WO2020252384A1

WO2020252384A1 - Treatment methods utilizing oxytocin receptor agonists

Info

Publication number: WO2020252384A1
Application number: PCT/US2020/037592
Authority: WO
Inventors: Gary VORSANGER
Original assignee: Vorsanger Gary
Priority date: 2019-06-14
Filing date: 2020-06-12
Publication date: 2020-12-17

Abstract

The present invention provides compositions and related methods of treating neuropsychiatric conditions such as Opioid use disorder (OUD), cocaine use disorder (CUD), post-traumatic stress disorder (PTSD), and unipolar post-partum depression (PPD) utilizing an oxytocin receptor agonist, such as e.g., oxytocin or carbetocin, in combination with opioid agonists, opioid antagonists and/or α-2 adrenergic receptor agonists.

Description

Treatment Methods Utilizing Oxytocin Receptor Agonists

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.

62/861,590, filed on June 14, 2019 and claims the benefit of U.S. Provisional Application No. 62/861,904, filed on June 14, 2019. The entire teachings of the above applications are incorporated herein by reference.

BACKGROUND

[0002] Neuropsychiatric conditions such as Opioid use disorder (OUD), cocaine use disorder (CUD), post-traumatic stress disorder (PTSD), and post-partum unipolar depression (PPD) are all clinical conditions that pose a significant public health problem.

SUMMARY

[0003] The present invention provides, in some aspects, methods of treating opioid use disorder (OUD), cocaine use disorder (CUD), post-traumatic stress disorder (PTSD) and post-partum unipolar depression (PPD) utilizing an oxytocin receptor regulator (e.g., an oxytocin receptor agonist), such as e.g. but not limited to, oxytocin or carbetocin, in combination with opioid agonists, opioid partial agonists, opioid antagonists, a-2c adrenergic receptor antagonists, a-2 adrenergic receptor agonists, NMD A receptor antagonists such as ketamine, esketamine, NMDA receptor agonists such as D-serine, D-cycloserine and/or 3,4- Methylenedioxymethamphetamine (MDMA), and/or cannabidiol.

[0004] In one aspect, the present invention provides methods of treating a

neuropsychiatric condition in a subject in need thereof, comprising administering to the subject:

a) a therapeutically effective amount of a first compound during a pretreatment step, wherein the first compound regulates an oxytocin receptor; and b) therapeutically effective amounts of the first compound and a second

compound during a treatment step, wherein the second compound regulates an opioid receptor, a cocaine receptor, an adrenergic receptor, an N-methyl-D- aspartate receptor (NMD A) receptor, is MDMA or a combination thereof, wherein the neuropsychiatric condition is selected from the group consisting of PTSD, OUD, CUD, PPD and combinations thereof.

[0005] In some embodiments, the treatment step comprises an induction step, a maintenance step and a tapering step.

[0006] In a further aspect, the present invention provides methods of conditioning a subject in need thereof for treatment of a neuropsychiatric condition, comprising

administering to the subject a therapeutically effective amount of a first compound during a pretreatment step, wherein the first compound regulates an oxytocin receptor, and the neuropsychiatric condition is selected from the group consisting of PTSD, OUD, CUD, PPD and combinations thereof.

[0007] In some embodiments, the methods further comprise a treatment step comprising administering to the subject therapeutically effective amounts of the first compound and a second compound, wherein the second compound regulates an opioid receptor, a cocaine receptor, an adrenergic receptor, an NMDA receptor, is MDMA, or a combination thereof. In some embodiments, the treatment step comprises an induction step, a maintenance step and a tapering step.

[0008] In a further aspect, the present invention provides methods of treating opioid use disorder (OUD) in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an opioid agonist to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an opioid partial agonist to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an opioid antagonist to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and a-2 adrenergic receptor agonist to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an A-methyl-D-aspartate receptor (NMD A) receptor antagonist to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and ketamine to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and esketamine to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and D-serine to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and D-cycloserine to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and cannabidiol to the subject.

[0009] In a further aspect, the present invention provides methods of treating or preventing or reducing the severity of post-traumatic stress disorder (PTSD) in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an opioid agonist to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an opioid antagonist to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an a-2 adrenergic receptor agonist to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and ketamine to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and esketamine to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and MDMA to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and D-serine to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and D-cycloserine to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and cannabidiol to the subject.

[0010] In some embodiments, the PTSD is acute and in other embodiments, the PTSD is chronic.

[0011] In another aspect, the present invention provides methods of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an opioid agonist to the subject. In another aspect, the present invention provides methods of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an a-2c adrenergic receptor antagonist to the subject. In another aspect, the present invention provides methods of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and ketamine to the subject. In another aspect, the present invention provides methods of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and esketamine to the subject. In another aspect, the present invention provides methods of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and D-serine to the subject. In another aspect, the present invention provides methods of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and D- cycloserine to the subject.

[0012] In some embodiments, the opioid agonist is selected from the group consisting of tramadol, buprenorphine (opioid partial agonist), tapentadol, methadone and a combination thereof. In one embodiment, the opioid agonist is tramadol, or a pharmaceutically acceptable salt thereof. In one embodiment, the opioid agonist is tapentadol, or a pharmaceutically acceptable salt thereof. In one embodiment, the opioid agonist is buprenorphine (opioid partial agonist), or a pharmaceutically acceptable salt thereof. In one embodiment, the opioid agonist is methadone, or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the opioid agonist is an extended-release form. In other embodiments, the opioid agonist is an immediate-release form. In some embodiments, the opioid partial agonist is an extended-release form. In other embodiments, the opioid partial agonist is an immediate-release form.

[0014] In some embodiments, the oxytocin receptor agonist and the opioid agonist are administered in a single dosage form. In some embodiments, the oxytocin receptor agonist and the opioid partial agonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[0015] In some embodiments, the oxytocin receptor agonist is administered prior to administration of the opioid agonist. In other embodiments, the oxytocin receptor agonist is administered after administration of the opioid agonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of the opioid agonist. In some embodiments, the oxytocin receptor agonist is administered prior to administration of the opioid partial agonist. In other embodiments, the oxytocin receptor agonist is

administered after administration of the opioid partial agonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of the opioid partial agonist.

[0016] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of an opioid antagonist to the subject. In some embodiments, the opioid antagonist is naltrexone, or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the opioid antagonist is an extended-release form. In other embodiments, the opioid antagonist is an immediate-release form.

[0018] In some embodiments, the oxytocin receptor agonist and the opioid antagonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[0019] In some embodiments, the oxytocin receptor agonist is administered prior to administration of the opioid antagonist. In other embodiments, the oxytocin receptor agonist is administered after administration of the opioid antagonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of the opioid antagonist.

[0020] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of an a-2 adrenergic receptor agonist to the subject. In some embodiments, the a-2 adrenergic receptor agonist is lofexidine, or a pharmaceutically acceptable salt thereof. In some embodiments, the a-2 adrenergic receptor agonist is clonidine, or a pharmaceutically acceptable salt thereof. In some embodiments, the a-2 adrenergic receptor agonist is selected from lofexidine, clonidine, or a combination thereof.

[0021] In some embodiments, the a-2 adrenergic receptor agonist is an extended-release form. In other embodiments, the a-2 adrenergic receptor agonist is an immediate-release form.

[0022] In some embodiments, the oxytocin receptor agonist and the a-2 adrenergic receptor agonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form. [0023] In some embodiments, the oxytocin receptor agonist is administered prior to administration of the a-2 adrenergic receptor agonist. In other embodiments, the oxytocin receptor agonist is administered after administration of the a-2 adrenergic receptor agonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of the a-2 adrenergic receptor agonist.

[0024] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of an a-2c adrenergic receptor antagonist to the subject.

[0025] In some embodiments, the a-2c adrenergic receptor antagonist is an extended- release form. In other embodiments, the a-2c adrenergic receptor antagonist is an immediate- release form.

[0026] In some embodiments, the oxytocin receptor agonist and the a-2c adrenergic receptor antagonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[0027] In some embodiments, the oxytocin receptor agonist is administered prior to administration of the a-2c adrenergic receptor antagonist. In other embodiments, the oxytocin receptor agonist is administered after administration of the a-2c adrenergic receptor antagonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of the a-2c adrenergic receptor antagonist.

[0028] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of an A-methyl-D-aspartate receptor (NMD A) receptor antagonist to the subject.

[0029] In some embodiments, the NMDA receptor antagonist is an extended-release form. In other embodiments, the NMDA receptor antagonist is an immediate-release form.

[0030] In some embodiments, the oxytocin receptor agonist and the NMDA receptor antagonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[0031] In some embodiments, the oxytocin receptor agonist is administered prior to administration of NMDA receptor antagonist. In other embodiments, the oxytocin receptor agonist is administered after administration of NMDA receptor antagonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of NMDA receptor antagonist.

[0032] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of ketamine to the subject.

[0033] In some embodiments, the ketamine is an extended-release form. In other embodiments, the ketamine is an immediate-release form.

[0034] In some embodiments, the oxytocin receptor agonist and the ketamine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[0035] In some embodiments, the oxytocin receptor agonist is administered prior to administration of ketamine. In other embodiments, the oxytocin receptor agonist is administered after administration of ketamine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of ketamine.

[0036] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of esketamine to the subject.

[0037] In some embodiments, the esketamine is an extended-release form. In other embodiments, the esketamine is an immediate-release form.

[0038] In some embodiments, the oxytocin receptor agonist and the esketamine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[0039] In some embodiments, the oxytocin receptor agonist is administered prior to administration of esketamine. In other embodiments, the oxytocin receptor agonist is administered after administration of esketamine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of esketamine.

[0040] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of MDMA to the subject. [0041] In some embodiments, the MDMA is an extended-release form. In other embodiments, the MDMA is an immediate-release form.

[0042] In some embodiments, the oxytocin receptor agonist and the MDMA are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[0043] In some embodiments, the oxytocin receptor agonist is administered prior to administration of MDMA. In other embodiments, the oxytocin receptor agonist is administered after administration of MDMA. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of MDMA.

[0044] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of D-serine to the subject.

[0045] In some embodiments, the D-serine is an extended-release form. In other embodiments, the D-serine is an immediate-release form.

[0046] In some embodiments, the oxytocin receptor agonist and the D-serine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[0047] In some embodiments, the oxytocin receptor agonist is administered prior to administration of D-serine. In other embodiments, the oxytocin receptor agonist is administered after administration of D-serine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of D-serine.

[0048] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of D-cycloserine to the subject.

[0049] In some embodiments, the D-cycloserine is an extended-release form. In other embodiments, the D-cycloserine is an immediate-release form.

[0050] In some embodiments, the oxytocin receptor agonist and the D-cycloserine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form. [0051] In some embodiments, the oxytocin receptor agonist is administered prior to administration of D-cycloserine. In other embodiments, the oxytocin receptor agonist is administered after administration of D-cycloserine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of D-cycloserine.

[0052] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of cannabidiol to the subject.

[0053] In some embodiments, the cannabidiol is an extended-release form. In other embodiments, the cannabidiol is an immediate-release form.

[0054] In some embodiments, the oxytocin receptor agonist and the cannabidiol are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[0055] In some embodiments, the oxytocin receptor agonist is oxytocin. In some embodiments, the oxytocin receptor agonist is carbetocin.

[0056] In some embodiments, the oxytocin receptor agonist is administered prior to administration of cannabidiol. In other embodiments, the oxytocin receptor agonist is administered after administration of cannabidiol. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of cannabidiol. In other

embodiments, the cannabidiol is administered after administration of oxytocin receptor agonist.

[0057] In some embodiments, the oxytocin receptor agonist is administered orally. In other embodiments, the oxytocin receptor agonist is administered intranasally. In further embodiments, the oxytocin receptor agonist is administered transdermally, intramuscularly or intravenously. In some embodiments, the oxytocin receptor agonist is administered intradermally.

