as if fully set forth herein.

[0068] Unless otherwise defined, all technical and scientific terms herein have the meanings commonly understood by those skilled in the art to which the present invention belongs. As a shorthand, they may be referred to as "technicians". Additional definitions that may help readers understand the disclosed embodiments are as follows; however, it should be understood that such definitions are not intended to limit the scope of the present invention. In view of the language used in the appended claims, the scope of the present invention should be correctly interpreted and understood by reference to the entire specification (and any ordinary meanings known to those skilled in the relevant art). The terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting.

[0069] Generally, the nomenclature and terminology used herein and the procedures performed are those known in the art related to one or more of the disclosed aspects, such as biology, pharmacology, neuroscience, organic chemistry, synthetic chemistry, medicinal chemistry and / or pharmaceutical science, and are well known and commonly employed in one or more of such fields. Standard techniques and procedures are those generally performed according to conventional methods in the art.

[0070] Herein, "in an embodiment" may be used as shorthand for and equivalent to "in some embodiments."

[0071] In this article, "enhancing interpersonal intimacy state of mind" can refer to a state of consciousness characterized by connection with the self. In some embodiments, the enhancing interpersonal intimacy state of mind promotes or enhances feelings of ecstasy, empathy, openness, compassion, peace, acceptance, healing, open-hearted tenderness, love, unity, and care. In some embodiments, the enhancing interpersonal intimacy state of mind promotes or enhances forgiveness of both others (one truly lets go of anger and resentment in the heart) and oneself (one truly lets go of guilt and shame in the heart). In some embodiments, the enhancing interpersonal intimacy state of mind promotes a person's ability to safely experience and consider pain (such as mental pain). In some embodiments, the interpersonal intimacy-enhancing state of mind can refer to the process or feeling of “inner touch,” as described in Brown 2021 (in a non-drug context): “So often, when we feel lost, adrift in our lives, our first instinct is to look outward, far away, for the nearest shore. But that shore, that solid ground, is within us. The anchor we are seeking is connection, and it is within. To connect meaningfully with others, we must first connect with ourselves, but to do that, we must first develop a shared understanding of the language of emotion and the human experience.” David Nichols, a professor of pharmacology and medicinal chemistry at Purdue University, coined the term “interpersonal intimacy-enhancing agent” in 1986 to provide a meaning for “inner touch” (Holland 2001 at 182n.2). The term "interpersonal intimacy enhancer" was adopted after the original term "empathy agonist" (meaning "a state of empathy"), which was independently coined by David Nichols and psychologist and psychopharmacologist Ralph Metzner in 1983-84 (ibid.) and is further elaborated herein.

[0072] In this article, "agent" can refer to a compound that regulates the activity of a target (such as a receptor). In some embodiments, the agent is a ligand for a receptor and regulates the activity of the receptor. In some embodiments, the agent binds, blocks, activates, inhibits or otherwise affects (e.g., by an allosteric reaction) the activity at a given receptor system. Various aspects of the present invention include therapeutic uses of I1 agents and any one of 5-HT2, 5-HT7 and / or CB1 agents. In some embodiments, any one of I1 agents, 5-HT2 agents, 5-HT7 agents and / or CB1 agents can be a receptor modulator, i.e., regulates the activity of I1 receptors, 5-HT2 receptors, 5-HT7 receptors and / or CB1 receptors, respectively.

[0073] In this article, "modulation" can refer to the interaction with a target, directly or indirectly, to change the activity of the target. In some embodiments, the target is a receptor. Non-limiting examples of changing the activity of a target (such as a receptor) are provided herein.

[0074] As used herein, "modulator" and "receptor modulator" may refer to a receptor ligand that modulates or alters receptor function. In some embodiments, the alteration is mediated by direct or indirect interaction with the receptor. By way of example only, modulating the activity of a receptor may enhance the activity of the receptor, inhibit the activity of the receptor, limit the activity of the receptor, or prolong the activity of the receptor. In some embodiments, the alteration 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 one of an I1 agent, a 5-HT2 agent, a 5-HT7 agent, and / or a 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.

[0075] As used herein, "activation" may refer to the binding of any of a receptor modulator, agent, or agonist to a receptor, wherein the binding results in a physiological or pharmacological response characteristic of the receptor.

[0076] As used herein, "inhibit" may refer to the binding of any of a receptor modulator, agent, or antagonist to a receptor, wherein the binding completely or partially blocks, inhibits, reduces, prevents, or delays a physiological or pharmacological response characteristic of the receptor.

[0077] As used herein, an "agonist" may refer to a compound that triggers or elicits an observable positive response from a receptor to which it is bound. In some embodiments, an agonist may refer to a chemical species that interacts with a receptor and activates the receptor, or increases or enhances the activity of a receptor, such as one or more receptors in the 5-HT2, 5-HT7, CB1, or I1 receptor family, and triggers a physiological or pharmacological response characteristic of the receptor. In some embodiments, an agonist may activate a variety of receptors, non-limiting examples of which include activating any one of 5-HT2, 5-HT7, CB1, I1, or a combination thereof. In some embodiments, any one of an I1 agent, a 5-HT2 agent, a 5-HT7 agent, and / or a CB1 agent may be an agonist, i.e., an I1 agonist, a 5-HT2 agonist, a 5-HT7 agonist, and / or a CB1 agonist.

[0078] In this article, "partial agonist" may refer to any compound that increases the activity of the receptor to which it binds, but its maximum efficacy is less than 100%. In some embodiments, a "partial agonist" may refer to any compound with lower intrinsic activity than an agonist that can achieve 100% efficacy. In fact, in a given functional assay, a "partial agonist" will produce a partial or incomplete functional effect. Due to these characteristics, if a partial agonist competes with an agonist that has the ability to achieve 100% efficacy at a given receptor, it can also act as a competitive antagonist. Partial agonists may produce weakened biological effects, so when partial agonists are used in treatment, the possibility of side effects and receptor desensitization may be significantly reduced. In some embodiments, partial agonists can be administered for longer periods of time and longer lasting responses can be achieved.

[0079] As used herein, an “inverse agonist” may refer to a compound that produces a conformational change in the receptor to which it binds, thereby “inactivating” it. Functionally, “inactivation” or “inactivity” may refer to a state in which the signal transduction associated with the receptor is less than that produced in the basal state, i.e., when the agonist is absent (“constitutively active”), or when an antagonist binds to the receptor. Thus, in the presence of an inverse agonist, the signal transduction pathway associated with the receptor is effectively shut down (Stahl, 2013). In other words, while agonists have “intrinsic efficacy,” inverse agonists have “negative” intrinsic efficacy.

[0080] Non-limiting examples of agonists useful in the disclosed embodiments are discussed, inter alia, in the Imidazolin-1 (11), Cannabinoid-1 (CB1), Serotonin-2 (5-HT2), and Serotonin-7 (5-HT7) sections herein.

[0081] As used herein, an "antagonist" may refer to a compound that binds to a given receptor and partially or completely blocks, inhibits (i.e., "inhibits" or "attenuates"), prevents, or delays a biological response characteristic of that receptor. Antagonists can prevent agonists from binding to a receptor and increase the activity of the receptor. Without being bound by theory, antagonists may do this by binding to any of the following: an active site that 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).

[0082] In some embodiments, the antagonist can be an "indirect antagonist" or a "physiological antagonist," as used interchangeably herein, wherein the antagonist partially or completely blocks, inhibits (i.e., "inhibits" or "attenuates"), prevents, or delays a biological response of a receptor without binding to the receptor.

[0083] As used herein, "selective" and "selective binding" may refer to the ability of an agent to bind to a target receptor with an affinity greater than that with which it binds to a non-target receptor. In some embodiments, the target receptor is any one of the following: an I1 receptor, a 5-HT2 receptor, a 5-HT7 receptor, and a CB1 receptor. In some embodiments, any of the agonists and antagonists provided herein may be described as selective.

[0084] Although any materials and methods similar or equivalent to those described herein can be used in embodiments of the present disclosure, certain example materials and methods are now described.

[0085] B. Imidazoline 1 (I1) Agent

[0086] In some embodiments, the therapeutic combination will include an imidazoline-1 agent. As used herein, a "therapeutic combination" may refer to two or more active agents administered in combination to achieve a therapeutic effect. A "combination" includes active agents administered as a "combination drug" or as part of a "combination therapy," as those terms are used herein and understood in the art, as well as such other embodiments that will become apparent in light of this disclosure and general knowledge in the art.

[0087] In some embodiments, an "imidazoline-1 agent" (or "I1 agent") may refer to a compound that modulates activity at an imidazoline-1 (I1) receptor. In embodiments, an I1 agent binds to, blocks, activates, inhibits, or otherwise affects (e.g., through an allosteric reaction) activity at an I1 receptor. In embodiments, an I1 agent acts as a receptor modulator, wherein the I1 agent changes the function of the receptor to which it binds, the change comprising 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 binds more selectively to the I1 receptor system relative to 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, selectivity for the I1 receptor system (as measured by K) is greater than that for receptors that are not part of the I1 receptor system. i 1, 1 : 1, 2: 1, 5: 1, 10: 1, 15: 1, 25: 1, 30: 1, 50: 1, 100: 1, etc.

[0088] In some embodiments, the selectivity of the I1 receptor system (e.g., by K i In some embodiments, the selectivity of the I1 receptor system (as measured by K) is about 1.1:1 compared to receptors that are not part of the I1 receptor system.i In some embodiments, the selectivity of the I1 receptor system (as measured by K) is about 1.5:1 compared to receptors that are not part of the I1 receptor system. i In some embodiments, the selectivity of the I1 receptor system (as measured by K) is about 2:1 compared to receptors that are not part of the I1 receptor system. i In some embodiments, the selectivity of the I1 receptor system (as measured by K) is about 5:1 compared to receptors that are not part of the I1 receptor system. i For example, in some embodiments, the selectivity of the I1 receptor system (as measured by K) is at least about 10:1 compared to receptors that are not part of the I1 receptor system. i In some preferred embodiments, the selectivity of the I1 receptor system (as measured by K) is about 10:1 compared to receptors that are not part of the I1 receptor system. i In other preferred embodiments, the selectivity of the I1 receptor system (as measured by K i In other preferred embodiments, the selectivity of the I1 receptor system (as measured by K i In some embodiments, the selectivity of the I1 receptor system (as measured by K) is at least about 30:1 compared to receptors that are not part of the I1 receptor system. i In some embodiments, the selectivity of the I1 receptor system (as measured by K) is about 50:1 compared to receptors that are not part of the I1 receptor system. i measured) is at least about 100:1.

[0089] In some embodiments, the selectivity of the I1 receptor system (e.g., by K) is compared to the receptors of the α2 (alpha-2) adrenergic receptor system. i In some embodiments, the selectivity of the I1 receptor system (as measured by K) compared to the α2 adrenergic receptor is about 1.1:1. i In some embodiments, the selectivity of the I1 receptor system (as measured by K) compared to the α2 adrenergic receptor is about 1.5:1. i In some embodiments, the selectivity of the I1 receptor system (as measured by K) compared to the α2 adrenergic receptor is about 2:1. i In some embodiments, the selectivity of the I1 receptor system (as measured by K) compared to the α2 adrenergic receptor is about 5:1. iFor example, in some embodiments, the selectivity of the I1 receptor system (as measured by K) is at least about 10:1 compared to the α2 adrenergic receptor. i In some preferred embodiments, the selectivity of the I1 receptor system (as measured by K) is about 10:1 compared to the α2 adrenergic receptor. i In other preferred embodiments, the selectivity of the I1 receptor system (as measured by K) compared to the α2 adrenergic receptor is about 25:1. i In other preferred embodiments, the selectivity of the I1 receptor system (as measured by K) compared to the α2 adrenergic receptor is about 30:1. i In some embodiments, the selectivity of the I1 receptor system (as measured by K) compared to the α2 adrenergic receptor is at least about 30:1. i In some embodiments, the selectivity of the I1 receptor system (as measured by K) compared to the α2 adrenergic receptor is about 50:1. i measured) is at least about 100:1.

[0090] In some embodiments, the I1 agent is an imidazoline-1 receptor agonist. Broadly speaking, an "imidazoline-1 receptor agonist" (or "imidazoline-1 agonist," "I1 receptor agonist," or "I1 agonist") is a compound that elicits a biological response when bound to an 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 the embodiments, and if a term is not otherwise defined or intended to have another meaning required to provide a technical effect, modified terms such as "high" and "low" are used comparatively, meaning that "high" specificity is simply higher than "low" specificity.

[0091] In embodiments, the I1 agonist binds to both the α2 adrenergic (alpha-2 adrenergic) receptor and the imidazoline-1 receptor but is less specific for the α2 adrenergic receptor than the imidazoline-1 receptor, such that the agent is more selective for the imidazoline-1 than for the α2 adrenergic receptor.

[0092] In some embodiments, the I1 agent is an imidazoline-1 receptor antagonist.Broadly speaking, an "imidazoline-1 receptor antagonist" (or "imidazoline-1 antagonist," "I1 receptor antagonist," or "I1 antagonist") is a compound that inhibits a biological response when it binds to the I1 receptor.

[0093] 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 the α2 (alpha-2) adrenergic receptor and the imidazoline-1 receptor, but has lower specificity for the α2 adrenergic receptor than the imidazoline-1 receptor, such that the agent is more selective for the imidazoline-1 than for the α2 adrenergic receptor.

[0094] While in some embodiments, a selective agent is 100-fold or more selective for its target receptor over all other receptors, in many embodiments, the selectivity of a selective agent will be less than 100-fold. Thus, while in some embodiments, an I1-selective agent is 100-fold or more selective for the I1 receptor over all other receptors, in other embodiments, the selectivity of an I1-selective agent will be less than 100-fold. For example, in some such embodiments, an I1-selective agent is about 30-fold or more selective for the I1 receptor over all other receptors. In some embodiments, an I1-selective agent has any degree of selectivity for the I1 receptor relative to all other receptors, wherein the degree of selectivity is as further described herein. In some embodiments, an I1-selective agent is about 30-fold or more selective for the I1 receptor relative to the α2 adrenergic receptor. In some embodiments, the I1-selective agent is moxonidine or rilmenidine. In some embodiments, a selective agent is selective for its target receptor relative to one or more other types of receptors, but not all other receptors.

[0095] In some embodiments, the imidazoline agent will be more than about 30-fold selective for I1 over the α2 receptor. For example, the imidazoline agents moxonidine and rilmenidine were shown to be about 33-fold and 30-fold selective for I1 over the α2 receptor, respectively (Ziegler, 1996):

[0096]

[0097] 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 the α2 adrenergic (alpha-2 adrenergic) receptor and the imidazoline-1 receptor, but has lower specificity for the α2 adrenergic receptor than the imidazoline-1 receptor, such that the agent is more selective for the imidazoline-1 than for the α2 adrenergic receptor.

[0098] Currently, additional I1 agonists that have no detectable affinity or activity for the α2-adrenergic receptor are 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 being inactive at α2, also has nanomolar affinity for I1; 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 latter of which has been shown to antagonize the I1 receptor system and has photoaffinity properties (Urosevic et al., 2004).

[0099] In some embodiments, clonidine is used in therapeutic combinations or pharmaceutical compositions and, according to the present invention, when administered in a therapeutically effective amount, can induce a state of mind that enhances interpersonal intimacy. In some embodiments, clonidine or another I1 agonist that exhibits affinity for α2-adrenergic receptors is used. In some embodiments, the I1 agent is clonidine. In other embodiments, the I1 agent is rilmenidine or moxonidine, or another selective I1 agonist.

[0100] In an embodiment, an I1 agent is used in therapeutic combination with one or more of a 5-HT2, 5-HT7, and / or CB1 agent. In such a combination, the interpersonal bonding effects of the I1 receptor system are elicited while avoiding the aforementioned undesirable side effects associated with MDMA and other known interpersonal bonding agents.

[0101] a. Exemplary I1 agents that can be used in embodiments of the present invention

[0102] In some embodiments, non-limiting examples of I1 agents that can be used in therapeutic combinations 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-(diaminomethylene)-2-(2,6-dichlorophenyl)acetamide (guanfacine), 1-(3-chlorophenyl)piperazine ( mCPP), (RS)-1-(1,3-benzo-dioxol-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-imidazole- 2-(1,2,3,4-tetrahydronaphthalen-1-yl)-4,5-dihydro-1H-imidazole (tetrahydrozoline, also known as tetrahydrozoline), 5-chloro-N-(4,5-dihydro-1H-imidazole, 2-(1,2,3,4-tetrahydronaphthalen-1-yl)-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 (tetrahydrozoline, also known as tetrahydrozoline), imidazol-2-yl)benzo[c][1,2,5]thiadiazol-4-amine (tizanidine), N-(2-chloro-4-methylphenyl)-4,5-dihydro-1H-imidazol-2-amine (tironitine), and the following additional compounds; and any salts, isomers (including structural isomers and stereoisomers, such as enantiomers), precursors, prodrugs, metabolites, derivatives, analogs, isotopologues or variants thereof, or combinations thereof (see, e.g., Nikolic et al., 2012). Certain other exemplary I1 agents that can be used in the disclosed embodiments include idazoxan, p-aminoclonidine, benazoline, BDF6143, and p-iodoclonidine.

[0103] Those skilled in the art will appreciate that by reference to the teachings herein in combination with general knowledge in the art, such as by reference to DrugCentral, DrugBank, and other drug data compilations, they can determine which other compounds are useful agents in the practice of the disclosed embodiments.

[0104] C. Cannabinoid-1 (CB1) Agents

[0105] In some embodiments, the therapeutic combination will comprise 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 otherwise affects (e.g., through an allosteric reaction) the activity at a CB1 receptor. In some embodiments, a CB1 agent acts as a receptor modulator, wherein the CB1 agent alters the function of the receptor to which it binds, 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.

[0106] In some embodiments, a CB1 agent is a "selective agent," which can refer to an agent that binds more selectively to the CB1 receptor system relative to 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, selectivity for the CB1 receptor system (as measured by K) is greater than 1.0 relative to receptors that are not part of the CB1 receptor system. i 1, 1.5:1, 2:1, 5:1, 10:1, 15:1, 25:1, 50:1, 100:1, etc.

[0107] It will be readily understood that selectivity here (as elsewhere herein for other receptor systems) for a single receptor system (e.g., the CB1 receptor system) as compared to all other receptor systems does not require selectivity or testing of compounds on every possible receptor system to determine whether such compounds are indeed "selective," but rather the term can be used and given the meaning as understood by those skilled in the art (e.g., Ray 2010), taking into account the other receptor systems disclosed herein.

[0108] In some embodiments, the CB1 agent is a CB1 receptor agonist. Broadly speaking, a "CB1 receptor agonist" (or "cannabinoid-1 agonist," "CB1 receptor agonist," or "CB1 agonist") is a compound that elicits a biological response upon binding to a CB1 receptor. In some embodiments, the CB1 agonist has high specificity for the CB1 receptor. In some embodiments, the CB1 agonist has low specificity for receptors that are not part of the endocannabinoid system.

[0109] In some embodiments, the CB1 agent is a CB1 receptor antagonist. Broadly speaking, a "CB1 receptor antagonist" (or "cannabinoid-1 antagonist," "CB1 receptor antagonist," or "CB1 antagonist") is a compound that inhibits a biological response when bound 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.

[0110] 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.

[0111] Functionally, the CB1 receptor binds to (-)-trans-Δ 9 -Tetrahydrocannabinol (Δ 9 -THC) binds and mediates Δ 9 - Most of the CNS effects of THC (Zimmer et al., 1999). 9 -THC is the most widely known cannabinoid extracted from cannabis, particularly for its intoxicating effects that cause the "high" associated with cannabis use.

[0112] THC and other cannabinoids may be ingested through inhalation of burning cannabis flower, such as in a pipe (bowl), a joint (butt), a hollowed-out cigar (flat-top) filled with cannabis, or a bong (including a water bong); as a vaporized extract, isolate, distillate, or concentrate (e.g., as wax, shatter, budder, crumbs, live resin, various oils, etc., including as a dab), or from a pen containing a cartridge or an electronic pen; or through ingestion of food (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 inherently has a different absorption mechanism, the duration of the effect and the time that elapses before the effect is felt may vary, but such knowledge is within the ordinary skill in the art. For example, administration via inhalation may be felt almost immediately by the subject, while ingestion via edibles may take 30 minutes to an hour or more to take effect (depending on age, weight, height, metabolism, etc.). There are numerous methods of administering cannabis and cannabinoids, which cannot be exhaustively listed here but will be readily understood by those skilled in the art.

[0113] In addition to the main THC isomer Δ 9 In addition to THC, there are many isomers, such as Δ8 -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 known or understood by those skilled in the art, or can be produced through practice by those of ordinary skill in the art. Therefore, in the embodiments, "THC" may refer to or be equivalent to (at least in certain embodiments) such naturally occurring or synthetic isomers, metabolites, salts, derivatives, analogs, and variants, including Δ 3 -THC, Δ 8 -THC, Δ 9 -THC, Δ 10 -THC, THCV, THCO, THCP and THCB. In the embodiments, "THC" may be a shorthand for Δ 9 -THC and its isomers, unless the context indicates otherwise. In the Examples, where the context permits, "THC" may refer to a single compound, such as any of the following: 3 -THC, Δ 8 -THC, Δ 9 -THC, Δ 10 -THC, THCV, THCO, THCP and THCB.

[0114] In an embodiment, the CB1 agent is a cannabinoid. "Cannabinoid" may refer to a compound in a class of structurally or functionally related compounds. Cannabinoids are functionally related because they each act on CB1 receptors, CB2 receptors, and GPRs. 55 Typically, ligands for these receptors include substances that may be referred to as "endocannabinoids" (i.e., cannabinoids produced endogenously in humans and other mammals), "phytocannabinoids" (i.e., cannabinoids from cannabis or other plants), and "synthetic cannabinoids" (i.e., synthetic analogs of natural cannabinoids).

