USO09517254B2

(12) United States Patent (10) Patent No.: US 9,517,254 B2 Sitchon et al. (45) Date of Patent: Dec. 13, 2016

(54) TREATMENT REGIMENS WO WO-200403.0524 A2 4/2004 WO WO-2004O78147 A2 9, 2004 (71) Applicant: S1 Biopharma, Inc., Jersey City, NJ WO WO-2005102342 A1 11 2005 (US) WO WO-2006055854 A2 5, 2006 (72) Inventors: Nicolas G. Sitchon, Jersey City, NJ WO WO-2006096435 A1 9, 2006 WO WO-2008075162 A2 6, 2008 (US); Robert E. Pyke, New Fairfield, WO WO-2011 140608 A1 11/2011 CT (US); John F. Kaufmann, WO WO-2011 146726 A1 11/2011 Beltsville, MD (US) WO WO-2012016229 A2 2, 2012 WO WO-2012.138653 A2 10/2012 (73) Assignee: S1 BIOPHARMA, INC., Jersey City, NJ (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this Bancroft. J Endrocrinology, 186, 411-427 (2005).* patent is extended or adjusted under 35 Clayton. Primary Psychiatry, 10(1), 55-61 (2003).* U.S.C. 154(b) by 0 days. Clark et al. Add Pharmacother. 34, 1007-1012 (2000).* International Search Report for PCT/US2013/053843 Dated Dec. 20, 2013. (21) Appl. No.: 14/420,112 Werneke, U. et al.; "Antidepressants and Sexual Dysfunction'. Acta Psychiatrica Scandinavica, 2006, Vo. 114, pp. 384-307. (22) PCT Fed: Aug. 6, 2013 Seagraves, R.T. et al.; “Bupropion Sustained Release (SR) for the Treatment of Hypoactive Sexual Desire Disorder (HSDD) in (86) PCT No.: Nondepressed Women': Journal of Sex & Marital Therapy, 2001. vol. 27, pp. 303-316. S 371 (c)(1), Lance, R. et al; "Oral Trazodone as Empirical Therapy for Erectile (2) Date: Feb. 6, 2015 Dysfunction: A Retrospective Review”; Urology, 1995, vol. 46, pp. 117-120. (87) PCT Pub. No.: WO2O14/O25814 D'Aquila, P. et al; "Anti-anhedonic Actions of the Novel Serotonergic Agent Flibanserin, a Potential Rapidly-Acting Antide PCT Pub. Date: Feb. 13, 2014 pressant': European Journal of Pharmacology, 1997, vol. 340, pp. 121-132. (65) Prior Publication Data American Psychiatric Association, “Sexual and Gender Identity Disorders”. Diagnostic and Statistical Manual of Mental Disorders, US 2015/O150946 A1 Jun. 4, 2015 4th Edition, 1994, pp. 493-522. Anderson-Hunt et al., Increased female sexual response after oxytocin. BMJ. Oct. 8, 1994:309(6959):929. Related U.S. Application Data Basson et al., Summary of the recommendations on sexual dys (60) Provisional application No. 61/679,999, filed on Aug. functions in women. J Sex Med. Jan. 2010;7(1 Pt 2):314-26. Berge et al., Pharmaceutical Salts. J. Pharm. Sci. Jan. 1977; 66(1):1- 6, 2012. 19. Brotto et al., Women's sexual desire and arousal disorders. J Sex (51) Int. C. Med. Jan. 2010;7(1 Pt 2):586-614. A6 IK 38/22 (2006.01) Burri et al., The acute effects of intranasal oxytocin administration A6 IK 3/496 (2006.01) on endocrine and sexual function in males. Psychoneuroendocrinol ogy. Jun. 2008:33(5):591-600. A6 IK3I/37 (2006.01) Chadman et al., New directions in the treatment of autism spectrum A6 IK 45/06 (2006.01) disorders from animal model research. Expert Opinion on Drug A6 IK 38/II (2006.01) Discovery, vol. 7, No. 5, 2012. pp. 407-416. U.S. C. Chinese Office Action for Chinese Application No. 201280027260. (52) 7, dated Dec. 22, 2014. CPC ...... A61K 38/22 (2013.01); A61K 3 1/137 Chinese Office Action for Chinese Application No. 201280027260. (2013.01); A61 K3I/496 (2013.01); A61 K 7, dated Nov. 2, 2015. 38/II (2013.01); A61K 45/06 (2013.01) Chinese Office Action for Chinese Application No. 2013800.52215. Field of Classification Search 1, dated May 5, 2016. (58) Clayton et al., Standards for clinical trials in sexual dysfunction in None women: research designs and outcomes assessment. J Sex Med. Jan. See application file for complete search history. 