[0058] In some embodiments, the oxytocin receptor agonist is selected from an extended- release form and an immediate-release form.

BRIEF DESCRIPTION OF THE DRAWING

[0059] FIGURE depicts a non-limiting example how a patient with post-traumatic stress disorder (PTSD), opioid use disorder (OUD), cocaine use disorder (CUD), and/or unipolar post-partum depression (PPD) would be treated with methods of the disclosure. A diagnosis of PTSD, OUT), CUD and/or PPD is made and pretreatment and treatment are performed (e.g., by someone knowledgeable and skilled in the art of treating this condition). An initial pretreatment step comprises administering the hormone Oxytocin (OT) for two to four weeks. The pretreatment step is followed by a treatment step that comprises an induction step with a number of medications including Oxytocin. During the induction step, the treatment is optimized and individualized for each subject. This is followed by a maintenance step where treatment established during the induction step continues as clinically needed, which is followed by a tapering step.

DETAILED DESCRIPTION

[0060] Oxytocin (OT) is a hypothalamo-pituitary neuropeptide well known for its role in social cognition and behavior (Lieberwirth and Wang, 2014; Meyer-Lindenberg A, 2011).

OT administration has demonstrated myriad anti -addiction effects in animal models of substance dependence (Sarnyai Z, 2014; Carson et al, 2013). For example, OT dose- dependently attenuates opioid and cocaine tolerance and opioid withdrawal reactions. This is important because tolerance and withdrawal are key drivers of physiological drug

dependence. Behaviorally, OT administration reduces stress-induced opioid seeking (Zanos et al, 2014), cue-induced cocaine seeking (Bentzley BS, 2014; Morales-Rivera et al, 2014), cocaine-induced stereotyped behavior (Carson et al, 2013), and opioid and cocaine self administration (Sarnyai Z, 2014) in rodents. Thus, OT functions at multiple levels to diminish the effects of both opioids and psychostimulants and, ultimately, reduce their consumption, making it a prime candidate for the treatment of co-occurring opioid use disorder (OUD) and cocaine use disorder (CUD).

[0061] A description of example embodiments follows.

[0062] Several aspects of the invention are described below, with reference to examples for illustrative purposes only. It should be understood that numerous specific details, relationships, and methods are set forth to provide a full understanding of the invention. One having ordinary skill in the relevant art, however, will readily recognize that the invention can be practiced without one or more of the specific details or practiced with other methods, protocols, reagents, and animals. The present invention is not limited by the illustrated ordering of acts or events, as some acts may occur in different orders and/or concurrently with other acts or events. Furthermore, not all illustrated acts, steps or events are required to implement a methodology in accordance with the present invention. Many of the techniques and procedures described, or referenced herein, are well understood and commonly employed using conventional methodology by those skilled in the art.

[0063] Prior to setting forth the invention in detail, it may be helpful to the understanding thereof to define several terms, and these are accordingly set forth in the next section, below. Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and/or as otherwise defined herein.

[0064] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the indefinite articles "a", "an" and "the" should be understood to include plural reference unless the context clearly indicates otherwise.

[0065] The phrase "and/or," as used herein, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases.

[0066] As used herein, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when separating a listing of items, "and/or" or "or" shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number of items, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of."

[0067] As used herein, the terms "including", "includes", "having", "has", "with", or variants thereof, are intended to be inclusive similar to the term "comprising."

[0068] As used herein, the term "subject" refers to an animal. Typically, the terms "subject" and "patient" may be used interchangeably herein in reference to a subject. As such, a "subject" includes an animal that is being treated by the methods described herein, or the recipient of a mixture of components as described herein. The term "animal," includes, but is not limited to, a mammal, such as a mouse, rat, dog, guinea pig, cow, horse, chicken, cat, rabbit, pig, monkey, chimpanzee, and human.

[0069] The term "therapeutically effective amount" or "effective amount," as applied to the compositions described herein, means the quantity necessary to render the desired therapeutic result. For example, an effective amount can be a dosage level effective to treat opioid use disorder. Some variation in dosage will necessarily occur depending upon many factors that would be known by those skilled in the art, and the physician or other individual administering such a composition, in any event, determine the appropriate dosage for an individual patient.

[0070] The term "pharmaceutically acceptable," as used herein, means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and/or in humans.

[0071] "Pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyljbenzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-di sulfonic acid, 2 -hydroxy ethanesulfonic acid,

benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2naphthalenesulfonic acid, 4- toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2]-oct-2-ene-l -carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced. Particularly useful are sodium and potassium salts of the active ingredients described herein.

[0072] The compositions described herein may be administered by way of a carrier. The term "carrier" refers to a diluent, adjuvant, excipient, and/or vehicle with which the compositions are administered. Proper formulation is dependent upon the route of

administration chosen. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, sucrose, gelatin, lactose, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, glycerol, propylene, glycol, water, ethanol and the like. The pharmaceutical composition(s) may also contain wetting or emulsifying agents or suspending/diluting agents, or pH buffering agents, or agents for modifying or maintaining the rate of release of the formulations. The compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, gels, creams, sustained-release formulations and the like. Formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, sodium saccharine, starch, magnesium stearate, cellulose, magnesium carbonate, etc. Such compositions will contain an effective amount of the active ingredient(s) together with a suitable amount of carrier so as to provide the proper form to the subject based on the mode of administration to be used.

[0073] If for intravenous administration, the compositions are packaged in solutions of sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent. The components of the composition are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or concentrated solution in a hermetically sealed container such as an ampoule or sachette indicating the amount of active agents. If the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water or saline can be provided so that the ingredients may be mixed prior to injection.

[0074] In some embodiments, one or more of the compositions described by the present disclosure are administered intradermally.

[0075] The compositions described herein can also be provided in blister packs, containing one or more of each of the compositions arranged in the blister packs based on dosing requirements.

[0076] Moreover, if a packaging material is utilized to package the pharmaceutical composition, it may be biologically inert or lack bioactivity, such as plastic polymers, silicone, etc. and may be processed internally by the subject without affecting the effectiveness of the components packaged and/or delivered therewith. Additionally, the pharmaceutical compositions and components may be packaged with additional agents.

[0077] "Preventing" or "prevention" refers to a reduction in risk of acquiring disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be predisposed to the disorder but does not yet experience or display symptoms of the disorder).

[0078] "Treating" or "treatment" of any disorder refers, in one embodiment, to ameliorating the disorder (i.e., arresting or reducing the development of the disorder (e.g., PTSD) or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), psychologically (e.g., reduction in measurement of anxiety in OUT), CUD or PTSD), or a combination. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disorder. In another embodiment, the“treating” or“treatment” refers to reducing opioid withdrawal symptoms such as nausea, diarrhea, vomiting, sweating, pupillary dilation, abdominal cramps, piloerection, muscle cramps/twitches, yawning, fever and/or insomnia, muscle/bone pain, anxiety, and/or rhinorrhea/lactimation. In some treatment embodiments, the likelihood of developing opioid dependence is reduced, the likelihood of developing opioid tolerance is reduced, the likelihood of needing to increase the dosage of the opioid is reduced, less total opioid is required to maintain pain control over time, the opioid can be tapered off more rapidly and/or subjects may experience fewer and/or less severe withdrawal symptoms after the cessation of opioid administration as compared with the effects of opioid treatment for pain control in the absence of the methods of the invention. In some embodiments, opioid tolerance is reduced.

[0079] In some treatment embodiments, there may be less depressed mood or less depression (due to the SSRI component for tramadol and/or tapentadol). In some treatment embodiments, there may be less social isolation (due to OT or carbetocin). The less withdrawal symptoms can also be true using tramadol and/or tapentadol.

[0080] As used herein "reducing opioid withdrawal symptoms" (and similar terms) indicates that there is a reduction in the frequency and/or intensity of one or more withdrawal symptoms experienced by the subject and/or a reduction in the number of episodes of withdrawal symptoms requiring pharmaceutical intervention and/or a reduction in the total amount of the pharmaceutical intervention required to treat the subject undergoing withdrawal and/or the rate of taper of such pharmaceutical intervention can be more rapid as compared with the level that would be experienced in the absence of the methods of the invention and/or no treatment and/or alternative methods (e.g., standard Medication Assisted Treatment).

[0081] Withdrawal symptoms can be physical and/or emotional and occur after the drug to which the subject has developed dependence is stopped or significantly reduced.

Withdrawal symptoms are addressed previously herein.

[0082] A "dependent" subject as used herein is a subject that has physical and/or psychological dependence on a drug, substance or activity.

[0083] An "addicted" subject as used herein is a subject that has physical and/or psychological addiction to a drug, substance or activity. While some subjects that are treated with opioids become dependent, not all are addicted. [0084] Administration can by any suitable route, including without limitation oral, rectal, transmucosal, intranasal, inhalation (e.g., via an aerosol), vaginal, intrathecal, intraocular, buccal (e.g., sublingual), transdermal, parenteral (e.g., intravenous, subcutaneous, intradermal, intramuscular (including administration to skeletal, diaphragm and/or cardiac muscle), intradermal, intracerebral, intrapleural, and intraarticular), topical (e.g., to both skin and mucosal surfaces, including airway surfaces, and transdermal administration), intralymphatic, and the like.

[0085] In some embodiments, administration is by intranasal delivery. Any suitable method of intranasal administration can be utilized. In some embodiments, intranasal administration is by inhalation (e.g., using an inhaler, atomizer or nebulizing device) or by spray, tube, catheter, syringe, dropper, pledget, packtail, etc. The compositions described herein can be administered intranasally as nose drops, powders or liquid sprays or aerosols, liquids or semisolids by syringe, liquids or semisolids by swab, pledgets, gels, creams or ointments, infusions, by injection, etc. In particular embodiments, the method of delivery is by nasal drops, spray or aerosol. In some embodiments of the invention, the compositions described herein can be administered as slow-release depots, e.g., implanted subcutaneously.

[0086] The compositions described herein can be administered to the central nervous system (CNS) of a patient by any route known in the art. In some embodiments, the compositions are administered in a liquid formulation by direct injection to the desired region in the CNS. In other embodiments, the compositions can be delivered to the CNS by topical application (either via skin or topical application during surgery) to the desired region or by intra-nasal administration (e.g., for delivery to the brain).

[0087] The compositions described herein can also be administered intraocular, intrathecal, intracerebral, intraventricular, intravenous (e.g., in the presence of a sugar such as mannitol), intranasal, intra-aural, intra-ocular (e.g., intra- vitreous, sub-retinal, anterior chamber) and peri-ocular delivery. In some embodiments, the compositions are administered in a liquid formulation by direct injection to the desired region.

[0088] It is also understood and contemplated that aspects of the present invention can provide more than two active ingredient components in the mixtures of compositions herein disclosed. For example, a mixture can comprise oxytocin and another active ingredient, such as but not limited to an opioid agonist. Also, the disclosed methods can comprise the simultaneous or separate administration of multiple active ingredients. Thus, the present invention may further include the administration of a third, fourth, etc. active ingredient, wherein the third, fourth, etc. active ingredient is administered separately, but at the same time as the other active ingredients, or hours or days after the first administration of active ingredients or hours or days before the first administration of active ingredients.

[0089] In some embodiments, the compositions described herein, or pharmaceutical composition containing them, can be delivered in a controlled release system. Such methods may include the use of a pump for administration (e.g., use of an intravenous drip).

“Controlled release,” as used herein, refers to any formulation or delivery system designed to release a drug substance in a controlled manner over a predefined period of time.

[0090] The compounds and compositions of the invention may also be utilized in pharmaceutically acceptable compositions in the methods provided herein. It would also be understood by a skilled artisan how to use the compositions described herein for therapeutic purposes without undue experimentation based on the teachings provided throughout the specification.