[0115] In some embodiments, the CB1 agent is an endogenous cannabinoid. In some embodiments, the endogenous cannabinoid is any one of anandamide, oleamide, 2-arachidonoylglycerol (2-AG), N-arachidonoylethanolamine (AEA), N-arachidonoylglycine (NAGly), N-arachidonoyl dopamine (NADA), 2-arachidonoyl-glycerol ether (2-AGE), and 9-octadecenoylamide (oleamide). In embodiments, the endogenous cannabinoid is the same as a cannabinoid that is endogenously produced but exogenously administered.

[0116] In certain embodiments, the CB1 agent is a phytocannabinoid. In certain embodiments, the CB1 agent is a natural phytocannabinoid, wherein "natural phytocannabinoid" may refer to a cannabinoid present in nature and produced by a plant (e.g., a cannabis plant). In certain embodiments, the phytocannabinoid is any one of tetrahydrocannabinol (THC), cannabidiol (CBD), cannabichromene (CBC), cannabinadiol (also known as cannabidiol) (CBND, CBDL), cannabinoids (CBE), cannabicycline (CBL), cannabidipyranocytol (CBTC), cannabitriol (CBT), cannabinol (CBV), cannabigerol monomethyl ether (CBGM), cannabidiolic acid (CBDP), tetrahydrocannabinol (THCP) and isotetrahydrocannabinol (isoTHC).

[0117] In an embodiment, the CB1 agent will be a phytocannabinoid from the cannabis plant. Broadly speaking, "cannabis" can refer to any plant belonging to the Cannabaceae family, including Cannabis sativa, Cannabis indica, and Cannabis ruderalis plants, their cultivars and chemical variants, and any plant part or tissue, such as preferably the female inflorescence and terminal leaves, but including stems, stalks, roots, etc., and preparations made therefrom, such as extracts, ingestibles, or consumables.

[0118] In embodiments, the phytocannabinoid (including from cannabis) is any of: CBD, CBDV, CBND, CBDL, CBE, CBL, CBTC, CBT, CBV, CBG, CBGV, CBGM, CBDP, THC (and further including, for example, THCP and THCV) and iso-THC, as well as acid forms thereof, propyl, methyl and ethyl homologues thereof, and acid forms of these homologues (i.e., acid propyl, acid methyl and acid ethyl homologue forms thereof).

[0119] In embodiments, the cannabinoid will be any one or more of the cannabinoids described and illustrated in 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, but not limited by theory, cannabinoids classified according to this classification include compounds having a characteristic C21 terpene phenol backbone that are part of one of 11 cannabinoid subclasses, namely: cannabichromene (CBC) type, cannabidiol (CBD) type, cannabinoid (CBE) type, cannabigerol (CBG) type, cannabicyclol (CBL) type, cannabinol (CBN) type, cannabinadiol (CBND) type, cannabitriol (CBT) type, (-)-Δ 8 -trans-tetrahydrocannabinol (Δ 8 -THC) type, (-)-Δ 9 -trans-tetrahydrocannabinol (Δ 9 -THC) type and heterotype cannabinoids. Non-limiting examples of such cannabinoids are known by reference to Radwan 2021 and the disclosures below, all of which will be understood to be useful in the practice of the present invention. For example, in an embodiment, the CB1 agent is one or more "Δ 9 -THC-type cannabinoids", which include ΔΔ 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, (-)-Δ9-trans-tetrahydrocannabinol β-fenchyl ester, (-)-Δ9-trans-tetrahydrocannabinol α-fenchyl ester, (-)-Δ9-trans-tetrahydrocannabinol epi-bornyl ester, (-)-Δ9-trans-tetrahydrocannabinol bornyl ester, (-)-Δ9-trans-tetrahydrocannabinol α-terpenyl ester, (-)-Δ9-trans-tetrahydrocannabinol 4-terpenyl ester, (-)-Δ9-trans-tetrahydrocannabinol α-biorhinol ester, (-)- Δ9-trans-tetrahydrocannabinol γ-eudesyl ester, 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-tetrahydrocannabinol and (-)-Δ9-trans-tetrahydrocannabinol.

[0120] In embodiments, the CB1 agent is one or more "Δ 8 -THC-type cannabinoids", which include Δ 8 -THC, Δ 8 -THCA, 10α-OH-Δ 8 -THC, 10β-OH-Δ 8 -THC and 10a-α-hydroxy-10-oxo-Δ8-THC.

[0121] In embodiments, the CB1 agent is one or more "CBG-type cannabinoids," including (E)CBG, (E)CBGA, (E)CBGG, (E)CBGAM, (E)CBGV, (E)CBGVA, (Z)CBGA, 5-acetyl-4-hydroxy-cannabigerol, (±)-6,7-trans-epoxycannabigerolic acid, (±)-6,7-cis-epoxycannabigerolic acid, (±)-6,7-cis-epoxycannabigerol, (±)-6,7-trans-epoxycannabigerol, camagerol, and sesquicannabigerol.

[0122] In an embodiment, the CB1 agent is one or more "CBD, CBND, CBE and CBL type cannabinoids," which include 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.

[0123] In an embodiment, 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-cannabichromene, 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-cannabinol esters.

[0124] In an embodiment, 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-homologs, (-)-trans-CBT-OEt-C5, (–)-trans-CBT-OEt-C3, 8,9-di-OH-CBT-C5, and CBDA-C5, as well as 9-OH-CBT-C5 esters.

[0125] In embodiments, the CB1 agent is one or more "heterocannabinoids" including DCBF-C5, CBF-C5, OH-isoHHCV-C3 OTHC, cannabidipyranocytidine, cis-Δ 9 -THC, CBCON-C5, CBR, CBTT, CBCN-C5, CBCN-C3, cis-isoΔ 7 -THCV, trans-isoΔ 7 -THCV, trans-isoΔ 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, 10aR-hydroxyhexahydro-cannabinol and 9α-hydroxy-10-oxo-Δ 6a,10a -THC.

[0126] In embodiments, the CB1 agent, cannabinoid, phytocannabinoid, or phytocannabinoid from cannabis is a hydrogenated derivative. For example, a hydrogenated derivative of THC is hexahydrocannabinol (HHC), a naturally occurring phytocannabinoid that has been identified as a trace component in certain cannabis species and can also be and has been produced synthetically by hydrogenation of cannabis extracts and has also been synthesized from citronellal and olivetol into both (+)-HHC isomers and (-)-HHC isomers. As with the other cannabinoids discussed herein, HHC can be administered via a suitable vaporizer device (e.g., a disposable e-cigarette) or any other suitable mode of administration described herein. Other structurally related hydrogenated derivatives are also within the scope of the present disclosure and can be used as CB1 agents, cannabinoids, phytocannabinoids, or phytocannabinoids from cannabis, including cannabinoids, 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexahydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10aR-hydroxyhexahydrocannabinol and 1'S-hydroxy-cannabinol, 10α-hydroxy-Δ(9,11)-hexahydrocannabinol and 9β,10β-epoxyhexahydrocannabinol. Other related compounds (sometimes also referred to as "HHCs") can also be used, and include, for example, 9-nor-9β-hydroxyhexahydrocannabinol (9-nor-9β-HHC), 9-hydroxyhexahydrocannabinol (9-OH-HHC), 11-hydroxyhexahydrocannabinol (11-OH-HHC and 7-OH-HHC).

[0127] In some embodiments, the CB1 agent is cannabidiol (CBD). Unlike THC, CBD does not produce an intoxicating effect on people, and it can in fact antagonize such effects of THC. CBD is an inverse agonist of the CB2 receptor, and acts as an indirect antagonist of the CB1 cannabinoid receptor agonist and the CB2 cannabinoid receptor agonist (i.e., an antagonist of other ligands at the CB1 receptor and CB2 receptor). Although THC directly activates the CB1 receptor and CB2 receptor, CBD does not bind to them, but indirectly affects them. Therefore, the pharmacology of CBD is more mysterious and involves interactions with multiple neurochemical systems, including the serotonergic system and the adenosine system. Mechanisms that may be related to the effects of CBD include activation of TRPV1 channels, inhibition of uptake and metabolism of the endogenous cannabinoid anandamide (partly through FAAH inhibition), inhibition of adenosine uptake, GPR 55 CBD can act as a 5-HT inhibitor and a stimulator of PPARγ receptors, as well as increase intracellular calcium. 1A Receptor agonists.

[0128] Thus, it should be understood that in some embodiments, an "agent" need not be an "agonist" (e.g., a CB1 agent need not be a CB1 agonist, and can be an antagonist, inverse agonist, receptor modulator, etc.), and that neither "agents" nor "agonists" need be limited to activity at a particular receptor or receptor system, but rather can have activity in multiple such systems, with multiple mechanisms of action (however, in some embodiments, including certain preferred embodiments herein, an agent or agonist at one receptor or receptor system will be selective therefor, with minimal or no activity at other sites).

[0129] It should be understood that in fresh cannabis plant material, cannabinoids are present almost exclusively in their "acidic" forms (e.g., THCA, CBDA, CBCA), rather than in their "neutral" forms (e.g., THC, CBD, CBC) (and may also have isomers, e.g., THCA-A and THCA-B). In embodiments, the CB1 agent will be a decarboxylated cannabinoid, including, for example, a fully decarboxylated, substantially decarboxylated, partially decarboxylated, or relatively decarboxylated cannabinoid. In embodiments, the CB1 agent will be an acidic cannabinoid (non-decarboxylated cannabinoid).

[0130] In some embodiments, the CB1 agent is a naturally occurring phytocannabinoid from the cannabis plant and is one or more of: CBD, CBDV, CBND, CBDL, CBE, CBL, CBTC, CBT, CBV, CBG, CBGV, CBGM, CBDP, THC (and further including, for example, THCP and THCV), and iso-THC.

[0131] Cannabinoids can also occur in the form of their propyl homologues, for example, as cannabichromene (CBCV), cannabigerol (CBGV), etc. Cannabinoids can also exist in acidic versions of these homologues (e.g., as acid propyl, acid methyl, and acid ethyl homologues). In some embodiments, the CB1 agent is an acid propyl, acid methyl, or acid ethyl homologue.

[0132] In embodiments, the CB1 agent is a synthetic cannabinoid. In embodiments, the synthetic cannabinoid is a synthetic classical cannabinoid, a synthetic non-classical cannabinoid mimetic compound, a mixed cannabinoid, an aminoalkyl indole and / or an eicosanoid, such as AKB48, CP55940, CP-47497, CP-47497C8, 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, e.g., U.S. Patent Application Nos. 16 / 110,728 and 16 / 110,954.

[0133] In some embodiments, synthetic cannabinoid mimetic compounds include compounds that generally act as CB1 receptor agonists, as described herein, and can include compounds from a number of structural classes, such as adamantane indole 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., For example, JWH-051, JWH-056); eicosanoids (for example, AM-883, AM-1346, O-585, O-689); naphthol (for example, JWH-171, JWH-176); indazole carboxamides (for example, AB-PINACA, AB-FUBINACA); indazole-3-carboxamides (for example, AB-CHMINACA, AB-FUBINACA, PX-2, PX-3); indole-3-carboxamides (for example, CUMYL-BICA, CUMYL-CBMICA, Org 28312, Org 28611); indole-3-carboxylate or aryloxycarbonyl indole (e.g., FDU-PB-22, FUB-PB-22); naphthoyl indazole (e.g., THJ-018, THJ-2201); naphthoyl indole (e.g., JWH-007, JWH-018); naphthoyl indole (e.g., JWH-398, AM-1221); naphthoyl indole (e.g., AM-2201, WIN-55,212-2); naphthoyl indole (e.g., JWH-073, JWH-200); phenylacetylindole (e.g., JWH-167, JWH-203); pyrazole carboxamide (e.g., 5F-AB-FUPPYCA, AB-CHFUPYCA); pyrrolobenzoxazine or naphthylindole (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 tetramethylcyclopropylcarbonyl indole (e.g., UR-144, XLR-11).

[0134] In embodiments, the CB1 agent will be a structurally related cannabinoid having a similar structure to any one or more of the above-described compounds, a direct modification of any such compound, or a salt, isomer (including structural isomers or stereoisomers, such as enantiomers), precursor, prodrug, metabolite, derivative, analog, isotopologue or variant thereof, including combinations thereof. Compounds have been described, for example, in U.S. Patent Nos. 5,532,237; 5,605,906; 5,631,297; 6,410,588; 6,610,737; 6,630,507, columns 3:36-6:66; 6,274,635, columns 8:63-20:11; and 8,071,641, columns 5:38-6:26; and references cited therein; Silva et al., 2020, and those skilled in the art will recognize or know or be able to produce many other cannabinoids through practice by those of ordinary skill in the art.

[0135] In some embodiments, the therapeutic combination comprises 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 comprises an I1 agent in combination with exemplary CB1 agents, such as those listed below. In some embodiments, administration of a therapeutic combination comprising a CB1 agent provides a therapeutic effect, such as producing one or more interpersonal bonding effects or interpersonal bonding-enhancing mental states.

[0136] a. Exemplary CB1 Agents Useful in Embodiments of the Invention

[0137] In some embodiments, the CB1 agent is any one of the following: 2-{[(5Z,8Z,11Z,14Z)-eicos-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), arachidonoyl-2'-chloroacetamide (ACEA), N-(1-(cyclohexyl-methyl)-2-((5-ethoxypyridin-2-yl)methyl)-1H-benzo[d]imidazol-5-yl)-N-methylthiophene-2-sulfonamide (AZ-11713 908), 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-55940), (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-naphthyl)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-naphthyl-methanone (JWH-146), 1-([(1E)-3-pentylinden-1-ylidene]methyl)naphthalene (JWH-176), (1-(2-morpholin-4-ylethyl)propane)-1-[(1-Heptyl-5-phenyl-1H-pyrrol-3-yl)-1-naphthyl-methanone) 1-Pentyl-3-(4-chloro-1-naphthoyl)indole (JWH-398), [1-(cyclohexylmethyl)-7-methoxyindol-3-yl]-[(3S)-3,4-dimethylpiperazin-1-yl]methanone (Org28611), 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 salt, isomer (including structural isomers and stereoisomers, such as enantiomers), precursor, prodrug, metabolite, derivative, analog, isotopologue or variant thereof, or a combination thereof.

[0138] Those skilled in the art will appreciate that by reference to the teachings herein in combination with general knowledge in the art, such as by reference to DrugCentral, DrugBank, and other drug data compilations, they can determine which other compounds are useful agents in the practice of the disclosed embodiments.

[0139] D. Serotonin-2 (5-HT2) agents

[0140] In some embodiments, the therapeutic combination will include a serotonin-2 agent. In some embodiments, a "serotonin-2 agent" may refer to a compound that modulates the activity of a serotonin-2 (5-HT2) receptor. In some embodiments, a 5-HT2 agent binds to, blocks, activates, inhibits, or otherwise affects (e.g., by an allosteric reaction) the activity of a serotonin-2 (5-HT2) receptor. In some embodiments, a 5-HT2 agent acts as a receptor modulator, wherein the 5-HT2 agent changes the function of the receptor to which it is bound, including activating the activity of the receptor, inhibiting the activity of the receptor, and activating or inhibiting the activity of the receptor, depending on the dose administered.

[0141] Many compounds that have affinity for one serotonin receptor subfamily may also bind to serotonin receptors of other subfamilies, or have affinity for receptors of the serotonin receptor system as a whole. Thus, in some embodiments, a 5-HT2 agent is a compound that also has affinity for another serotonin receptor. In embodiments, the 5-HT2 agent is a phenylethylamine or tryptamine disclosed herein as a serotonin receptor agent, which, in addition to the 5-HT2 receptor, may also have affinity for other serotonin receptor subfamilies. However, a 5-HT2 agent may also be distinguished from other serotonin receptor agents, for example, based on potency at the 5-HT2 receptor (e.g., measured in absolute terms, such as K i ), or by its selectivity for the 5-HT2 receptor subfamily or a specific 5-HT2 receptor subtype relative to another receptor system or relative to another serotonin receptor subfamily (e.g., 5-HT7) (e.g., by comparing K i selectivity for a given receptor).

[0142] In some embodiments, a 5-HT2 agent is a "selective agent," which can refer to an agent that binds more selectively to the 5-HT2 receptor system relative to 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. In some embodiments, selectivity for the 5-HT2 receptor system (as measured by K) is greater than 1.0 relative to receptors that are not part of the 5-HT2 receptor system. i In embodiments, the selectivity of the 5-HT7 receptor system (as measured by K) is at least 1.1:1, 1.5:1, 2:1, 5:1, 10:1, 15:1, 25:1, 50:1, 100:1, etc., as measured by K. i ) is greater than 1.0, such as 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. In an embodiment, the selectivity of the 5-HT7 receptor system (as K) is greater than 1.0, such as 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. i ) is greater than 1.0, such as 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.

[0143] In embodiments, the serotonin-2 agent is an agonist. Broadly speaking, a "serotonin-2 receptor agonist" (or "serotonin-2 agonist," "5-HT2 receptor agonist," or "5-HT2 agonist") is a compound that elicits a biological response when bound to a serotonin-2 receptor. "Serotonin-2 receptor" would include serotonin-2A, 2B, and 2C receptors. In embodiments, 5-HT2 agonists have high specificity for 5-HT2 receptors. In embodiments, 5-HT2 agonists have low specificity for receptors that are not part of the serotonin-2 receptor system.

[0144] In some embodiments, the serotonin-2 agent is an antagonist. Broadly speaking, 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 when bound to a serotonin-2 receptor. "Serotonin-2 receptor" would include serotonin-2A, 2B, and 2C receptors. In some embodiments, 5-HT2 antagonists have high specificity for the 5-HT2 receptor. In some embodiments, 5-HT2 antagonists have low specificity for receptors that are not part of the serotonin-2 receptor system.

[0145] In some embodiments, the 5-HT2 agent is an inverse agonist. Broadly speaking, 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. "5-HT2 receptor" would include serotonin-2A, 2B, and 2C receptors. In embodiments, a 5-HT2 inverse agonist has high specificity for the 5-HT2 receptor. In embodiments, a 5-HT2 inverse agonist has low specificity for receptors that are not part of the 5-HT2 receptor system.

[0146] In some embodiments, a "5-HT2 agonist" is a 5-HT 2A or 5-HT 2C Selectivity over 5-HT 2B In some embodiments, the 5-HT2 agonist has selectivity for 5-HT 2A and 5-HT 2C Selectivity over 5-HT 2B In some embodiments, the 5-HT2 agonist has selectivity for 5-HT 2A Selectivity over 5-HT 2B or 5-HT 2C In some embodiments, the 5-HT2 agonist has selectivity for 5-HT 2A Selectivity over 5-HT 2B and 5-HT 2C In some embodiments, the 5-HT2 agonist has selectivity for 5-HT 2C and selective over 5-HT 2A or 5-HT 2B In some embodiments, the 5-HT2 agonist has selectivity for 5-HT 2C Selectivity over 5-HT 2A and 5-HT 2B In some embodiments, the 5-HT2 agonist has selectivity for 5-HT 2B Selectivity over 5-HT 2A or 5-HT 2C In some embodiments, the 5-HT2 agonist has selectivity for 5-HT 2B The selectivity is higher than that for 5-HT 2A and 5-HT 2C In some embodiments, the 5-HT2 agonist has selectivity for 5-HT 2A , 5-HT 2B and 5-HT 2CIn some embodiments, the 5-HT2 agonist is selective for any one or more of 5-HT7 over 5-HT7. 2A , 5-HT 2B and 5-HT 2C In some embodiments, the 5-HT2 agonist has a selectivity for 5-HT7 over all other agonists. 2A The selectivity exceeds that for 5-HT7.

[0147] In some embodiments, the disclosed 5-HT 2A Agonists and other 5-HT 2A The agents do not cause hallucinogenic effects when administered as part of the disclosed interpersonal intimacy enhancing combinations and pharmaceutical compositions. In some embodiments, the disclosed 5-HT 2A Agonists and 5-HT 2A The agents, when administered as part of the disclosed interpersonal intimacy enhancing combinations and pharmaceutical compositions, do not cause hallucinogenic effects when administered at doses or by methods that would cause hallucinogenic effects when administered alone.

[0148] Serotonin receptor agents generally include tryptamine and phenylethylamine. In an embodiment, an exemplary 5-HT2 agent is tryptamine. In an embodiment, an exemplary 5-HT2 agent is phenylethylamine.

[0149] It will be readily understood by those skilled in the art that examples of "tryptamine" and tryptamines useful in the practice of the present invention include, but are not limited to, beta-cystein, norbeta-cystein, tryptamine, 4-hydroxytryptamine (or simply "4-hydroxytryptamine," wherein 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 T, N-methyl-N-propyl T, N-methyl-N-isopropyl T, N-methyl-N-allyl T, N-ethyl-N-propyl T, N-ethyl-N-isopropyl T, N-ethyl-N-allyl T, N-propyl-N-isopropyl T, N-propyl-N-allyl T, N-isopropyl-N-allyl T, 4-hydroxy-T, 4-hydroxy-N-methyl T, 4-hydroxy-N-ethyl T, 4-hydroxy-N-propyl T, 4-hydroxy-N-isopropyl T, 4-hydroxy-N-allyl T, 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-propyl-N-isopropyl T, 4-hydroxy-N-propyl-N-allyl T, 4-hydroxy-N-isopropyl-N-allyl T, 5-hydroxy-T, 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-allyl-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-allyl T, 4-methoxy-N-isopropyl-N-allyl T, 5-methoxy-T, 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, 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-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, 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 (tetrahydroharmaline), N,N-diethyl-D-lysergic acid amide (LSD), 6-allyl-N,N-diethyl-nor-lysergic acid (6-allyl-N,N-diethyl-nor-lysergic acid), 9,10-dihydro-N,N,6-triethylergoline-8b-carboxamide (6,N,N-triethyl-nor-lysergic acid), 9,10-dihydro-6-propyl-N,N-diethylergoline-8b-carboxamide (6-propyl-nor-lysergic 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 pharmaceutically acceptable salts, hydrates, solvates, precursors, prodrugs, metabolites, derivatives, analogs, isotopologues, variants, tautomers, isomers or stereoisomers thereof (including pure or substantially pure single enantiomers and any enantiomerically enriched mixtures having an enantiomeric excess greater than 0%), or combinations thereof (and including all amorphous and polymorphic forms).

