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(12) Patent Application Publication (10) Pub. No.: US 2017/0135984 A1 Solomon (43) Pub

(12) Patent Application Publication (10) Pub. No.: US 2017/0135984 A1 Solomon (43) Pub

US 20170135984A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0135984 A1 Solomon (43) Pub. Date: May 18, 2017

(54) INTRANASAL AND TRANSIDERMAL Publication Classification ADMINISTRATION OF (51) Int. Cl. KAPPA-OPOID-RECEPTORAGONSTS: A63L/366 (2006.01) FOR THE TREATMENT OF A636/537 (2006.01) NEUROPSYCHATRIC AND ADDICTIVE A63/37 (2006.01) DSORDERS A6IR 9/00 (2006.01) A636/85 (2006.01) (71) Applicant: Atlee Solomon, Vienna, VA (US) (52) U.S. Cl. CPC ...... A61 K3I/366 (2013.01); A61K 9/0014 (72) Inventor: Atlee Solomon, Vienna, VA (US) (2013.01); A61K 9/0043 (2013.01); A61 K 36/185 (2013.01); A61K 31/137 (2013.01); (21) Appl. No.: 15/354,078 A61K 36/537 (2013.01) (57) ABSTRACT Methods of treating neuropsychiatric disorders including (22) Filed: Nov. 17, 2016 affective disorders and addiction involve intranasal or trans dermal administration of a Substantially selective kappa - that is also a partial D2 agonist, Such Related U.S. Application Data as the compound salvinorin A. Also disclosed are intranasal, (60) Provisional application No. 62/256,409, filed on Nov. transdermal and/or inhalation systems for delivering the 17, 2015. kappa-opioid-receptor agonist. US 2017/O 135984 A1 May 18, 2017

INTRANASAL AND TRANSIDERMAL ropsychiatric conditions (Dhuria, 2010; Djupesland, 2014). ADMINISTRATION OF In spite of this, the neuropsychiatric drug is KAPPA-OPOID-RECEPTORAGONSTS: currently under experimental investigation using the intra SALVINORIN A FOR THE TREATMENT OF nasal route of administration for treatment of acute and NEUROPSYCHATRIC AND ADDICTIVE chronic pain, autism, depression and other conditions (Af DISORDERS ridi, 2013: Yeaman, 2014: Clark, 2014, Lapidus, 2014: Graudins, 2015). can potentiate the effects of CROSS-REFERENCE TO RELATED ketamine (Krystal et al., 2006). APPLICATIONS 0008 Similar to the intranasal route of administration, transdermal administration presents challenges and only a 0001. This application claims the benefit of U.S. Provi few medications can be delivered through the transdermal sional Application No. 62/256,409, filed Nov. 17, 2015, and route in therapeutic amounts (Paudel, 2010; Ita, 2015). incorporated by reference herein in its entirety. 0009. As noted above, numerous studies have evaluated different routes of administration for salvinorin A. Never BACKGROUND OF THE INVENTION theless, none of the routes of administration that have been 0002 (1) Field of the Invention studied are particularly Suited for use in neuropsychiatry. 0003. The present invention is related to the treatment of neuropsychiatric conditions with kappa-opioid-receptor BRIEF SUMMARY OF THE INVENTION and, in particular, to intranasal, transdermal and 0010. Accordingly, the applicant herein has invented an inhalation systems and methods of administration of kappa intranasal system and method and a transdermal system and opioid-receptor agonists for the treatment of neuropsychi method for administration of kappa-opioid-selective ago atric conditions. nists such as Salvinorin A, for the treatment of neuropsy 0004 (2) Description of the Related Art chiatric conditions. 0005 Salvinorin A is a naturally occurring psychoactive 0011 Thus in various embodiments, the present inven compound isolated from . Studies have tion involves a method of treating an affective disorder in a demonstrated that salvinorin A is a uniquely selective kappa patient in need thereof. The method may comprise admin opioid-receptor agonist with no significant effect on a bat istering intranasally to the patient, a therapeutically effective tery of 50 other receptors, transporters and ion channels amount of a Substantially selective kappa-opioid-receptor including mu- and delta-opioid receptors (Roth et al., 2004). agonist in a pharmaceutically acceptable preparation. In In addition to having kappa-opioid-agonist activity, Salvi various embodiments, the kappa-opioid-receptor agonist norin A has been found to be a D2 receptor partial agonist may be devoid of activity on 5HT receptors, in particular (Seeman et al., 2009). Notably, salvinorin Ahas been shown 5HT receptors, such that it produces Substantially no to have no significant effect on 5HTP receptors and as a manic effect. In various embodiments, the kappa-opioid result, administration of Salvinorin A to a subject would not receptor agonist also has D2 agonist activity and, in par be expected to produce mania (Yatham et al., 2010). Recent ticular, partial D2 agonist activity. In certain embodiments, studies have Suggested that salvinorin A may have anti the kappa-opioid-receptor agonist may be salvinorin A. depression and anti-addiction properties among other poten Administration may be with an intranasal delivery device. tially beneficial properties (Morani et al., 2009; Prevatt 0012. In various embodiments, the affective disorder may Smith et al., 2011; Harden et al., 2012: Orton et al., 2014). be depression, bipolar disorder or anxiety disorder. 0006. Several routes of administration have been used for 0013. In various aspects of this embodiment, the kappa Salvia divinorum and for Salvinorin A with varying degrees opioid-receptor agonist may be administered with either or of Success. In traditional practice among the Mazatec people both of a compound and ketamine in a phar of Mexico, Salvia divinorum was ingested by chewing the maceutically acceptable preparation. The pharmaceutically fresh leaves as a quid or by smoking (Valdes, 1994; Siebert, acceptable preparation for the cannabinoid compound and/ 1994). Absorption upon chewing is apparently by the buccal or ketamine may include the same carrier system in which route in as much as encapsulated Salvinorin A is inactive the kappa-opioid-receptor agonist is administered and the when administered orally (Siebert, 1994; Ott, 1995). Sub Substances may be administered together or separately in lingual administration has generally yielded inconsistent any combination thereof. Alternatively, the carrier system results or no absorption at all (Siebert, 1994; Mendelson et for the cannabinoid compound and/or ketamine may be al., 2011). The most common route of administration of different from that of the kappa-opioid-receptor agonist and Salvia divinorum has been inhalation by Smoking the leaves the Substances may be administered separately. In some (Giroud et al., 2000). More recently, the inhalation route of embodiments, naltrexone is included. administration has been used for the active component, 0014. In various embodiments, the present invention may salvinorin A, in human Subjects (Johnson et al., 2011; involve a method of treating addiction in a Subject in need Maqueda et al., 2015). thereof. The method may comprise administering intrana 0007 Although infrequently used, the intranasal route of Sally to the patient, a therapeutically effective amount of a administration has been proposed for use in pharmacologic Substantially selective kappa-opioid-receptor agonist in a treatment of neuropsychiatric conditions. Potential advan pharmaceutically acceptable preparation. In various tages of intranasal administration are rapid onset of action, embodiments, the kappa-opioid-receptor agonist may be the ability to bypass the blood-brain barrier, improvement in devoid of activity on 5HT, receptors, in particular 5HT, and avoidance of parenteral administration receptors, such that it produces Substantially no manic effect. (Andrade, 2015). Nevertheless, there are numerous chal In various embodiments, the kappa-opioid-receptor agonist lenges and potential problems that have limited the use of also has D2 agonist activity and, in particular, partial D2 intranasal administration of drugs for the treatment of neu agonist activity. In certain embodiments, the kappa-opioid US 2017/O 135984 A1 May 18, 2017 receptor agonist may be salvinorin A. Administration may which the kappa-opioid-receptor agonist is administered and be with an intranasal delivery device. the Substances may be administered together or separately in 0015. In various embodiments, the addiction may be an any combination thereof. Alternatively, the carrier system addiction to nicotine, , , , meth for the cannabinoid compound and/or ketamine may be amphetamine, ethanol, , , , different from that of the kappa-opioid-receptor agonist and 3.4-methylenedioxy-, as well as other the Substances may be administered separately. In some addictive substances and addictive behaviors. embodiments, naltrexone is included. 