[0091] A suitable dosage of the compositions described herein can be administered to give the desired response. Dosages of the compositions can be determined by methods known in the art, see, e.g., Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton,

Pa). In particular embodiments, the dosage of the composition ranges in potency from at least about 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 7, 10, 15, 20, 25, 30, 40, 50 international units (IU) of the compound and/or less than about 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 300, 500 or 1000 IU of the compound for a typical (e.g., 70 kg) human subject (including any combination of the lower and upper dosages as long as the lower value is less than the upper value). In particular embodiments, the dosage is from about 1 to about 100 IU, optionally from about 4 to about 25 or 50 IU.

[0092] In some embodiments, the dosage of the composition is from about 0.03 mg to about 9600mg. In some embodiments, the dosage of the composition is from about lOmg to about 400mg. In some embodiments, the dosage of the composition is from about 0.03 mg to about 2.5mg. In some embodiments, the dosage of the composition is from about 0.03 mg to about lOmg. In some embodiments, the dosage of the composition is from about 0.03 mg to about 50mg. In some embodiments, the dosage of the composition is from about 0.03 mg to about lOOmg. In some embodiments, the dosage of the composition is from about 10 mg to about lOOmg. In some embodiments, the dosage of the composition is from about 10 mg to about lOOOmg. In some embodiments, the dosage of the composition is from about 10 mg to about 2000mg. In some embodiments, the dosage of the composition is from about 10 mg to about lOOOOmg. In some embodiments, the dosage of the composition is from about 100 mg to about lOOOOmg.

[0093] In one example embodiment, the oxytocin receptor agonist can be administered at a dosage range of about 0.5 milliunit to about 10 milliunit/minute for intravenous or about 8 IU to about 24 IU for nasal spray.

[0094] In one example embodiment, cannabidiol can be administered at a dosage range of about 12.5 mg to about 1280mg.

[0095] In one example embodiment, methadone can be administered at a dosage range of about 60mg to about lOOmg.

[0096] In one example embodiment, tramadol can be administered at a dosage range of about 25mg to about 400mg.

[0097] In one example embodiment, tapentadol can be administered at a dosage range of about 50mg to about 700mg.

[0098] In one example embodiment, buprenorphine can be administered at a dosage range of about 0.3 mg to about 16mg.

[0099] In one example embodiment, naltrexone can be administered at a dosage range of about 12.5mg to about 380mg.

[00100] In one example embodiment, lofexidine can be administered at a dosage range of about 0.18mg to about 2.88mg.

[00101] In one example embodiment, clonidine can be administered at a dosage range of about 0.03mg to about 2.4mg.

[00102] In one example embodiment, ketamine can be administered at a dosage range of about 0.3mg to about 3600mg. [00103] In one example embodiment, esketamine can be administered at a dosage range of about 28mg to about 84mg.

[00104] In one example embodiment, MDMA can be administered at a dosage range of about 120mg to about 400mg.

[00105] In one example embodiment, D-serine can be administered at a dosage range of about 2400mg to about 9600mg.

[00106] In one example embodiment, D-cycloserine can be administered at a dosage range of about 50mg to about lOOOmg.

[00107] Additionally, in vitro assays may be employed to help identify optimal dosage ranges. The precise dose to be utilized will also depend on the route of administration, and the seriousness of the disorder being treated, and should also be decided according to the sound medical judgment of the clinician and each patient's individual circumstances. The specific therapeutically effective dosage level for any particular patient will depend upon a variety of factors including: the type and degree of the response to be achieved; the specific composition and other agent(s), if any, employed; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the composition; the duration of the treatment; other drugs used in combination or coincidental with the composition; and any other factors well known in the medical arts. Effective dosages may also be extrapolated from dose-response curves derived from in vitro or animal model testing systems.

[00108] When reference is made to administering one drug prior to or after another drug, it should be understood to include all reasonable intervals as under by one skilled in the art, e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks.

[00109] Treatment can be short-term (e.g., for hours or days) or can be a long- term, e.g., a chronic regimen. In some embodiments, the treatment is a maintenance regimen that lasts for days, months, years or the life of the subject. For example, with respect to opioid use disorders, a short-term treatment can be used to treat (reduce) withdrawal symptoms (e.g., for 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days). To treat (e.g., reduce) craving and/or relapse, long-term treatment can be used, e.g., weeks, months, years, life of the patient. In one embodiment, the treatment is for ultra- rapid detox. For ultra-rapid detox, general anesthesia is induced in an opiate addicted subject. While under anesthesia, the subject is treated with naltrexone. The subject will then undergo opiate withdrawal.

[00110] An example dosage scheme is administration from about 1, 2, 3, 4, 5 or 6 to about 2, 3, 4, 5, 10, 15 or 20 times a day (including any combination of the lower and upper values as long as the lower value is less than the upper value). In other embodiments, dosing is done once about every two days, every three days, every four days, every five days, every six days, every week, every two weeks or once a month. In some embodiments, dosing is done on an as-needed basis (based on exacerbation of symptoms, craving, anxiety, etc.). In a specific embodiment, the dosing is done once every other day. Those skilled in the art will understand that for acute indications (e.g., detoxification), dosing will generally be one or more times per day. Also, in dependence disorders, the dosage or frequency of dosing may taper off over time.

[00111] The present disclosure further contemplates the use of one or more adjunct therapies along with the methods described for treatment of OUT), PTSD and/or postpartum unipolar depression. Examples of adjunct therapies include e.g., psychotherapy, participation in social support groups, and/or additional therapies with one or more additional

pharmaceutical agents. For example, when treating opioid dependence, the adjunct therapy can include e.g, therapies that can be administered to treat specific withdrawal symptoms, e.g., an anti-emetic for nausea and/or vomiting (e.g., promethazine), a substance to treat diarrhea (e.g., loperamide), muscle cramps/twitches (e.g., cyclobenzaprine), abdominal cramps (e.g., dicyclomine), muscle/bone pain (e.g., acetaminophen, ibuprofen),

rhinorrhea/lactimation (e.g., diphenhydramine) and/or anxiety (e.g., lorazepam).

[00112] In some embodiments, the present invention provides methods of treating a neuropsychiatric condition selected from the group consisting of post-traumatic stress disorder (PTSD), opioid use disorder (OUD), cocaine use disorder (CUD), unipolar post partum depression (PPD) and combinations thereof in a subject in need thereof, comprising administering to the subject:

a) a therapeutically effective amount of a first compound during a pretreatment step, wherein the first compound regulates an oxytocin receptor; and b) therapeutically effective amounts of the first compound and a second compound during a treatment step, wherein the second compound regulates an opioid receptor, a cocaine receptor, an adrenergic receptor, an N-methyl-D- aspartate receptor (NMD A) receptor, is MDMA or a combination thereof.

[00113] In some embodiments, the treatment step comprises an induction step, a maintenance step and a tapering step.

[00114] In some embodiments, the subject has acute PTSD. In some embodiments, the subject has chronic PTSD. In some embodiments, the subject has OUD. In some

embodiments, the subject has CUD. In some embodiments, the subject has OUD and CUD.

In some embodiments, the subject has PPD.

The First Compound

[00115] In some embodiments, the first compound comprises, consists essentially of, or consists of oxytocin. In some embodiments, the first compound comprises, consists essentially of, or consists of carbetocin. In some embodiments, the first compound is selected from the group consisting of oxytocin receptor ligands, oxytocin, carbetocin, analogues thereof, pharmaceutically acceptable salts thereof and combinations thereof. Non-limiting examples of oxytocin analogues include [7-glycine] oxytocin, 1-beta-mercaptopropionic acid, 7-glycineoxytocin and 7-alanineoxytoin, [Se-Se]-OT-OH(6) and [Se-Se]-OT-OH(7), etc.

[00116] In some embodiments, the first compound binds to the oxytocin receptor, e.g., is a ligand of the oxytocin receptor. In other embodiments, the first compound regulates the oxytocin receptor without direct binding, e.g., bind to a protein in physical approximation to the receptor, to effect changes.

[00117] In some embodiments, the first compound is formulated in an immediate-release form. In some embodiments, the first compound is formulated in an extended-release form.

[00118] In some embodiments, the first compound is administered intranasally, e.g., as a nasal spray. In some embodiments, the first compound is administered at about 4 IU to about 48 IU, e.g., about 4-36 IU, about 4-24 IU, about 4-12 IU, about 6-48 IU, about 6-36 IU, about 6-24 IU, about 6-12 IU, about 8-48 IU, about 8-36 IU, about 8-24 IU, about 8-12 IU, about 10-48 IU, about 10-36 IU, about 10-24 IU or about 10-12 IU. [00119] In some embodiments, the first compound is administered intravenously. In some embodiments, the first compound is administered at an rate of about 0.5 milliunit/minute to about 10 milliunits/minute, e.g., about 0.5-9, about 1-9, about 1-8, about 1-7, about 2-7, about 2-6, about 3-6, about 3-5, or about 4-5 milliunits/minute.

[00120] In some embodiments, the first compound is administered orally. In some embodiments, the first compound is administered transdermally. In some embodiments, the first compound is administered intramuscularly.

The Second Compound

[00121] In some embodiments, the second compound comprises:

a) a ligand, an agonist, a partial agonist, and/or an antagonist of the opioid

receptor;

b) a ligand, an agonist, and/or an antagonist of the a-2c adrenergic receptor; c) a ligand, an agonist, and/or an antagonist of the NMD A receptor;

d) MDMA; or

e) a combination thereof.

[00122] In some embodiments, the second compound is selected from the group consisting of buprenorphine, methadone, tapentadol, tramadol, naltrexone, Lofexidine, clonidine, D- serine, D-cycloserine, ketamine, esketamine, MDMA, analogues thereof, pharmaceutically acceptable salts thereof and combinations thereof.

[00123] In some embodiments, the second compound comprises, consists essentially of, or consists of an opioid agonist. Non-limiting examples of opioid agonist include

buprenorphine, methadone, tapentadol, tramadol, pharmaceutically acceptable salts thereof, and combinations thereof. In some embodiments, the subject has PTSD and/or PPD and the second compound comprises, consists essentially of, or consists of tramadol and/or tapentadol during the induction and/or maintenance phase. In some embodiments, the subject has OUD and/or CUD and the second compound comprises, consists essentially of, or consists of buprenorphine, methadone, tramadol, tapentadol or a combination thereof during the induction and/or maintenance phase.

[00124] In some embodiments, buprenorphine is administered at a dosage range of about 0.3 mg to about 16 mg, e.g., about 0.3-14 mg, about 0.5-14 mg, about 0.5-12 mg, about 1-12 mg, about 1-10 mg, about 1.5-10 mg, about 1.5-8 mg, about 2-8 mg, about 2-6 mg, about 3-6 mg, or about 3-5 mg. In some embodiments, methadone is administered at a dosage range of about 60 mg to about 100 mg, e.g., about 65-100 mg, about 65-95 mg, about 70-95 mg, about 70-90 mg, about 75-90 mg, or about 75-80 mg. In some embodiments, tramadol is administered at a dosage range of about 25 mg to about 400 mg, e.g., about 25-350 mg, about 30-350 mg, about 30-300 mg, about 35-300 mg, about 35-250 mg, about 40-250 mg, about 40-200 mg, about 45-200 mg, about 45-150 mg, about 50-150 mg, or about 50-100 mg. In some embodiments, tapentadol is administered at a dosage range of about 50mg to about 700mg, e.g., about 50-600 mg, about 60-600 mg, about 60-500 mg, about 70-500 mg, about 70-400 mg, about 80-400 mg, about 80-300 mg, about 90-300 mg, about 90-200 mg, or about 100-200 mg.

[00125] In some embodiments, the second compound comprises, consists essentially of, or consists of an opioid antagonist. Non-limiting examples of opioid antagonists include naltrexone or pharmaceutically acceptable salts thereof. In some embodiments, the subject has PTSD, OUD, CUD or a combination thereof, and the second compound comprises, consists essentially of, or consists of naltrexone during the induction and/or maintenance phase. In some embodiments, naltrexone is administered at a dosage range of about 12.5 mg to about 380 mg, e.g., about 25-380 mg, about 25-350 mg, about 40-350 mg, about 40-300 mg, about 50-300 mg, about 50-250 mg, about 75-250 mg, about 75-200 mg, about 100-200 mg, or about 100-150 mg.