[0150] In embodiments where the compound is a tryptamine, ring-substituted derivatives thereof known in the art may be used in the practice of the present invention. For example, when the compound is DALT, ring-substituted derivatives (including other known derivatives) include, for example, 2-phenyl-, 4-acetoxy, 4-hydroxy, 5-methoxy, 5-methoxy-2-methyl, 5-fluoro, 5-fluoro-2-methyl, 5-bromo, and 7-ethyl derivatives thereof (Klein, 2018). When the compound is another tryptamine, those of ordinary skill in the art will readily appreciate similar ring-substituted derivatives, such as the derivatives described above (and others).

[0151] 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, as well as its selectivity for one or more receptor systems. For example, using the data available in Klein 2018, the order of relative affinity for 5-HT7 listed above is: 4-OH-DALT, 5-Br-DALT, 5-MeO-DALT, 4-AcO-DALT, 5-F-DALT, 5-F-2-Me-DALT. The order of relative affinity for 5-HT2 is: 7-Et-DALT, DALT, 2-Ph-DALT, 5-MeO-2-Me-DALT. Those skilled in the art will understand how to perform such analysis and ranking for any compound taught or suggested herein, whether based on already published data or data that can be generated based on the teachings herein and general skill in the art.

[0152] Other psychoactive tryptamines contemplated for use in the practice of the present invention include: 6-allyl-N,N-diethyl-norlysergide (AL-LAD), N,N-dibutyltryptamine ("N,N-dibutyltryptamine T," using the abbreviation described elsewhere; DBT), α,N-dimethyltryptamine (α,N-DMT), 6,N,N-triethylnorlysergide (ETH-LAD), 3,4-dihydro-7-methoxy-1-methylcarboline (harmaline), 7-methoxy-1-methylcarboline (harmaline), N,N-dibutyl-4-hydroxytryptamine (4-HO-DBT), N,N-diethyl-4-hydroxytryptamine (4-HO-DET), N,N-diisopropyl N,N-dimethyl-4-hydroxy-T (4-HO-DMT), N,N-dimethyl-5-hydroxy-T (5-HO-DMT, bufotenine), N,N-dipropyl-4-hydroxy-T (4-HO-DPT), N-ethyl-4-hydroxy-N-methyl-T (4-HO-MET), 4-hydroxy-N-isopropyl-N-methyl-T (4-HO-MiPT), 4-hydroxy-N,N-tetramethylene-T (4-HO-pyr-T), 12-methoxyibogamine (ibogamine), N-butyl-N-methyl-T (MBT), N,N-diisopropyl-4,5 -methylenedioxy T (4,5-MDO-DiPT), N,N-diisopropyl-5,6-methylene-dioxy T (5,6-MDO-DiPT), N,N-dimethyl-4,5-methylenedioxy T (4,5-MDO-DMT), N,N-dimethyl-5,6-methylene-dioxy T (5,6-MDO-DMT), N-isopropyl-N-methyl-5,6-methylenedioxy T (5,6-MDO-MiPT), N,N-diethyl-2-methyl T (2-Me-DET), 2,N,N-trimethyl T (2-Me-DMT), N-acetyl-5-methoxy T (melatonin), N,N-diethyl-5 -methoxy T (5-MeO-DET), N,N-diisopropyl-5-methoxy T (5-MeO-DiPT), N-isopropyl-4-methoxy-N-methyl T (4-MeO-MiPT), N-isopropyl-5-methoxy-N-methyl T (5-MeO-MiPT), 5,6-dimethoxy-N-isopropyl-N-methyl T (5,6-MeO-MiPT), 5-methoxy-N,N-tetramethylene T (5-MeO-pyr-T), 6-methoxy-1-methyl-1,2,3,4-tetrahydrocarboline (6-MeO-THH), 5-methoxy-2,N,N-trimethyl T (5-MeO-TMT), N,N-dimethyl-5-methylthio ...

[0153] It will be readily appreciated that while some of the psychoactive tryptamines of the present invention can be obtained from fungal sources, other disclosed tryptamine compounds can be obtained from a variety of other plant and botanical sources. For example, N,N-DMT can be extracted from sources such as Phalaris, Delosperma, Acacia, Desmodium, Mimosa, Virola, and Psychotria spp.

[0154] In embodiments, the tryptamine will be a substituted tryptamine having the structure wherein R N1 、R N2 、R ɑ 、R β 、R 2 、R 4 、R 5 、R 6 and R 7 It will be as taught herein and commonly understood in the art:

[0155]

[0156] For example, in some embodiments, R N1 、R N2 、R ɑ 、R β 、R 2 、R 4 、R 5 、R 6 and R 7are independently hydrogen, deuterium, halogen, hydroxy, methoxy, phosphoryloxy, C1-C5 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl (independently or in a ring closed with nitrogen), C3-C8 cycloalkenyl (independently or in a ring closed with nitrogen), aryl, or heterocyclyl, any of which is optionally substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxyl, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, —OP(O)(OH)2, —OC(O)H, —OSO2OH, —OC(O)NH2, and —SONH. Additionally, the tryptamines useful in the practice of the present invention must also include any salts, isomers (including structural isomers and stereoisomers, such as enantiomers), precursors, prodrugs, metabolites, derivatives, analogs, isotopologues or modifications thereof, or combinations thereof.

[0157] In embodiments, the tryptamine will be a tryptamine N-substituted with any of the following: methyl, ethyl, propyl, isopropyl, or allyl, and in embodiments may include tryptamine, N-methyltryptamine, N-ethyltryptamine, N-propyltryptamine, N-isopropyltryptamine, N-allyltryptamine, N,N-dimethyltryptamine, N,N-diethyltryptamine, N,N-dipropyltryptamine, N,N-diisopropyltryptamine, N,N-diallyltryptamine, 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.

[0158] In some embodiments, the tryptamines of the present invention will be "complex tryptamines" or other indoleamines, and include such non-limiting examples as (chemical classes are generally known in the art, and include at least such exemplary compounds generally known in the art, and analogs and derivatives thereof) ergolines and ergoline alkaloids (including ergoline derivatives such as lysergamide, ergopeptine or ergopeptide, and clavine; and including such synthetic ergoline derivatives as cabergoline, pergolide, and lisuride), natural and synthetic ibogaine alkaloids, and other plant alkaloids including harmine, harmane, norharmine, harmine, perlolyrine, harmol, and other beta-carbolines, such as from Banisteriopsis caapi and Peganum harmala. Harmala), or other monoamine oxidase inhibitors (MAOIs), when used in combination with tryptamine in the practice of the present invention, will enhance the pharmacological efficacy of tryptamine. Thus, in some embodiments, and in some preferred embodiments in which tryptamine or a combination of tryptamines is orally administered (especially in cases where such tryptamines are not orally active), an MAOI will be an additional active agent in the composition or therapeutic combination, in a dosage that provides oral activity of the tryptamine or a combination of tryptamines, as known to those skilled in the art.

[0159] Non-limiting examples of “phenethylamines” readily apparent to those skilled in the art include: α-ethyl-3,4,5-trimethoxyphenethylamine (or abbreviated as “α-ethyl-3,4,5-trimethoxyPEA”, wherein “PEA” refers to “phenethylamine”; AEM), 4-allyloxy-3,5-dimethoxyPEA (AL), 2,5-diformyl-4-methyl-thioamphetamine (or abbreviated as “2,5-dimethoxy-4-methylthio A”, wherein “A” represents “amphetamine”; ALEPH), 2,5-dimethoxy-4-ethylthio A (ALEPH-2), 2,5-dimethoxy-4-isopropylthio A (ALEPH-4), 2,5-dimethoxy-4-phenylthiophene (ALEPH-4), 2,5-dimethoxy-4-methyl-thioamphetamine ... Thio-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 PEA (BEATRICE), 2,5-bismethylthio-4-methyl PEA (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 4-Bromo-3,5-dimethoxy-PEA (4-Br-3,5-DMA), 2-Bromo-4,5-methylenedioxy-PEA (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 A(3C-E), 2,5-dimethoxy-4-fluoroPEA(2C-F), 2,5-dimethoxy-3,4-dimethylPEA(2C-G), 2,5-dimethoxy-3,4-trimethylenePEA(2C-G-3), 2,5-dimethoxy-3,4-tetramethylene-PEA(2C-G-4), 3,4-norbornyl-2,5-dimethoxyPEA(2C-G-5), 1,4-dimethoxynaphthyl-2-ethylamine(2C-GN), 2,5-dimethoxyPEA(2C-H), 4-iodo-2,5-dimethoxyPEA(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-propyl 4-(t)-butylthio-2,5-dimethoxy-PEA (2C-T-9), 2,5-dimethoxy-4-(2-methoxyethylthio)PEA (2C-T-13), 4-cyclopropylthio-2,5-dimethoxy-PEA (2C-T-15), 4-(s)-butylthio-2,5-dimethoxy-PEA (2C-T-17), 2,5-dimethoxy-4-(2-fluoroethylthio)PEA (2C-T-21), 3,5-dimethoxy-4-trideuteriomethyl PEA (4-D), β,β-dideuterio-3,4,5-trimethoxy PEA EA(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-dimethoxyPEA(DMPEA), 4-pentyl-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-dihydrobenzofuran (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 2,5-dimethoxy-3,4-dimethylthiophene (G-3), 2,5-dimethoxy-3,4-dimethylthiophene (G-4), 3,6-dimethoxy-4-(2-aminopropyl)benzonorbornane (G-5), 2,5-dimethoxy-3,4-dimethylthiophene (GANESHA), 1,4-dimethoxynaphthyl-2-isopropylamine (GN), 2,5-dimethoxy-4-ethylthio-N-hydroxy PEA (HOT-2), 2,5-dimethoxy-N-hydroxy-4-(n)-propylthiophene (HOT-7), 4-(s)-butylthio-2,5-dimethoxy-N-hydroxy PEA (HOT-17), 2,5-dimethoxy-N,N-dimethyl-4-iodophene ( IDNNA), 2,3,4-trimethoxy PEA (IM), 3,5-dimethoxy-4-isopropoxy PEA (IP), 5-ethoxy-2-methoxy-4-methyl A (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-methylallyloxy PEA (MAL), 3,4-methylenedioxy A (MDA), N-allyl methyl-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-methoxyethyl)-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-Methylthiothio 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-tetramethoxy A (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-dimethoxyPEA (TB), 4-ethoxy-5-methoxy-3-methylthioPEA (3-TE), 3,5-dimethoxy-4-ethylthioPEA (TE, 4-TE), 3,4-dimethoxy-2-methylthioPEA (2-TIM), 2,4-dimethoxy-3-methylthioPEA (3-TIM), 2,3-dimethoxy-4-methylthioPEA (4-TIM), 3,4-dimethoxy-5-methylthioPEA (3-TM), 3,5-dimethoxy-4-methylthioPEA (4-TM), 3,4,5-trimethoxy PEA (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-MMD A-3a), 2-methoxy-4,5-methylene-thioxoyl A (4T-MMDA-2), 2,4,5-trimethoxyPEA (TMPEA), 4-ethyl-5-methoxy-2-methylthio A (2-TOET), 4-ethyl-2-methoxy-5-methylthio A (5-TOET), 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 A(TP), 3,4,5-triethoxyPEA(TRIS), 3-ethoxy-5-ethylthio-4-methoxyPEA(3-TSB), 3,5-diethoxy-4-methylthioPEA(4-TSB), 3,4-diethoxy-5-ethylthioPEA(3-T-TRIS), 3,5-diethoxy-4-ethylthioPEA(4-T-TRIS), (R)-2,5-dimethoxy-4-iodo-A(R-DOI), or a pharmaceutically acceptable isomer, salt, ester, hydrate, polymorph, solvate, prodrug, isotopologue or metabolite thereof, or a combination thereof. See Shulgin and Shulgin, PIHKAL: A Chemical Love Story, Transformation Press (1994), which is incorporated herein by reference in its entirety.

[0160] 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. For example, such compounds can act as extremely potent and relatively selective 5-HT inhibitors. 2A Agonists. Without being bound by theory, and understanding that there are exceptions, some of which are listed below, NBOMe compounds are typically N-benzylphenethylamine (although the N-benzyl phenyl ring can be replaced by other heterocycles, such as thiophene, pyridine, furan, tetrahydrofuran, benzodioxole, or naphthalene, etc.), with methoxy groups at the 2 and 5 positions of the phenyl ring, a substitution such as a halogen or alkyl group at the 4 position of the phenyl ring, and a methoxy group or other substitution (e.g., hydroxyl, fluoro) at the 2 position of the N-benzyl ring. Other substitution patterns are also possible (e.g., NBOMe-mescaline, 25G-NBOMe, 2CBFly-NBOMe, and 25C-NB3OMe). NBOMe compounds generally differ from the 2C series by the presence of an N-benzyl moiety. In some compounds, an α-methyl group is present (making the compound an N-benzylamphetamine); this generally reduces potency and activity. In some compounds, the side chain methyl group is cyclized back to the ring (e.g., 2CBCB-NBOMe) or connects the two α positions (e.g., DMBMPP), which can improve the 5-HT 2A Receptor subtype selectivity.

[0161] 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-[(pyridin-2-yl)methyl]-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25I-NB), N-[(thiophen-2-yl)methyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NMeTh), N-[(pyridin-2-yl)methyl]-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25I-NB), N-[(thiophen-2-yl)methyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NMeTh), N-[(pyridin-2-yl)methyl]-1-(2,5-dimethoxy-4-bromophenyl)-2-aminoethane (25I- 5B-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-NB25DM), 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-aminopropane (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 N-(2-Methoxybenzyl)-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-ethylphenyl)-2-aminoethane (25E-NBOMe), 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-dimethoxy-4-ethylphenyl)-2-aminoethane5-dimethoxyphenyl)-2-aminoethane (25H-NBOMe), N-(3,4-methylenedioxybenzyl)-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 oxy-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-chlorophenyl)-2-aminoethane N-(2-Methoxybenzyl)-1-(2,5-dimethoxy-4-iodophenyl)-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-aminopropane (DOI-NBOMe), N-[2-(hydroxymethyl)benzyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NBMeOH), N-[2-(amino methyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-NMe7DHBF), 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-amino-ethane (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-methoxybenzyl)-1-[2,5-dimethoxy-4-(propylthio)phenyl]-2-aminoethane (2 5T7-NBOMe), 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-aminopropyl alkane (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 alkane (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-dihydrobenzo[1,2-b:4,5-b']difuran-4-yl]-2-aminoethane [2-(2-methoxy-benzylamino)ethyl]-1H-quinazoline-2,4-dione (RH-34), N-(2-methoxybenzyl)-5-methoxy-T-[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ ), N-[(3-methoxythiophen-2-yl)methyl]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoethane (25I-N3MT2M), 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).

[0162] In some embodiments, the phenethylamine useful in the practice of the present invention will be a 4-substituted 2,5-dimethoxyamphetamine or "DOx" compound, an α-methyl substituted phenethylamine, i.e., a substituted amphetamine. Without being bound by theory, DOx compounds typically have methoxy groups at the 2- and 5-positions of the phenyl ring and a substituent such as an alkyl or halogen group at the 4-position of the phenyl ring. Such compounds may be potent and long-lasting agents that are highly selective for 5-HT. 2A , 5-HT 2B and / or 5-HT 2CReceptor partial agonists. Non-limiting examples of "DOx compounds" that can be used in the practice of the present invention include 2,5-dimethoxy-4-pentylamphetamine (or abbreviated as "2,5-dimethoxy-4-pentyl 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 (DOMOE), 2,5-dimethoxy-4-ethyl A (DOET), 2,5-dimethoxy-4-ethyl A (DOET), 2,5-dimethoxy-4-bromo-2,5-dimethoxy-4-butyl-2,5-dimethoxy-4-chloro-2,5-dimethoxy-4-ethoxy ... Methoxy-4-ethyl-thiothio 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-isopropylthiothio A (Aleph-4), 2,5-dimethoxy-4-methyl A (DOM), 2,5-dimethoxy-4-methylthiothio A (Aleph-1), 2,5-dimethoxy-4-nitro A (DON), 2,5-dimethoxy-4-phenylthiothio-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-chloro-phenyl)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), dimethoxymethyl A ("Beatrice") (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).

[0163] In some embodiments, the phenethylamine will be a substituted phenethylamine having the structure wherein R N 、R ɑ 、R β and R 2 -R 6 It will be as taught herein and commonly understood in the art:

[0164]

[0165] For example, in some embodiments, R N 、R ɑ 、R β and R 2-6 are independently hydrogen, deuterium, halogen, C1-C5 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl (when R N When, independently or with nitrogen closed ring), C3-C8 cycloalkyl (when R N when, independently or with nitrogen-enclosed ring), aryl or heterocyclic; including wherein R 3 and R 4can be joined together to form dioxoles (such as MDMA), furans, tetrahydrofurans, thiophenes, pyrroles, pyridines, pyrrolidines, ethylene oxides, ethylene imines, trimethylene oxides, pyrans, piperidines, imidazoles, thiazoles, dioxanes, morpholines, pyrimidines, or otherwise generate benzene heterocycles; and any of which is optionally substituted at one or more positions with deuterium, halogens, alkyls, alkyl esters, hydroxyls, alkoxyls, carboxyls, formyls, aryls, aryloxyls, heterocyclyls, aminos, alkylaminos, arylamidos, alkylamides, thiols, alkylthios, arylthios, alkylsulfonyls, alkylcarbamoyls, arylcarbamoyls, nitros, cyanos, nitrates, —OP(O)(OH)2, —OC(O)H, —OSO2OH, —OC(O)NH2, and —SONH. In some embodiments, the hallucinogen phenethylamine is a tertiary amine wherein the additional R N Independently as defined above, and having all other substituents as described above. In addition, the phenylethylamine that can be used for the practice of the present invention must also include any salt, isomer (including structural isomers and stereoisomers, such as enantiomers), precursor, prodrug, metabolite, derivative, analog, isotopologue or variant or its combination.

[0166] Other phenethylamines and tryptamines that can be used 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, since the beginning of the twenty-first century, more than 300 "new psychoactive substances" (NPS) have been synthesized, and the number is increasing. These substances belong to multiple chemical classes, such as tryptamines, phenethylamines, cathinones, cannabinoids, and piperazines (EMCDDA, 2014). Although almost all contemporary research is explained by focusing on a small number of compounds, and particularly "classic" hallucinogens, in accordance with the present disclosure, such NPS (e.g., Winter, 2009) may also have clinical utility when used in the combinations, compositions, and methods of the present invention.

[0167] a. Exemplary 5-HT2 Agents Useful in Embodiments of the Invention

[0168] In some exemplary embodiments, the 5-HT2 agent is any one of the following: 3-[2-(dimethylamino)ethyl]-1-methylindole-4-ol (1-methylpsilocin), 1-(5-methoxy-1H-indol-3-yl)propan-2-amine (5-MeO-aMTb), 2-(4-bromo-2,3,6,7-tetrahydrofuro[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)methanamine (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 salt (e.g., hydrochloride, hydrobromide, fumarate), hydrate, solvate, precursor, prodrug, metabolite, derivative, analog, isotopologue, variant, tautomer, isomer or stereoisomer thereof (including pure or substantially pure single enantiomers and any enantiomerically enriched mixture having an enantiomeric excess greater than 0%) or combinations thereof (including all amorphous and polymorphic forms).

[0169] Those skilled in the art will appreciate that by reference to the teachings herein in combination with general knowledge in the art, such as by reference to DrugCentral, DrugBank, and other drug data compilations, they can determine which other compounds are useful agents in the practice of the disclosed embodiments.

[0170] E. Serotonin 7 (5-HT7) Agents

[0171] 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 otherwise affects (e.g., through an allosteric reaction) the activity at the serotonin-7 (5-HT7) receptor. As used herein, the terms "serotonin-7 receptor" and "5-HT7 receptor" refer to the 5-HT7 receptor subtype (i.e., HT 7(a) HT 7(b) HT 7(d) ) or the 5-HT7 receptor system as a whole. In some embodiments, the 5-HT7 agent acts as a receptor modulator, wherein the 5-HT7 agent changes the function of the receptor to which it binds, 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.

[0172] Many compounds that have affinity for one serotonin receptor subfamily may also bind to serotonin receptors of other subfamilies, or have affinity for receptors of the serotonin receptor system as a whole. Thus, in some embodiments, a 5-HT7 agent is a compound that also has affinity for another serotonin receptor. In embodiments, the 5-HT7 agent is a phenylethylamine or tryptamine disclosed herein as a serotonin receptor agent, which, in addition to the 5-HT7 receptor, may also have affinity for other serotonin receptor subfamilies. However, a 5-HT7 agent may also be distinguished from other serotonin receptor agents, for example, based on potency at the 5-HT7 receptor (e.g., measured in absolute terms, such as K i ), or by its selectivity for the 5-HT7 receptor subfamily or a specific 5-HT7 receptor subtype relative to another receptor system or relative to another serotonin receptor subfamily (e.g., 5-HT2) (e.g., by comparing K i selectivity for a given receptor).

[0173] In some embodiments, the 5-HT7 receptor K of the 5-HT7 agent is i 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. In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i Less than 5 nM. In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i Less than 10 nM. In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i Less than 15 nM. In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K iLess than 20 nM. In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i Less than 25 nM. In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i Less than 50 nM. In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i Less than 100 nM. In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K i Less than 1 μM. In some embodiments, the 5-HT7 receptor K i In some embodiments, the 5-HT7 receptor K of the 5-HT7 agent is about 1 to 5 nM, 5 to 10 nM, 5 to 15 nM, 5 to 20 nM, 5 to 25 nM, 5 to 50 nM, 5 to 100 nM, and 5 nM to 1 μM. i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K of about 1 to 5 nM. i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K of about 5 to 10 nM. i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K of about 5 to 15 nM. i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K of about 5 to 20 nM. i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K of about 5 to 25 nM. i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K of about 5 to 50 nM. i In some embodiments, the 5-HT7 agent has a 5-HT7 receptor K of about 5 to 100 nM. i It is about 5nM to 1μM.