0016. In various aspects of this embodiment, the kappa 0021. In various other embodiments, the present inven opioid-receptor agonist may be administered with either or tion involves a method of treating an affective disorder in a both of a cannabinoid compound and ketamine in a phar patient in need thereof. The method may comprise admin maceutically acceptable preparation. The pharmaceutically istering transdermally to the patient, a therapeutically effec acceptable preparation for the cannabinoid compound and/ tive amount of a Substantially selective kappa-opioid-recep or ketamine may include the same carrier system in which tor agonist in a pharmaceutically acceptable preparation. In the kappa-opioid-receptor agonist is administered and the various embodiments, the kappa-opioid-receptor agonist Substances may be administered together or separately in may be devoid of activity on 5HT receptors, in particular any combination thereof. Alternatively, the carrier system 5HT, receptors, such that it produces substantially no for the cannabinoid compound and/or ketamine may be manic effect. In various embodiments, the kappa-opioid different from that of the kappa-opioid-receptor agonist and receptor agonist also has D2 agonist activity and, in par the Substances may be administered separately. In some ticular, partial D2 agonist activity. In certain embodiments, embodiments, naltrexone is included. the kappa-opioid-receptor agonist may be salvinorin A. 0017. In yet another embodiment, the present invention Administration may be with a transdermal delivery device or may involve an intranasal delivery system. The system may system. comprise an intranasal delivery device and a therapeutically 0022. In various embodiments, the affective disorder may effective amount of a Substantially selective kappa-opioid be depression, bipolar disorder or anxiety disorder. receptor agonist in a pharmaceutically acceptable prepara 0023. In various aspects of this embodiment, the kappa tion. In various embodiments, the kappa-opioid-receptor opioid-receptor agonist may be administered with either or agonist may be devoid of activity on 5HT receptors, in both of a cannabinoid compound and ketamine in a phar particular 5HT receptors, such that it does not produce maceutically acceptable preparation. The pharmaceutically mania. In various embodiments, the kappa-opioid-receptor acceptable preparation for the cannabinoid compound and/ agonist also has D2 agonist activity and, in particular, partial or ketamine may include the same carrier system in which D2 agonist activity. In certain embodiments, the kappa the kappa-opioid-receptor agonist is administered and the opioid-receptor agonist may be salvinorin A. Substances may be administered together or separately in 0018. In various aspects of this embodiment, the system any combination thereof. Alternatively, the carrier system may include, in addition to the kappa-opioid-receptor ago for the cannabinoid compound and/or ketamine may be nist, either or both of a cannabinoid compound and ketamine different from that of the kappa-opioid-receptor agonist and in a pharmaceutically acceptable preparation. The pharma the Substances may be administered separately. In some ceutically acceptable preparation for the cannabinoid com embodiments, naltrexone is included. pound and/or ketamine may include the same carrier system 0024. In various embodiments, the present invention may in which the kappa-opioid-receptor agonist is administered involve a method of treating addiction in a Subject in need and the Substances may be administered together or sepa thereof. The method may comprise administering transder rately in any combination thereof. Alternatively, the carrier mally to the patient, a therapeutically effective amount of a system for the cannabinoid compound and/or ketamine may Substantially selective kappa-opioid-receptor agonist in a be different from that of the kappa-opioid-receptor agonist pharmaceutically acceptable preparation. In various and the Substances may be administered separately. In some embodiments, the kappa-opioid-receptor agonist may be embodiments, naltrexone is included. devoid of activity on 5HT receptors, in particular 5HT. 0019. In various other embodiments, the present inven receptors, such that it produces Substantially no manic effect. tion may involve an inhalation delivery system. The system In various embodiments, the kappa-opioid-receptor agonist may comprise an inhalation delivery device and a therapeu also has D2 agonist activity and, in particular, partial D2 tically effective amount of a Substantially selective kappa agonist activity. In certain embodiments, the kappa-opioid opioid-receptor agonist in a pharmaceutically acceptable receptor agonist may be salvinorin A. Administration may preparation. In various embodiments, the kappa-opioid be with a transdermal delivery device or system. receptor agonist may be devoid of activity on 5HT2 recep 0025. In various embodiments, the addiction may be an tors, in particular 5HT receptors, such that it produces addiction to nicotine, cocaine, opioids, amphetamine, meth Substantially no manic effect. In various embodiments, the amphetamine, ethanol, heroin, morphine, phencyclidine, kappa-opioid-receptor agonist also has D2 agonist activity 3.4-methylenedioxy-methamphetamine, as well as other and, in particular, partial D2 agonist activity. In certain addictive substances and addictive behaviors. embodiments, the kappa-opioid-receptor agonist may be 0026. In various aspects of this embodiment, the kappa salvinorin A. opioid-receptor agonist may be administered with either or 0020. In various aspects of this embodiment, the system both of a cannabinoid compound and ketamine in a phar may include, in addition to the kappa-opioid-receptor ago maceutically acceptable preparation. The pharmaceutically nist, either or both of a cannabinoid and ketamine in a acceptable preparation for the cannabinoid compound and/ pharmaceutically acceptable preparation. The pharmaceuti or ketamine may include the same carrier system in which cally acceptable preparation for the cannabinoid compound the kappa-opioid-receptor agonist is administered and the and/or ketamine may include the same carrier system in Substances may be administered together or separately in US 2017/O 135984 A1 May 18, 2017

any combination thereof. Alternatively, the carrier system 0033. The term “cannabinoid compound as used herein, for the cannabinoid compound and/or ketamine may be is intended to refer to terpenophenolic compounds that act different from that of the kappa-opioid-receptor agonist and on cannabinoid CB1 and/or CB2 receptors in cells including the Substances may be administered separately. In some phytocannabinoids, endocannabinoids and synthetic can embodiments, naltrexone is included. nabinoids. Phytocannabinoids can be found in 0027. In yet another embodiment, the present invention plants, endocannabinoids are produced naturally in the body may involve a transdermal delivery system. The system may and synthetic are man-made. comprise a transdermal delivery device and a therapeutically 0034 Examples of phytocannabinoids include cannab effective amount of a Substantially selective kappa-opioid igerol (CBG), (CBC), (CBD), receptor agonist in a pharmaceutically acceptable prepara (THC), (CBN), cannabiel tion. In various embodiments, the kappa-opioid-receptor soin (CBE), iso-tetrahydrocannabinol (iso-THC), cannabi agonist may be devoid of activity on 5HT receptors, in cyclol (CBL) and cannabicitran (CBT). particular 5HT receptors, such that it does not produce 0035. The endocannabinoids bind to central (CB1) and mania. In various embodiments, the kappa-opioid-receptor peripheral (CB2) cannabinoid