[00126] In some embodiments, the second compound comprises, consists essentially of, or consists of an a-2c adrenergic receptor agonist. Non-limiting examples of a-2c adrenergic receptor agonists include Lofexidine, clonidine, pharmaceutically acceptable salts thereof, and combinations thereof. In some embodiments, the subject has OUD and/or CUD, and the second compound comprises, consists essentially of, or consists of Lofexidine and/or clonidine during the induction and/or maintenance phase. In some embodiments, Lofexidine is administered at a dosage range of about 0.18 mg to about 2.88 mg, e.g., about 0.2-2.88 mg, about 0.2-2.5 mg, about 0.3-2.5 mg, about 0.3-2 mg, about 0.4-2 mg, about 0.4-1.5 mg, about 0.5-1.5 mg, about 0.5-1 mg, or about 0.6-1 mg. In some embodiments, clonidine is administered at a dosage range of about 0.03 mg to about 2.4 mg, e.g., about 0.06-2.4 mg, about 0.06-2 mg, about 0.1-2 mg, about 0.1-1.5 mg, about 0.2-1.5 mg, about 0.2-1 mg, about 0.4-1 mg, about 0.4-0.8 mg, or about 0.6-0.8 mg.

[00127] In some embodiments, the second compound comprises, consists essentially of, or consists of an a-2c adrenergic receptor antagonist.

[00128] In some embodiments, the second compound comprises, consists essentially of, or consists of an NMD A receptor agonist. Non-limiting examples of NMD A receptor agonists include D-serine, D-cycloserine, pharmaceutically acceptable salts thereof, and combinations thereof. In some embodiments, the subject has PTSD, OUD, CUD, PPD or a combination thereof, and the second compound comprises, consists essentially of, or consists of ketamine and/or Esketamine during the induction and/or maintenance phase. In some embodiments, D- serine is administered at a dosage range of about 2,400 mg to about 9,600 mg, e.g., about 2,400-8,800 mg, about 3,200-8,800 mg, about 3,200-8,000 mg, about 4,000-8,000 mg, about 4,000-7,200 mg, about 4,800-7,200 mg, about 4,800-6,400 mg, or about 5,600-6,400 mg, In some embodiments, D-cycloserine is administered at a dosage range of about 50 mg to about 1,000 mg, e.g., about 50-900 mg, about 100-900 mg, about 150-800 mg, about 150-750 mg, about 200-750 mg, about 200-700 mg, about 250-650 mg, about 250-600 mg, about 300-600 mg, about 300-550 mg, about 350-550 mg, about 350-500 mg, or about 400-500 mg.

[00129] In some embodiments, the second compound comprises, consists essentially of, or consists of an NMDA receptor antagonist. Non-limiting examples of NMDA receptor antagonists include ketamine, Esketamine, pharmaceutically acceptable salts thereof, and combinations thereof. In some embodiments, the subject has PTSD, OUD, CUD, PPD or a combination thereof, and the second compound comprises, consists essentially of, or consists of ketamine and/or Esketamine during the induction and/or maintenance phase. In some embodiments, ketamine is administered at a dosage range of about 0.3 mg to about 3600 mg, e.g., about 0.6-3,600 mg, about 0.6-1,800 mg, about 1.2-1,800 mg, about 1.2-900 mg, about 2.4-900 mg, about 2.4-450 mg, about 5-450 mg, about 5-250 mg, about 10-250 mg, about 10- 125 mg, about 20-125 mg, or about 20-60 mg. In some embodiments, esketamine is administered at a dosage range of about 28 mg to about 84 mg, e.g., about 30-84 mg, about 30-80 mg, about 35-80 mg, about 35-75 mg, about 40-75 mg, about 40-70 mg, about 45-70 mg, about 45-65 mg, about 50-65 mg, or about 50-60 mg. [00130] In some embodiments, the second compound comprises, consists essentially of, or consists of MDMA (commonly known as ecstasy or molly) and pharmaceutically acceptable salts thereof. In some embodiments, the subject has PTSD, and the second compound comprises, consists essentially of, or consists of MDMA during the induction and/or maintenance phase. In some embodiments, the second compound comprises, consists essentially of, or consists of MDMA. In some embodiments, MDMA is administered at a dosage range of about 120 mg to about 400 mg, e.g., about 150-400 mg, about 150-350 mg, about 200-350 mg, about 200-300 mg, or about 250-300 mg.

[00131] In some embodiments, the second compound is selected from the group consisting of an opioid agonist, an opioid partial agonist, an opioid antagonist, an a-2c adrenergic receptor agonist, an a-2c adrenergic receptor antagonist, an NMDA receptor agonist, an NMDA receptor antagonist, MDMA and combinations thereof.

[00132] In some embodiments, the second compound binds to the receptor it regulates, e.g., is a ligand of the receptor it regulates. In other embodiments, the second compound regulates the receptor without direct binding, e.g., bind to a protein in physical approximation to the receptor, to effect changes.

[00133] In some embodiments, the second compound is formulated in an immediate- release form. In some embodiments, the second compound is formulated in an extended- release form.

[00134] In some embodiments, the second compound is administered orally. In some embodiments, the second compound is administered intranasally. In some embodiments, the second compound is administered transdermally. In some embodiments, the second compound is administered intramuscularly. In some embodiments, the second compound is administered intravenously.

[00135] In some embodiments, the first and the second compounds are administered in a single dosage form during the pretreatment step. In some embodiments, the first compound is administered prior to the second compound during the pretreatment step. In some

embodiments, the first compound is administered after the second compound during the pretreatment step. [00136] In some embodiments, the first and the second compounds are administered in a single dosage form during the induction step. In some embodiments, the first compound is administered prior to the second compound during the induction step. In some embodiments, the first compound is administered after the second compound during the induction step.

[00137] In some embodiments, the first and the second compounds are administered in a single dosage form during the maintenance step. In some embodiments, the first compound is administered prior to the second compound during the maintenance step. In some

embodiments, the first compound is administered after the second compound during the maintenance step.

[00138] In some embodiments, the first and the second compounds are administered in a single dosage form during the tapering step. In some embodiments, the first compound is administered prior to the second compound during the tapering step. In some embodiments, the first compound is administered after the second compound during the tapering step.

[00139] In some embodiments, the first and the second compounds are administered in a single dosage form during the pretreatment step, the induction step, the maintenance step, the tapering step or a combination thereof. In some embodiments, the first compound is administered prior to the second compound during the pretreatment step, the induction step, the maintenance step, the tapering step or a combination thereof. In some embodiments, the first compound is administered after the second compound during the pretreatment step, the induction step, the maintenance step, the tapering step or a combination thereof.

[00140] In some embodiments, the pretreatment step occurs about two to about four weeks before the induction step, e.g., about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34 days, before the induction step.

The Third Compound

[00141] In some embodiments, the tapering step further comprises administering to the subject a therapeutically effective amount of a third compound, wherein the third compound regulates an opioid receptor, a cannabinoid receptor or both.

[00142] In some embodiments, the third compound comprises:

a) a ligand and/or an agonist of the cannabidiol receptor;

b) a ligand and/or an antagonist of the opioid receptor; c) or a combination thereof.

[00143] In some embodiments, the third compound is selected from the group consisting of cannabidiol, naltrexone, analogues thereof, pharmaceutically acceptable salts thereof and combinations thereof.

[00144] In some embodiments, the third compound comprises, consists essentially of or consists of a cannabidiol receptor agonist. Non-limiting examples of cannabidiol receptor agonists include Cannabidiol (CBD) or pharmaceutically acceptable salts thereof. In some embodiments, the subject has PTSD, OUD, CUD, PPD or a combination thereof and the third compound comprises, consists essentially of, or consists of CBD. In some embodiments, cannabidiol is administered at a dosage range of about 12.5 mg to about 1,280 mg, e.g., about 25 1,280 mg, about 25 1,200 mg, about 50 1,200 mg, about 50 1,000 mg, about 100 1,000 mg, about 100-800 mg, about 150-800 mg, about 150-600 mg, about 200-600 mg, about 200 400 mg, or about 300-400 mg.

[00145] In some embodiments, the third compound comprises, consists essentially of or consists of an opioid receptor antagonist. Non-limiting examples of opioid receptor antagonists include naltrexone or pharmaceutically acceptable salts thereof. In some embodiments, the subject has PTSD, OUD, CUD, PPD or a combination thereof and the third compound comprises, consists essentially of, or consists of naltrexone.

[00146] In some embodiments, the third compound is selected from the group consisting of a cannabidiol agonist, a cannabidiol analogue, a cannabidiol ligand, an opioid antagonist, an opioid analogue, an opioid ligand or a combination thereof.

[00147] In some embodiments, the third compound binds to the receptor it regulates, e.g., is a ligand of the receptor it regulates. In other embodiments, the third compound regulates the receptor without direct binding, e.g., bind to a protein in physical approximation to the receptor, to effect changes.

[00148] In some embodiments, the third compound is formulated in an immediate-release form. In some embodiments, the third compound is formulated in an extended-release form.

[00149] In some embodiments, the third compound is administered orally. In some embodiments, the third compound is administered intranasally. In some embodiments, the third compound is administered transdermally. In some embodiments, the third compound is administered intramuscularly. In some embodiments, the third compound is administered intravenously.

[00150] In some embodiments, the first and the third compounds are administered in a single dosage form during the tapering step. In some embodiments, the first compound is administered prior to the third compound during the tapering step. In some embodiments, the first compound is administered after the third compound during the tapering step.

[00151] In some embodiments, the second and the third compounds are administered in a single dosage form during the tapering step. In some embodiments, the second compound is administered prior to the third compound during the tapering step. In some embodiments, the second compound is administered after the third compound during the tapering step.

Table. Non-limiting Examples of The First, Second and Third Compounds

[00152] In some embodiments, the method further comprises providing psychological counseling to the subject during the pretreatment step, the induction step, the maintenance step, the tapering step or a combination thereof. In some embodiments, the subject has PTSD, and the psychological counseling is cognitive behavioral therapy (CBT).

[00153] In some embodiments the present invention also provides methods of conditioning a subject in need thereof for treatment of a neuropsychiatric condition selected from the group consisting of PTSD, OUD, CUD, PPD and combinations thereof, comprising administering to the subject a therapeutically effective amount of a first compound during a pretreatment step, wherein the first compound regulates an oxytocin receptor.

[00154] In some embodiments, the method further comprises a treatment step comprising administering to the subject therapeutically effective amounts of the first compound and a second compound, wherein the second compound regulates an opioid receptor, a cocaine receptor, an adrenergic receptor, an N-methyl-D-aspartate receptor (NMD A) receptor, is MDMA, or a combination thereof.

[00155] In some embodiments, the treatment step comprises an induction step, a maintenance step and a tapering step.

[00156] In some embodiments The present invention provides methods of treating opioid use disorder, post-traumatic stress disorder and post-partum unipolar depression utilizing an oxytocin receptor agonist, such as e.g. but not limited to, oxytocin or carbetocin, in combination with opioid agonists, opioid partial agonists, opioid antagonists, a-2c adrenergic receptor antagonists, NMD A receptor antagonists including but not limited to ketamine, esketamine, 3,4-Methylenedioxymethamphetamine (MDMA), D-serine, D-cycloserine, cannabidiol and/or a-2 adrenergic receptor agonists.