2010;7(1 Pt 2):541-60. Craven et al., What are the Altenatives to Nefazodone? Canadian (56) References Cited Psychiatric Association Bulletin, 2004:36(4):21. Derogatis et al., Characterization of hypoactive sexual desire dis U.S. PATENT DOCUMENTS order (HSDD) in men. J Sex Med. Mar. 2012:9(3):812-20. 4,687,771 A 8, 1987 Gamble et al. (Continued) 6,337,328 B1 1/2002 Fang et al. Primary Examiner — Amber D Steele 2005.0245539 A1 11/2005 Mendla et al. Assistant Examiner — Schuyler Milton 2006, O154908 A1 7/2006 Patel et al. ir Mi 2006/0211685 A1 9/2006 Pyke et al. E. C.E.", Firm – Mintz Levin Cohn Ferris 2011/0105519 A1 5, 2011 Mendla et al. ovsky and Popeo, F.U. 2012/0172304 A1 7/2012 Leonard et al. (57) ABSTRACT The invention further relates to compounds, pharmaceutical FOREIGN PATENT DOCUMENTS compositions and methods for treating all disorders of CN 1946404 A 4/2007 human sexual function including hypoactive sexual desire DE 432.1965 A1 1, 1995 disorder (HSDD) in a subject. JP 2002322085 A 11 2002 20 Claims, No Drawings US 9,517,254 B2 Page 2

(56) References Cited Rowland et al., Bupropion and sexual function: a placebo-controlled prospective study on diabetic men with erectile dysfunction. J. Clin Psychopharmacol. Oct. 1997:17(5):350-7. OTHER PUBLICATIONS Scandroglio et al., Ex vivo binding of flibanserin to serotonin Eurasian Office Action for Eurasian Application No. 201391459, 5-HT1A and 5-HT2A receptors. Pharmacol Res. Feb. dated Apr. 2, 2015. 2001:43(2): 179-83. European Office Action for European Application No. 1276.8489.2, Schencket al., Combined bupropion-levodopa-trazodone therapy of dated Feb. 1, 2016. European Search Report for European Application No. 1276.8489.2, sleep-related eating and sleep disruption in two adults with chemical dated Jul. 21, 2014. dependency. Sleep. Aug. 1, 2000:23(5):587-8. European Search Report for European Application No. 13827390.9, Search Report for Singapore Application No. 2013074083, dated dated Jan. 29, 2016. Sep. 5, 2014. European Search Report for European Application No. 13827390.9, Shifren et al., Sexual problems and distress in United States women: dated Apr. 22, 2016. prevalence and correlates. ObstetGynecol. Nov. 2008; 112(5):970 Fink et al., Trazodone for erectile dysfunction: a systematic review 8. and meta-analysis. BJU Int. Sep. 2003:92(4):441-6. Stryjer et al., Trazodone for the treatment of sexual dysfunction Fooladi et al... An update on the pharmacological management of induced by serotonin reuptake inhibitors: a preliminary open-label female sexual dysfunction. Expert Opin Pharmacother. Oct. study. Clin Neuropharmacol. Mar.-Apr. 2009:32(2):82-4. 2012; 13(15):2131-42. Tordjman. Treatment of Inhibition of Sexual Desire in Women by Ghanbari et al., Sustained administration of trazodone enhances Trazodone. Contraception Fertilite Sexualite. 1986; 14(10): 935 serotonergic neurotransmission: in vivo electrophysiological study 939. in the rat brain. J Pharmacol Exp. Ther. Oct. 2010:335(1): 197-206. Written Opinion for Singapore Application No. 1120 1500919P, Hatzichristou et al., Recommendations for the clinical evaluation of dated Feb. 16, 2016. men and women with sexual dysfunction. J Sex Med. Jan. 2010;7(1 Written Opinion for Singapore Application No. 2013074083, dated Pt 2):337-48. Feb. 22, 2016. Herrera-Guzmán et al., Cognitive predictors of treatment response Written Opinion for Singapore Application No. 2013074083, dated to bupropion and cognitive effects of bupropion in patients with major depressive disorder. Psychiatry Res. Jul. 15, 2008; 160(1): 72 May 21, 2015. 82. Written Opinion for Singapore Application No. 2013074083, dated International Search Report for PCT/US2012/031991, dated Oct. Oct. 3, 2014. 