receptors. Examples of endo agonist also has D2 agonist activity and, in particular, partial cannabinoids include arachidonoylethanolamine (anand D2 agonist activity. In certain embodiments, the kappa amide), 2-arachidonoylglycerol, 2-arachidonyl glyceryl opioid-receptor agonist may be salvinorin A. ether, N-arachidonoyl dopamine and lysophosphatidylinosi 0028. In various aspects of this embodiment, the system tol. may include, in addition to the kappa-opioid-receptor ago 0036) Numerous have been made nist, either or both of a cannabinoid compound and Ket some of which have been used medicinally, for example, amine in a pharmaceutically acceptable preparation. The and . pharmaceutically acceptable preparation for the cannabinoid compound and/or ketamine may include the same carrier 0037. The term “cannabinoid compound can also refer system in which the kappa-opioid-receptoragonist is admin to any individual cannabinoid or combination of cannabi istered and the Substances may be administered together or noid compounds such as the non-limiting example of THC+ separately in any combination thereof. Alternatively, the CBD+CBN or any other combination. carrier system for the cannabinoid compound and/or ket 0038. The term “about when used before a numerical amine may be different from that of the kappa-opioid designation, e.g., pH, temperature, amount, concentration, receptor agonist and the substances may be administered and molecular weight, including range, indicates approxi separately. In some embodiments, naltrexone is included. mations which may vary by (+) or (-) 5%, 1% or 0.1%. 0039. As used in the specification and claims, the singu DETAILED DESCRIPTION OF THE lar form “a”, “an and “the include plural references unless INVENTION the context clearly dictates otherwise. For example, the term “a pharmaceutically acceptable carrier may include a plu 0029. The present invention involves the treatment of rality of pharmaceutically acceptable carriers, including neuropsychiatric conditions and disorders by administration of a Substantially selective kappa-opioid-receptor agonist in mixtures thereof. a pharmaceutically acceptable preparation. Administration 0040. The term “and/or is intended to mean either or may be intranasal, transdermal or by inhalation. The Sub both of two components of the invention. stantially selective kappa-opioid-receptor agonists include, 0041. The term “subject,” “individual” or “patient” is in particular, Salvinorin Aas well as derivatives of Salvinorin used interchangeably herein, and refers to a human. A (see for example U.S. Pat. No. 7,687,538, which is 0042. The term “agonist,” as used herein, refers to a incorporated by reference). moiety that interacts with and activates a receptor, and 0030. As used herein, the following terms are defined thereby initiates a physiological or pharmacological with the following meanings, unless explicitly stated other response characteristic of that receptor. The term “antago wise. nist,” as used herein, refers to a moiety that competitively 0031 Salvia is the genus name for annual, biennial, or binds to a receptor at the same site as an agonist (for perennial herbs in the mint family. Salvia divinorum is a example, the endogenous ), but which does not acti species containing psychoactive compounds, of which the vate the intracellular response initiated by the active form of diterpenoid compound, salvinorin A, is the principal com the receptor and can thereby inhibit the intracellular ponent. Salvinorin A is a selective kappa-opioid-receptor responses by an agonist or partial agonist. An antagonist agonist (Roth et al., 2004) and D2 receptor partial agonist does not diminish the baseline intracellular response in the (Seeman et al., 2009) with no substantial effect on 5-HTP absence of an agonist or partial agonist. The term “inverse receptors (Roth et al., 2004). agonist” refers to a moiety that binds to the endogenous form 0032 Cannabis is the genus name for the annual, dioe of the receptor or to the constitutively activated form of the cious flowering herb in which psychoactive constituents, receptor and which inhibits the baseline intracellular principally tetrahydrocannabinol (THC), occur in the floral response initiated by the active form of the receptor below calyces. Cannabis plants include , Cannabis the normal base level of activity which is observed in the indica, and as well as various crosses absence of an agonist or partial agonist. and hybrids. There are also known strains of Cannabis 0043. The term “device,” as used herein, refers to an including "drug strains which contain high levels of THC apparatus or system capable of delivering a drug to patient and low levels cannabidiol (CBD) and “non-drug strains in need thereof. such as hemp which contain high levels of CBD and low 0044. The term “in need of treatment” and the term “in levels of THC. need thereof when referring to treatment are used inter US 2017/O 135984 A1 May 18, 2017

changeably and refer to a judgment made by a caregiver (e.g. 0054 Intranasal delivery devices are known in the art. physician, nurse, nurse practitioner, that a patient will ben Thus, any device suitable for delivery of drug to nasal efit from treatment. mucosa may be used. Non-limiting examples of devices 0045. The term “nostril, as used herein, is synonymous useful for the administration of liquid compositions include with “naris.’ vapor devices (e.g., vapor inhalers), drop devices (e.g., 0046. The term “nasal delivery”, “intranasal delivery', catheters, single-dose droppers, multi-dose droppers, and “nasal administration' or “intranasal administration” refers unit-dose pipettes), mechanical spray pump devices (e.g., to a route of administration wherein the pharmaceutical Squeeze bottles, multi-dose metered-dose spray pumps, and dosage form is taken to, or through, the nose (e.g., nasal single/duo-dose spray pumps), bi-directional spray pumps cavity). Similarly, a “nasal delivery device' or an “intranasal (e.g., breath-actuated nasal delivery devices), gas-driven delivery device is intended to mean an apparatus that spray Systems/atomizers (e.g., single- or multi-dose HFA or administers a drug into the nasal cavity. Non-limiting nitrogen propellant-driven metered-dose inhalers, including examples of intranasal administration include introduction traditional and circumferential velocity inhalers), and elec of a solution or Suspension in the form of a nasal spray or trically powered nebulizers/atomizers (e.g., pulsation mem drops (direct instillation) or intranasal application of gel. brane nebulizers, vibrating mechanical nebulizers, and emulsion or ointment. hand-held mechanical nebulizers). Non-limiting examples 0047. The term “inhalation delivery” or “inhalation of devices useful for the administration of powder compo administration” refers to a route of administration wherein sitions (e.g., lyophilized or otherwise dried pooled compo the pharmaceutical dosage form is taken into the airways sitions) include mechanical powder sprayers (e.g., hand and lungs by inhaling a gaseous, vaporized, or aerosolized actuated capsule-based powder spray devices and hand drug preparation. Similarly, an “inhalation delivery device' actuated powder spray devices, hand actuated gel delivery is intended to mean an apparatus that administers a drug into devices), breath-actuated inhalers (e.g., single- or multi-dose the airways and lungs. The drug preparation may aerosolized nasal inhalers and capsule-based single- or multi-dose nasal inhalers), and insufllators (e.g., breath-actuated nasal deliv using, e.g. a nebulizer. ery devices). 