[00157] Opioid Use Disorder and Cocaine Use Disorder

[00158] Opioid dependence and withdrawal

[00159] Individuals who have consumed opioid prescription or street drugs (e.g., morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, heroin) daily or numerous times per week for sustained periods (more than 1-2 weeks), particularly at high doses, become physically and and/or psychologically dependent on these drugs. Symptoms of opioid dependence include: requiring increasing doses of opioid drugs to obtain the same physical and/or psychological effects, a number of behavior changes, and usually the onset of specific withdrawal symptoms if consumption of opioid drugs is abruptly ceased or significantly reduced. The physical symptoms of withdrawal include dysphoric mood, muscle aches and cramps, diarrhea and abdominal pain due to contractions of the bowels, sweating, nausea and/or vomiting, shakes, yawning, pupillary dilation, piloerection (hairs standing on end), lacrimation (tear formation), rhinorrhea (secretions from the nose), fever, and/or insomnia. Symptoms vary in their number and severity depending on the degree of dependence.

[00160] Typically, medical detoxification of opioid dependent patients can be achieved either by (1) gradual tapering and then stopping opioid doses (in a hospital or outpatient setting), (2) replacing the opioid drugs that are being abused with a combination of a mixed opioid agonist (and the opioid antagonist naltrexone) or methadone treatment, or (3) abruptly stopping opioid drug administration (in a hospital setting) and administering medications that diminish the severity of withdrawal symptoms over a treatment period of approximately 4-7 days. The doses of these medications are gradually tapered over the treatment course and stopped at the end of the treatment course. In patients whose history indicates that they will not be able to tolerate abstaining, withdrawal symptoms are often controlled by substituting the opioid drugs that have been misused by opioid drugs, such as methadone or

buprenorphine, that can be given and monitored at an outpatient clinic.

[00161] Individuals with opioid dependence usually experience craving for opioid drugs, especially after medical detoxification or during periods when they try to cut back on the opioid drugs they consume. Craving consists of chronic or frequent intrusive thoughts (obsessions) about opioid drugs, how much better the patient would feel if they could take those drugs and where to find them. Craving is usually accompanied by strong urges to consume. Dependent individuals usually have difficulty keeping these obsessional thoughts out of their mind and controlling impulses to use. Craving and urges to consume opioid drugs are exacerbated by the chronic anxiety and difficulty coping with stress that opioid dependent subjects experience for long periods of time after consumption is stopped (weeks to months). Many opioid dependent individuals also suffer chronic pain of various types (treatment of these conditions with opioids is often how they became dependent) which intensifies after stopping opioid drugs. Cravings and urges to consume often lead to relapse.

[00162] Resumption of drug use is reinforced because it decreases cravings and diminishes anxiety and, therefore, once the user starts consuming again opioid dependent individuals fmd it very difficult to stop. Because dependent individuals have a high tolerance for opioid drugs, when they relapse they tend to consume large amounts because these quantities are necessary to control anxiety, cope with stress and suppress craving.

[00163] In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an opioid agonist to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an opioid partial agonist to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an opioid antagonist to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and a-2 adrenergic receptor agonist to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an iV-methyi-D-aspartate receptor (NMD A) receptor antagonist to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and ketamine to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and esketamine to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and D-serine to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and D-cycloserine to the subject. In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and cannabidiol to the subject.

[00164] In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and one or more of the following: an opioid agonist, an opioid partial agonist, an a-2 adrenergic receptor agonist, an NMDA receptor antagonist (e.g., but not limited to, ketamine or esketamine), D-serine, D-cycloserine, and cannabidiol, to the subject.

[00165] In another aspect, the present invention provides methods of treating cocaine use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and one or more of the following: an opioid antagonist, an opioid partial agonist, an a-2 adrenergic receptor agonist, an NMDA receptor antagonist (e.g., but not limited to, ketamine or esketamine), D-serine, D-cycloserine, and cannabidiol, to the subject.

[00166] In one aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of oxytocin and an opioid agonist to the subject. In another aspect, the present invention provides methods of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of carbetocin and an opioid agonist to the subject.

[00167] Methods of the invention can be carried out with any suitable oxytocin receptor agonist, including oxytocin and/or an oxytocin analog such as carbetocin (1- butanoic acid-2- (O-methyl-L-tyrosine)-l-carbaoxytocin; Hunter et ah, Clin. Pharmacol. Ther. 52: 60-67 (1992)). A number of other oxytocin receptor agonists are known in the art and include peptide and non-peptide molecules, all of which are contemplated for use in the disclosed methods. Nonlimiting examples of oxytocin receptor agonists include: 4-threonine-l- hydroxy- deaminooxytocin, 9-deamidooxytocin (an analog of oxytocin containing a glycine residue in place of the glycinamide residue; du Vigneuaud, J. Med. Chem. 9:55-57 (1966)), 4- deamido-oxytocin (an analog of oxytocin containing a glutamic acid residue in place of glutamine; Photaki and du Vigneaud, J Am. Chem. Soc. 87: 908- 913 (1965)), 7-D-proline- oxytocin and its deamino analog (du Vigneuaud, J Am. Chem. Soc. 88: 3847-3850 (1966)), (2,4-diisoleucine)-oxytocin and its deamino oxytocin analog (Hruby et al., J. Med. Chem. 13: 185-187 (1970); Urry et al., Proc. Natl. Acad. Sci. USA 66: 111-116 (1970)), 1-desamino-l- monocarba-E12-Tyr(OMe)- oxytocin (Veznik et al., Am. J. Vet. Res. 4): 425-429 (1979); Cort et al, Am. J. Vet. Res. 43: 1283-1285 (1982); Cort et al, Am. J. Vet. Res. 40:430-432 (1979)), [Thr4- Gly7] -oxytocin (Chadio and Antoni, J. Mol. Endocrinol. 10: 107-114 (1993)), oxypressin, deamino-6-carba-oxytoxin (Krejci et al, Regul. Pept. 2: 285-291 (1981)), 4-P- alanine-oxytocin (Manning and du Vigneaud, Biochemistry 4: 1884-1888 (1965)), Ile- conopressin, atosiban, desmopressin, and 1 -deamino-oxytocin in which the disulfide bridge between residues 1 and 6 is replaced by a thioether.

[00168] Oxytocin receptor agonists include biologically active fragments of oxytocin. For example, oxytocin fragment 4-9 has been reported to be more potent than the full-length molecule (Burbach et al., Eur. J. Pharmacol. 94: 125-131 (1983)). Use of the term,

"biologically active," is meant that the fragment substantially retains (e.g., at least about 50%, 60%, 70%, 80%, 90%, 95% or more) at least one biological activity of full-length oxytocin, e.g., with respect to reducing a withdrawal symptom(s), craving and/or relapse in a dependent subject.

[00169] Other useful forms of oxytocin or other oxytocin receptor agonists for use in the present methods include pharmaceutically acceptable active salts of oxytocin or other oxytocin receptor agonists as well as active isomers, enantiomers, polymorphs, solvates, hydrates and/or prodrugs of the same.

[00170] In some embodiments, the opioid agonist is selected from the group consisting of tramadol, buprenorphine, tapentadol, methadone and a combination thereof. In one embodiment, the opioid agonist is tramadol, or a pharmaceutically acceptable salt thereof. In one embodiment, the opioid agonist is tapentadol, or a pharmaceutically acceptable salt thereof. In one embodiment, the opioid partial agonist is buprenorphine, or a

pharmaceutically acceptable salt thereof.

[00171] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of an opioid antagonist to the subject. In some embodiments, the opioid antagonist is naltrexone, or a pharmaceutically acceptable salt thereof. In some embodiments, the oxytocin receptor agonist and the opioid agonist or the opioid partial agonist or the opioid antagonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form.

[00172] In some embodiments, the oxytocin receptor agonist is administered orally. In other embodiments, the oxytocin receptor agonist is administered intranasally. In further embodiments, the oxytocin receptor agonist is administered transdermally, intramuscularly or intravenously. In some embodiments, the oxytocin receptor agonist is administered intradermally.

[00173] In some embodiments, the oxytocin receptor agonist is selected from an extended- release form and an immediate-release form.

[00174] In some embodiments, the opioid agonist is an extended-release form. In other embodiments, the opioid agonist is an immediate-release form.

[00175] In some embodiments, the oxytocin receptor agonist is administered prior to administration of the opioid agonist.

[00176] In some embodiments, the oxytocin receptor agonist is administered after administration of the opioid agonist. In some embodiments, the oxytocin receptor agonist is administered both before and after administration of the opioid agonist. For example, the oxytocin receptor agonist may be administered first, the opioid agonist is then administered, and then the oxytocin receptor agonist may be administered following the opioid agonist.

[00177] In an example embodiment, the oxytocin receptor agonist is administered for about two weeks prior to Induction with an opioid agonist in combination with an oxytocin receptor agonist; alternatively, about 1 week or 1 month prior. In a further example embodiment, the oxytocin receptor agonist is administered for about two to about four weeks prior to induction with an opioid agonist in combination with an oxytocin receptor agonist. During Stabilization, the subject is treated for adverse events associated with withdrawal on an individualized basis. Next, the opioid agonist is tapered off with continued oxytocin receptor agonist treatment. Maintenance treatment is then done using an oxytocin receptor agonist either alone or in combination with the opioid agonist at reduced doses or with a partial opioid agonist such as buprenorphine and opioid antagonist, such as, e.g., naltrexone. Alternatively, after the patient has been tapered off an opioid agonist or partial opioid agonist, Maintenance treatment can be done with an oxytocin receptor agonist and/or cannabidiol with or without an opioid antagonist such as naltrexone.

[00178] For example, during stabilization, oxytocin agonist treatment may continue and the dose of opioid agonist, partial opioid agonist, or opioid antagonist is adjusted, if needed, and adverse events treated on an individualized basis.

[00179] In another example embodiment, an oxytocin receptor agonist is administered for any of 1, 2, 3, or 4 weeks prior to, such as about two to about 4 weeks prior to, induction with an a-2 adrenergic receptor agonist in combination with an oxytocin receptor agonist. During stabilization, the subject is treated for adverse events associate with withdrawal on an individualized basis. Next, the a-2 adrenergic receptor agonist is tapered off with continued oxytocin receptor agonist treatment. Maintenance treatment is then done using oxytocin receptor agonist in combination with the a-2 adrenergic receptor agonist with or without an opioid antagonist, such as e.g., naltrexone.

[00180] In some embodiments, the oxytocin receptor agonist and the opioid agonist or opioid partial agonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form. In some embodiments, the oxytocin receptor agonist and the alpha- 2-receptor agonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00181] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of an a-2c adrenergic receptor antagonist to the subject.

[00182] In some embodiments, the a-2c adrenergic receptor antagonist is an extended- release form. In other embodiments, the a-2c adrenergic receptor antagonist is an immediate- release form.

[00183] In some embodiments, the oxytocin receptor agonist and the a-2c adrenergic receptor antagonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form. [00184] In some embodiments, the oxytocin receptor agonist is administered prior to administration of the a-2c adrenergic receptor antagonist. In other embodiments, the oxytocin receptor agonist is administered after administration of the a-2c adrenergic receptor antagonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of the a-2c adrenergic receptor antagonist.

[00185] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of an -methyl-D-aspartate receptor (NMD A) receptor antagonist to the subject.

[00186] In some embodiments, the NMDA receptor antagonist is an extended-release form. In other embodiments, the NMDA receptor antagonist is an immediate-release form.

[00187] In some embodiments, the oxytocin receptor agonist and the NMDA receptor antagonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00188] In some embodiments, the oxytocin receptor agonist is administered prior to administration of NMDA receptor antagonist. In other embodiments, the oxytocin receptor agonist is administered after administration of NMDA receptor antagonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of NMDA receptor antagonist.

[00189] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of ketamine to the subject.

[00190] In some embodiments, the ketamine is an extended-release form. In other embodiments, the ketamine is an immediate-release form.

[00191] In some embodiments, the oxytocin receptor agonist and the ketamine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00192] In some embodiments, the oxytocin receptor agonist is administered prior to administration of ketamine. In other embodiments, the oxytocin receptor agonist is administered after administration of ketamine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of ketamine.