[0174] In some embodiments, a 5-HT7 agent is a "selective agent," which can refer to an agent that binds more selectively to the 5-HT7 receptor system relative to 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. In some embodiments, selectivity for the 5-HT7 receptor system (as measured by K) is greater than 1.0 relative to receptors that are not part of the 5-HT7 receptor system. i 1, such as, 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 an embodiment, the 5-HT2 receptor (e.g., 5-HT 2A receptors, 5-HT 2B receptors and / or 5-HT2C receptors), the selectivity of the 5-HT7 receptor system (as K i ) is greater than about 1.0, such as, 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. In embodiments, the selectivity of the 5-HT7 receptor system (as K) is greater than about 1.0, such as, 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. i ) is greater than 1.0, such as, 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 an embodiment, the selectivity of the 5-HT7 receptor system (as K) is greater than 1.0, such as, 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 ) is greater than 1.0, such as, 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 of less than 1.0. In some embodiments, the selectivity (as a function of K) of the 5-HT7 receptor system relative to receptors that are not part of the 5-HT7 receptor system is expressed as a function of K. i ) is less than 1.0, such as 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.

[0175] In some embodiments, the selectivity (as a Ki) for the 5-HT7 receptor system compared to receptors that are not part of the 5-HT7 receptor system is about 0.5:1 to 500:1. In some embodiments, the selectivity (as a Ki) for the 5-HT7 receptor system compared to receptors that are not part of the 5-HT7 receptor system is about 0.5:1 to 500:1. i ) is about 0.5:1 to 1:1. In some embodiments, the selectivity of the 5-HT7 receptor system (as a function of K) is about 0.5:1 to 1:1 compared to receptors that are not part of the 5-HT7 receptor system. i) is about 0.6:1. In some embodiments, the selectivity (as Ki) of the 5-HT7 receptor system as compared to receptors that are not part of the 5-HT7 receptor system is about 50:1 to 500:1. In some embodiments, the selectivity (as Ki) of the 5-HT7 receptor system as compared to receptors that are not part of the 5-HT7 receptor system is about 100:1 to 500:1. In some embodiments, the selectivity (as Ki) of the 5-HT7 receptor system as compared to receptors that are not part of the 5-HT7 receptor system is about 100:1 to 300:1. In some embodiments, the selectivity (as Ki) of the 5-HT7 receptor system as compared to receptors that are not part of the 5-HT7 receptor system is about 150:1 to 250:1. In embodiments, the selectivity (as Ki) of the 5-HT7 receptor system as compared to receptors that are not part of the 5-HT7 receptor system is about i ) is about 200:1.

[0176] In some embodiments, the selectivity of the 5-HT7 receptor system (as a function of K) compared to the 5-HT2 receptor system is i ) is about 0.5:1 to 500:1. In some embodiments, the selectivity of the 5-HT7 receptor system (as K i ) is about 0.5:1 to 1:1. In some embodiments, the selectivity of the 5-HT7 receptor system (as K i ) is about 0.6:1. In some embodiments, the selectivity of the 5-HT7 receptor system (as a function of K) is about 0.6:1 compared to the 5-HT2 receptor. i ) is about 50:1 to 500:1. In some embodiments, the selectivity of the 5-HT7 receptor system (as K i ) is about 100:1 to 500:1. In some embodiments, the selectivity of the 5-HT7 receptor system (as K i ) is about 100:1 to 300:1. In some embodiments, the selectivity of the 5-HT7 receptor system (as K i ) is about 150:1 to 250:1. In some embodiments, the selectivity of the 5-HT7 receptor system (as K i ) is about 200:1.

[0177] In some embodiments, the serotonin-7 agent is an agonist. Broadly speaking, a "serotonin-7 receptor agonist" (or "serotonin-7 agonist," "5-HT7 receptor agonist," or "5-HT7 agonist") is a compound that elicits a biological response when bound to the 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.

[0178] In some embodiments, the serotonin-7 agent is an antagonist. Broadly speaking, 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 when bound to the 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.

[0179] In some embodiments, the serotonin-7 agent is an inverse agonist. Broadly speaking, 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 the 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.

[0180] Exemplary 5-HT7 agents include, but are not limited to, tryptamines (including ergoline and other complex tryptamines), phenylalkylamines, and phenylethylamines, such as, but not limited to, the tryptamines disclosed herein, including, as described above for 5-HT7. 2A In certain embodiments, it will be understood that tryptamines and tryptamine complexes such as ergoline (generally and broadly as a chemical class) will have a greater relative affinity for 5-HT7 than phenylethylamines and other phenylalkylamines (generally and broadly as a chemical class), and such determinations will be readily made by one of ordinary skill in the art based on the teachings herein and the general knowledge in the art (see, e.g., Ray 2010).

[0181] In some embodiments, exemplary 5-HT7 agents will include (and in some embodiments, listed in descending order of priority based on decreasing relative affinity at 5-HT7) the tryptamines DMT, 6-F-DMT, 5-MeO-MiPT, LSD, 5-MeO-DMT, 5-MeO-TMT, cis-2a, DPT, 5-MeO-DiPT, psilocybin, RR-2b, EMDT, lisuride, DiPT, SS-2c; and the phenylalkylamines TMA, 2C-B, 2C-E, and MDA (see also, e.g., Ray 2010).

[0182] a. Exemplary 5-HT7 Agents Useful in Embodiments of the Invention

[0183] 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-1amine (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-ethyl)- imidazol-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-triazol-2-yl)piperazin-1-yl)butoxy}-3,4-dihydroquinolin-2(1H)-one methyl-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-naphthyl)-1-piperazinehexanamide) (LP-44), (6aR,9R)-N , N-diethyl-7-methyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide (LSD) or a pharmaceutically acceptable salt, hydrate, solvate, precursor, prodrug, metabolite, derivative, analog, isotopologue, variant, tautomer, isomer or stereoisomer (including pure or substantially pure single enantiomers and any enantiomerically enriched mixture with an enantiomeric excess greater than 0%) or a combination thereof (and including all amorphous and polymorphic forms).

[0184] 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 psilocybin 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.

[0185] In embodiments, including some preferred embodiments, the 5-HT7 agent is 5-MeO-DMT or 5-MeO-MiPT or a pharmaceutically acceptable salt thereof.

[0186] Those skilled in the art will appreciate that by reference to the teachings herein in combination with general knowledge in the art, such as by reference to DrugCentral, DrugBank, and other drug data compilations, they can determine which other compounds are useful agents in the practice of the disclosed embodiments.

[0187] F. Receptor Selectivity and Modulatory Activity

[0188] The present invention provides combinations of agents that exhibit selectivity for receptors that contribute to a state of mind that promotes interpersonal intimacy. In embodiments, imidazoline-1 (I1), 5-HT2, 5-HT7, and CB1 are among the receptors that contribute to a state of mind that promotes interpersonal intimacy. In embodiments, the agents provided herein are selective for one or more of the I1 receptor, the 5-HT2 receptor, the 5-HT7 receptor, and the CB1 receptor. In embodiments, the combinations provided herein exhibit selectivity for the I1 receptor and one or more of the 5-HT2 receptor, the 5-HT7 receptor, and the CB1 receptor. In embodiments, the agents provided herein modulate the activity of one or more of the I1 receptor, the 5-HT2 receptor, the 5-HT7 receptor, and the CB1 receptor. In embodiments, the combinations provided herein modulate the activity of the I1 receptor and one or more of the 5-HT2 receptor, the 5-HT7 receptor, and the CB1 receptor. In embodiments, the agents provided herein selectively modulate the activity of one or more of the I1 receptor, the 5-HT2 receptor, the 5-HT7 receptor, and the CB1 receptor. In embodiments, the combinations provided herein selectively modulate activity at I1 and one or more of the 5-HT2 receptor, the 5-HT7 receptor, and the CB1 receptor. In some embodiments, the combinations provided herein are therapeutic combinations that elicit a state of mind that enhances interpersonal intimacy.

[0189] a. Selectivity

[0190] The therapeutic combinations provided herein may comprise 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 its highest relative affinity for the receptor. In some embodiments, an agent is selective for a receptor if it only works at the receptor. In some embodiments, a selective agent neither exhibits its maximum affinity nor works only at the target receptor, but rather exhibits a greater affinity for one receptor than another. It is noteworthy that the selectivity of a compound is determined in the context of the target and receptor being measured. In some embodiments, the selectivity of a ligand for its target (such as a receptor) can be expressed as a measure of binding strength, referred to as binding affinity. In some embodiments, selectivity is assessed by determining a measure of binding available to those skilled in the art, for example, the dissociation constant (K D ), association constant (K A ) and inhibition constant (K i ) In some embodiments, the target receptor is I1, 5-HT2, 5-HT7, or CB1. In some embodiments, provided therapeutic combinations comprising an agent (e.g., a selective agent) induce a state of mind that enhances interpersonal intimacy.

[0191] In some embodiments, selectivity can be assessed by determining binding affinity, such as the binding affinity of 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 of a compound and a receptor.

[0192] In some embodiments, selectivity can be assessed by determining the inhibition constant of an agent provided herein and a receptor system, such as I1, 5-HT2, 5-HT7, or CB1. i ) can be described as the concentration at which 50% of the radiolabeled ligand (e.g., agonist) is displaced by the test ligand. Therefore, as represented by the Cheng-Prusoff equation, the observed IC 50 Can be used to determine K i , where Ki = IC50 / (1+[R] / Kd), where IC 50 is the concentration of competitive inhibitor that produces 50% inhibition, R is the concentration of radioligand used in the competition binding assay, and Kd is the equilibrium dissociation constant of the radioligand in the assay.

[0193] Competition binding assays or radioligand displacement assays can also be used to determine K according to methods known in the art. i (Toro-Sazo, 2019). In some instances, the displaced radioligand can be an antagonist, for example, against 5-HT 2A of[ 3 H]Ketanserin and 5-HT 2C of[ 3 In some instances, the displaced radioligand may be an agonist, such as an agonist directed against 5-HT 2B of[ 3 H]LSD.

[0194] In determining K i In another example, one or more agents are first screened against each receptor system to determine the K i Activity at a given receptor was determined beforehand. Compounds were initially assayed at 10 μM for each receptor, transporter, or ion channel as described by Glennon et al. Those that induced >50% inhibition were then assayed at 1, 10, 100, 1,000, and 10,000 nM to determine the K. i Each K value was then calculated based on at least three replicates.i value (Glennon, 2000).

[0195] In some embodiments, such metrics described herein are compared to other metrics known to those skilled in the art to determine relative affinities. In some embodiments, metrics of binding affinity (such as K) are compared to A or K D ) to determine relative affinity. In some instances, a relatively low K A indicates a weaker binding affinity and a higher K A Indicates greater binding affinity. In some instances, a relatively high K D Indicates weaker binding affinity and a lower K D In some embodiments, the equilibrium inhibition constant (K i ) to determine relative affinity. In some instances, a relatively high K i Indicates weaker affinity and lower K i Indicates stronger affinity.

[0196] In some instances, K is distributed over several orders of magnitude. i The values ​​can be logarithmically transformed to facilitate comparison, as described by Ray et al. For example, by calculating pKi = -log10(Ki). In such instances, the higher pK i A higher affinity is indicated by a lower pKi value. In some instances, the log-transformed values ​​can then be normalized. Normalizing such values ​​provides advantages for ease of comparison, including excluding potency, allowing direct comparison of agents with different potencies. In one example, the highest pKi value for each drug was adjusted to a value of 4, and all pKi values ​​reported as >10,000 were normalized. i The values ​​are set to zero to normalize the values ​​(Ray, 2010). In some embodiments, relative affinity can be determined by comparing the transformed and / or normalized metrics described herein. When determining relative affinity, only values ​​that have undergone the same transformation are compared.

[0197] In embodiments, selective affinity can be measured by known methods, including using the NIMH Psychoactive Drug Screening Program (PDSP). i Database (available at the time of submission at https: / / pdsp.unc.edu / databases / kidb.php ), a public domain resource that provides information on the ability of drugs to interact with different molecular targets. PDSP K i The database serves as a collection of published and in-house derived pK values ​​for a large number of drugs and drug candidates on a growing number of G protein-coupled receptors, ion channels, transporters and enzymes.i The PDSP website also provides commonly used protocols and assays for measuring pK i values, for example at the different 5-HT receptors and such other receptor systems discussed herein.

[0198] In certain embodiments, the affinity of the medicament to the receptor is compared with the affinity of the same medicament to different receptors to determine relative affinity. In certain embodiments, the relative affinity of the medicament provided herein to the receptor of one or more targets is at least 1.1 times, such as 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 certain embodiments, the receptor of the target is I1, 5-HT2, 5-HT7 or CB1 receptor. In certain embodiments, selection demonstrates relatively high selectivity of the medicament to I1, 5-HT2, 5-HT7 or CB1 receptor for therapeutic combination described herein.

[0199] In an embodiment, the affinity of the medicament to the receptor is compared with the affinity of different medicaments to the same receptor to determine relative affinity. In an embodiment, the relative affinity of the medicament provided herein to the receptor of one or more targetings is at least 1.1 times that of different medicaments to the affinity of the same receptor, such as 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 an embodiment, the receptor of targeting is I1, 5-HT2, 5-HT7 or CB1 receptor (i.e., the receptor 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, 5-HT2, 5-HT7, or CB1 receptors (i.e., selective agents for any of 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.

[0200] In some embodiments, the disclosed interpersonal intimacy-enhancing combinations comprise 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 that is selective for one or more receptors (or, as similarly described and used interchangeably elsewhere unless the context indicates otherwise, a "receptor system") modulates the activity of the receptors (i.e., the receptor system). In some embodiments, a therapeutic combination comprising a selective agent modulates the activity 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 measurements can be determined by binding assays, such as radioligand binding assays, or binding assays that incorporate functional activity, such as by measuring the functional response of the system to the drug in the presence of an antagonist, as known to those skilled in the art.

[0201] b. Regulating activity

[0202] Combinations of agents that modulate certain receptors to produce therapeutic effects (e.g., enhancing interpersonal intimacy and mental states) are provided. In some embodiments, I1, 5-HT2, 5-HT7, and CB1 are among the receptors modulated to provide an enhanced interpersonal intimacy and mental state. Also provided are selectivity and efficacy profiles of the agents described herein.

[0203] In some embodiments, the agents in the disclosed interpersonal intimacy enhancing combinations modulate the activity of the imidazoline-1 (I1) receptor (I1 receptor system). In some embodiments, the agents in the disclosed interpersonal intimacy enhancing combinations modulate the activity of the cannabinoid-1 (CB1) receptor (CB1 receptor system). In some embodiments, the agents in the disclosed interpersonal intimacy enhancing combinations modulate the activity of the serotonin-2 (5-HT2) receptor and its subtypes (5-HT2 receptor system). In embodiments, the agents in the therapeutic combination modulate the activity of the serotonin-7 (5-HT7) receptor (5-HT7 receptor system).

[0204] In some embodiments, the agents in the disclosed interpersonal intimacy-enhancing combinations modulate the activity of 5-HT2 and 5-HT7 receptors. In some embodiments, the agents in the disclosed interpersonal intimacy-enhancing combinations modulate the activity of I1 receptors and CB1 receptors. In some embodiments, the agents in the disclosed interpersonal intimacy-enhancing combinations modulate the activity of I1 receptors and 5-HT2 receptors. In some embodiments, the agents in the disclosed interpersonal intimacy-enhancing combinations modulate the activity of I1 receptors and 5-HT7 receptors. In some embodiments, the agents in the disclosed interpersonal intimacy-enhancing combinations modulate the activity of I1 receptors and 5-HT2 and 5-HT7 receptors. In some embodiments, the agents in the disclosed interpersonal intimacy-enhancing combinations modulate the activity of CB1 receptors and 5-HT2 receptors. In some embodiments, the agents in the disclosed interpersonal intimacy-enhancing combinations modulate the activity of CB1 receptors and 5-HT7 receptors. In some embodiments, the agents in the disclosed interpersonal intimacy-enhancing combinations modulate the activity of CB1 receptors, 5-HT2 receptors, and 5-HT7 receptors. In some embodiments, the agents of the disclosed interpersonal intimacy enhancing combinations modulate the activity of the I1 receptor, the CB1 receptor, and the 5-HT2 receptor. In some embodiments, the agents of the disclosed interpersonal intimacy enhancing combinations modulate the activity of the I1 receptor, the CB1 receptor, and the 5-HT7 receptor. In embodiments, the agents of the therapeutic combination modulate the activity of the I1 receptor, the CB1 receptor, the 5-HT2 receptor, and the 5-HT7 receptor.

[0205] i. Excitement

[0206] In some embodiments, modulation comprises agonistic activity. In some embodiments, modulation comprises partial agonism. In some embodiments, modulation comprises inverse agonism. In some embodiments, agonism is determined using in vitro techniques, such as ligand binding assays, Furchgott's receptor inactivation method, which involves analyzing concentration / response curves of an agonist before and after partial inactivation of a receptor with an irreversible antagonist, or comparative methods in functional assays, which compare concentration-response curves of full and partial agonists (Strange, 2008).

[0207] In some embodiments, an agonist is measured by its "efficacy". In this context, "efficacy" can refer to the ability of a substance to affect a receptor and its associated signaling system. Imidazoline-1 receptors may help regulate sympathetic nerve activity. In one example, the I1 receptor agonist moxonidine activates I1 receptors in the rostral ventrolateral medulla (RVLM), which reduces the activity of the sympathetic nervous system (Ziegler, 1996). In some examples, the activity of imidazoline-1 can be determined from electrophysiological recordings of brain cells (Hayar and Guyenet, 2000). The efficacy of the imidazoline-1 agonist moxonidine in a norepinephrine release assay has been described ( 2002). Such measures of efficacy are exemplary only and should not be construed as limiting.

[0208] In some embodiments, receptor activation and efficacy can be determined by evaluating the interaction of components of GPCRs (Harrison, 2003). In one example, 5-HT2 receptor activation and GPCR subunit interactions are assessed using bioluminescence resonance energy transfer (BRET) and compared to serotonin as a benchmark (WO 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 exemplary and should not be construed as limiting.

[0209] In an embodiment, the measure of efficacy is expressed as, for example, EC 50 , which is the induction between the baseline and the maximum threshold E max The concentration of the agent that provides an intermediate response (which is the maximal effect of the agonist); K obs / EC 50 , which is the ratio of the agonist dissociation constant to the concentration of agonist that produces a half-maximal effect in a functional assay (where K obs refers to the measurement of agonist affinity using ligand binding); and E max K obs / EC 50 , which is a combined parameter (Strange, 2008). In the Examples, efficacy is assessed by determining activity in a suitable assay system associated with the receptor using a range of concentrations of the test substance, thereby generating a concentration / response experiment (Strange, 2008).

[0210] In some embodiments, the agonist exhibits greater than 0% of maximal efficacy when bound to the target receptor system, including 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 50. In some embodiments, the receptor is I1, CB1, 5-HT2, 5-HT7, or a combination thereof.

[0211] In some embodiments, the imidazoline-1 agonist, cannabinoid-1 agonist, serotonin-2 agonist, serotonin-7 agonist, or a combination thereof, when bound to the I1 receptor system, the CB1 receptor system, the 5-HT2 receptor system, the 5-HT7 receptor system, or a combination thereof, has a maximum efficacy greater than 0%, including 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 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, 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 71%, 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 81%, At least 42.5%, at least 45%, 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.

[0212] In some embodiments, one or more of the provided agents is a partial agonist. In some embodiments, any of an I1 agent, a 5-HT2 agent, a 5-HT7 agent, and / or a 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 thus, unless otherwise expressly indicated or implied, 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.

[0213] In some embodiments, the disclosed agents are partial agonists, wherein the maximum efficacy of the compound in binding to and activating a given receptor is less than 100%, including 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 6 ... 7.5%, less than 65%, less than 62.5%, 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.

[0214] In some embodiments, the disclosed agents are partial agonists of imidazoline-1, wherein the compound activates imidazoline-1 at the I1 receptor with less than 100% of maximal efficacy.

[0215] In some embodiments, the disclosed agents are partial agonists of cannabinoid-1, wherein the compound activates cannabinoid-1 at the CB1 receptor with less than 100% of maximal efficacy.

[0216] In some embodiments, the disclosed agents are partial agonists of serotonin-2, wherein the compounds activate serotonin-2 at the 5-HT2 receptor with less than 100% of maximal efficacy.

[0217] In some embodiments, the disclosed agents are partial agonists of serotonin-7, wherein the compound activates serotonin-7 at the 5-HT7 receptor with less than 100% of its maximal efficacy.

[0218] In some embodiments, the disclosed agents are partial agonists of imidazoline-1 and cannabinoid-1, wherein imidazoline-1 and cannabinoid-1 are activated at less than 100% of maximal efficacy at the I1 receptor and the CB1 receptor.

[0219] In some embodiments, the disclosed agents are partial agonists of imidazoline-1 and serotonin-2, wherein the compounds activate imidazoline-1 and serotonin-2 with less than 100% of maximal efficacy at the I1 receptor and the 5-HT2 receptor.

[0220] In some embodiments, the disclosed agents are partial agonists of imidazoline-1 and serotonin-7, wherein the compounds activate imidazoline-1 and serotonin-7 with less than 100% of maximal efficacy at the I1 receptor and the 5-HT7 receptor.

[0221] In some embodiments, the disclosed agents are partial agonists of cannabinoid-1 and serotonin-2, wherein the compounds activate cannabinoid-1 and serotonin-2 at less than 100% of their maximal efficacy at the CB1 receptor and the 5-HT2 receptor.