0048. The term “transdermal delivery” refers to a route of 0055 Inhalation delivery devices are known in the art. administration in which the pharmaceutical dosage form is Thus, any device suitable for delivery of drug to the lungs taken up through the skin. Similarly, a “transdermal delivery may be used. Non-limiting examples of Suitable inhalation device' is intended to mean any apparatus or system that devices for inhalation include various types of modern administers a drug to be taken up through the skin. inhalers based on different aerosolization technologies. For 0049. The term “pharmaceutically acceptable,” as used example, a metered-dose inhaler, a dry powder inhaler, a soft herein, refers to a component of a pharmaceutical compo mist inhaler, or a nebulizer may be used. Metered-dose sition that is compatible with the other ingredients of the inhalers are typically pressurized, i.e. the active ingredient formulation and not overly deleterious to the recipient and optional inactive constituents are dispersed or dissolved thereof. in a liquid, pressurized propellant. A metered-dose inhaler 0050. The term “carrier” refers to a diluent, adjuvant, typically comprises a canister which may be made of plastic, excipient, or vehicle with which the therapeutic is admin glass, aluminum, stainless steel, or any other Suitable mate istered and includes, but is not limited to Such liquids and rial; a metering valve allowing a metered quantity of the powders that are hydrophilic substances, hydrophobic sub formulation to be dispensed with each actuation; and an stances and Substances that possess both hydrophilic and actuator which is often combined with a mouthpiece to hydrophobic properties such as emulsifiers. allow the subject to operate the device and direct the aerosol 0051. By the term “substantially selective kappa-opioid into the patient's lungs via the mouth. receptor agonist' it is meant that the agent has an affinity for 0056 Transdermal delivery devices are known in the art. kappa-opioid receptors and/or kappa-opioid biological Thus, any device suitable for delivery of drug across the skin activity, for example ECs (concentration of compound that of a patient may be used. Devices known in the art include gives half-maximal response) of at least 10-fold, at least reservoir type devices involving membranes that control the 100-fold, at least 1000-fold or greater than that for mu- and rate of drug release to the skin and devices where the drug delta-opioid receptors (see for example, Cunningham, is dispersed or dissolved in a matrix Such as a pressure 2011). sensitive adhesive. Transdermal delivery devices may be 0052. The term “substantially no effect on 5HT, recep made in the form of an article Such as a tape, a patch, a sheet, tors' and, in particular “substantially no effect on 5HT. a dressing or any other form known to those skilled in the receptors' is intended to mean a compound has receptor art. Generally, the device may in the form of a patch of a size affinity and/or elicits receptor mediated biological activity suitable to deliver a preselected amount of drug through the that is less than 0.1, less than 0.01, less than 0.001 or lesser skin. Generally, the device will have a surface area of about than that for the kappa- (see for example 5 cm to about 100 cm and, in particular, about 10 cm to Roth, 2004). Similarly, the term “produces substantially no about 40 cm. manic effect' it is meant that the compound does not 0057 Transdermal drug delivery devices typically produce a meaningfully significant manic effect in a popu involve a carrier (such as a liquid, gel, or Solid matrix, or a lation of Subjects. pressure sensitive adhesive) into which a compound of the 0053. The term “therapeutically effective amount,” as invention is incorporated. used herein, refers to the amount of active compound or 0.058 For inhalation, or intranasal administration the pharmaceutical agent that elicits the biological or medicinal preparation may contain a compound of the invention in a response in a tissue, system, or individual that is being liquid carrier for aerosol application. In various embodi sought by a researcher, healthcare provider or individual. ments, the composition may be in the form of an aqueous or US 2017/O 135984 A1 May 18, 2017

non-aqueous solution, Suspension, liposomal dispersion, Cannabis plant or in a purified form of the cannabinoid emulsion, microemulsion or a combination thereof. The compound. When Cannabis plant is administered, the dose carrier can contain additives Such as solubilizing agents, is calculated in terms of the amount of the cannabinoid e.g., propylene glycol, Surfactants, absorption enhancers compound administered from the preparation. The dose of Such as lecithin (phosphatidylcholine) or cyclodextrin, the cannabinoid compound when administered by inhalation mucoadhesives and/or preservatives such as parabens. may be in a range of from as low as about 200 ug, about 500 0059 Methods well known in the art for making formu ug, about 1000 ug, about 2000 ug or about 5 ug up to about lations may be found, for example, in Remington, 2000. 10,000 ug, about 15,000 ug, about 20,000 ug, about 25,000 Further, methods for formulating compounds for intranasal ug, about 50,000 ug, about 75,000 ug, about 100,000 ug, and transdermal administration, including for extending the about 150,000 ug, or about 250,000 ug, or about 500,000 ug presence in in the nasal cavity, creating various emulsions, or about 750,000 ug, or about 1,000,000 ug, or about combining with cyclodextrins and other agents to enhance 1,500,000 ug or about 2,000,000 ug, or about 2,500,000 ug, solubility, creating prodrugs, analogs, and increasing bio or about 3,000,000 ug, or about 3,500,000 ug, or about availability, etc. are well known. See, e.g., Bitter et al., 2011; 4,000,000 ug, or about 4,500,000 ug, or about 5,000,000 ug. Pastore et al., 2014. 0.066 Administration may be once a day (q.d.), twice a 0060. The compounds of the present invention may be day (b.i.d.), three times a day (t.i.d.), four times a day (q.i.d.) used for the treatment of neuropsychiatric disorders includ or at more or less frequent intervals such as once every other ing affective disorders such as depression, bipolar disorder day (q.a.d.), once every third day, twice a week (bis in 7 d.), or anxiety disorder. once a week (QWK), once every other week, etc. Alterna 0061 Thus, the compounds may be used to treat abnor tively, administration may be as needed (p.r.n.). malities of mood or emotion including depression, bipolar 0067 Preferred embodiments are described in the fol disorder, dysthymia, post-traumatic stress disorder, Schizo lowing examples. Other embodiments within the scope of affective disorder, Schizophrenia and other psychotic disor the claims herein will be apparent to one skilled in the art ders, anxiety disorders, panic disorder, traumatic stress from consideration of the specification or practice of the disorders, phobic disorders, and personality disorders with invention as disclosed herein. It is intended that the speci abnormal mood, such as borderline personality disorder, fication, together with the examples, be considered exem Schizoid and Schizotypal disorders and Suicide ideation. plary only, with the scope and spirit of the invention being 0062. The compounds of the present invention may also indicated by the claims, which follow the examples. be used for treating addiction. Such addictions may be addiction to drugs, non-limiting examples of which may Example 1. Salvinorin A Administration is include nicotine, alcohol, cocaine, opioids, amphetamine, Anxiolytic, Antidepressant and Motivationally methamphetamine, heroin, morphine, phencyclidine, 3,4- Stimulating with No Manic Side Effects methylenedioxy-methamphetamine, as well as other addic tive substances. Additions may also include addictive behav 0068. The effects of salvinorin A were evaluated in one iors, non-limiting examples of which may include eating, subject with bipolar disorder following Salvia divinorum gambling, sex, pornography, Videogames, work, exercise, administration by combustion and inhalation at a dose of spiritual obsession, self-harm, travel and shopping addic approximately 8 mg of enhanced leaf of regular strength tion. from a known online source (sagewisdom.com). After a 0063 Salvinorin A may be administered as Salvia divi brief, 2-5 minute period of mild accompanied norin or in a purified form of salvinorin A. When Salvia by euphoria, the Subject experienced anxiolytic, antidepres divinorin is administered, the dose is calculated in terms of sant and motivationally stimulating effects for a period of 24 the amount of Salvinorin A administered from the prepara hours or greater with no manic side effects. It is noteworthy tion. The dose of salvinorin A when administered by inha that this subject had experienced mania even on very Small, lation may be in a range of from as low as about 50 ug, about Sub-therapeutic doses of traditional antidepressants includ 75 ug, about 100 lug, about 250 ug or about 400 ug up to ing celexa and Sertraline—serotonin agonists and partial about 500 ug, about 1000 ug, about 2000 ug, about 5000 ug agonists. A slight tremor appeared shortly after administra or about 10,000 ug. The dose of salvinorin A when admin tion, however, co-administration of cannabis by combustion istered intranasally may be in a range of from as low as about and inhalation along with the Salvia divinorum eliminated 5ug, about 7.5 ug, about 10 ug, about 25 ug or about 50 g the tremor. This method was repeated approximately 20 or about 100 ug up to about 200 ug, about 500 ug, about times with consistent results. 