[00193] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of esketamine to the subject.

[00194] In some embodiments, the esketamine is an extended-release form. In other embodiments, the esketamine is an immediate-release form.

[00195] In some embodiments, the oxytocin receptor agonist and the esketamine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00196] In some embodiments, the oxytocin receptor agonist is administered prior to administration of esketamine. In other embodiments, the oxytocin receptor agonist is administered after administration of esketamine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of esketamine.

[00197] In some embodiments, the methods described herein (e.g., for treatment of PTSD) comprise administering a therapeutically effective amount of MDMA to the subject.

[00198] In some embodiments, the MDMA is an extended-release form. In other embodiments, the MDMA is an immediate-release form.

[00199] In some embodiments, the oxytocin receptor agonist and the MDMA are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00200] In some embodiments, the oxytocin receptor agonist is administered prior to administration of MDMA. In other embodiments, the oxytocin receptor agonist is administered after administration of MDMA. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of MDMA.

[00201] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of D-serine to the subject.

[00202] In some embodiments, the D-serine is an extended-release form. In other embodiments, the D-serine is an immediate-release form. [00203] In some embodiments, the oxytocin receptor agonist and the D-serine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00204] In some embodiments, the oxytocin receptor agonist is administered prior to administration of D-serine. In other embodiments, the oxytocin receptor agonist is administered after administration of D-serine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of D-serine.

[00205] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of D-cycloserine to the subject.

[00206] In some embodiments, the D-cycloserine is an extended-release form. In other embodiments, the D-cycloserine is an immediate-release form.

[00207] In some embodiments, the oxytocin receptor agonist and the D-cycloserine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00208] In some embodiments, the oxytocin receptor agonist is administered prior to administration of D-cycloserine. In other embodiments, the oxytocin receptor agonist is administered after administration of D-cycloserine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of D-cycloserine.

[00209] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of cannabidiol to the subject.

[00210] In some embodiments, the cannabidiol is an extended-release form. In other embodiments, the cannabidiol is an immediate-release form.

[00211] In some embodiments, the oxytocin receptor agonist and the cannabidiol are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00212] In some embodiments, the oxytocin receptor agonist is oxytocin. In some embodiments, the oxytocin receptor agonist is carbetocin. [00213] In some embodiments, the oxytocin receptor agonist is administered prior to administration of cannabidiol. In other embodiments, the oxytocin receptor agonist is administered after administration of cannabidiol. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of cannabidiol.

[00214] In some embodiments, the oxytocin receptor agonist is administered orally. In other embodiments, the oxytocin receptor agonist is administered intranasally. In further embodiments, the oxytocin receptor agonist is administered transdermally, intramuscularly or intravenously.

[00215] In some embodiments, the oxytocin receptor agonist is selected from an extended- release form and an immediate-release form.

[00216] The treatment method aspects for OUD may include:

- treatment of patients with oxytocin or carbetocin prior to treatment with opioid agonists and/or a-2c adrenergic receptor antagonist or an NMDA receptor antagonist (e.g., but not limited to, ketamine or esketamine) or D-serine or D- cycloserine or cannabidiol, with continued oxytocin treatment with or without cannabidiol throughout and after taper;

-treatment using a combination of buprenorphine +/- naltrexone + oxytocin for treatment and as a single pill regimen;

-combined use of alpha-2c adrenergic compounds + oxytocin administered and as a single pill;

-use of tramadol + oxytocin for the treatment and with the combination administered as a single pill;

-use of tapentadol + oxytocin for the treatment and with the combination administered as a single pill;

-maintenance phase using drug combination plus oxytocin to be administered as a single pill;

-naltrexone may be added to the maintenance phase treatment (drug combination + oxytocin) if clinically necessary following complete taper of the opioid agonist; and/or -use of combination therapy of drug combination + oxytocin + naltrexone, optionally in a single dosage form. Cannabidiol may be added to the maintenance phase treatment (drug combination + oxytocin) if clinically necessary.

[00217] The methods described herein can be utilized for treatment of abuse of opioids, e.g., oxycodone, hydrocodone, hydromorphone, fentanyl, heroin, and kratom.

[00218] In some embodiments, the methods described herein are applicable and can be applied to subjects having both OUT) and cocaine-use disorder conditions concurrently.

[00219] Treatment of Post-Traumatic Stress Disorder

[00220] In a further aspect, the present invention provides methods of treating or preventing or reducing the severity of post-traumatic stress disorder (PTSD) in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an opioid agonist to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an opioid antagonist to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an a-2 adrenergic receptor agonist to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and ketamine to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and esketamine to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and MDMA to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and D-serine to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and D-cycloserine to the subject. In another aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and cannabidiol to the subject.

[00221] In some embodiments, the methods described herein are applicable and can be applied to subjects having both OUD and PTSD conditions concurrently.

[00222] In one aspect, the present invention provides methods of treating or preventing or reducing the severity of PTSD in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and one or more of the following: an opioid agonist, an a-2 adrenergic receptor agonist, an NMDA receptor antagonist (e.g., but not limited to, ketamine or esketamine), D-serine, D-cycloserine, MDMA and cannabidiol, to the subject.

[00223] In some embodiments, the PTSD is acute and in other embodiments, the PTSD is chronic.

[00224] In some embodiments, the opioid agonist is selected from the group consisting of tramadol, tapentadol, methadone and a combination thereof. In one embodiment, the opioid agonist is tramadol, or a pharmaceutically acceptable salt thereof. In one embodiment, the opioid agonist is tapentadol, or a pharmaceutically acceptable salt thereof. In one

embodiment, the opioid agonist is methadone, or a pharmaceutically acceptable salt thereof.

[00225] In some embodiments, the opioid agonist is an extended-release form. In other embodiments, the opioid agonist is an immediate-release form.

[00226] In some embodiments, the oxytocin receptor agonist and the opioid agonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00227] In some embodiments, the oxytocin receptor agonist is administered prior to administration of the opioid agonist. In other embodiments, the oxytocin receptor agonist is administered after administration of the opioid agonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of the opioid agonist. [00228] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of an opioid antagonist to the subject. In some embodiments, the opioid antagonist is naltrexone, or a pharmaceutically acceptable salt thereof.

[00229] In some embodiments, the opioid antagonist is an extended-release form. In other embodiments, the opioid antagonist is an immediate-release form.

[00230] In some embodiments, the oxytocin receptor agonist and the opioid antagonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00231] In some embodiments, the oxytocin receptor agonist is administered prior to administration of the opioid antagonist. In other embodiments, the oxytocin receptor agonist is administered after administration of the opioid antagonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of the opioid antagonist.

[00232] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of an a-2 adrenergic receptor agonist to the subject. In some embodiments, the a-2 adrenergic receptor agonist is lofexidine, or a pharmaceutically acceptable salt thereof. In some embodiments, the a-2 adrenergic receptor agonist is clonidine, or a pharmaceutically acceptable salt thereof. In some embodiments, the a-2 adrenergic receptor agonist is selected from lofexidine, clonidine, or a combination thereof.

[00233] In some embodiments, the a-2 adrenergic receptor agonist is an extended-release form. In other embodiments, the a-2 adrenergic receptor agonist is an immediate-release form.

[00234] In some embodiments, the oxytocin receptor agonist and the a-2 adrenergic receptor agonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00235] In some embodiments, the oxytocin receptor agonist is administered prior to administration of the a-2 adrenergic receptor agonist. In other embodiments, the oxytocin receptor agonist is administered after administration of the a-2 adrenergic receptor agonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of the a-2 adrenergic receptor agonist.

[00236] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of an A^-methyl-D-aspartate receptor (NMD A) receptor antagonist to the subject.

[00237] In some embodiments, the NMDA receptor antagonist is an extended-release form. In other embodiments, the NMDA receptor antagonist is an immediate-release form.

[00238] In some embodiments, the oxytocin receptor agonist and the NMDA receptor antagonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00239] In some embodiments, the oxytocin receptor agonist is administered prior to administration of NMDA receptor antagonist. In other embodiments, the oxytocin receptor agonist is administered after administration of NMDA receptor antagonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of NMDA receptor antagonist.

[00240] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of ketamine to the subject.

[00241] In some embodiments, the ketamine is an extended-release form. In other embodiments, the ketamine is an immediate-release form.

[00242] In some embodiments, the oxytocin receptor agonist and the ketamine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00243] In some embodiments, the oxytocin receptor agonist is administered prior to administration of ketamine. In other embodiments, the oxytocin receptor agonist is administered after administration of ketamine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of ketamine.

[00244] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of esketamine to the subject. [00245] In some embodiments, the esketamine is an extended-release form. In other embodiments, the esketamine is an immediate-release form.

[00246] In some embodiments, the oxytocin receptor agonist and the esketamine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00247] In some embodiments, the oxytocin receptor agonist is administered prior to administration of esketamine. In other embodiments, the oxytocin receptor agonist is administered after administration of esketamine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of esketamine.

[00248] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of MDMA to the subject.

[00249] In some embodiments, the MDMA is an extended-release form. In other embodiments, the MDMA is an immediate-release form.

[00250] In some embodiments, the oxytocin receptor agonist and the MDMA are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00251] In some embodiments, the oxytocin receptor agonist is administered prior to administration of MDMA. In other embodiments, the oxytocin receptor agonist is administered after administration of MDMA. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of MDMA.

[00252] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of D-serine to the subject.

[00253] In some embodiments, the D-serine is an extended-release form. In other embodiments, the D-serine is an immediate-release form.

[00254] In some embodiments, the oxytocin receptor agonist and the D-serine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form. [00255] In some embodiments, the oxytocin receptor agonist is administered prior to administration of D-serine. In other embodiments, the oxytocin receptor agonist is administered after administration of D-serine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of D-serine.

[00256] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of D-cycloserine to the subject.

[00257] In some embodiments, the D-cycloserine is an extended-release form. In other embodiments, the D-cycloserine is an immediate-release form.

[00258] In some embodiments, the oxytocin receptor agonist and the D-cycloserine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00259] In some embodiments, the oxytocin receptor agonist is administered prior to administration of D-cycloserine. In other embodiments, the oxytocin receptor agonist is administered after administration of D-cycloserine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of D-cycloserine.

[00260] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of cannabidiol to the subject.

[00261] In some embodiments, the cannabidiol is an extended-release form. In other embodiments, the cannabidiol is an immediate-release form.

[00262] In some embodiments, the oxytocin receptor agonist and the cannabidiol are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00263] In some embodiments, the oxytocin receptor agonist is oxytocin. In some embodiments, the oxytocin receptor agonist is carbetocin.

[00264] In some embodiments, the oxytocin receptor agonist is administered prior to administration of cannabidiol. In other embodiments, the oxytocin receptor agonist is administered after administration of cannabidiol. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of cannabidiol. [00265] In some embodiments, the oxytocin receptor agonist is administered orally. In other embodiments, the oxytocin receptor agonist is administered intranasally. In further embodiments, the oxytocin receptor agonist is administered transdermally, intramuscularly or intravenously.

In some embodiments, the oxytocin receptor agonist is selected from an extended-release form and an immediate-release form.

[00266] The treatment method aspects for PTSD may include:

-treatment of PTSD patients with oxytocin or carbetocin prior to treatment with opioid agonists and/or opioid antagonist or a-2 adrenergic receptor agonist or an NMDA receptor antagonist (e.g., but not limited to, ketamine or esketamine) or D- serine or D-cycloserine or MDMA or cannabidiol, with continued oxytocin treatment with or without cannabidiol throughout and after taper;

-treatment using a combination of buprenorphine +/- naltrexone + oxytocin for PTSD treatment and as a single pill regimen;

-combined use of alpha-2 adrenergic compounds + oxytocin administered and as a single pill;

-use of tramadol + oxytocin for the treatment of PTSD and with the combination administered as a single pill;

-use of tapentadol + oxytocin for the treatment of PTSD and with the combination administered as a single pill;

-naltrexone may be added to the maintenance phase treatment (drug combination + oxytocin) if clinically necessary following complete taper of the opioid agonist; and/or

-use of combination therapy of drug combination + oxytocin + naltrexone, optionally in a single dosage form. Cannabidiol may be added to the maintenance phase treatment (drug combination + oxytocin) if clinically necessary.