12, 2012. Zourkova et al., The Efficacy of Bupropion and Trazodone in the Ishaket al., Male anorgasmia treated with Oxytocin. J Sex Med. Apr. Treatment of Hypoactive Sexual Desire Disorder and Orgasm 2008:5(4): 1022-4. Dysfunction in Non-Depressed Women. Ceska A Slovenska Japanese Office Action for Japanese Application No. 2014-503.910, Psychiatrie. 2008: 104(2): 1068. dated Feb. 9, 2016. American Psychiatric Association, Diagnostic and Statistical Kirsch et al., Oxytocin modulates neural circuitry for Social cog Manual of Mental Disorders, 5th Edition, 2013, pp. 423-450. nition and fear in humans. J Neurosci. Dec. 7, 2005:25(49): 11489 Eurasian Office Action for Eurasian Application No. 201590349, 93. dated Jun. 20, 2016. Laumann et al., Sexual dysfunction in the United States: prevalence Harrison et al., Harrison's Principles of Internal Medicine, 13th and predictors. JAMA. Feb. 10, 1999:281 (6):537-44. Edition, McGraw-Hill, 1994, pp. 267-268, 2407-2408, 2459. MacDonald et al. A review of safety, side-effects and subjective Lough, W.J. Chiral Liquid Chromatography, Chapman and Hall, reactions to intranasal oxytocin in human research. 1989, pp. 14-35. Psychoneuroendocrinology. Sep. 2011:36(8): 1114-26. The Physicians' Desk Reference, 50th Edition, 1997, pp. 308, 316, MacDonald et al., Dramatic improvement in sexual function 503-505, 1204-1207, 2679. induced by intranasal oxytocin. J Sex Med. May 2012:9(5): 1407 Australian Examination Report for Application No. 2012240388, 10. dated Jun. 6, 2016. Mexican Office Action for Mexican Application No. MX/a/2013/ Wikipedia, "Diagnostic and Statistical Manual of Mental Disor 0 1 1623, dated Mar. 1, 2016. ders,” Wikipedia.org. . nondepressed subjects: a pilot study. J Sex Marital Ther. Jul.-Sep. European Neuropsychopharmacology: The Journal of the European 2000:26(3):231-40. College of Neuropsychopharmacology, V. 19, Suppl. 3, S362. Monleón et al., Antidepressant drugs and memory: insights from Papers of the 22nd ECNP Congress. Sep. 12-16, 2009, Istanbul, animal studies. Eur Neuropsychopharmacol. Apr. 2008;18(4):235 Turkey. 48. Office Action for Israeli Application No. 228729, dated Aug. 14. Nierenberg et al., Trazodone for antidepressant-associated insom 2016. English translation and original. nia. Am J Psychiatry. Jul. 1994; 151(7):1069-72. Office Action for Japanese Application No. 2014-503910, dated Oct. Peterson et al., Anxiety and sexual stress in men and women 4, 2016. English translation and original. undergoing infertility treatment. Fertil Steril. Oct. 2007:88(4):911 4. * cited by examiner US 9,517,254 B2 1. 2 TREATMENT REGIMENS significant sexual distress, the disorder is called Male Orgas mic Disorder (MOD; delayed ejaculation). Male dysfunc CROSS REFERENCE TO RELATED tionally premature ejaculation (PE) is much more frequent APPLICATIONS than any of these problems, occurring in up to 30% of younger men (Laumann et al., Sexual dysfunction in the This application is the national phase under 35 U.S.C. United States: Prevalence and predictors, JAMA, 1999; S371 of PCT International Application No, PCT/US2013/ 281:537–44). 053843, filed Aug. 6, 2013, which claims the benefit of U.S. Sexual dysfunction may also be manifested as a signifi Provisional Application No. 61/679,999 filed on Aug. 6, cant burden in the course of physical diseases. Sexual 2012, the entire disclosures of which is are hereby incorpo 10 dysfunction is frequent in women with chronic, fatiguing rated in its entirety. medical illness, especially Female HSDD or FSAD due to BACKGROUND OF THE INVENTION breast cancer, diabetes mellitus, or irritable bowel syndrome or due to combined factors including one of these medical Sexual Dysfunction (SD) is described as a disorder of or 15 diseases. These conditions occur mainly in middle-aged to an interruption in sexual