[0222] In some embodiments, the disclosed agents are partial agonists of cannabinoid-1 and serotonin-7, wherein the compounds activate cannabinoid-1 and serotonin-7 at less than 100% of their maximal efficacy at the CB1 receptor and the 5-HT7 receptor.

[0223] In some embodiments, the disclosed agents are partial agonists of serotonin-2 and serotonin-7, wherein the compounds activate serotonin-2 and serotonin-7 with less than 100% of maximal efficacy at the 5-HT2 receptor and the 5-HT7 receptor.

[0224] In some embodiments, the disclosed agents are partial agonists of imidazoline-1, cannabinoid-1, and serotonin-2, wherein the compounds bind to and activate imidazoline-1, cannabinoid-1, and serotonin-2 at the I1 receptor, CB1 receptor, and 5-HT2 receptor with less than 100% of maximal efficacy.

[0225] In some embodiments, the disclosed agents are partial agonists of imidazoline-1, cannabinoid-1, and serotonin-7, wherein the compounds bind to and activate imidazoline-1, cannabinoid-1, and serotonin-7 at the I1 receptor, CB1 receptor, and 5-HT7 receptor with less than 100% of maximal efficacy.

[0226] In some embodiments, the disclosed agents are partial agonists of imidazoline-1, serotonin-2, and serotonin-7, wherein the compounds bind to and activate imidazoline-1, serotonin-2, and serotonin-7 at the I1 receptor, 5-HT2 receptor, and 5-HT7 receptor with less than 100% of maximal efficacy.

[0227] In some embodiments, the disclosed agents are partial agonists of cannabinoid-1, serotonin-2, and serotonin-7, wherein the compounds bind to and activate cannabinoid-1, serotonin-2, and serotonin-7 at the CB1 receptor, 5-HT2 receptor, and 5-HT7 receptor with less than 100% of maximal efficacy.

[0228] In embodiments, the disclosed agents are partial agonists of imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7, wherein the compounds bind to and activate imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7 at the I1 receptor, CB1 receptor, 5-HT2 receptor, and 5-HT7 receptor with less than 100% of maximal efficacy.

[0229] In some embodiments, one or more of the agents provided herein are inverse agonists. In some embodiments, any one of an I1 agent, a 5-HT2 agent, a 5-HT7 agent, and / or a CB1 agent can be an inverse agonist, i.e., an I1 inverse agonist, a 5-HT2 inverse agonist, a 5-HT7 inverse agonist, and / or a CB1 inverse agonist. Unless the context indicates otherwise, "agonist" includes "inverse agonist," and therefore, unless otherwise expressly indicated or implied, an I1 agonist includes an I1 inverse agonist, a 5-HT2 agonist includes a 5-HT2 inverse agonist, a 5-HT7 agonist includes a 5-HT7 inverse agonist, and a CB1 agonist includes a CB1 inverse agonist.

[0230] In some embodiments, the disclosed agents are inverse agonists of imidazoline-1, wherein the compounds bind to the I1 receptor system and reduce its constitutive activity below its basal state.

[0231] In some embodiments, the disclosed agents are inverse agonists of cannabinoid-1, wherein the compounds bind to the CB1 receptor system and reduce its constitutive activity below its basal state.

[0232] In embodiments, the disclosed agents are inverse agonists of serotonin-2, wherein the compounds bind to the 5-HT2 receptor system and reduce its constitutive activity below its basal state.

[0233] In embodiments, the disclosed agents are inverse agonists of serotonin-7, wherein the compounds bind to the 5-HT7 receptor system and reduce its constitutive activity below its basal state.

[0234] In some embodiments, the disclosed agents are inverse agonists of imidazoline-1 and cannabinoid-1, wherein the compounds bind to either the I1 receptor system and the CB1 receptor system and reduce their constitutive activity below their basal state.

[0235] In some embodiments, the disclosed agents are inverse agonists of imidazoline-1 and serotonin-2, wherein the compounds bind to either the I1 receptor system and the 5-HT2 receptor system and reduce their constitutive activity below their basal state.

[0236] In some embodiments, the disclosed agents are inverse agonists of imidazoline-1 and serotonin-7, wherein the compounds bind to either the I1 receptor system and the 5-HT7 receptor system and reduce their constitutive activity below their basal state.

[0237] In some embodiments, the disclosed agents are inverse agonists of cannabinoid-1 and serotonin-2, wherein the compounds bind to and reduce the constitutive activity of either the CB1 receptor system or the 5-HT2 receptor system below its basal state.

[0238] In some embodiments, the disclosed agents are inverse agonists of cannabinoid-1 and serotonin-7, wherein the compounds bind to either the CB1 receptor system and the 5-HT7 receptor system and reduce their constitutive activity below their basal state.

[0239] In some embodiments, the disclosed agents are inverse agonists of serotonin-2 and serotonin-7, wherein the compounds bind to and reduce the constitutive activity of either the 5-HT2 receptor system or the 5-HT7 receptor system below its basal state.

[0240] In some embodiments, the disclosed agents are inverse agonists of imidazoline-1, cannabinoid-1, and serotonin-2, wherein the compounds bind to any of the I1 receptor system, the CB1 receptor system, and the 5-HT2 receptor system and reduce their constitutive activity below their basal state.

[0241] In some embodiments, the disclosed agents are inverse agonists of imidazoline-1, cannabinoid-1, and serotonin-7, wherein the compounds bind to any of the I1 receptor system, the CB1 receptor system, and the 5-HT7 receptor system and reduce their constitutive activity below their basal state.

[0242] In some embodiments, the disclosed agents are inverse agonists of imidazoline-1, serotonin-2, and serotonin-7, wherein the compounds bind to any of the I1 receptor system, the 5-HT2 receptor system, and the 5-HT7 receptor system and reduce their constitutive activity below their basal state.

[0243] In some embodiments, the disclosed agents are inverse agonists of cannabinoid-1, serotonin-2, and serotonin-7, wherein the compounds bind to any of the CB1 receptor system, the 5-HT2 receptor system, and the 5-HT7 receptor system and reduce their constitutive activity below their basal state.

[0244] In some embodiments, the disclosed agents are inverse agonists of imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7, wherein the compounds bind to any of the I1 receptor system, the CB1 receptor system, the 5-HT2 receptor system, and the 5-HT7 receptor system and reduce their constitutive activity below their basal state.

[0245] In some embodiments, the disclosed agents are inverse agonists, wherein the compound binds to a given receptor and reduces its constitutive activity below its basal state, including reducing its constitutive activity by up to 100%, including 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 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.

[0246] In some embodiments, agonists can be distinguished by their selectivity for a given receptor or group of receptors. In such embodiments, the compound is an agonist of at least one desired receptor (i.e., any of the following: I1 receptor, 5-HT2 receptor, 5-HT7 receptor, or CB1 receptor, or a combination thereof) and has a selectivity for at least one desired receptor greater than a ratio of 1.0. This means that the ratio of selectivity of the compound for at least one desired receptor system as compared to receptors that are not part of the at least one desired receptor system (as measured by K i measured) is greater than 1.1:1, 1.5:1, 2:1, 5:1, 10:1, 15:1, 25:1, 50:1, 100:1, etc.

[0247] ii. Antagonism

[0248] In some embodiments, one or more of the provided agents is an antagonist. The antagonistic activity of the disclosed agents may be reversible or irreversible and competitive or non-competitive, depending on the mechanism of antagonist binding. In some embodiments, an "antagonist" may refer to an agent that has an IC 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 A substance that inhibits the receptor to which it binds.

[0249] 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 greater than 100-fold, including intervening values, at a target receptor compared to a receptor that is not part of the target receptor system (as measured by a functional or competitive binding assay).

[0250] 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.

[0251] In certain embodiments, one or more medicaments in the medicament provided herein are indirect or physiological antagonists. In certain embodiments, indirect antagonists or physiological antagonists can refer to the medicament that produces biological effect at a receptor, which partially or completely blocks, inhibits, i.e., "inhibits" or "weakens", prevents or delays the biological effect caused by the agonist combined with a separate receptor system. Without being bound by theory, a non-limiting example of such effect includes that epinephrine increases arterial pressure by vasoconstriction mediated by α-1 adrenergic receptor activation. Therefore, epinephrine shows antihistamine properties when not physiologically combined with histamine receptors or "antagonizing" histamine receptors, making it a physiological antagonist of histamine.

[0252] In some embodiments, the disclosed agents are physiological antagonists, wherein the compounds bind to and modulate a receptor in a manner that antagonizes the effects of an agonist that binds to a receptor system useful in the practice of the invention.

[0253] In some embodiments, the disclosed agents are physiological antagonists of imidazoline-1, wherein the compounds bind to and modulate the receptor in a manner that antagonizes the effects of agonists that bind to the I1 receptor system.

[0254] In some embodiments, the disclosed agents are physiological antagonists of cannabinoid-1, wherein the compounds bind to and modulate the receptor in a manner that antagonizes the effects of agonists that bind to the CB1 receptor system.

[0255] In some embodiments, the disclosed agents are physiological antagonists of serotonin-2, wherein the compounds bind to and modulate the receptor in a manner that antagonizes the effects of agonists that bind to the 5-HT2 receptor system.

[0256] In some embodiments, the disclosed agents are physiological antagonists of serotonin-7, wherein the compounds bind to and modulate the receptor in a manner that antagonizes the effects of agonists that bind to the 5-HT7 receptor system.

[0257] In some embodiments, the disclosed agents are physiological antagonists of imidazoline-1 and cannabinoid-1, wherein the compounds bind to and modulate the receptors in a manner that antagonizes the effects of agonists that bind to either the I1 receptor system and the CB1 receptor system.

[0258] In some embodiments, the disclosed agents are physiological antagonists of imidazoline-1 and serotonin-2, wherein the compounds bind to and modulate the receptors in a manner that antagonizes the effects of agonists that bind to either the I1 receptor system and the 5-HT2 receptor system.

[0259] In some embodiments, the disclosed agents are physiological antagonists of imidazoline-1 and serotonin-7, wherein the compounds bind to and modulate the receptors in a manner that antagonizes the effects of agonists that bind to either the I1 receptor system and the 5-HT7 receptor system.

[0260] In some embodiments, the disclosed agents are physiological antagonists of cannabinoid-1 and serotonin-2, wherein the compounds bind to and modulate the receptors in a manner that antagonizes the effects of agonists that bind to either the CB1 receptor system and the 5-HT2 receptor system.

[0261] In some embodiments, the disclosed agents are physiological antagonists of cannabinoid-1 and serotonin-7, wherein the compounds bind to and modulate the receptors in a manner that antagonizes the effects of agonists that bind to either the CB1 receptor system and the 5-HT7 receptor system.

[0262] In some embodiments, the disclosed agents are physiological antagonists of serotonin-2 and serotonin-7, wherein the compounds bind to and modulate the receptors in a manner that antagonizes the effects of agonists that bind to either the 5-HT2 receptor system and the 5-HT7 receptor system.

[0263] In some embodiments, the disclosed agents are physiological antagonists of imidazoline-1, cannabinoid-1, and serotonin-2, wherein the compounds bind to and modulate the receptors in a manner that antagonizes the effects of agonists that bind to any of the I1 receptor system, the CB1 receptor system, and the 5-HT2 receptor system.

[0264] In some embodiments, the disclosed agents are physiological antagonists of imidazoline-1, cannabinoid-1, and serotonin-7, wherein the compounds bind to and modulate the receptors in a manner that antagonizes the effects of agonists that bind to any of the I1 receptor system, the CB1 receptor system, and the 5-HT7 receptor system.

[0265] In some embodiments, the disclosed agents are physiological antagonists of imidazoline-1, serotonin-2, and serotonin-7, wherein the compounds bind to and modulate the receptors in a manner that antagonizes the effects of agonists that bind to any of the I1 receptor system, the 5-HT2 receptor system, and the 5-HT7 receptor system.

[0266] In some embodiments, the disclosed agents are physiological antagonists of cannabinoid-1, serotonin-2, and serotonin-7, wherein the compounds bind to and modulate the receptors in a manner that antagonizes the effects of agonists that bind to any of the CB1 receptor system, the 5-HT2 receptor system, and the 5-HT7 receptor system.

[0267] In embodiments, the disclosed agents are physiological antagonists of imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7, wherein the compounds bind to and modulate the receptors in a manner that antagonizes the effects of agonists that bind to any of the I1 receptor system, the CB1 receptor system, the 5-HT2 receptor system, and the 5-HT7 receptor system.

[0268] In some embodiments, antagonists can be distinguished by their selectivity for a given receptor or group of receptors. In such embodiments, the compound is an antagonist of at least one desired receptor (i.e., any of the following: I1 receptor, 5-HT2 receptor, 5-HT7 receptor, or CB1 receptor, or a combination thereof) and has a selectivity for at least one desired receptor greater than a ratio of 1.0. This means that the ratio of selectivity of the compound for at least one desired receptor system compared to receptors that are not part of the at least one desired receptor system (as measured by K i Measured) greater than 1.1:1, 1.5:1, 2:1, 5:1, 10:1, 15:1, 25:1, 50:1, 100:1, etc.

[0269] iii. Selective agonism

[0270] In some embodiments, whether a compound is a selective agonist can be determined by activity or efficacy (e.g., as an EC 50 ), rather than being measured by binding affinity, for example, in some embodiments, as a measure of selective agonist activity of a compound, and in this regard, a compound that selectively binds to one receptor but not another can be considered a selective agonist.

[0271] In embodiments, compounds of the invention suitable for use herein may be selective agonists of at least one of I1, CB1, 5-HT2, and 5-HT7, wherein the EC of the compound for at least one of I1, CB1, 5-HT2, and 5-HT7 as measured by a binding or functional assay is less than or equal to 0. 50 EC for receptors that are not part of the I1 receptor system, the CB1 receptor system, the 5-HT2 receptor system, and the 5-HT7 receptor system 50 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.

[0272] In embodiments, the disclosed agents are selective agonists of I1, wherein the EC of the compound for I1 as measured by binding or functional assays is 50 is the EC for receptors that are not part of the I1 receptor system50 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.

[0273] In embodiments, the disclosed agents are selective agonists of CB1, wherein the EC of the compound for CB1 as measured by binding or functional assays is 50 is an EC for receptors that are not part of the CB1 receptor system 50 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.

[0274] In embodiments, the disclosed agents are selective agonists of 5-HT2, wherein the EC of the compound for 5-HT2 as measured by binding or functional assays is 50 is the EC for receptors that are not part of the 5-HT2 receptor system 50 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.

[0275] In embodiments, the disclosed agents are selective agonists of 5-HT7, wherein the EC of the compound for 5-HT7 as measured by binding or functional assays is 50 is the EC for receptors that are not part of the 5-HT7 receptor system 50 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.

[0276] In embodiments, the disclosed agents are selective agonists of imidazoline-1 and cannabinoid-1, wherein the EC values ​​of the compound for imidazoline-1 and cannabinoid-1 as measured by binding or functional assays are 50 is an EC for a receptor that is not part of the I1 receptor system or the CB1 receptor system 50at 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.

[0277] In embodiments, the disclosed agents are selective agonists of imidazoline-1 and serotonin-2, wherein the EC values ​​of the compound for imidazoline-1 and serotonin-2 as measured by binding or functional assays are 50 is the EC for receptors that are not part of the I1 receptor system or the 5-HT2 receptor system 50 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.

[0278] In embodiments, the disclosed agents are selective agonists of imidazoline-1 and serotonin-7, wherein the EC values ​​of the compound for imidazoline-1 and serotonin-7 as measured by binding or functional assays are 50 is the EC for receptors that are not part of the I1 receptor system or the 5-HT7 receptor system 50 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.

[0279] In embodiments, the disclosed agents are selective agonists of cannabinoid-1 and serotonin-2, wherein the EC values ​​of the compound for cannabinoid-1 and serotonin-2 as measured by binding or functional assays are 50 is the EC for receptors that are not part of the CB1 receptor system or the 5-HT2 receptor system 50 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.

[0280] In embodiments, the disclosed agents are selective agonists of cannabinoid-1 and serotonin-7, wherein the EC values ​​of the compound for cannabinoid-1 and serotonin-7 as measured by binding or functional assays are 50EC for receptors that are not part of the CB1 receptor system or the 5-HT7 receptor system 50 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.

[0281] In embodiments, the disclosed agents are selective agonists of serotonin-2 and serotonin-7, wherein the EC values ​​of the compound for serotonin-2 and serotonin-7 as measured by binding or functional assays are 50 EC for receptors that are not part of the 5-HT2 receptor system or the 5-HT7 receptor system 50 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.

[0282] In embodiments, the disclosed agents are selective agonists of imidazoline-1, cannabinoid-1, and serotonin-2, wherein the EC values ​​of the compound for imidazoline-1, cannabinoid-1, and serotonin-2 as measured by binding or functional assays are 50 EC for receptors that are not part of the I1 receptor system, the CB1 receptor system, or the 5-HT2 receptor system 50 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.

[0283] In embodiments, the disclosed agents are selective agonists of imidazoline-1, cannabinoid-1, and serotonin-7, wherein the EC values ​​of the compound for imidazoline-1, cannabinoid-1, and serotonin-7 as measured by binding or functional assays are 50 EC for receptors that are not part of the I1 receptor system, the CB1 receptor system, or the 5-HT7 receptor system 50 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.

[0284] In embodiments, the disclosed agents are selective agonists of imidazoline-1, serotonin-2, and serotonin-7, wherein the affinity of the compound for imidazoline-1, serotonin-2, and serotonin-7 as measured by binding or functional assays 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, as compared to the affinity for a receptor that is not part of the I1 receptor system, the 5-HT2 receptor system, or the 5-HT7 receptor system.

[0285] In embodiments, the disclosed agents are selective agonists of cannabinoid-1, serotonin-2, and serotonin-7, wherein the affinity of the compound for cannabinoid-1, serotonin-2, and serotonin-7 as measured by binding or functional assays 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, as compared to the affinity for a receptor that is not part of the CB1 receptor system, the 5-HT2 receptor system, or the 5-HT7 receptor system.

[0286] In embodiments, the disclosed agents are selective agonists of imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7, wherein the affinity of the compound for imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7 as measured by binding or functional assays 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, as compared to the affinity for a receptor that is not part of the I1 receptor system, the CB1 receptor system, the 5-HT2 receptor system, or the 5-HT7 receptor system.

[0287] In some preferred embodiments, the disclosed agents are agonists that are more selective for imidazoline-1 relative to α2, wherein the affinity of the compound for imidazoline-1 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, relative to the α2 adrenergic receptor. 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.

[0288] In some preferred embodiments, the disclosed agents are agonists that are more selective for serotonin-2A and serotonin-2C relative to serotonin-2B, wherein the affinity of the compound for serotonin-2A and serotonin-2C 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, for serotonin-2A and serotonin-2C relative to serotonin-2B receptors. In such embodiments, the 5-HT2 agonist may also be selective for at least one of the I1 receptor system, the 5-HT7 receptor system, and the CB1 receptor system.

[0289] iv. Selective antagonism

[0290] In embodiments, the agents provided herein are selective antagonists. In embodiments, the selective antagonists have an IC 50 is its IC for receptors other than the target receptor 50 Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0291] In embodiments, the compounds of the present invention suitable herein may be selective antagonists of at least one of imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7, wherein the IC of the compound for at least one of imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7 as measured by a binding or functional assay is less than or equal to 1:1. 50 is its IC for receptors that are not part of the I1 receptor system, CB1 receptor system, 5-HT2 receptor system, and 5-HT7 receptor system 50 Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0292] In embodiments, the disclosed agents are selective antagonists of imidazoline-1, wherein the compound has an IC of 50 is its IC for receptors that are not part of the I1 receptor system 50 Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0293] In embodiments, the disclosed agents are selective antagonists of serotonin-2, wherein the compound has an IC of 50 is its IC for receptors that are not part of the 5-HT2 receptor system 50 Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0294] In embodiments, the disclosed agents are selective antagonists of serotonin-7, wherein the compound has an IC of 50 is its IC for receptors that are not part of the 5-HT7 receptor system 50 Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0295] In embodiments, the disclosed agents are selective antagonists of serotonin-2 and serotonin-7, wherein the compound has an IC of 5. 50 is its IC for receptors that are not part of the 5-HT2 receptor system or the 5-HT7 receptor system 50 Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0296] In embodiments, the disclosed agents are selective antagonists of CB1, wherein the compound has an IC of 50 is its IC for receptors that are not part of the CB1 receptor system 50 Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0297] In embodiments, the disclosed agents are selective antagonists of I1 and CB1, wherein the IC 50 is its IC for receptors that are not part of the I1 receptor system or the CB1 receptor system 50Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0298] In embodiments, the disclosed agents are selective antagonists of I1 and 5-HT2, wherein the IC values ​​of the compounds for I1 and 5-HT2 are 50 is its IC for receptors that are not part of the I1 receptor system or the 5-HT2 receptor system 50 Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0299] In embodiments, the disclosed agents are selective antagonists of I1 and 5-HT7, wherein the IC values ​​of the compounds for I1 and 5-HT7 are 50 is its IC for receptors that are not part of the I1 receptor system or the 5-HT7 receptor system 50 Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0300] In embodiments, the disclosed agents are selective antagonists of imidazoline-1, serotonin-2, and serotonin-7, wherein the IC values ​​of the compounds for imidazoline-1, serotonin-2, and serotonin-7 are 50 is its IC for a receptor that is not part of the I1 receptor system, the 5-HT2 receptor system, or the 5-HT7 receptor system 50 Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0301] In embodiments, the disclosed agents are selective antagonists of imidazoline-1, cannabinoid-1, and serotonin-2, wherein the IC values ​​of the compounds for imidazoline-1, cannabinoid-1, and serotonin-2 are 50 is its IC for receptors that are not part of the I1 receptor system, the CB1 receptor system, or the 5-HT2 receptor system 50Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0302] In embodiments, the disclosed agents are selective antagonists of imidazoline-1, cannabinoid-1, and serotonin-7, wherein the IC values ​​of the compounds for imidazoline-1, cannabinoid-1, and serotonin-7 are 50 is its IC for receptors that are not part of the I1 receptor system, the CB1 receptor system, or the 5-HT7 receptor system 50 Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0303] In embodiments, the disclosed agents are selective antagonists of imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7, wherein the IC values ​​of the compounds for imidazoline-1, cannabinoid-1, serotonin-2, and serotonin-7 are 50 is its IC for a receptor that is not part of the I1 receptor system, the CB1 receptor system, the 5-HT2 receptor system, or the 5-HT7 receptor system 50 Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0304] In embodiments, the disclosed agents are selective antagonists of CB1 and 5-HT2, wherein the IC values ​​of the compounds for CB1 and 5-HT2 are 50 is its IC for receptors that are not part of the CB1 receptor system or the 5-HT2 receptor system 50 Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0305] In embodiments, the disclosed agents are selective antagonists of CB1 and 5-HT7, wherein the IC values ​​of the compounds for CB1 and 5-HT7 are 50 is its IC for receptors that are not part of the CB1 receptor system or the 5-HT7 receptor system 50Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0306] In embodiments, the disclosed agents are selective antagonists of cannabinoid-1, serotonin-2, and serotonin-7, wherein the IC values ​​of the compounds for cannabinoid-1, serotonin-2, and serotonin-7 are 50 is its IC for receptors that are not part of the CB1 receptor system, the 5-HT2 receptor system, or the 5-HT7 receptor system 50 Up to 1 / 2, including 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 11, 1 / 12, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 500 and values ​​in between.