Treatment of Post-Partum Unipolar Depression [00267] In another aspect, the present invention provides methods of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an opioid agonist to the subject. In another aspect, the present invention provides methods of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and an a-2c adrenergic receptor antagonist to the subject. In another aspect, the present invention provides methods of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and ketamine to the subject. In another aspect, the present invention provides methods of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and esketamine to the subject. In another aspect, the present invention provides methods of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and D-serine to the subject. In another aspect, the present invention provides methods of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and D- cycloserine to the subject.

[00268] In one aspect, the present invention provides methods of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and one or more of the following: an opioid agonist, an a-2c adrenergic receptor antagonist, an NMDA receptor antagonist (e.g., but not limited to, ketamine or esketamine), D-serine, and D-cycloserine, to the subject.

[00269] In one aspect, the present invention provides methods of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of an oxytocin receptor agonist and one or more of the following: an a-2c adrenergic receptor antagonist, an NMDA receptor antagonist (e.g., but not limited to, ketamine or esketamine), D-serine, and D-cycloserine, to the subject.

[00270] In some embodiments, the opioid agonist is selected from the group consisting of tramadol, buprenorphine (opioid partial agonist), tapentadol, methadone and a combination thereof. In one embodiment, the opioid agonist is tramadol, or a pharmaceutically acceptable salt thereof. In one embodiment, the opioid agonist is tapentadol, or a pharmaceutically acceptable salt thereof.

[00271] In some embodiments, the opioid agonist is an extended-release form. In other embodiments, the opioid agonist is an immediate-release form.

[00272] In some embodiments, the oxytocin receptor agonist and the opioid agonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00273] In some embodiments, the oxytocin receptor agonist is administered prior to administration of the opioid agonist. In other embodiments, the oxytocin receptor agonist is administered after administration of the opioid agonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of the opioid agonist.

[00274] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of an opioid antagonist to the subject. In some embodiments, the opioid antagonist is naltrexone, or a pharmaceutically acceptable salt thereof.

[00275] In some embodiments, the opioid antagonist is an extended-release form. In other embodiments, the opioid antagonist is an immediate-release form.

[00276] In some embodiments, the oxytocin receptor agonist and the opioid antagonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00277] In some embodiments, the oxytocin receptor agonist is administered prior to administration of the opioid antagonist. In other embodiments, the oxytocin receptor agonist is administered after administration of the opioid antagonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of the opioid antagonist.

[00278] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of an a-2c adrenergic receptor antagonist to the subject. [00279] In some embodiments, the a-2c adrenergic receptor antagonist is an extended- release form. In other embodiments, the a-2c adrenergic receptor antagonist is an immediate- release form.

[00280] In some embodiments, the oxytocin receptor agonist and the a-2c adrenergic receptor antagonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00281] In some embodiments, the oxytocin receptor agonist is administered prior to administration of the a-2c adrenergic receptor antagonist. In other embodiments, the oxytocin receptor agonist is administered after administration of the a-2c adrenergic receptor antagonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of the a-2c adrenergic receptor antagonist.

[00282] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of an iV-m ethyl -D-aspartate receptor (NMD A) receptor antagonist to the subject.

[00283] In some embodiments, the NMDA receptor antagonist is an extended-release form. In other embodiments, the NMDA receptor antagonist is an immediate-release form.

[00284] In some embodiments, the oxytocin receptor agonist and the NMDA receptor antagonist are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00285] In some embodiments, the oxytocin receptor agonist is administered prior to administration of NMDA receptor antagonist. In other embodiments, the oxytocin receptor agonist is administered after administration of NMDA receptor antagonist. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of NMDA receptor antagonist.

[00286] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of ketamine to the subject.

[00287] In some embodiments, the ketamine is an extended-release form. In other embodiments, the ketamine is an immediate-release form. [00288] In some embodiments, the oxytocin receptor agonist and the ketamine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00289] In some embodiments, the oxytocin receptor agonist is administered prior to administration of ketamine. In other embodiments, the oxytocin receptor agonist is administered after administration of ketamine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of ketamine.

[00290] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of esketamine to the subject.

[00291] In some embodiments, the esketamine is an extended-release form. In other embodiments, the esketamine is an immediate-release form.

[00292] In some embodiments, the oxytocin receptor agonist and the esketamine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00293] In some embodiments, the oxytocin receptor agonist is administered prior to administration of esketamine. In other embodiments, the oxytocin receptor agonist is administered after administration of esketamine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of esketamine.

[00294] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of D-serine to the subject.

[00295] In some embodiments, the D-serine is an extended-release form. In other embodiments, the D-serine is an immediate-release form.

[00296] In some embodiments, the oxytocin receptor agonist and the D-serine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00297] In some embodiments, the oxytocin receptor agonist is administered prior to administration of D-serine. In other embodiments, the oxytocin receptor agonist is administered after administration of D-serine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of D-serine.

[00298] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of D-cycloserine to the subject.

[00299] In some embodiments, the D-cycloserine is an extended-release form. In other embodiments, the D-cycloserine is an immediate-release form.

[00300] In some embodiments, the oxytocin receptor agonist and the D-cycloserine are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00301] In some embodiments, the oxytocin receptor agonist is administered prior to administration of D-cycloserine. In other embodiments, the oxytocin receptor agonist is administered after administration of D-cycloserine. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of D-cycloserine.

[00302] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of cannabidiol to the subject.

[00303] In some embodiments, the cannabidiol is an extended-release form. In other embodiments, the cannabidiol is an immediate-release form.

[00304] In some embodiments, the oxytocin receptor agonist and the cannabidiol are administered in a single dosage form. In one embodiment, the single dosage form is an extended-release form. In one embodiment, the single dosage form is an immediate-release form.

[00305] In some embodiments, the oxytocin receptor agonist is oxytocin. In some embodiments, the oxytocin receptor agonist is carbetocin.

[00306] In some embodiments, the oxytocin receptor agonist is administered prior to administration of cannabidiol. In other embodiments, the oxytocin receptor agonist is administered after administration of cannabidiol. In some embodiments, the oxytocin receptor agonist is administered concurrently with administration of cannabidiol.

[00307] In some embodiments, the oxytocin receptor agonist is administered orally. In other embodiments, the oxytocin receptor agonist is administered intranasally. In further embodiments, the oxytocin receptor agonist is administered transdermally, intramuscularly or intravenously.

[00308] In some embodiments, the oxytocin receptor agonist is selected from an extended- release form and an immediate-release form.

[00309] The treatment method aspects for post-partum unipolar depression may include:

-treatment of patients with oxytocin or carbetocin prior to treatment with opioid agonists and/or a-2c adrenergic receptor antagonist or an NMDA receptor antagonist (e.g., but not limited to, ketamine or esketamine) or D-serine or D- cycloserine or cannabidiol, with continued oxytocin treatment with or without cannabidiol throughout and after taper;

[00310] All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification. By citation of various references in this document, Applicants do not admit any particular reference is "prior art" to their invention. [00311] While example embodiments have been particularly shown and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the embodiments encompassed by the appended claims.

Claims

CLAIMS What is claimed is:

1. A method of treating a neuropsychiatric condition in a subject in need thereof,

comprising administering to the subject:

compound during a treatment step, wherein the second compound regulates an opioid receptor, a cocaine receptor, an adrenergic receptor, an N-methyl-D- aspartate receptor (NMD A) receptor, is MDMA, or a combination thereof; wherein the neuropsychiatric condition is selected from the group consisting of post- traumatic stress disorder (PTSD), opioid use disorder (OUD), cocaine use disorder (CUD), unipolar post-partum depression (PPD) and combinations thereof.

2. A method for conditioning a subject in need thereof for treatment of a

neuropsychiatric condition, comprising administering to the subject a therapeutically effective amount of a first compound during a pretreatment step, wherein the first compound regulates an oxytocin receptor, and the neuropsychiatric condition is selected from the group consisting of post-traumatic stress disorder (PTSD), opioid use disorder (OUD), cocaine use disorder (CUD), post-partum unipolar depression (PPD) and combinations thereof.

3. The method of Claim 2, further comprising a treatment step, wherein the treatment step comprises administering to the subject therapeutically effective amounts of the first compound and a second compound, wherein the second compound regulates an opioid receptor, a cocaine receptor, an adrenergic receptor, an N-methyl-D-aspartate receptor (NMD A) receptor, is MDMA, or a combination thereof.

4. The method of Claim 1 or 3, wherein the treatment step comprises an induction step, a maintenance step and a tapering step.

5. The method of Claim 4, further comprising administering to the subject a therapeutically effective amount of a third compound during the tapering step, wherein the third compound regulates an opioid receptor, a cannabinoid receptor or both.

6. The method of any one of Claims 1-5, wherein the first compound, the second

compound, and/or the third compound binds to the receptor it regulates, optionally, the first compound, the second compound, and/or the third compound is a ligand of the receptor it regulates.

7. The method of any one of Claims 1-6, wherein the pretreatment step occurs about two to about four weeks before the treatment step.

8. The method of any one of Claims 1-7, wherein the subject has acute or chronic PTSD.

9. The method of any one of Claims 1-7, wherein the subject has OUT), CUD or both.

10. The method of any one of Claims 1-7, wherein the subject has PPD.

11. The method of any one of Claims 1-10, wherein the first compound is selected from the group consisting of oxytocin, carbetocin, analogues thereof, pharmaceutically acceptable salts thereof and combinations thereof.

12. The method of any one of Claims 1-11, wherein the second compound comprises: a) a ligand, an agonist, a partial agonist, and/or an antagonist of the opioid

receptor;

b) a ligand, an agonist, and/or an antagonist of the a-2c adrenergic receptor; c) a ligand, an agonist, and/or an antagonist of the NMDA receptor;

d) MDMA; or

e) a combination thereof.

13. The method of Claim 12, wherein the second compound is selected from the group consisting of buprenorphine, methadone, tapentadol, tramadol, naltrexone,

Lofexidine, clonidine, D-serine, D-cycloserine, ketamine, esketamine, MDMA, analogues thereof, pharmaceutically acceptable salts thereof and combinations thereof.

14. The method of any one of Claims 5-13, wherein the third compound comprises: a) a ligand and/or an agonist of the cannabidiol receptor;

b) a ligand and/or an antagonist of the opioid receptor;

c) or a combination thereof.

15. The method of any one of Claims 5-13, wherein the third compound is selected from the group consisting of cannabidiol, naltrexone, analogues thereof, pharmaceutically acceptable salts thereof and combinations thereof.

16. The method of any one of Claims 4-15, wherein the first and the second compounds are administered in a single dosage form during the induction step, the maintenance step, or both.

17. The method of any one of Claims 4-15, wherein the first compound is administered prior to the second compound during the induction step, the maintenance step, or both.

18. The method of any one of Claims 4-15, wherein the first compound is administered after the second compound during the induction step, the maintenance step, or both.

19. The method of any one or Claims 1-18, wherein the first and/or the second compound is administered orally, intranasally, transdermally, intramuscularly or intravenously.

20. The method of any one of Claims 1-19, wherein the first and/or the second compound is formulated in an immediate-release form.

21. The method of any one or Claims 1-19, wherein the first and/or the second compound is formulated in an extended-release form.

22. The method of any one or Claims 1-21, further comprising providing psychological counseling to the subject.

23. A method of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of oxytocin and an opioid agonist to the subject.

24. The method of claim 23, wherein the opioid agonist is tramadol, or a

pharmaceutically acceptable salt thereof.