functioning. In women, the most older patients. Collectively, these conditions cause sexual common type of sexual disorder is generalized, acquired dysfunction, mainly desire disorder, in over 7.8 million HSDD defined by the Diagnostic and Statistical Manual, 4" women age 45-64 in the US (breast or gynecologic cancer, Edition, Text Revision (American Psychiatric Association, 1.5 million; diabetes, at least 3.4 million; irritable bowel, at 2000; DSM-IV-TR) as: “The persistent lack (or absence) of least 2.9 million). SD in Men with chronic diseases is little sexual fantasies or desire for any form of sexual activity studied but can be presumed from the ample evidence on marked by distress or interpersonal difficulty and not better women to be another large set of clinically and epidemio accounted for by another disorder (except another sexual logically significant health problems. The most authoritative dysfunction) direct physiological effects of a Substance arbiter of diagnostic names and criteria on sexual dysfunc (including medications) or a general medical condition.” 25 tion, the DSM-IV-TR, recognizes eight kinds of sexual The presence of distress or interpersonal difficulty is an disorders due to chronic physical disease: Sexual Dysfunc integral part of sexual disorders and is central to the diag tion due to General Medical Conditions (e.g., irritable bowel nosis of the condition. Approximately 1 in 10 women syndrome, diabetes, cancer); Female HSDD due to General reported low sexual desire with associated distress, which Medical Conditions (e.g., irritable bowel syndrome, diabe may be HSDD. 30 tes, cancer); Male HSDD due to General Medical Condi Synonyms for HSDD include sexual aversion, i.e., tions (e.g., irritable bowel syndrome, diabetes, cancer); Male extreme aversion to, absence of, and avoidance of all, or Erectile Disorder due to General Medical Conditions (e.g., almost all, sexual contact with a partner, inhibited sexual irritable bowel syndrome, diabetes, cancer); Female Dys desire; sexual apathy; loss of libido; decreased sexual desire; pareunia due to General Medical Conditions (e.g., irritable distressing loss of sexual desire; and sexual anorexia. HSDD 35 bowel syndrome, diabetes, cancer); Male Dyspareunia due occurs in both sexes. It is considered to be the most common to General Medical Conditions (e.g., irritable bowel syn of all female sexual disorders, possibly occurring in as many drome, diabetes, cancer); Other Female Sexual Dysfunction as 10% of women in the United States. due to General Medical Conditions (e.g., irritable bowel In women, a majority of HSDD cases are generalized in syndrome, diabetes, cancer) if some other feature is pre Subtype, though a Substantial minority of cases may relate to 40 dominant (e.g., Orgasmic Disorder) or no feature predomi dissatisfaction or loss of interest in the sexual partner. Either nates; and Other Male Sexual Dysfunction due to General subtype of HSDD can lead to general feelings of dissatis Medical Conditions (e.g., irritable bowel syndrome, diabe faction in the person and/or discord in their personal rela tes, cancer) if some other feature is predominant (e.g., tionships, including for example marital discord. Sexual Orgasmic Disorder) or no feature predominates. disorders, whether generalized or situational, often do not 45 Collectively, in this document, all of the sexual dysfunc respond to counseling therapy, and frequently culminate in tions and disorders described above are called sexual dys separation, finding a new sexual partner, and divorce. functions, sexual disorders, or SD. The other phases of sexual function, sexual arousal and As there is no currently approved treatment for HSDD or orgasm, are