[0307] G. Exemplary Therapeutic Combinations

[0308] In embodiments, the therapeutic combinations of the invention comprise an I1 agent and a CB1 agent. In embodiments, the therapeutic combinations of the invention comprise an I1 agonist and a CB1 agonist. In embodiments, the therapeutic combinations of the invention comprise an I1 agonist and a CB1 antagonist. In embodiments, the therapeutic combinations of the invention comprise an I1 antagonist and a CB1 agonist. In embodiments, the therapeutic combinations of the invention comprise an I1 antagonist and a CB1 antagonist.

[0309] In embodiments, the therapeutic combinations of the present invention comprise an I1 agent and a 5-HT2 agent. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist and a 5-HT2 agonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist and a 5-HT2 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist and a 5-HT2 agonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist and a 5-HT2 antagonist.

[0310] In embodiments, the therapeutic combinations of the present invention comprise an I1 agent and a 5-HT7 agent. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist and a 5-HT7 agonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist and a 5-HT7 agonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist and a 5-HT7 antagonist.

[0311] In embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, and a 5-HT2 agent. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a CB1 agonist, and a 5-HT2 agonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a CB1 agonist, and a 5-HT2 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a CB1 antagonist, and a 5-HT2 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a CB1 antagonist, and a 5-HT2 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, and a 5-HT2 agent. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a CB1 agonist, and a 5-HT2 agonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a CB1 agonist, and a 5-HT2 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a CB1 agonist, and a 5-HT2 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a CB1 antagonist, and a 5-HT2 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a CB1 antagonist, and a 5-HT2 agonist. In an embodiment, the therapeutic combination of the invention comprises an I1 antagonist, a CB1 antagonist, and a 5-HT2 antagonist.

[0312] In embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, and a 5-HT7 agent. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a CB1 agonist, and a 5-HT7 agonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a CB1 agonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a CB1 antagonist, and a 5-HT7 agonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a CB1 antagonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, and a 5-HT7 agent. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a CB1 agonist, and a 5-HT7 agonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a CB1 agonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a CB1 agonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a CB1 antagonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a CB1 antagonist, and a 5-HT7 agonist. In an embodiment, the therapeutic combination of the invention comprises an I1 antagonist, a CB1 antagonist, and a 5-HT7 antagonist.

[0313] In embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a 5-HT2 agent, and a 5-HT7 agent. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a 5-HT2 agonist, and a 5-HT7 agonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a 5-HT2 antagonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a 5-HT2 antagonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a 5-HT2 antagonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a 5-HT2 agent, and a 5-HT7 agent. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a 5-HT2 agonist, and a 5-HT7 agonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a 5-HT2 agonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist. In an embodiment, the therapeutic combination of the invention comprises an I1 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist.

[0314] In embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, a 5-HT2 agent, and a 5-HT7 agent. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a CB1 agonist, a 5-HT2 agonist, and a 5-HT7 agonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a CB1 agonist, a 5-HT2 agonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a CB1 antagonist, a 5-HT2 agonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combinations of the present invention comprise 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 embodiments, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, a 5-HT2 antagonist, and a 5-HT7 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist. In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist, 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 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combination of the invention comprises an I1 antagonist, a CB1 antagonist, a 5-HT2 agonist, and a 5-HT7 antagonist. In embodiments, the therapeutic combination of the invention comprises an I1 antagonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist. In embodiments, the therapeutic combination of the invention comprises an I1 antagonist, a CB1 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist.

[0315] In embodiments, the therapeutic combinations of the present invention comprise an I1 agent and a CB1 agent administered together but not formulated as part of a single pharmaceutical composition; in other embodiments, the therapeutic combinations of the present invention comprise an I1 agent and a CB1 agent, wherein 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 comprise an I1 agonist and a CB1 agonist, wherein 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 comprise an I1 agonist and a CB1 antagonist, wherein 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 comprise an I1 antagonist and a CB1 agonist, wherein 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 comprise an I1 antagonist and a CB1 antagonist, wherein 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 comprise an I1 antagonist and a CB1 antagonist, wherein the combination is formulated as a single pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

[0316] In embodiments, the therapeutic combinations of the present invention comprise an I1 agent and a 5-HT2 agent administered together but not formulated as part of a single pharmaceutical composition; in other embodiments, the therapeutic combinations of the present invention comprise an I1 agent and a 5-HT2 agent, wherein 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 comprise an I1 agonist 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 combinations of the present invention comprise an I1 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 embodiments, the therapeutic combinations of the present invention comprise an I1 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 invention comprises an I1 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.

[0317] In embodiments, the therapeutic combinations of the present invention comprise an I1 agent and a 5-HT7 agent administered together but not formulated as part of a single pharmaceutical composition; in other embodiments, the therapeutic combinations of the present invention comprise an I1 agent and a 5-HT7 agent, wherein 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 comprise an I1 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 embodiments, the therapeutic combinations of the present invention comprise an I1 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 embodiments, the therapeutic combinations of the present invention comprise an I1 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 embodiments, the therapeutic combination of the invention comprises an I1 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.

[0318] In embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, and a 5-HT2 agent administered together but not formulated as part of a single pharmaceutical composition; in other embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, and a 5-HT2 agent, wherein 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 comprise an I1 agonist, a CB1 agonist, 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 combinations of the present invention comprise an I1 agonist, 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 embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, 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. In embodiments, the therapeutic combination of the present invention comprises an I1 agonist, 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. In embodiments, the therapeutic combination of the present invention comprises an I1 antagonist, a CB1 agonist, 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 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 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. In an embodiment, the therapeutic combination of the 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.

[0319] In embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, and a 5-HT7 agent administered together but not formulated as part of a single pharmaceutical composition; in other embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, and a 5-HT7 agent, wherein 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 comprise an I1 agonist, 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 embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, 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 embodiments, the therapeutic combinations of the present invention comprise 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 embodiments, 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 embodiments, 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 embodiments, 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 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. In an embodiment, the therapeutic combination of the 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.

[0320] In embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a 5-HT2 agent, and a 5-HT7 agent that are administered together but not formulated as part of a single pharmaceutical composition; in other embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a 5-HT2 agent, and a 5-HT7 agent, wherein the combination is formulated as a single pharmaceutical composition that further comprises a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a 5-HT2 agonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition that further comprises a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a 5-HT2 agonist, and a 5-HT7 antagonist, wherein the combination is formulated as a single pharmaceutical composition that further comprises a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the therapeutic combinations of the present invention comprise an I1 agonist, a 5-HT2 antagonist, and a 5-HT7 agonist, wherein the combination is formulated as a single pharmaceutical composition that further comprises a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, 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 embodiments, 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 embodiments, 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 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. In embodiments, the therapeutic combination of the 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.

[0321] In embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, a 5-HT2 agent, and a 5-HT7 agent administered together but not formulated as part of a single pharmaceutical composition; in other embodiments, the therapeutic combinations of the present invention comprise an I1 agent, a CB1 agent, a 5-HT2 agent, and a 5-HT7 agent, wherein 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 comprise an I1 agonist, 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 embodiments, the therapeutic combinations of the present invention comprise 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 embodiments, 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 embodiments, 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 embodiments, 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 embodiments, 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 embodiments, 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 embodiments, 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 embodiments, 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 embodiments, 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 embodiments, 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 embodiments, 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 embodiments, 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. In embodiments, 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. In embodiments, 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 embodiments, 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.

[0322] H. Exemplary Synergistic Combinations

[0323] In embodiments, "synergy," "synergistic effects," or "synergy" shall refer to a pharmaceutical composition or combination therapy (comprising at least two agents) that, when administered to a subject, produces an effect, whether mental, physical, physiological, or a combination thereof, that the patient would not experience when taking one of the at least two agents alone. In embodiments, the effect will be an effect that enhances the experience of interpersonal intimacy or "state of mind," as defined herein.

[0324] In an embodiment, "synergy" can refer to a pharmaceutical composition or combination therapy that is more effective than the additive effect of any two or more single agents. For example, synergy allows the individual therapy of lower amounts (dosages) to be used to effectively treat a disease. This includes lower dosages of the first or second agent ("apparent unidirectional synergy"), or lower dosages of both agents ("bidirectional synergy") compared to the dosage typically required when using any one agent alone. In fact, lower dosages can produce lower toxicity without reducing efficacy. Synergy can additionally produce improved efficacy, including better avoidance or reduction of disease compared to any monotherapy.

[0325] "Synergy" will also be understood to include an increase in potency, biological activity, bioaccessibility, bioavailability, or therapeutic effect (including one or more additional therapeutic effects) that is greater than the additive contributions of the components acting alone, and / or greater than the contribution of the isolated compounds themselves.

[0326] It is known to those skilled in the art that there are many methods to determine whether a particular effect is a synergistic effect, that is, when two or more components are mixed together, whether the effect is greater than the sum of the effects of the individual components applied separately, thereby producing "1+1>2". Suitable methods include isobologram (or contour) analysis (Huang et al. 2019), or Loewe summation equation (Loewe and Muischnek, 1926, "Archived Experiments: Pathology and Pharmacology (Arch. Exp. Pathol Pharmacol.)" 114: 313-326). Synergism can also be calculated using methods such as Sigmoid-Emax equation (Holford and Scheiner, 1981, "Clinical Pharmacokinet. (Clin. Pharmacokinet.)" 6: 429-453) and median effect equation (Chou and Talalay, 1984, "Adv. Enzyme Regul. (Adv. Enzyme Regul.)" 22: 27-55). The corresponding graphs associated with the equations mentioned above are the concentration-effect curve and the combination index curve. Each of the equations mentioned above can be applied to experimental data to generate corresponding graphs to help evaluate the effect of drug combinations.

[0327] In embodiments, therapeutic combinations comprising an I1 agent and a CB1 agent will be synergistic or provide a synergistic effect. That is, in embodiments, therapeutic combinations will also be "synergistic combinations." In embodiments, therapeutic combinations of the present invention comprising an I1 agonist and a CB1 agonist will be synergistic or provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist and a CB1 antagonist will be synergistic or provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist and a CB1 agonist will be synergistic or provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist and a CB1 antagonist will be synergistic or provide a synergistic effect. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist and a CB1 antagonist will be synergistic or provide a synergistic effect.

[0328] In embodiments, therapeutic combinations comprising an I1 agent and a 5-HT2 agent will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist and a 5-HT2 agonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist and a 5-HT2 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist and a 5-HT2 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist and a 5-HT2 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist and a 5-HT2 antagonist will be synergistic or provide synergy.

[0329] In embodiments, therapeutic combinations comprising an I1 agent and a 5-HT7 agent will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist and a 5-HT7 agonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist and a 5-HT7 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist and a 5-HT7 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist and a 5-HT7 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist and a 5-HT7 antagonist will be synergistic or provide synergy.

[0330] In embodiments, therapeutic combinations comprising an I1 agent, a CB1 agent, and a 5-HT2 agent will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 agonist, and a 5-HT2 agonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 agonist, and a 5-HT2 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 antagonist, and a 5-HT2 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 antagonist, and a 5-HT2 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 agonist, and a 5-HT2 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 agonist, and a 5-HT2 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 agonist, and a 5-HT2 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the invention comprising an I1 antagonist, a CB1 antagonist, and a 5-HT2 agonist will be synergistic or provide a synergistic effect. In embodiments, therapeutic combinations of the invention comprising an I1 antagonist, a CB1 antagonist, and a 5-HT2 antagonist will be synergistic or provide a synergistic effect.

[0331] In embodiments, therapeutic combinations comprising an I1 agent, a CB1 agent, and a 5-HT7 agent will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 agonist, and a 5-HT7 agonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 agonist, and a 5-HT7 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 antagonist, and a 5-HT7 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 agonist, a CB1 antagonist, and a 5-HT7 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 agonist, and a 5-HT7 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 agonist, and a 5-HT7 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the present invention comprising an I1 antagonist, a CB1 agonist, and a 5-HT7 antagonist will be synergistic or provide synergy. In embodiments, therapeutic combinations of the invention comprising an I1 antagonist, a CB1 antagonist, and a 5-HT7 agonist will be synergistic or provide a synergistic effect. In embodiments, therapeutic combinations of the invention comprising an I1 antagonist, a CB1 antagonist, and a 5-HT7 antagonist will be synergistic or provide a synergistic effect.

[0332] In embodiments, therapeutic combinations comprising an I1 agent, a 5-HT2 agent, and a 5-HT7 agent will be synergistic or provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. In embodiments, the therapeutic combinations of the invention comprising an I1 antagonist, a 5-HT2 antagonist, and a 5-HT7 agonist will be synergistic or provide a synergistic effect. In embodiments, the therapeutic combinations of the invention comprising an I1 antagonist, a 5-HT2 antagonist, and a 5-HT7 antagonist will be synergistic or provide a synergistic effect.

[0333] In embodiments, therapeutic combinations comprising an I1 agent, a CB1 agent, a 5-HT2 agent, and a 5-HT7 agent will be synergistic or provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. 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 provide synergy. In embodiments, the 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 provide synergy. In embodiments, the 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 provide synergy. In embodiments, the 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 provide synergy. In embodiments, the 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 provide synergy. In embodiments, the 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 provide synergy. In embodiments, the 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 provide synergy.

[0334] In embodiments where MDMA is used as an I1 agent, it may be combined with at least one of a CB1, 5-HT2, and 5-HT7 agent, wherein the combination exhibits synergistic effects. In such embodiments, significantly smaller doses of MDMA may be required to induce the interpersonal bonding state characteristic of MDMA, reduce the likelihood of adverse effects, or reduce the likelihood of or delay the loss of therapeutic or interpersonal bonding effects ("mojo loss").

[0335] I. Exemplary Embodiments of the Present Invention

[0336] Although a person skilled in the art will understand many embodiments by reviewing the specification and claims, a plurality of exemplary and non-limiting embodiments are disclosed. In some such exemplary embodiments, a "combination" may refer to a "therapeutic combination", in which two or more compounds are administered together (whether simultaneously, sequentially or individually). In some such exemplary embodiments, a "combination" may refer to a pharmaceutical composition, in which two or more compounds are administered as a single formulation with a pharmaceutically acceptable carrier, diluent or excipient. In some such exemplary embodiments, a "combination" may refer to a therapeutic combination or a pharmaceutical composition, in which any two or more compounds in the combination exhibit synergy or synergistic effect. In some such exemplary embodiments, a "combination" may be used in the methods of the present invention, such as any method disclosed or claimed herein. In some such exemplary embodiments, a "combination" will induce a state of mind that enhances interpersonal intimacy. Below are exemplary such embodiments, each of which can be used in other disclosed embodiments of the present invention.

[0337] In an embodiment, a combination comprises agmatine and 2-AGE. In an embodiment, a combination comprises agmatine and A-834,735. In an embodiment, a combination comprises agmatine and ACEA. In an embodiment, a combination comprises agmatine and AZ-11713908. In an embodiment, a combination comprises agmatine and AZD-1940. In an embodiment, a combination comprises agmatine and CBN. In an embodiment, a combination comprises agmatine and CP-47497. In an embodiment, a combination comprises agmatine and CP55940. In an embodiment, a combination comprises agmatine and HU-210. In an embodiment, a combination comprises agmatine and JWH-007. In an embodiment, a combination comprises agmatine and JWH-051. In an embodiment, agmatine and JWH-146. In an embodiment, agmatine and JWH-176. In an embodiment, agmatine and JWH-200. In an embodiment, agmatine and JWH-398. In embodiments, the combination comprises agmatine and Org 28611. In embodiments, the combination comprises agmatine and rimonabant. In embodiments, the combination comprises agmatine and THC. In embodiments, the combination comprises agmatine and WIN 55,212-2. In embodiments, the combination comprises agmatine and XLR11. In embodiments, the combination comprises agmatine and 1-methylpsilocin. In embodiments, the combination comprises agmatine and 2C-B-FLY. In embodiments, the combination comprises agmatine and 5-MeO-AMT. In embodiments, the combination comprises 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 an embodiment, the combination comprises agmatine and LP-44.

[0338] In an embodiment, a combination comprises BDBM50091347 and 2-AGE. In an embodiment, a combination comprises BDBM50091347 and A-834,735. In an embodiment, a combination comprises BDBM50091347 and ACEA. In an embodiment, a combination comprises BDBM50091347 and AZ-11713908. In an embodiment, a combination comprises BDBM50091347 and AZD-1940. In an embodiment, a combination comprises BDBM50091347 and CBN. In an embodiment, a combination comprises BDBM50091347 and CP-47497. In an embodiment, a combination comprises BDBM50091347 and CP55940. In an embodiment, a combination comprises BDBM50091347 and HU-210. In an embodiment, a combination comprises BDBM50091347 and JWH-007. In an embodiment, the combination comprises BDBM50091347 and JWH-051. In an embodiment, the combination comprises BDBM50091347 and JWH-146. In an embodiment, the combination comprises BDBM50091347 and JWH-176. In an embodiment, the combination comprises BDBM50091347 and JWH-200. In an embodiment, the combination comprises BDBM50091347 and JWH-398. In an embodiment, the combination comprises BDBM50091347 and Org 28611. In an embodiment, the combination comprises BDBM50091347 and rimonabant. In an embodiment, the combination comprises BDBM50091347 and THC. In an embodiment, the combination comprises BDBM50091347 and WIN 55,212-2. In an embodiment, the combination comprises BDBM50091347 and XLR11. In an embodiment, the combination comprises BDBM50091347 and 1-methylpsilocin. In an embodiment, the combination comprises BDBM50091347 and 2C-B-FLY. In an embodiment, the combination comprises BDBM50091347 and 5-MeO-AMT. In an embodiment, the combination comprises BDBM50091347 and AL-37350A. In an embodiment, the combination comprises BDBM50091347 and CP 809101. In an embodiment, the combination comprises BDBM50091347 and DALT. In an embodiment, the combination comprises BDBM50091347 and DOB. In an embodiment, the combination comprises BDBM50091347 and DOET. In an embodiment, the combination comprises BDBM50091347 and DOHx. In an embodiment, the combination comprises BDBM50091347 and MEM. In an embodiment, the combination comprises BDBM50091347 and CPP. In an embodiment, 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 an embodiment, the combination comprises BDBM50091347 and E-55888. In an embodiment, the combination comprises BDBM50091347 and LSD. In an embodiment, the combination comprises BDBM50091347 and LP-211. In an embodiment, the combination comprises BDBM50091347 and LP-44.

[0339] In an embodiment, the combination comprises clonidine and 2-AGE. In an embodiment, the combination comprises clonidine and A-834,735. In an embodiment, the combination comprises clonidine and ACEA. In an embodiment, the combination comprises clonidine and AZ-11713908. In an embodiment, the combination comprises clonidine and AZD-1940. In an embodiment, the combination comprises clonidine and CBN. In an embodiment, the combination comprises clonidine and CP-47497. In an embodiment, the combination comprises clonidine and CP55940. In an embodiment, the combination comprises clonidine and HU-210. In an embodiment, the combination comprises clonidine and JWH-007. In an embodiment, the combination comprises clonidine and JWH-051. In an embodiment, the combination comprises clonidine and JWH-146. In an embodiment, the combination comprises clonidine and JWH-176. In an embodiment, the combination comprises clonidine and JWH-200. In an embodiment, 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 embodiments, the combination comprises clonidine and DALT. In embodiments, the combination comprises clonidine and DOB. In embodiments, the combination comprises clonidine and DOET. In embodiments, the combination comprises clonidine and DOHx. In embodiments, the combination comprises clonidine and MEM. In embodiments, 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 embodiments, the combination comprises clonidine and LSD. In embodiments, the combination comprises clonidine and LP-211.In an embodiment, the combination comprises clonidine and LP-44.

[0340] 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 embodiments, the combination comprises guanfacine and CP 809101. In embodiments, the combination comprises guanfacine and DALT. In embodiments, the combination comprises guanfacine and DOB. In embodiments, the combination comprises guanfacine and DOET. In embodiments, 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 an embodiment, the combination comprises guanfacine and LP-44.