1000 ug, about 2000 ug, about 5000 ug or about 10,000 ug. 0069 Co-administration of cannabis by combustion and The dose of salvinorin A when administered transdermally inhalation and/or ketamine (ketamine hydrochloride, at may be in a range of from as low as about 5 ug, about 7.5 varying doses, generally about 30 to about 75 mg) by ug, about 10 ug, about 25 ug or about 50 ug or about 100 g intranasal administration along with Salvia divinorum by up to about 200 ug, about 500 ug, about 1000 ug, about 2000 combustion and inhalation appeared to potentiate the anxi ug, about 5000 ug or about 10,000 ug. olytic and antidepressant effects of Salvia divinorum alone. 0064. Ketamine may be administered intranasally as the 0070 The subject also takes clonazepam, orally and/or hydrochloride at a dose in a range of from as low as about Sublingually, and has reported that clonazepam (at varying 5ug, about 10 ug, about 20 Jug, about 30 ug up to about 75 doses, generally about 1.5 mg., b.i.d. and occasionally, about ug, about 125 ug, about 200 ug, or about 300 ug. In some 0.5 mg up to about 2.5 mg p.r.n.), along with co-adminis embodiments, naltrexone is also administered to potentiate tration of cannabis by combustion and inhalation and/or the effects of the ketamine administration. ketamine by intranasal administration with Salvia divinorum 0065. The cannabinoid compound may be administered by combustion and inhalation appeared to potentiate the by combustion and inhalation of the floral calyces of a anxiolytic and antidepressant effects of the Salvia divinorum US 2017/O 135984 A1 May 18, 2017 alone and helped to further alleviate any anxiety, tremor or receive a 5 mg/kg injection (i.p.) of tracazolate, a non any other side effect before, during or after administration of benzodiazepine anxiolytic compound (Thompson et al., the Salvia divinorum. 2002). As a negative control, FG7142 (5 mg/kg i.p.) is administered to produce anxiogenic behavior (Pellow and Example 2. Effects of Intranasal or Transdermal File, 1986). The normal control group receives an i.p. Administration of Salvinorin A on Behavioral injection of an equivalent Volume (2 ml/kg) of sterile Saline. Activity All control groups also receive an equivalent Volume of 0071 Preparation of the intranasal and transdermal sal vehicle delivered in an identical manner to that used for the vinorin A is by known methods. See, e.g., Bitter et al., 2011; test article (i.e. intranasal or transdermal administration). Pastore et al., 2015. (0078. A total of 60 Sprague-Dawley male CD rats -45 0072 Following intranasal or transdermal delivery of days old are utilized for each administration method (Table salvinorin A at 3 separate dosages, with a negative control 2). administered vehicle only, rats are monitored for a total of 40 minutes by an experimenter who is blinded to condition. TABLE 2 Signs of altered behavior, including staring, immobility, Summary of Treatment Groups increased or decreased response to stimuli (e.g. tactile, auditory), and changes in locomotor patterns are recorded. Group Treatment Purpose Number 0.073 For each method of administration, a total of 48 T1 Concentration 1 Test Article (Dose 1) 10 Sprague-Dawley male & female CD rats ~45 days old are T2 Concentration 2 Test Article (Dose 2) 10 T-3 Concentration 3 Test Article (Dose 3) 10 utilized (Table 1). Weh Vehicle Normal Control 10 POS Tracazolate Anxiolytic 10 TABLE 1. Neg FG7142 Anxiogenic 10 Summary of Treatment Groups 0079. Following a minimum 7 day acclimation phase, Number rats are randomly divided into 6 groups (T1, T2, T3, Veh, Group Treatment Purpose d Pos, Neg: Table 2). 0080 Forty-five minutes prior to behavioral testing, an T1 Concentration 1 Test Article (Dose 1) 6 6 T2 Concentration 2 Test Article (Dose 2) 6 6 i.p. injection is administered to all animals in a volume of 2 T-3 Concentration 3 Test Article (Dose 3) 6 6 ml/kg as follows: rats in the anxiolytic control group, receive C-1 Vehicle only Negative Control 6 6 tracazolate (5 mg/kg), a pyrazolopyridine that reduces anxi ety-like behaviors in rodents (Pellow and File, 1986), an 0074. Following a 5-7 day acclimation phase, rats are effect believed to result from allosteric modulation of extra randomly divided into 4 groups (C1, T1, T2, T3: Table 1) synaptic GABAA receptor function (Thompson et al., 2002: and receive intranasal or transdermal administration of the Belelli et al., 2009). As an anxiogenic control, a second appropriate dosage of Compound X. group of rats receive FG7142 (N-methyl-fl-carboline-3- carboxamide), a beta-carboline that acts as a partial inverse 0075 Visual (real-time) monitoring is performed for 10 agonist at the benzodiazepine allosteric site (Evans and minutes pre-administration and 30 minutes post-administra Lowry, 2007) and produces demonstrated increases in anxi tion of the compound. ety-like behaviors in various tasks (Thompson et al., 2002: 0.076 Animals are observed in real time to assess behav Arrant et al., 2013). Rats in experimental groups (i.e. those ioral anomalies, with 4 animals monitored simultaneously (1 who have received a test compound), as well as rats in the from each condition). Periods of staring, increased or normal control group receive an injection of sterile Saline. decreased response to stimuli (e.g. tactile, auditory), and any I0081. Thirty minutes prior to behavioral testing, rats in other unusual behaviors are noted. Animals are also video test article groups receive intranasal or transdermal admin recorded, with locomotor activity, rearing, grooming, and istration of salvinorin A at one of the 3 dosage levels. periods of immobility assessed using the AnyMazeTM behav Animals in the normal control group receive administration ioral scoring system (Stoelting Co., Wood Dale Ill. 60191 of vehicle only in a volume equivalent to that utilized for the US). All behavioral evaluations are performed by an experi experimental animals. Following treatment as per its menter blinded to condition. The following 2 phases are assigned group, each rat is tested in either the Open Field used to allow for within and between animal comparisons: (OF) test or the Elevated Plus Maze (EPM) to assess Parametric data is evaluated using 2-way ANOVA (SEX by anxiety-like behaviors. One week later, the same rats receive TREATMENT). Statistically significant main effects are the same group treatment (experimental or control) and further investigated using Tukey's post hoc analysis. Non undergo testing in the paradigm not yet experienced (i.e. OF parametric analyses are assessed using a Kruskal-Wallis test or EPM). All tests are video recorded for scoring and with Dunn-Bonferroni pairwise comparisons for post hoc documentation purposes. analysis. Significance level for all tests is ps0.05. I0082 Ultrasonic vocalizations (USVs) is also recorded and analyzed to provide an additional level of anxiety Example 3. Effects of Intranasal or Transdermal related measures. Administration of Salvinorin a on Anxiety I0083. The following behavioral tests are performed: 0077 Salvinorin A is administered intranasally or trans I0084 Elevated Plus test (Bailey and Crawley, 2009)– dermally to rats at one of 3 different dose levels (1, 2 or 3). The arena for this test consists of four arms, two with In addition to a normal control, there is both a positive and sidewalls, and two open (a 'plus configuration), thus pro a negative control group. For the positive control, rats viding a measure of anxiety associated with open space, US 2017/O 135984 A1 May 18, 2017