also subject to impairment. In women, dysfunc any other sexual disorder except (male) erectile dysfunction tions in these sexual phases, if Sufficiently distressing, are 50 in the United States, a therapeutic composition and methods known, respectively, as Female Sexual Arousal Disorder for ameliorating sexual disorders is an unmet need for a (FSAD) and Female Orgasmic Disorder (FOD) in DSM-IV significant portion of the population and their quality of life. TR. Collectively, they impair sexual function in almost as Delineated herein are compositions and methods of treat many women as does HSDD (Shifren J L et al. Sexual ment that may be useful to address this unmet need based on problems and distress in United States women: prevalence 55 heretofore unexpected properties possessed by the Subject and correlates. Obstet Gynecol. 2008 November; 112(5): compositions. 970-81. Women in the peri- and post-menopause are the Erectile Dysfunction (ED) is the only male sexual dys most affected subpopulation with such problems. In the US, function for which pharmacotherapies are broadly available. in the age group 45-64 years, the prevalence of FSAD is Sexual disorders other than ED, e.g., HSDD, are also about 3.1 million; of FOD, 2.4 million. Little overlap of 60 common in men, although research on non-ED male sexual these disorders was found in the largest, most representative disorders has lagged compared to that in women. However, survey of women's sexual function (the PRESIDE study, the cross-national US survey published in 1999 by Laumann Shifren et al., ibid.), so the overall number of US women et al. showed that male lack of interest in sex, at 15% of men affected with FSAD or FOD is over 5 million. aged 18-59, was about as frequent as erectile dysfunction In men, dysfunction in arousal (in erection) is well 65 (18%). In March (Derogatis et al, J Sex Med 2012: 9:812 recognized; dysfunctional delay in, or absence of orgasm 820), a research group applied a battery of validated Scales (ejaculation) also occurs with some frequency. If it causes to men with HSDD vs. those with no sexual dysfunction. US 9,517,254 B2 3 4 The men with HSDD had dramatic impairments on all rating because the effective dose can be given immediately due to scales relating to HSDD: on the Sexual Concerns Index the low expected side effects, instead of requiring weeks of Male, a measure of male sexual distress; the UCLA Psy up-titration to overcome side effects over time. This makes chosexual Diary’s measure of sexual activity; and the Male LorexyS(R), a fixed combination of bupropion and traZodone, Desire Scale, a measure of sexual desire; but did not have of special value for male HSDD and sexual performance ED: International Index of Erectile Function (IIEF)-5 anxiety as disorders that cause distress and disrupt quality of median score or depression Beck Depression scale or low life on the days when a man is to have sex with a partner. testosterone: men with low or low-normal testosterone lev The current invention relates to combinations of a 5-HT els (<300 ng/dL) were excluded. Their data show that male receptor agonist and/or 5-HT, receptor antagonist (e.g., HSDD is a real problem of clinical magnitude. *p-0.0001 10 traZodone, nefazodone, mirtazapine, flibanserin ketanserin, for each variable; sample sizes were about 100 ritanserin, clozapine, olanzapine, quetiapine, risperidone, No pharmacologic treatment is available in most countries asenapine, MDL-100.907, cyproheptadine, aripiprazole, and including the US for either men or women with sexual the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido disorders other than for men with ED, although a testoster azepines), a norepinephrine-dopamine reuptake