[0341] In embodiments, the combination comprises mCPP and 2-AGE. In embodiments, the combination comprises mCPP and A-834,735. In embodiments, the combination comprises mCPP and ACEA. In embodiments, the combination comprises mCPP and AZ-11713908. In embodiments, the combination comprises mCPP and AZD-1940. In embodiments, the combination comprises mCPP and CBN. In embodiments, the combination comprises mCPP and CP-47497. In embodiments, the combination comprises mCPP and CP55940. In embodiments, the combination comprises mCPP and HU-210. In embodiments, the combination comprises mCPP and JWH-007. In embodiments, the combination comprises mCPP and JWH-051. In embodiments, the combination comprises mCPP and JWH-146. In embodiments, the combination comprises mCPP and JWH-176. In embodiments, the combination comprises mCPP and JWH-200. In embodiments, the combination comprises mCPP and JWH-398. In embodiments, the combination comprises mCPP and Org28611. In embodiments, the combination comprises mCPP and rimonabant. In embodiments, the combination comprises mCPP and THC. In embodiments, the combination comprises mCPP and WIN 55,212-2. In embodiments, the combination comprises mCPP and XLR11. In embodiments, the combination comprises mCPP and 1-methylpsilocin. In embodiments, the combination comprises mCPP and 2C-B-FLY. In embodiments, the combination comprises mCPP and 5-MeO-AMT. In embodiments, the combination comprises mCPP and AL-37350A. In embodiments, the combination comprises 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 comprises mCPP and TCB-2. In embodiments, the combination comprises mCPP and WAY 161503. In embodiments, the combination comprises mCPP and 5-CT. In embodiments, the combination comprises mCPP and 5-MeO-DALT. In embodiments, the combination comprises mCPP and 5-MeO-DMT. In embodiments, the combination comprises mCPP and 5-MeO-MiPT. In embodiments, the combination comprises mCPP and AGH-192. In embodiments, the combination comprises mCPP and AGH-107. In embodiments, the combination comprises mCPP and AMT. In embodiments, the combination comprises mCPP and aripiprazole. In embodiments, the combination comprises mCPP and AS-19. In embodiments, the combination comprises mCPP and E-55888.In an embodiment, the combination comprises mCPP and LSD. In an embodiment, the combination comprises mCPP and LP-211. In an embodiment, the combination comprises mCPP and LP-44.

[0342] In embodiments, the combination comprises MDMA and 2-AGE. In embodiments, the combination comprises MDMA and A-834,735. In embodiments, the combination comprises MDMA and ACEA. In embodiments, the combination comprises MDMA and AZ-11713908. In embodiments, the combination comprises MDMA and AZD-1940. In embodiments, the combination comprises MDMA and CBN. In embodiments, the combination comprises MDMA and CP-47497. In embodiments, the combination comprises MDMA and CP55940. In embodiments, the combination comprises MDMA and HU-210. In embodiments, the combination comprises MDMA and JWH-007. In embodiments, the combination comprises MDMA and JWH-051. In embodiments, the combination comprises MDMA and JWH-146. In embodiments, the combination comprises MDMA and JWH-176. In embodiments, the combination comprises MDMA and JWH-200. In embodiments, the combination comprises MDMA and JWH-398. In embodiments, the combination comprises MDMA and Org28611. In embodiments, the combination comprises MDMA and rimonabant. In embodiments, the combination comprises MDMA and THC. In embodiments, the combination comprises MDMA and WIN 55,212-2. In embodiments, the combination comprises MDMA and XLR11. In embodiments, the combination comprises MDMA and 1-methylpsilocybin. In embodiments, the combination comprises MDMA and 2C-B-FLY. In embodiments, the combination comprises MDMA and 5-MeO-AMT. In embodiments, the combination comprises MDMA and AL-37350A. In embodiments, the combination comprises MDMA and CP 809101. In embodiments, the combination comprises 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 comprises MDMA and TCB-2. In embodiments, the combination comprises MDMA and WAY 161503. In embodiments, the combination comprises MDMA and 5-CT. In embodiments, the combination comprises MDMA and 5-MeO-DALT. In embodiments, the combination comprises MDMA and 5-MeO-DMT. In embodiments, the combination comprises MDMA and 5-MeO-MiPT. In embodiments, the combination comprises MDMA and AGH-192. In embodiments, the combination comprises MDMA and AGH-107. In embodiments, the combination comprises MDMA and AMT. In embodiments, the combination comprises MDMA and aripiprazole. In embodiments, the combination comprises MDMA and AS-19. In embodiments, the combination comprises MDMA and E-55888.In an embodiment, the combination comprises MDMA and LSD. In an embodiment, the combination comprises MDMA and LP-211. In an embodiment, the combination comprises MDMA and LP-44.

[0343] In embodiments, the combination comprises memantine and 2-AGE. In embodiments, the combination comprises memantine and A-834,735. In embodiments, the combination comprises memantine and ACEA. In embodiments, the combination comprises memantine and AZ-11713908. In embodiments, the combination comprises memantine and AZD-1940. In embodiments, the combination comprises memantine and CBN. In embodiments, the combination comprises memantine and CP-47497. In embodiments, the combination comprises memantine and CP55940. In embodiments, the combination comprises memantine and HU-210. In embodiments, the combination comprises memantine and JWH-007. In embodiments, the combination comprises memantine and JWH-051. In embodiments, the combination comprises memantine and JWH-146. In embodiments, the combination comprises 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 Org28611. 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.

[0344] 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 Org28611. 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 embodiments, the combination comprises moxonidine and CPP. In embodiments, the combination comprises moxonidine and NBOH-2C-CN. In embodiments, the combination comprises moxonidine and TCB-2. In embodiments, the combination comprises moxonidine and WAY 161503. In embodiments, the combination comprises moxonidine and 5-CT. In embodiments, the combination comprises moxonidine and 5-MeO-DALT. In embodiments, the combination comprises moxonidine and 5-MeO-DMT. In embodiments, the combination comprises moxonidine and 5-MeO-MiPT. In embodiments, the combination comprises moxonidine and AGH-192. In embodiments, the combination comprises moxonidine and AGH-107. In embodiments, the combination comprises moxonidine and AMT. In embodiments, the combination comprises moxonidine and aripiprazole. In embodiments, the combination comprises moxonidine and AS-19. In embodiments, 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.

[0345] In an embodiment, a combination comprises naphazoline and 2-AGE. In an embodiment, a combination comprises naphazoline and A-834,735. In an embodiment, a combination comprises naphazoline and ACEA. In an embodiment, a combination comprises naphazoline and AZ-11713908. In an embodiment, a combination comprises naphazoline and AZD-1940. In an embodiment, a combination comprises naphazoline and CBN. In an embodiment, a combination comprises naphazoline and CP-47497. In an embodiment, a combination comprises naphazoline and CP55940. In an embodiment, a combination comprises naphazoline and HU-210. In an embodiment, a combination comprises naphazoline and JWH-007. In an embodiment, a combination comprises naphazoline and JWH-051. In an embodiment, a combination comprises naphazoline and JWH-146. In an embodiment, a combination comprises naphazoline and JWH-176. In an embodiment, a combination comprises naphazoline and JWH-200. In embodiments, the combination comprises naphazoline and JWH-398. In embodiments, the combination comprises naphazoline and Org28611. In embodiments, the combination comprises naphazoline and rimonabant. In embodiments, the combination comprises naphazoline and THC. In embodiments, the combination comprises naphazoline and WIN 55,212-2. In embodiments, the combination comprises naphazoline and XLR11. In embodiments, the combination comprises naphazoline and 1-methylpsilocin. In embodiments, the combination comprises naphazoline and 2C-B-FLY. In embodiments, the combination comprises naphazoline and 5-MeO-AMT. In embodiments, the combination comprises 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 comprises naphazoline and CPP. In embodiments, the combination comprises naphazoline and NBOH-2C-CN. In embodiments, the combination comprises naphazoline and TCB-2. In embodiments, the combination comprises naphazoline and WAY 161503. In embodiments, the combination comprises naphazoline and 5-CT. In embodiments, the combination comprises naphazoline and 5-MeO-DALT. In embodiments, the combination comprises naphazoline and 5-MeO-DMT. In embodiments, the combination comprises naphazoline and 5-MeO-MiPT. In embodiments, the combination comprises naphazoline and AGH-192. In embodiments, the combination comprises naphazoline and AGH-107. In embodiments, the combination comprises naphazoline and AMT. In embodiments, the combination comprises naphazoline and aripiprazole. In embodiments, the combination comprises naphazoline and AS-19. In embodiments, the combination comprises naphazoline and E-55888.In an embodiment, the combination comprises naphazoline and LSD. In an embodiment, the combination comprises naphazoline and LP-211. In an embodiment, the combination comprises naphazoline and LP-44.

[0346] In an embodiment, the combination comprises oxymetazoline and 2-AGE. In an embodiment, the combination comprises oxymetazoline and A-834,735. In an embodiment, the combination comprises oxymetazoline and ACEA. In an embodiment, the combination comprises oxymetazoline and AZ-11713908. In an embodiment, the combination comprises oxymetazoline and AZD-1940. In an embodiment, the combination comprises oxymetazoline and CBN. In an embodiment, the combination comprises oxymetazoline and CP-47497. In an embodiment, the combination comprises oxymetazoline and CP55940. In an embodiment, the combination comprises oxymetazoline and HU-210. In an embodiment, the combination comprises oxymetazoline and JWH-007. In an embodiment, the combination comprises oxymetazoline and JWH-051. In an embodiment, the combination comprises oxymetazoline and JWH-146. In an embodiment, the combination comprises oxymetazoline and JWH-176. In an embodiment, the combination comprises oxymetazoline and JWH-200. In embodiments, the combination comprises oxymetazoline and JWH-398. In embodiments, the combination comprises oxymetazoline and Org28611. In embodiments, the combination comprises oxymetazoline and rimonabant. In embodiments, the combination comprises oxymetazoline and THC. In embodiments, the combination comprises oxymetazoline and WIN 55,212-2. In embodiments, the combination comprises oxymetazoline and XLR11. In embodiments, the combination comprises oxymetazoline and 1-methylpsilocin. In embodiments, the combination comprises oxymetazoline and 2C-B-FLY. In embodiments, the combination comprises oxymetazoline and 5-MeO-AMT. In embodiments, the combination comprises 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 comprises oxymetazoline and DOHx. In embodiments, the combination comprises oxymetazoline and MEM. In embodiments, the combination comprises oxymetazoline and CPP. In embodiments, the combination comprises oxymetazoline and NBOH-2C-CN. In embodiments, the combination comprises oxymetazoline and TCB-2. In embodiments, the combination comprises oxymetazoline and WAY 161503. In embodiments, the combination comprises oxymetazoline and 5-CT. In embodiments, the combination comprises oxymetazoline and 5-MeO-DALT. In embodiments, the combination comprises oxymetazoline and 5-MeO-DMT. In embodiments, the combination comprises oxymetazoline and 5-MeO-MiPT. In embodiments, the combination comprises oxymetazoline and AGH-192. In embodiments, the combination comprises oxymetazoline and AGH-107. In embodiments, the combination comprises 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 an embodiment, the combination comprises oxymetazoline and LSD. In an embodiment, the combination comprises oxymetazoline and LP-211. In an embodiment, the combination comprises oxymetazoline and LP-44.

[0347] In an embodiment, the combination comprises rilmenidine and 2-AGE. In an embodiment, the combination comprises rilmenidine and A-834,735. In an embodiment, the combination comprises rilmenidine and ACEA. In an embodiment, the combination comprises rilmenidine and AZ-11713908. In an embodiment, the combination comprises rilmenidine and AZD-1940. In an embodiment, the combination comprises rilmenidine and CBN. In an embodiment, the combination comprises rilmenidine and CP-47497. In an embodiment, the combination comprises rilmenidine and CP55940. In an embodiment, the combination comprises rilmenidine and HU-210. In an embodiment, the combination comprises rilmenidine and JWH-007. In an embodiment, the combination comprises rilmenidine and JWH-051. In an embodiment, the combination comprises rilmenidine and JWH-146. In an embodiment, the combination comprises rilmenidine and JWH-176. In an embodiment, the combination comprises rilmenidine and JWH-200. In embodiments, the combination comprises rilmenidine and JWH-398. In embodiments, the combination comprises rilmenidine and Org28611. 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 AL-37350A. In embodiments, the combination comprises rilmenidine and CP 809101. In embodiments, the combination comprises rilmenidine and DALT. In embodiments, the combination comprises rilmenidine and DOB. In embodiments, the combination comprises rilmenidine and DOET. In embodiments, the combination comprises rilmenidine and DOHx. In embodiments, the combination comprises rilmenidine and MEM. In embodiments, the combination comprises rilmenidine and CPP. In embodiments, the combination comprises rilmenidine and NBOH-2C-CN. In embodiments, the combination comprises rilmenidine and TCB-2. In embodiments, the combination comprises rilmenidine and WAY 161503. In embodiments, the combination comprises rilmenidine and 5-CT. In embodiments, the combination comprises rilmenidine and 5-MeO-DALT. In embodiments, the combination comprises rilmenidine and 5-MeO-DMT. In embodiments, the combination comprises rilmenidine and 5-MeO-MiPT. In embodiments, the combination comprises rilmenidine and AGH-192. In embodiments, the combination comprises rilmenidine and AGH-107. In embodiments, the combination comprises rilmenidine and AMT. In embodiments, the combination comprises rilmenidine and aripiprazole. In embodiments, the combination comprises rilmenidine and AS-19. In embodiments, 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.

[0348] In an embodiment, a combination comprises tetrahydrozoline and 2-AGE. In an embodiment, a combination comprises tetrahydrozoline and A-834,735. In an embodiment, a combination comprises tetrahydrozoline and ACEA. In an embodiment, a combination comprises tetrahydrozoline and AZ-11713908. In an embodiment, a combination comprises tetrahydrozoline and AZD-1940. In an embodiment, a combination comprises tetrahydrozoline and CBN. In an embodiment, a combination comprises tetrahydrozoline and CP-47497. In an embodiment, a combination comprises tetrahydrozoline and CP55940. In an embodiment, a combination comprises tetrahydrozoline and HU-210. In an embodiment, a combination comprises tetrahydrozoline and JWH-007. In an embodiment, a combination comprises tetrahydrozoline and JWH-051. In an embodiment, a combination comprises tetrahydrozoline and JWH-146. In an embodiment, a combination comprises tetrahydrozoline and JWH-176. In an embodiment, a combination comprises tetrahydrozoline and JWH-200. In an embodiment, the combination comprises tetrahydrozoline and JWH-398. In an embodiment, the combination comprises tetrahydrozoline and Org28611. In an embodiment, the combination comprises tetrahydrozoline and rimonabant. In an embodiment, the combination comprises tetrahydrozoline and THC. In an embodiment, the combination comprises tetrahydrozoline and WIN 55,212-2. In an embodiment, the combination comprises tetrahydrozoline and XLR11. In an embodiment, the combination comprises tetrahydrozoline and 1-methylpsilocin. In an embodiment, the combination comprises tetrahydrozoline and 2C-B-FLY. In an embodiment, the combination comprises tetrahydrozoline and 5-MeO-AMT. In an embodiment, the combination comprises tetrahydrozoline and AL-37350A. In an embodiment, the combination comprises tetrahydrozoline and CP 809101. In an embodiment, the combination comprises tetrahydrozoline and DALT. In an embodiment, the combination comprises tetrahydrozoline and DOB. In an embodiment, the combination comprises tetrahydrozoline and DOET. In an embodiment, the combination comprises tetrahydrozoline and DOHx. In embodiments, the combination comprises tetrahydrozoline and MEM. In embodiments, the combination comprises tetrahydrozoline and CPP. In embodiments, the combination comprises tetrahydrozoline and NBOH-2C-CN. In embodiments, the combination comprises tetrahydrozoline and TCB-2. In embodiments, the combination comprises tetrahydrozoline and WAY 161503. In embodiments, the combination comprises tetrahydrozoline and 5-CT. In embodiments, the combination comprises tetrahydrozoline and 5-MeO-DALT. In embodiments, the combination comprises tetrahydrozoline and 5-MeO-DMT. In embodiments, the combination comprises tetrahydrozoline and 5-MeO-MiPT. In embodiments, the combination comprises tetrahydrozoline and AGH-192. In embodiments, the combination comprises tetrahydrozoline and AGH-107. In embodiments, the combination comprises tetrahydrozoline and AMT. In embodiments, the combination comprises tetrahydrozoline and aripiprazole. In embodiments, the combination comprises tetrahydrozoline and AS-19. In embodiments, the combination comprises tetrahydrozoline and E-55888.In an embodiment, the combination comprises tetrahydrozoline and LSD. In an embodiment, the combination comprises tetrahydrozoline and LP-211. In an embodiment, the combination comprises tetrahydrozoline and LP-44.

[0349] In an embodiment, the combination comprises tizanidine and 2-AGE. In an embodiment, the combination comprises tizanidine and A-834,735. In an embodiment, the combination comprises tizanidine and ACEA. In an embodiment, the combination comprises tizanidine and AZ-11713908. In an embodiment, the combination comprises tizanidine and AZD-1940. In an embodiment, the combination comprises tizanidine and CBN. In an embodiment, the combination comprises tizanidine and CP-47497. In an embodiment, the combination comprises tizanidine and CP55940. In an embodiment, the combination comprises tizanidine and HU-210. In an embodiment, the combination comprises tizanidine and JWH-007. In an embodiment, the combination comprises tizanidine and JWH-051. In an embodiment, the combination comprises tizanidine and JWH-146. In an embodiment, the combination comprises tizanidine and JWH-176. In an embodiment, the combination comprises tizanidine and JWH-200. In an embodiment, the combination comprises tizanidine and JWH-398. In an embodiment, the combination comprises tizanidine and Org28611. In an embodiment, the combination comprises tizanidine and rimonabant. In an embodiment, the combination comprises tizanidine and THC. In an embodiment, the combination comprises tizanidine and WIN 55,212-2. In an embodiment, the combination comprises tizanidine and XLR11. In an embodiment, the combination comprises tizanidine and 1-methylpsilocybin. In an embodiment, the combination comprises tizanidine and 2C-B-FLY. In an embodiment, the combination comprises tizanidine and 5-MeO-AMT. In an embodiment, the combination comprises tizanidine and AL-37350A. In an embodiment, the combination comprises tizanidine and CP 809101. In an embodiment, the combination comprises tizanidine and DALT. In an embodiment, the combination comprises tizanidine and DOB. In an embodiment, the combination comprises tizanidine and DOET. In an embodiment, 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 an embodiment, the combination comprises tizanidine and LSD. In an embodiment, the combination comprises tizanidine and LP-211. In an embodiment, the combination comprises tizanidine and LP-44.

[0350] In an embodiment, the combination comprises tolonidine and 2-AGE. In an embodiment, the combination comprises tolonidine and A-834,735. In an embodiment, the combination comprises tolonidine and ACEA. In an embodiment, the combination comprises tolonidine and AZ-11713908. In an embodiment, the combination comprises tolonidine and AZD-1940. In an embodiment, the combination comprises tolonidine and CBN. In an embodiment, the combination comprises tolonidine and CP-47497. In an embodiment, the combination comprises tolonidine and CP55940. In an embodiment, the combination comprises tolonidine and HU-210. In an embodiment, the combination comprises tolonidine and JWH-007. In an embodiment, the combination comprises tolonidine and JWH-051. In an embodiment, the combination comprises tolonidine and JWH-146. In an embodiment, the combination comprises tolonidine and JWH-176. In an embodiment, the combination comprises tolonidine and JWH-200. In embodiments, the combination comprises tolonidine and JWH-398. In embodiments, the combination comprises tolonidine and Org28611. In embodiments, the combination comprises tolonidine and rimonabant. In embodiments, the combination comprises tolonidine and THC. In embodiments, the combination comprises tolonidine and WIN 55,212-2. In embodiments, the combination comprises tolonidine and XLR11. In embodiments, the combination comprises tolonidine and 1-methylpsilocin. In embodiments, the combination comprises tolonidine and 2C-B-FLY. In embodiments, the combination comprises tolonidine and 5-MeO-AMT. In embodiments, the combination comprises tolonidine and AL-37350A. In embodiments, the combination comprises tolonidine and CP 809101. In embodiments, the combination comprises tolonidine and DALT. In embodiments, the combination comprises tolonidine and DOB. In embodiments, the combination comprises tolonidine and DOET. In embodiments, the combination comprises tolonidine and DOHx. In embodiments, the combination comprises tolonidine and MEM. In embodiments, the combination comprises tolonidine and CPP. In embodiments, the combination comprises tolonidine and NBOH-2C-CN. In embodiments, the combination comprises tolonidine and TCB-2. In embodiments, the combination comprises tolonidine and WAY 161503. In embodiments, the combination comprises tolonidine and 5-CT. In embodiments, the combination comprises tolonidine and 5-MeO-DALT. In embodiments, the combination comprises tolonidine and 5-MeO-DMT. In embodiments, the combination comprises tolonidine and 5-MeO-MiPT. In embodiments, the combination comprises tolonidine and AGH-192. In embodiments, the combination comprises tolonidine and AGH-107. In embodiments, the combination comprises tolonidine and AMT. In embodiments, the combination comprises tolonidine and aripiprazole. In embodiments, the combination comprises tolonidine and AS-19. In embodiments, the combination comprises tolonidine and E-55888.In embodiments, the combination comprises tolonidine and LSD. In embodiments, the combination comprises tolonidine and LP-211. In embodiments, the combination comprises tolonidine and LP-44.