unprotected regions. The maze is elevated -2 feet above the during each 5 minute block to provide a baseline evaluation. floor. Rats are started in the center (neutral) Zone of the test, Twenty-four hours later, rats are once again placed in an and behavioral measures include latency to enter and percent inescapable water-filled container, and measures are of time spent in the closed arms as recorded during a 10 recorded for 5 minutes (test phase). minute trial. 0093. To provide an additional level of affective state, I0085 Open Field test (Gould et al., 2009) The open USV emissions are recorded for 5 minutes prior to, and field test allows assessment of activity levels, locomotion, following, the pre-test phase. In addition, USVs will be and anxiety-related behaviors. Rats are started in the center recorded on the testing day for 5 minutes prior to the test of the arena (~4.5 foot diameter), and measures during a 10 phase, 5 minutes immediately following compound admin minute test period may include: latency to reach the outer istration, and 5 minutes following the test phase. wall region, time spent in thigmotaxic behavior, number of 0094 Parametric data is evaluated using ANOVA, with entries into and time spent in the center region, distance repeated measures utilized where appropriate. Statistically traveled, average speed in each region, number and time significant main effects are further investigated using spent rearing, number and time spent grooming, and com Tukey's post hoc analysis. Non-parametric analyses will be parison of activities during the first and last minute, and first assessed using a Kruskal-Wallis test with Dunn-Bonferroni and last half of the task. pairwise comparisons for post hoc analysis. The Friedman 0.086 Ultrasonic Vocalizations—Ultrasonic vocalization test will be used to evaluate non-parametric repeated mea emissions are recorded during testing, with number, dura sures data. Significance level for all tests will be ps0.05. tion, and frequency range of calls assessed to provide an 0.095 See also Bogdanova et al., 2013: Krishnan and additional measure of affective state during testing. See also Nestler, 2011; Abelaira et al., 2013; Gould and Einat, 2007: Bourin, 2015; and Campos et al., 2013. and Abulseoud et al., 2014. Example 4. Antidepressant Effects of Intranasal or Example 5. Effects of Intranasal or Transdermal Transdermal Administration of Salvinorin A Administration of Salvinorin A on Chronic 0087. For confirming its antidepressant effects, salvinorin Depression A is administered intranasally or transdermally to rats at one of 3 different dose levels (1, 2 or 3), with a control group that 0096 Chronic exposure to mild, unpredictable stress is receives an equivalent volume of vehicle delivered in an used as a rodent model of long-term depression. This identical fashion to the test article. paradigm results in decreased consumption of Sweetened 0088 A total of 40 Sprague-Dawley male CD rats ~45 water, a treat that is generally rewarding to rats. days old are utilized for each administration method (Table 0097. For confirming its effects on chronic depression, 3). salvinorin A is administered intranasally or transdermally to rats at one of 3 different dose levels (1, 2 or 3), with a control TABLE 3 group that receives an equivalent volume of vehicle deliv ered in an identical fashion to the test article. Summary of Treatment Groups (0098. A total of 60 male Wistar CD rats -45 days old are Group Treatment Purpose Number utilized for each administration method (Table 4). T1 Concentration 1 Test Article (Dose 1) 10 TABLE 4 T2 Concentration 2 Test Article (Dose 2) 10 T-3 Concentration 3 Test Article (Dose 3) 10 Summary of Treatment Groups Weh Vehicle Normal Control 10 Group Treatment Stress Purpose Number 0089. Following the acclimation phase, rats are randomly A. Compound X1 Yes Test Article Dose 1 12 B Compound X2 Yes Test Article Dose 2 12 divided into 4 groups (T1, T2, T3, Veh; Table 3). C Compound X3 Yes Test Article Dose 3 12 0090. On the day of the test phase, ultrasonic vocalization D Vehicle Yes Negative Control 12 (USV) emissions are recorded from each rat at 3 time E Vehicle No Normal Control 12 points—prior to compound administration, immediately fol lowing compound administration, and immediately after the test phase. Thirty minutes prior to the test phase, rats in 0099 Starting 24 hours after arrival in the facility, rats experimental groups receive intranasal or transdermal will be acclimated to a Sugar water solution (1% Sucrose), to administration of the appropriate dosage of Salvinorin A avoid neophobic behaviors during the testing period. Base (T-1, T-2, or T-3). Rats in control groups receive an equiva line measures of sucrose preference will be obtained prior to lent volume of vehicle delivered in an identical manner. model induction. 0091. Following treatment as per its assigned group, each 0100. Upon study initiation, rats are randomly divided rat is tested in the Forced Swim Test (FST) to assess into 5 groups (X1, X2, X3, Negative Control, Normal depressive behaviors. All tests are video recorded for scoring Control; Table 4). and documentation purposes. 0101 Chronic mild stress protocols are performed for a 6 0092. The forced swim test is based on a rodent’s aver week period as outlined below, with a 24 hour sucrose sion to water, and Subsequent desire to try and escape when preference test administered weekly. Submerged. To induce the model, rats are placed in an 0102 For the final 3 weeks of the chronic mild stress inescapable water-filled container (-8" diameterx20" deep) protocol, each rat receives daily salvinorin Aadministration for 15 minutes (pre-test phase). Duration of struggling/ as per its assigned group. Control (non-stressed) rats receive climbing, immobility, and Swimming activities are measured an equivalent volume of vehicle, delivered in an identical US 2017/O 135984 A1 May 18, 2017

fashion as the test article. As during the induction phase, a TABLE 5 24 hour Sucrose preference test is administered weekly. 0103) To produce a model of chronic depression, a series Summary of Treatment Groups of mild, unpredictable stressors will be utilized, with pro Group Treatment Purpose Number tocols adapted from previous literature (Harden et al., 2012: A. Compound X1 Test Article Dose 1 10 Lopez-Lopez et al., 2016; Papp et al., 1996). A decrease in B Compound X2 Test Article Dose 2 10 consumption of a rewarding treat (Sugar water) over a 24 C Compound X3 Test Article Dose 3 10 hour presentation period (tested once per week; see Behav D Saline? vehicle Negative Control 10 ioral Testing section below) is considered indicative of E Cocaine, vehicle Positive Control 10 depressed behavior (anhedonia). 0104 Stressors to be utilized include a 16 hour food 0113. Upon study initiation, rats are randomly divided deprivation period, 15 hour water deprivation followed by 1 into 5 groups (X1, X2, X3, Pos, Neg: Table 5). All phases of hour empty water bottle presentation, 36 hours continuous the study are performed under reverse light cycle. light, 9 hours wet cage bedding, 15 minute immersion in 0114. One day prior to the habituation phase of the study, cold water, 5 hour foreign object presentation (some objects rats receive a single intraperitoneal (i.p.) injection of saline will restrict movement in cage), 5 hours inclined (45' cage), prior to being returned to the home cage. and 3 hours noise (~40 dB) to be presented with or without 0.115. During habituation, rats are exposed to the testing other stressors. apparatus for 15 minutes per day for 3 days. 0116. During the conditioning phase, each animal is 0105. Prior to model induction, a baseline level for administered the appropriate compound (cocaine or saline sucrose preference is established over a 24 hour period as alternated over days) and immediately be placed in the outlined below. associated chamber (drug or vehicle as appropriate) of the 0106 Sucrose Preference Testing Once per week, for a apparatus for 30 minutes per day for 8 consecutive days. 24 hour period, regular water bottles will be replaced with Saline control animals receive saline only each day, with two pre-weighed bottles, one containing regular water, and chamber presentation alternated over days. one with a 1% Sucrose solution (Sugar water). After 24 0117. On the testing day, 24 hours after the last condi hours, bottles will be weighed again, and consumption of tioning trial, each rat receives intranasal or transdermal each will be recorded. No stressors will be administered compound administration as per its assigned group, and is during or for 12 hours prior to this time period. tested at the post-administration time point as specified by 0107 Parametric data will be analyzed using ANOVA, the sponsor to determine the effects of the various dosage with repeated measures where appropriate. Statistically sig levels of the compound on cocaine-induced CPP. All tests nificant main effects will be further investigated using are video recorded for scoring and documentation purposes Tukey's post hoc analysis. Significance level for all tests by experimenters blinded to rat condition. will be ps0.05. 