25. The method of claim 23, wherein the opioid agonist is tapentadol, or a

pharmaceutically acceptable salt thereof.

26. The method of claim 23, wherein the opioid agonist is buprenorphine, or a

pharmaceutically acceptable salt thereof.

27. The method of claim 23, further comprising administering a therapeutically effective amount of an opioid antagonist to the subject.

28. The method of claim 27, wherein the opioid antagonist is naltrexone, or a

pharmaceutically acceptable salt thereof.

29. The method of claim 23, wherein the opioid agonist is selected from the group

consisting of tramadol, buprenorphine, tapentadol, methadone and a combination thereof.

30. The method of any one of claims 23-29, wherein oxytocin is administered orally.

31. The method of any one of claims 23-29, wherein oxytocin is administered

intranasally.

32. The method of any one of claims 23-29, wherein oxytocin is administered

transdermally, intramuscularly or intravenously.

33. The method of any one of claims 23-29, wherein oxytocin is selected from an

extended-release form and an immediate-release form.

34. The method of any one of claims 23-33, wherein the opioid agonist is an extended- release form.

35. The method of any one of claims 23-33, wherein the opioid agonist is an immediate- release form.

36. The method of any one of claims 23-35, wherein oxytocin is administered prior to administration of the opioid agonist.

37. The method of any one of claims 23-35, wherein oxytocin is administered after

administration of the opioid agonist.

38. The method of any one of claims 23-29, wherein oxytocin and the opioid agonist are administered in a single dosage form.

39. The method of claim 38, wherein the single dosage form is an extended-release form.

40. The method of claim 27, wherein oxytocin, the opioid agonist, and the opioid

antagonist are administered in a single dosage form.

41. The method of claim 40, wherein the single dosage form is an extended-release form.

42. The method of any one of claims 23-41, further comprising administering a

therapeutically effective amount of ketamine.

43. The method of any one of claims 23-41, further comprising administering a

therapeutically effective amount of esketamine.

44. A method of treating opioid use disorder in a subject in need thereof, comprising administering a therapeutically effective amount of carbetocin and an opioid agonist to the subject.

45. The method of claim 44, wherein the opioid agonist is tramadol, or a

pharmaceutically acceptable salt thereof.

46. The method of claim 44, wherein the opioid agonist is tapentadol, or a pharmaceutically acceptable salt thereof.

47. The method of claim 44, wherein the opioid agonist is buprenorphine, or a

pharmaceutically acceptable salt thereof.

48. The method of claim 44, further comprising administering a therapeutically effective amount of an opioid antagonist to the subject.

49. The method of claim 48, wherein the opioid antagonist is naltrexone, or a

pharmaceutically acceptable salt thereof.

50. The method of claim 44, wherein the opioid agonist is selected from the group

51. The method of any one of claims 44-50, wherein carbetocin is administered orally.

52. The method of any one of claims 44-50, wherein carbetocin is administered

intranasally.

53. The method of any one of claims 44-50, wherein carbetocin is administered

transdermally, intramuscularly or intravenously.

54. The method of any one of claims 44-50, wherein carbetocin is selected from an extended-release form and an immediate-release form.

55. The method of any one of claims 44-54, wherein the opioid agonist is an extended- release form.

56. The method of any one of claims 44-54, wherein the opioid agonist is an immediate- release form.

57. The method of any one of claims 44-56, wherein carbetocin is administered prior to administration of the opioid agonist.

58. The method of any one of claims 44-56, wherein carbetocin is administered after administration of the opioid agonist.

59. The method of any one of claims 44-50, wherein carbetocin and the opioid agonist are administered in a single dosage form.

60. The method of claim 59, wherein the single dosage form is an extended-release form.

61. The method of claim 48, wherein carbetocin, the opioid agonist, and the opioid

antagonist are administered in a single dosage form.

62. The method of claim 61, wherein the single dosage form is an extended-release form.

63. The method of any one of claims 44-62, further comprising administering a

therapeutically effective amount of ketamine.

64. The method of any one of claims 44-62, further comprising administering a

therapeutically effective amount of esketamine.

65. A method of treating, preventing or reducing severity of post-traumatic stress disorder (PTSD) in a subject in need thereof, comprising administering a therapeutically effective amount of oxytocin and an opioid agonist to the subject.

66. The method of claim 65, wherein the opioid agonist is tramadol, or a

pharmaceutically acceptable salt thereof.

67. The method of claim 65, wherein the opioid agonist is tapentadol, or a

pharmaceutically acceptable salt thereof.

68. The method of claim 65, wherein the opioid agonist is selected from the group

consisting of tramadol, tapentadol and a combination thereof.

69. The method of any one of claims 65-68, wherein oxytocin is administered orally.

70. The method of any one of claims 65-68, wherein oxytocin is administered

intranasally.

71. The method of any one of claims 65-68, wherein oxytocin is administered

transdermally, intramuscularly or intravenously.

72. The method of any one of claims 65-71, wherein oxytocin is selected from an

extended-release form and an immediate-release form.

73. The method of any one of claims 65-72, wherein the opioid agonist is an extended- release form.

74. The method of any one of claims 65-72, wherein the opioid agonist is an immediate- release form.

75. The method of any one of claims 65-74, wherein oxytocin is administered prior to administration of the opioid agonist.

76. The method of any one of claims 65-74, wherein oxytocin is administered after

administration of the opioid agonist.

77. The method of claim 76, further comprising administering cannabidiol.

78. The method of any one of claims 65-68, wherein oxytocin and the opioid agonist are administered in a single dosage form.

79. The method of claim 78, wherein the single dosage form is an extended-release form.

80. The method of claim 65, wherein the PTSD is acute PTSD.

81. The method of claim 65, wherein the PTSD is chronic PTSD.

82. The method of any one of claims 65-81, further comprising administering a

therapeutically effective amount of ketamine.

83. The method of any one of claims 65-81, further comprising administering a

therapeutically effective amount of esketamine.

84. The method of any one of claims 65-81, further comprising administering a therapeutically effective amount of MDMA (ecstasy).

85. The method of any one of claims 65-81, further comprising administering a

therapeutically effective amount of D-cycloserine.

86. The method of any one of claims 65-81, further comprising administering a

therapeutically effective amount of D-serine.

87. A method of treating, preventing or reducing severity of post-traumatic stress disorder in a subject in need thereof, comprising administering a therapeutically effective amount of carbetocin and an opioid agonist to the subject.

88. The method of claim 87, wherein the opioid agonist is tramadol, or a

pharmaceutically acceptable salt thereof.

89. The method of claim 87, wherein the opioid agonist is tapentadol, or a

pharmaceutically acceptable salt thereof.

90. The method of claim 87, wherein the opioid agonist is selected from the group

consisting of tramadol, tapentadol and a combination thereof.

91. The method of any one of claims 87-90, wherein oxytocin is administered orally.

92. The method of any one of claims 87-91, wherein carbetocin is administered

intranasally.

93. The method of any one of claims 87-91, wherein carbetocin is administered

transdermally, intramuscularly or intravenously.

94. The method of any one of claims 87-93, wherein carbetocin is selected from an

extended-release form and an immediate-release form.

95. The method of any one of claims 87-94, wherein the opioid agonist is an extended- release form.

96. The method of any one of claims 87-94, wherein the opioid agonist is an immediate- release form.

97. The method of any one of claims 87-96, wherein carbetocin is administered prior to administration of the opioid agonist.

98. The method of any one of claims 87-96, wherein carbetocin is administered after administration of the opioid agonist.

99. The method of claim 98, further comprising administering cannabidiol.

100. The method of any one of claims 87-90, wherein carbetocin and the opioid agonist are administered in a single dosage form.

101. The method of claim 100, wherein the single dosage form is an extended-release form.

102. The method of claim 87, wherein the PTSD is acute PTSD.

103. The method of claim 87, wherein the PTSD is chronic PTSD.

104. The method of any one of claims 87-103, further comprising administering a

therapeutically effective amount of ketamine.

105. The method of any one of claims 87-103, further comprising administering a

therapeutically effective amount of esketamine.

106. The method of any one of claims 87-103, further comprising administering a

therapeutically effective amount of MDMA (ecstasy).

107. The method of any one of claims 87-103, further comprising administering a

therapeutically effective amount of D-cycloserine.

108. The method of any one of claims 87-103, further comprising administering a

therapeutically effective amount of D-serine.

109. A method of treating post-traumatic stress disorder in a subject in need thereof, comprising administering a therapeutically effective amount of oxytocin and ketamine to the subject.

110. A method of treating post-traumatic stress disorder in a subject in need thereof,

comprising administering a therapeutically effective amount of oxytocin and esketamine to the subject.

111. A method of treating post-traumatic stress disorder in a subject in need thereof,

comprising administering a therapeutically effective amount of carbetocin and ketamine to the subject.

112. A method of treating post-traumatic stress disorder in a subject in need thereof,

comprising administering a therapeutically effective amount of carbetocin and esketamine to the subject.

113. A method of treating opioid use disorder in a subject in need thereof, comprising

administering a therapeutically effective amount of oxytocin and an a-2 adrenergic receptor agonist to the subject.

114. The method of claim 113, wherein the a-2 adrenergic receptor agonist is lofexidine, or a pharmaceutically acceptable salt thereof.

115. The method of claim 113, further comprising administering a therapeutically effective amount of an opioid antagonist to the subject.

116. The method of claim 113, wherein oxytocin and the a-2 adrenergic receptor agonist are administered in a single dosage form.

117. The method of claim 116, wherein the single dosage form is an extended-release

form.

118. A method of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of carbetocin and an opioid agonist to the subject.

119. The method of claim 118, wherein the opioid agonist is tramadol, or a

pharmaceutically acceptable salt thereof.

120. The method of claim 118, wherein the opioid agonist is tapentadol or a

pharmaceutically acceptable salt thereof.

121. The method of claim 118, wherein the opioid agonist is selected from the group

consisting of tramadol, tapentadol and a combination thereof.

122. The method of any one of claims 118-121, wherein carbetocin is administered orally.

123. The method of any one of claims 118-122, wherein carbetocin is administered

intranasally.

124. The method of any one of claims 118-122, wherein carbetocin is administered

transdermally, intramuscularly or intravenously.

125. The method of any one of claims 118-124, wherein carbetocin is selected from an extended-release form and an immediate-release form.

126. The method of any one of claims 118-125, wherein the opioid agonist is an extended- release form.

127. The method of any one of claims 118-125, wherein the opioid agonist is an

immediate-release form.

128. The method of any one of claims 118-127, wherein carbetocin is administered prior to administration of the opioid agonist.

129. The method of any one of claims 118-127, wherein carbetocin is administered after administration of the opioid agonist.

130. The method of claim 129, further comprising administering cannabidiol.

131. The method of any one of claims 118-121, wherein carbetocin and the opioid agonist are administered in a single dosage form.

132. The method of claim 131, wherein the single dosage form is an extended-release form.

133. The method of claim 118, wherein the post-partum unipolar depression is acute.

134. The method of claim 118, wherein the post-partum unipolar depression is chronic.

135. The method of any one of claims 118-134, further comprising administering a

therapeutically effective amount of ketamine.

136. The method of any one of claims 118-134, further comprising administering a

therapeutically effective amount of esketamine.

137. A method of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of oxytocin and ketamine to the subject.

138. A method of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of oxytocin and esketamine to the subject.

139. A method of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of carbetocin and ketamine to the subject.

140. A method of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of carbetocin and esketamine to the subject.

141. A method of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of oxytocin and D-serine to the subject.

142. A method of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of carbetocin and D- serine to the subject.

143. A method of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of oxytocin and D- cycloserine to the subject.

144. A method of treating post-partum unipolar depression in a subject in need thereof, comprising administering a therapeutically effective amount of carbetocin and D- cycloserine to the subject.