[0351] In embodiments, the combination comprises agmatine, a CB1 agent, and 1-methylpsilocin. In embodiments, the combination comprises agmatine, a CB1 agent, and 2C-B-FLY. In embodiments, the combination comprises agmatine, a CB1 agent, and 5-MeO-AMT. In embodiments, the combination comprises agmatine, a CB1 agent, and AL-37350A. In embodiments, the combination comprises agmatine, a CB1 agent, and CP809101. In embodiments, the combination comprises agmatine, a CB1 agent, and DALT. In embodiments, the combination comprises agmatine, a CB1 agent, and DOB. In embodiments, the combination comprises agmatine, a CB1 agent, and DOET. In embodiments, the combination comprises agmatine, a CB1 agent, and DOHx. In embodiments, the combination comprises agmatine, a CB1 agent, and MEM. In embodiments, the combination comprises agmatine, a CB1 agent, and CPP. In embodiments, the combination comprises agmatine, a CB1 agent, and NBOH-2C-CN. In embodiments, the combination comprises agmatine, a CB1 agent, and TCB-2. In embodiments, the combination comprises agmatine, a CB1 agent, and WAY 161503. In embodiments, the combination comprises agmatine, a CB1 agent, and 5-CT. In embodiments, the combination comprises agmatine, a CB1 agent, and 5-MeO-DALT. In embodiments, the combination comprises agmatine, a CB1 agent, and 5-MeO-DMT. In embodiments, the combination comprises agmatine, a CB1 agent, and 5-MeO-MiPT. In embodiments, the combination comprises agmatine, a CB1 agent, and AGH-192. In embodiments, the combination comprises agmatine, a CB1 agent, and AGH-107. In embodiments, the combination comprises agmatine, a CB1 agent, and AMT. In embodiments, the combination comprises agmatine, a CB1 agent, and aripiprazole. In embodiments, the combination comprises agmatine, a CB1 agent, and AS-19. In embodiments, the combination comprises agmatine, a CB1 agent, and E-55888. In embodiments, the combination comprises 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.

[0352] In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and 1-methyl psilocybin. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and 2C-B-FLY. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and 5-MeO-AMT. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and AL-37350A. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and CP 809101. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and DALT. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and DOB. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and DOET. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and DOHx. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and MEM. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and CPP. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and NBOH-2C-CN. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and TCB-2. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and WAY161503. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and 5-CT. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and 5-MeO-DALT. In an embodiment, the combination comprises BDBM50091347, a CB1 agent, and 5-MeO-DMT. In an embodiment, 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 comprises BDBM50091347, a CB1 agent, and aripiprazole. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and AS-19. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and E-55888. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and LSD. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and LP-211. In embodiments, the combination comprises BDBM50091347, a CB1 agent, and LP-44.

[0353] 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 CP809101. 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 comprises clonidine, a CB1 agent, and CPP. In embodiments, the combination comprises clonidine, a CB1 agent, and NBOH-2C-CN. In embodiments, the combination comprises clonidine, a CB1 agent, and TCB-2. In embodiments, the combination comprises clonidine, a CB1 agent, and WAY 161503. In embodiments, the combination comprises clonidine, a CB1 agent, and 5-CT. In embodiments, the combination comprises clonidine, a CB1 agent, and 5-MeO-DALT. In embodiments, the combination comprises clonidine, a CB1 agent, and 5-MeO-DMT. In embodiments, the combination comprises clonidine, a CB1 agent, and 5-MeO-MiPT. In embodiments, the combination comprises 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.

[0354] In embodiments, the combination comprises guanfacine, a CB1 agent, and 1-methylpsilocin. In embodiments, the combination comprises guanfacine, a CB1 agent, and 2C-B-FLY. In embodiments, the combination comprises guanfacine, a CB1 agent, and 5-MeO-AMT. In embodiments, the combination comprises guanfacine, a CB1 agent, and AL-37350A. In embodiments, the combination comprises guanfacine, a CB1 agent, and CP809101. In embodiments, the combination comprises guanfacine, a CB1 agent, and DALT. In embodiments, the combination comprises guanfacine, a CB1 agent, and DOB. In embodiments, the combination comprises guanfacine, a CB1 agent, and DOET. In embodiments, the combination comprises guanfacine, a CB1 agent, and DOHx. In embodiments, the combination comprises guanfacine, a CB1 agent, and MEM. In embodiments, the combination comprises guanfacine, a CB1 agent, and CPP. In embodiments, the combination comprises guanfacine, a CB1 agent, and NBOH-2C-CN. In embodiments, the combination comprises guanfacine, a CB1 agent, and TCB-2. In embodiments, the combination comprises guanfacine, a CB1 agent, and WAY 161503. In embodiments, the combination comprises guanfacine, a CB1 agent, and 5-CT. In embodiments, the combination comprises guanfacine, a CB1 agent, and 5-MeO-DALT. In embodiments, the combination comprises guanfacine, a CB1 agent, and 5-MeO-DMT. In embodiments, the combination comprises guanfacine, a CB1 agent, and 5-MeO-MiPT. In embodiments, the combination comprises guanfacine, a CB1 agent, and AGH-192. In embodiments, the combination comprises guanfacine, a CB1 agent, and AGH-107. In embodiments, the combination comprises guanfacine, a CB1 agent, and AMT. In embodiments, the combination comprises guanfacine, a CB1 agent, and aripiprazole. In embodiments, the combination comprises guanfacine, a CB1 agent, and AS-19. In embodiments, the combination comprises guanfacine, a CB1 agent, and E-55888. In embodiments, the combination comprises guanfacine, a CB1 agent, and LSD. In embodiments, the combination comprises guanfacine, a CB1 agent, and LP-211. In embodiments, the combination comprises guanfacine, a CB1 agent, and LP-44.

[0355] In embodiments, the combination comprises mCPP, a CB1 agent, and 1-methylpsilocybin. In embodiments, the combination comprises mCPP, a CB1 agent, and 2C-B-FLY. In embodiments, the combination comprises mCPP, a CB1 agent, and 5-MeO-AMT. In embodiments, the combination comprises mCPP, a CB1 agent, and AL-37350A. In embodiments, the combination comprises mCPP, a CB1 agent, and CP 809101. In embodiments, the combination comprises mCPP, a CB1 agent, and DALT. In embodiments, the combination comprises mCPP, a CB1 agent, and DOB. In embodiments, the combination comprises mCPP, a CB1 agent, and DOET. In embodiments, the combination comprises mCPP, a CB1 agent, and DOHx. In embodiments, the combination comprises mCPP, a CB1 agent, and MEM. In embodiments, the combination comprises mCPP, a CB1 agent, and CPP. In embodiments, the combination comprises mCPP, a CB1 agent, and NBOH-2C-CN. In embodiments, the combination comprises mCPP, a CB1 agent, and TCB-2. In embodiments, the combination comprises mCPP, a CB1 agent, and WAY 161503. In embodiments, the combination comprises mCPP, a CB1 agent, and 5-CT. In embodiments, the combination comprises mCPP, a CB1 agent, and 5-MeO-DALT. In embodiments, the combination comprises mCPP, a CB1 agent, and 5-MeO-DMT. In embodiments, the combination comprises mCPP, a CB1 agent, and 5-MeO-MiPT. In embodiments, the combination comprises mCPP, a CB1 agent, and AGH-192. In embodiments, the combination comprises mCPP, a CB1 agent, and AGH-107. In embodiments, the combination comprises mCPP, a CB1 agent, and AMT. In embodiments, the combination comprises mCPP, a CB1 agent, and aripiprazole. In embodiments, the combination comprises mCPP, a CB1 agent, and AS-19. In embodiments, the combination comprises mCPP, a CB1 agent, and E-55888. In embodiments, the combination comprises mCPP, a CB1 agent, and LSD. In embodiments, the combination comprises mCPP, a CB1 agent, and LP-211. In embodiments, the combination comprises mCPP, a CB1 agent, and LP-44.

[0356] In embodiments, the combination comprises MDMA, a CB1 agent, and 1-methylpsilocybin. In embodiments, the combination comprises MDMA, a CB1 agent, and 2C-B-FLY. In embodiments, the combination comprises MDMA, a CB1 agent, and 5-MeO-AMT. In embodiments, the combination comprises MDMA, a CB1 agent, and AL-37350A. In embodiments, the combination comprises MDMA, a CB1 agent, and CP 809101. In embodiments, the combination comprises MDMA, a CB1 agent, and DALT. In embodiments, the combination comprises MDMA, a CB1 agent, and DOB. In embodiments, the combination comprises MDMA, a CB1 agent, and DOET. In embodiments, the combination comprises MDMA, a CB1 agent, and DOHx. In embodiments, the combination comprises MDMA, a CB1 agent, and MEM. In embodiments, the combination comprises MDMA, a CB1 agent, and CPP. In embodiments, the combination comprises MDMA, a CB1 agent, and NBOH-2C-CN. In embodiments, the combination comprises MDMA, a CB1 agent, and TCB-2. In em...

Claims

1. A therapeutic combination for inducing a state of mind that enhances interpersonal intimacy, the therapeutic combination comprising an imidazoline-1 (I1) agent and a 5-HT7 agent.

2. The therapeutic combination according to claim 1, wherein the I1 agent is an I1 agonist.

3. The therapeutic combination of claim 1, wherein the I1 agent has a selectivity for the I1 receptor as compared to its selectivity for the α2 (alpha-2) adrenergic receptor of at least about 30:

1.

4. The therapeutic combination of claim 1, wherein the I1 agent is agmatine, BDBM50091347, clonidine, guanfacine, mCPP, memantine, moxonidine, naphazoline, oxymetazoline, rilmenidine, tetryzoline, tizanidine or tolonidine, or a pharmaceutically acceptable salt thereof.

5. The therapeutic combination of claim 4, wherein the I1 agent is clonidine, moxonidine or rilmenidine or a pharmaceutically acceptable salt thereof.

6. The therapeutic combination of claim 5, wherein the I1 agent is clonidine or a pharmaceutically acceptable salt thereof.

7. The therapeutic combination of claim 5, wherein the I1 agent is moxonidine or a pharmaceutically acceptable salt thereof.

8. The therapeutic combination of claim 5, wherein the I1 agent is rilmenidine or a pharmaceutically acceptable salt thereof.

9. The therapeutic combination of claim 1, wherein the 5-HT7 agent is a 5-HT7 agonist.

10. The therapeutic combination of claim 1, wherein the 5-HT7 agent has a 5-HT7 receptor K i Less than 10nM.

11. The therapeutic combination of claim 1, wherein the 5-HT7 agent is a tryptamine.

12. The therapeutic combination of claim 11, wherein the 5-HT7 agent is 5-MeO-DMT or 5-MeO-MiPT or a pharmaceutically acceptable salt thereof.

13. The therapeutic combination of claim 12, wherein the 5-HT7 agent is 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

14. The therapeutic combination of claim 12, wherein the 5-HT7 agent is 5-MeO-MiPT or a pharmaceutically acceptable salt thereof.

15. The therapeutic combination of claim 1, wherein the therapeutic combination comprises clonidine or a pharmaceutically acceptable salt thereof and 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

16. The therapeutic combination of claim 1, wherein the therapeutic combination comprises moxonidine or a pharmaceutically acceptable salt thereof and 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

17. The therapeutic combination of claim 1, wherein the therapeutic combination comprises rilmenidine or a pharmaceutically acceptable salt thereof and 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

18. The therapeutic combination of claim 1, wherein the therapeutic combination comprises clonidine or a pharmaceutically acceptable salt thereof and 5-MeO-MiPT or a pharmaceutically acceptable salt thereof.

19. The therapeutic combination of claim 1, wherein the therapeutic combination comprises moxonidine or a pharmaceutically acceptable salt thereof and 5-MeO-MiPT or a pharmaceutically acceptable salt thereof.

20. The therapeutic combination of claim 1, wherein the therapeutic combination comprises rilmenidine or a pharmaceutically acceptable salt thereof and 5-MeO-MiPT or a pharmaceutically acceptable salt thereof.

21. The therapeutic combination according to any one of claims 1 to 20, further comprising a 5-HT2 agent, a CB1 agent, an additional I1 agent or an additional 5-HT7 agent.

22. The therapeutic combination according to any one of claims 1 to 20, further comprising a 5-HT2 agent.

23. The therapeutic combination of claim 22, wherein the 5-HT2 agent is a 5-HT2 agonist.

24. The therapeutic combination of claim 23, wherein the 5-HT2 agonist is 1-methylpsilocybin, 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.

25. The therapeutic combination according to any one of claims 1 to 20, further comprising a CB1 agent.

26. The therapeutic combination of claim 25, wherein the CB1 agent is a cannabinoid.

27. The therapeutic combination of claim 25, wherein 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.

28. The therapeutic combination according to any one of claims 1 to 20, further comprising an additional I1 agent.

29. The therapeutic combination of claim 28, wherein the additional I1 agent is an I1 agonist.

30. The therapeutic combination of claim 28, wherein the additional I1 agent has a selectivity for the I1 receptor as compared to its selectivity for the α2 (alpha-2) adrenergic receptor of at least about 30:

1.

31. The therapeutic combination of claim 28, wherein the additional I1 agent is agmatine, BDBM50091347, clonidine, guanfacine, mCPP, MDMA, memantine, moxonidine, naphazoline, oxymetazoline, rilmenidine, tetrahydrozoline, tizanidine, or tolonidine, or a pharmaceutically acceptable salt thereof.

32. The therapeutic combination of claim 31, wherein the additional I1 agent is clonidine, moxonidine or rilmenidine or a pharmaceutically acceptable salt thereof.

33. The therapeutic combination according to any one of claims 1 to 20, further comprising an additional 5-HT7 agent.

34. The therapeutic combination of claim 33, wherein the additional 5-HT7 agent is a 5-HT7 agonist.

35. The therapeutic combination of claim 33, wherein the 5-HT7 receptor K of the additional 5-HT7 agent is i Less than 10nM.

36. The therapeutic combination of claim 33, wherein 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, psilocybin, RR-2b, EMDT, lisuride, DiPT, SS-2c, TMA, 2C-B, 2C-E or MDA or a pharmaceutically acceptable salt thereof.

37. The therapeutic combination of claim 36, wherein the additional 5-HT7 agent is 5-MeO-DMT or 5-MeO-MiPT or a pharmaceutically acceptable salt thereof.

38. The therapeutic combination according to any one of claims 1 to 20, further comprising: a.5-HT2 agents and CB1 agents; b. 5-HT2 agents and additional I1 agents; c. 5-HT2 agents and additional 5-HT7 agents; d. 5-HT2 agents and other 5-HT2 agents; e. CB1 agent and another I1 agent; f. a CB1 agent and an additional 5-HT7 agent; or g. CB1 agents and additional CB1 agents.

39. The therapeutic combination of claim 38, wherein the 5-HT2 agent is a 5-HT2 agonist.

40. The therapeutic combination of claim 40, wherein the 5-HT2 agonist is 1-methylpsilocybin, 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.

41. The therapeutic combination of claim 38, wherein the additional 5-HT2 agent is a 5-HT2 agonist.

42. The therapeutic combination of claim 41, wherein the additional 5-HT2 agonist is 1-methylpsilocybin, 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.

43. The therapeutic combination of claim 38, wherein the CB1 agent is a cannabinoid.

44. The therapeutic combination of claim 38, wherein 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.

45. The therapeutic combination of claim 38, wherein the additional CB1 agent is a cannabinoid.

46. ​​The therapeutic combination of claim 38, wherein 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.

47. The therapeutic combination of claim 38, wherein the additional I1 agent is an I1 agonist.

48. The therapeutic combination of claim 38, wherein the additional I1 agent has a selectivity for the I1 receptor as compared to its selectivity for the α2 (alpha-2) adrenergic receptor of at least about 30:

1.

49. The therapeutic combination of claim 38, wherein the additional I1 agent is agmatine, BDBM50091347, clonidine, guanfacine, mCPP, MDMA, memantine, moxonidine, naphazoline, oxymetazoline, rilmenidine, tetrahydrozoline, tizanidine, or tolonidine, or a pharmaceutically acceptable salt thereof.

50. The therapeutic combination of claim 79, wherein the additional I1 agent is clonidine, moxonidine, or rilmenidine, or a pharmaceutically acceptable salt thereof.

51. The therapeutic combination of claim 38, wherein the 5-HT7 receptor K of the additional 5-HT7 agent is i Less than 10nM.

52. The therapeutic combination of claim 38, wherein 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, psilocybin, RR-2b, EMDT, lisuride, DiPT, SS-2c, TMA, 2C-B, 2C-E or MDA or a pharmaceutically acceptable salt thereof.

53. The therapeutic combination of claim 52, wherein the additional 5-HT7 agent is 5-MeO-DMT or 5-MeO-MiPT or a pharmaceutically acceptable salt thereof.

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

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

56. The pharmaceutical composition of claim 54, wherein the composition is provided in unit dosage form.

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

58. A method of inducing a mental state in a subject that enhances interpersonal intimacy, the method comprising administering to the subject the therapeutic combination of any one of claims 1 to 20 or the pharmaceutical composition of claim 54.

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

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

61. The method of claim 58, wherein the agent is administered alone.

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

63. The method of claim 62, wherein the I1 agent is administered prior to the 5-HT7 agent.

64. The method of claim 62, wherein when the therapeutic combination or the composition comprises a CB1 agent, the CB1 agent is administered prior to the 5-HT7 agent.

65. The method of claim 62, wherein when the therapeutic combination or the composition comprises a CB1 agent, the CB1 agent is administered after the I1 agent.

66. The method of claim 58, wherein the I1 agent is administered orally.

67. The method of claim 58, wherein the 5-HT7 agent is administered orally, sublingually, intranasally, or by inhalation.

68. The method of claim 58, wherein when the therapeutic combination or the composition comprises a CB1 agent, the CB1 agent is administered orally, sublingually, or by inhalation.

69. The method of claim 58, wherein the I1 agent is administered at a dose of about 0.1 mg to 1.0 mg.

70. The method of claim 58, wherein the 5-HT7 agent is administered at a dose of about 2 mg to 20 mg.

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

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

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

74. The method of claim 58, wherein the intimacy-enhancing mental state is a better intimacy-enhancing mental state than MDMA or another known intimacy-enhancing agent, wherein the intimacy-enhancing mental state is determined by brain imaging or by measuring the levels of one or more neurotransmitters in the subject.

75. The method of claim 58, wherein the better intimacy-enhancing mental state is an extended intimacy-enhancing mental state or an enhanced intimacy-enhancing mental state when compared to MDMA or another known intimacy-enhancing agent, wherein the intimacy-enhancing mental state is determined by brain imaging or by measuring the levels of one or more neurotransmitters in the subject.

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

77. The method of claim 58, wherein the method produces no or reduced adverse effects of MDMA or another known interpersonal bonding agent.

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

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. 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 intimacy enhancing agent; b) oxidative stress and dopamine-based quinones; c) mitochondrial dysfunction; and d) activation of glial cells.

81. The method of claim 80, wherein the reduction in neurotoxic effect is at least 5%, 10%, 25%, 50%, 75%, 100%, 150% or 200% relative to one or more comparators.

82. A method for modulating neurotransmission in a mammal, said method comprising administering to said mammal a therapeutic combination according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 54.

83. The method of claim 82, wherein the neurotransmission is mediated by: an I1 receptor, a 5-HT2 receptor, a 5-HT7 receptor, or a CB1 receptor.

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

85. A method of treating a medical condition in a human in need of such treatment, said method 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. The method of claim 85, wherein the medical condition is a disorder associated with dysregulation or insufficiency of neurotransmission.

87. The method of claim 86, wherein the condition is associated with dysregulation or insufficiency of neurotransmission mediated by: the I1 receptor, the 5-HT2 receptor, the 5-HT7 receptor, or the CB1 receptor.

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

89. The method of claim 88, wherein the CNS disorder is any one 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 disorder, phobia, indulgence 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 disease), motor neurone disease, multiple system atrophy, progressive supranuclear palsy, migraine, cluster headache, short-lasting unilateral neuralgia-like headache, fibromyalgia, traumatic brain injury, and mild traumatic brain injury (mTBI).

90. The method of claim 88, wherein the CNS disorder is a disorder associated with rigid thought patterns.

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

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

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

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

95. The method of claim 94, wherein the improvement in psychological health or function is a decrease in neuroticism or psychological defensiveness, increased creativity or openness to experience, improved decision making, improved ability to fall asleep or stay asleep, increased well-being or contentment, improved ability to forgive oneself or others, improved ability to experience or consider pain, including psychic pain, or improved ability to be "inner in touch," including in and during daily life and activities.

96. The method of claim 95, wherein the creativity enhancement is an enhancement of intentional cognitive creativity, intentional emotional creativity, spontaneous cognitive creativity, or spontaneous emotional creativity.

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

98. A therapeutic combination for inducing a state of mind that enhances interpersonal intimacy, the therapeutic combination comprising: a. The therapeutic combination according to any one of claims 1 to 53; or b. I1 agent and one or more of the following: a 5-HT2 agent, a 5-HT7 agent, and a CB1 agent.

99. A pharmaceutical composition comprising the therapeutic combination according to any one of the preceding claims and a pharmaceutically acceptable carrier, diluent or excipient.

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

101. The pharmaceutical composition of claim 99 or 100, wherein the composition is provided in unit dosage form.

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

103. A method of inducing a mental state in a subject that enhances interpersonal intimacy, the method comprising administering to the subject a therapeutic combination or pharmaceutical composition according to any one of the preceding claims.

104. A method for modulating neurotransmission in a mammal, the method comprising administering to the mammal a therapeutic combination or pharmaceutical composition according to any one of the preceding claims.

105. A method of treating a medical condition in a human in need of such treatment, said method comprising administering to said human a therapeutic combination or pharmaceutical composition according to any one of the preceding claims.

106. A method of improving the psychological health or functioning of a human, the method comprising identifying a human in need of such improvement, and administering to the human a therapeutic combination or pharmaceutical composition according to any one of the preceding claims.

107. A method of reducing symptoms of a CNS disorder in a human, the method comprising identifying a human in need of such reduction, and administering to the human a therapeutic combination or pharmaceutical composition according to any one of the preceding claims.

108. The method of any of the preceding claims, wherein the pharmaceutical composition or the therapeutic combination is administered with psychotherapy.

109. The method of any one of the preceding claims, wherein the pharmaceutical composition or the therapeutic combination is administered together with psychological support.

110. The method of any of the preceding claims, wherein the pharmaceutical composition or the therapeutic combination is administered with patient monitoring.

111. The method of any of the preceding claims, wherein the pharmaceutical composition or the therapeutic combination is administered in conjunction with the patient's performance of a therapeutically beneficial activity.

112. The method of any one of the preceding claims, wherein the pharmaceutical composition or the therapeutic combination is administered without psychotherapy or psychological support.

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