0118. An i.p. injection of either cocaine (20 mg/kg) or saline in a maximum volume of 10 ml/kg will be adminis 0108) See also Lynch et al., 2010 and Planeta, 2013. tered to rats during conditioning trials as specified in the behavioral testing section below. Example 6. Effects of Intranasal or Transdermal 0119 The following behavioral tests are performed: Administration of Salvinorin A on Addictive 0120 Cocaine-induced Conditioned Place Preference Behaviors test (CPP)(Buccafusco, 2009; Gala et al. 2014) This test provides an assessment of the degree of reward associated 0109 Reinforcing effects of drugs of abuse are believed with cocaine administration. The testing apparatus consists to play a key role in Substance abuse and addiction; para of two compartment chambers plus a center “tunnel area digms that measure drug reinforced behaviors allow for (unforced choice) separated by doors, with the two larger evaluation of compounds that may interfere with these outer chambers varying in both color (e.g. black Vs white) processes. The conditioned place preference paradigm pro and floor texture (e.g. horizontal grid VS cross-grid). The vides assessment of a drugs rewarding effects, and when center connecting chamber has no special characteristics, is used with a known addictive Substance, the paradigm allows not paired with any compound and is not accessible during for Screening of compounds with potentially therapeutic habituation. Measures that are evaluated include time spent benefits. in each chamber, first chamber chosen, chamber entries, 0110. For confirming its effects on addictive behaviors, speed, and distance traveled. salvinorin A is administered intranasally or transdermally to I0121 There are three stages: rats at one of 3 different dose levels (1, 2 or 3), with a control 0.122 1) Habituation rats are placed in the test appara group that receives an equivalent volume of vehicle deliv tus and allowed free access for 15 minutes per day for a total ered in an identical fashion to the test article. of 3 days to eliminate novelty as a confounding variable. Time spent in each compartment is recorded to determine 0111 Control groups are saline only exposure (negative compartment preference prior to conditioning. control) or cocaine only exposure (positive control) plus I0123. In order to habituate rats to injections, an i.p. administration of an equivalent volume of vehicle delivered injection of Saline is administered one day prior to the first in an identical fashion to the test article (i.e. intranasal apparatus exposure. Following this injection, rats are placed administration). back in their home cage. 0112 A total of 50 Sprague-Dawley male SD rats ~45 0.124 2) Conditioning rats are conditioned over 8 con days old upon arrival in the facility will be utilized for each secutive days, with cocaine administration repeated once administration method (Table 5). every other day for a total of 4 cocaine conditioning days. US 2017/O 135984 A1 May 18, 2017

On cocaine conditioning days, rats are given an injection of 0141 Dhuria et al., Intranasal delivery to the central cocaine (20 mg/kg i.p.), and are immediately confined for 30 nervous system: mechanisms and experimental consider minutes in the compartment for which they showed the least ations, J Pharm Sci., 99:1654-1673 (2011). preference during the habituation stage (biased procedure). 0142. Djupesland et al., The nasal approach to delivering On alternate days, rats are given an injection of Saline, and treatment for brain diseases: an anatomic, physiologic, are confined to the opposite chamber to that utilized during and delivery technology overview, Therapeutic Delivery cocaine conditioning. The order of cocaine conditioning is 5, 709-733 (2014). counterbalanced across rats. One group of rats (negative 0.143 Evans, A. K. Lowry, C. A. CNS Drug Reviews control) will receive a daily injection of vehicle only and 13(4): 475-501 (2007). alternately be exposed to each compartment. 0144 Galaj, E., Manuszak, M., Arastehmanesh, D., 0.125 3) Testing 24 hours following the last condition Ranaldi, R. Beh Brain Research. 272: 279-285 (2014). ing session, all rats receive intranasal administration of the 0145 Giroud et al., Salvia divinorum: an hallucinogenic appropriate test article dose or an equivalent Volume of mint which might become a new recreational drug in vehicle. Cocaine-induced CPP is assessed by placing the rat Switzerland, Forensic Sci. Int. 112:143-150 (2000). in the center compartment and allowing free access to the 0146 Gould and Einat, 2007, Animal models of bipolar entire apparatus for 15 minutes. Time spent in each com disorder and mood stabilizer efficacy: a critical need for partment is measured. improvement, Neurosci. Biobehav. Rev. 31:824-831 0126 Parametric data will be analyzed using ANOVA. (2007). Statistically significant main effects are further investigated 0147 Gould, T. D., Dao, D. T., Kovacsics, C. E. Neu using Tukey's post hoc analysis. Significance level for all romethods v42, Humana Press: p. 1-20 (2009). tests will be ps0.05. 0148 Graudins et al., The PICHFORK (Pain in Children or Ketamine) trial: a randomized controlled trial REFERENCES comparing intranasal ketamine and fentanyl for the relief of moderate to severe pain in children with limb injuries, 0127. Abelaira et al., Animal models as tools to study the Ann Emerg Med. 65:248-254 (2015). pathophysiology of depression, Revista Brasileira de 0149 Harden et al., Antidepressive effects of the K-opioid Psiquiatria 35:S112-S120 (2013). receptor agonist Salvinorin A in a rat model of anhedonia, 0128. Abulseoud et al., Lateral hypothalamic kindling Behav Pharmacol. 23:710-715 (2012). induces manic-like behavior in rats: a novel animal 0150 Ita, Transdermal Delivery of Drugs with model, International J. Bipolar Disorders 2:7 (2014). Microneedles—Potential and Challenges, Pharmaceutics 0129 Afridi. A randomized controlled trial of intranasal 7,90-105 (2015). ketamine in migraine with prolonged aura, Neurology 0151 Johnson et al., Human psychopharmacology and 80:642-647 (2013). dose-effects of Salvinorin A, a kappa-opioid agonist hal 0130. Andrade, Intranasal Drug Delivery in Neuropsy lucinogen present in the plant Salvia divinorum Drug chiatry: Focus on Intranasal Ketamine for Refractory Alcohol Depend, 115:150-155 (2011). Depression, J. Clin. Psychiatry, 76:628-631 (2015). 0152 Krishnan and Nesler, Animal models of depres 0131 Arrant, A. E., Schramm-Sapyta, N. L., Kuhn, C. M. sion: molecular perspectives, Curr: Top. Behav. Neurosci. Behavioural Brain Research 256: 119-127 (2013). 7:121-147 (2011). (0132 Bailey and Crawley, Chapter 5 in Methods of 0153 Krystal et al., Potentiation of low dose ketamine Behavior Analysis in Neuroscience, 2" Ed., J. J. Bucca effects by naltrexone: potential implications for the phar fusco, editor (2009). macotherapy of alcoholism, Neuropsychopharmacology 0.133 Belelli, D., Harrison, N. L., Maguire, J., Macdon 31:1793-1800 (2006). ald, R. L., Walker, M. C., Cope, D. W. The Journal of 0154 Lapidus. A randomized controlled trial of intrana Neuroscience 29(41): 12757-12763 (2009). sal ketamine in major depressive disorder, Biol Psychiatry 0134 Bitter et al., Nasal Drug Delivery in Humans, Curr: 76:970-976 (2014). Prol. Dermatol. 40:20-35 (2011). 0155 Lopez-Lopez, A. L., Jaime, H. B., Escobar-Villa 0135 Bogdanova, O. V., Kanekar, S., D'Anci, K. E., neuva, M., Padilla, M. B., Palacios, G. V., Aguilar, F. J. Renshaw, P. F. Physiology and Behavior, 118: 227-239 Physiology & Beh. 161: 15-23 (2016). 0156 Lynch et al., Animal models of substance abuse and (2013). addiction: Implications for Science, animal welfare, and 0.136 Bourin, Animal models for screening anxiolytic society, Comparative Medicine 60:177-188 (2010). like drugs: a perspective, Dialogues in Clinical Neuro 0157 Maqueda et al., Salvinorin-A Induces Intense Dis science 17:295-303 (2015). sociative Effects, Blocking External Sensory Perception 0137 Buccafusco, J. J. Ed. Methods of Behavior Analy and Modulating Interoception and Sense of Body Own sis in Neuroscience (2nd ed). CRC Press (2009). ership in Humans, Int. J. of Neuropsychopharmacol., 1-14 0138 Campos et al., Animal models of anxiety disorders (EPub ahead of print)(2015). and stress. Revista Brasileira de Psiquiatria 35:S101 0158 Mendelson et al., Lack of effect of sublingual S111 (2013). Salvinorin A, a naturally occurring kappa opioid, in 0139 Clark, Treatment-refractory depression: a case of humans: a placebo-controlled trial Psychopharmacol, successful treatment with intranasal ketamine 10%, Ann 214:933-939 (2011). Clin Psychiatry 26:145 (2014). 0159 Morani et al., Effect of kappa-opioid receptor ago 0140. Cunningham et al., Neuropharmacology of the nists U69593, U50488H, and Salvinorin A on Naturally Occurring K-Opioid Salvinorin A, cocaine-induced drug-seeking in rats, Pharmacol Bio Pharmacol Rev 63:316-347 (2011). chem Behav 94: 244-249 (2009). US 2017/O 135984 A1 May 18, 2017

(0160 Orton et al., Salvinorin A: A Mini Review of Selective kappa-opioid-receptor agonist in a pharma Physical and Chemical Properties Affecting. Its Transla ceutically acceptable preparation, wherein said agonist tion from Research to Clinical Applications in Humans, has substantially no effect on 5HT receptors and it Transl. Perioper. Pain Med., 1:9-11 (2014). produces Substantially no manic effect. 016.1 Ott, Ethnopharmacognosy and Human Pharmacol 2. The method of claim 1, wherein the kappa-opioid ogy of Salvia divinorum and Salvinorin A. Curare 181: receptor agonist also has D2 agonist activity. 103-129 (1995). 3. The method of claim 1, wherein the kappa-opioid (0162 Papp, M., Moryl, E., Willner, P. Eurj Pharmacol receptor agonist is a partial D2 agonist. ogy. 196: 129-136 (1996). 0163 Pastore et al., Transdermal patches: history, devel 4. The method of claim 1, wherein the kappa-opioid opment and pharmacology, British J. Pharmacol. 172: receptor agonist is Salvinorin A. 2179-2209 (2015). 5. The method of claim 1, wherein the pharmaceutically 0164 Paudel et al., Challenges and opportunities in der acceptable preparation comprises an aqueous or non-aque mal/transdermal delivery, Ther. Deliv. 1:109-131 (2010). ous Solution, Suspension, liposomal dispersion, emulsion or (0165 Pellow, S., File, S. E., Pharmacology Biochemistry microemulsion formulation. & Behavior 24: 525-529 (1986). 6. The method of claim 1, wherein the affective disorder 0166 Planeta, Animal models of alcohol and drug depen is depression, bipolar disorder or anxiety disorder. dence, Revista Brasileira de Psiquiatria 35:S140-S146 7. The method of claim 1, wherein the affective disorder (2013). is depression. (0167 Prevatt-Smith et al. Potential Drug Abuse Thera peutics Derived from the Hallucinogenic Natural Product 8. The method of claim 1, wherein the affective disorder Salvinorin A, Med. Chem. Comm. 2:1217-1222 (2011). is anxiety disorder. 0168 Remington: The Science and Practice of Phar 9. The method of claim 1, further comprising administer macy” (20th ed.), ed. A. R. Gennaro, 2000, Lippincott ing either or both of a cannabinoid compound and ketamine Williams & Wilkins. in the pharmaceutically acceptable preparation. 0169 Roth et al., Salvinorin A: A potent naturally occur 10. A method of treating addiction in a subject in need ring nonnitrogenous K opioid selective agonist, PNAS thereof: the method comprising: 99: 11934-11939 (2004). administering intranasally or transdermally to the patient, 0170 Seeman et al., Dopamine D2 High receptors stimu a therapeutically effective amount of substantially lated by , lysergic acid diethylamide, Sal Selective kappa-opioid-receptor agonist in a pharma vinorin A, and modafinil, Synapse 63:698-704 (2009). ceutically acceptable preparation, wherein said agonist 0171 Siebert, Salvia divinorum and Salvinorin A: new has substantially no effect on 5HT, receptors and it pharmacologic findings, J. Ethnopharmacol. 43:53-56 produces Substantially no manic effect. (1994). 0172 Thompson, S., Wingrove, P. B., Connelly, L., Whit 11. The method of claim 10, wherein the kappa-opioid ing, P. J. Wafford, K. A. Molecular Pharmacology 61(4): receptor agonist is Salvinorin A. 861-869 (2002). 12. The method of claim 10, wherein the addiction is to 0173 Valdes, Salvia divinorum and the unique diterpene an addictive substance or an addictive behavior. hallucinogen, Salvinorin (divinorin) A. J. Psychoactive 13. The method of claim 10, wherein the addition is to an Drugs 26, 277-283 (1994). addictive Substance selected from the group consisting of 0.174 Yatham et al., Brain serotonin-2 receptors in acute nicotine, alcohol, cocaine, opioids, amphetamine, metham mania, The British J. Psych. 196:47-51 (2010). phetamine, heroin, morphine, phencyclidine and 3.4-meth 0175 Yeaman, Sub--dose intranasal ket ylenedioxy-methamphetamine. amine for moderate to severe pain in adult emergency 14. The method of claim 10, wherein the addition is to an department patients, Emerg Med Australas (2014). addictive behavior selected from the group consisting of (0176). In view of the above, it will be seen that several eating, gambling, sex, pornography, Videogames, work, objectives of the invention are achieved and other advan exercise, spiritual obsession, self-harm, travel and shopping tages attained. addiction. 0177. As various changes could be made in the above methods and compositions without departing from the scope 15. The method of claim 10, further comprising admin of the invention, it is intended that all matter contained in the istering either or both of a cannabinoid compound and above description and shown in the accompanying drawings ketamine in the pharmaceutically acceptable preparation. shall be interpreted as illustrative and not in a limiting sense. 16. An intranasal or transdermal delivery system com 0.178 All references cited in this specification are hereby prising an intranasal or transdermal delivery device and a incorporated by reference. The discussion of the references therapeutically effective amount of substantially selective herein is intended merely to Summarize the assertions made kappa-opioid-receptor agonist in a pharmaceutically accept by the authors and no admission is made that any reference able preparation, wherein said agonist has Substantially no constitutes prior art. Applicants reserve the right to chal effect on 5HT, receptors and it produces substantially no lenge the accuracy and pertinence of the cited references. manic effect. What is claimed is: 17. The system of claim 16, wherein the kappa-opioid 1. A method of treating an affective disorder in a patient receptor agonist is Salvinorin A. in need thereof, the method comprising: 18. The system of claim 16, further comprising either or administering intranasally or transdermally to the patient, both of a cannabinoid compound and ketamine in the a therapeutically effective amount of substantially pharmaceutically acceptable preparation. US 2017/O 135984 A1 May 18, 2017 11

19. The delivery system of claim 16, which is an intra nasal delivery system. 20. The delivery system of claim 16, which is a transder mal delivery system.

k k k k k

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