inhibitor one transdermal system was approved for women with 15 (e.g., bupropion), and/or an oxytocin receptor (OXTR) ago postmenopausal HSDD in Europe in 2005. nist (e.g., carbetocin, oxytocin, Syntocinon R) and their use Yet another male sexual dysfunction is frequent, though to augment sexual desire, arousal, and orgasm. Their ability not the subject of a DSM-IV-TR diagnosis: Male sexual to help men feel desire will also aid male sexual perfor performance anxiety was a problem for 17% of US men age mance anxiety. These combinations will be particularly 18-59 in the cross-national survey published by Laumann in effective for each of these disorders in men and women 1999 in JAMA, about the same incidence as for erectile because they will allow the corrective effects of the indi dysfunction (ED) and male lack of sexual interest. Male vidual agents to become manifest without being masked by sexual performance anxiety was about twice as prevalent as the side effects of either drug, and in particular it will allow ED in US men under age 50. It is little studied but can cause rapid relief of symptoms because the effective dose can be significant distress, especially in male patients in infertility 25 given immediately due to the low expected side effects, clinics. Peterson B D, Newton C R. and Feingold T. in instead of requiring weeks of up-titration to overcome side “Anxiety and sexual stress in men and women undergoing effects over time. This makes Lorexys(R), a fixed combina infertility treatment,” in Fertility and Sterility 2007 October; tion of bupropion and traZodone, of special value for male 88(4):911-4, Epub 2007 Apr. 11, found in a prospective HSDD and sexual performance anxiety as disorders that study at a University-affiliated teaching hospital for in vitro 30 cause distress and disrupt quality of life on the days when a fertilization and intrauterine insemination (306 women, 295 man is to have sex with a partner. men) a strong linkage between anxiety and sexual stress in The current invention also relates to combinations of a men and concluded that sexual stress among infertile men 5-HT, receptor agonist and/or 5-HT, receptor antagonist may be more closely tied to performance anxiety rather than (e.g., traZodone, nefazodone, mirtazapine, flibanserin ketan to a more general deterioration in sexual satisfaction asso 35 serin, ritanserin, clozapine, olanzapine, quetiapine, risperi ciated with infertility. done, asenapine, MDL-100.907, cyproheptadine, aripipra Male sexual performance anxiety, while not a disorder Zole, and the general class of 2-alkyl-4-aryl-tetrahydro recognized in DSM-IV-TR or ICD-10, is recognized as a pyrimido-azepines), and/or a 5-HT, receptor antagonist, necessary focus in the recommended clinical evaluation of and/or a 5HT-2c receptor agonist, (e.g., lorcaserin, vabica men with sexual dysfunction according to the Third Inter 40 serin, PRX-00933, YM348, and metachlorophenylpipera national Consultation on Sexual Medicine (Paris, July zine, mCPP), a norepinephrine-dopamine reuptake inhibitor 2009). Hatzichristou D. Rosen R C, Derogatis L. R. et al. (e.g., bupropion), and/or other non-abusable agents (agents Recommendations for the Clinical Evaluation of Men and not scheduled by the DEA) that augment dopamine and/or Women with Sexual Dysfunction, J Sex Med 2010; 7:337 norepinephrine in the brain, e.g., atomoxetine, reboxetine, 348. These experts recommend diagnostic workup for male 45 amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, sexual performance anxiety because it may cause or result lortalamine, mazindol, nisoxetine, talopram, talsupram, tan from the recognized male sexual disorders such as ED damine, Viloxazine, maprotiline, ciclazindol, manifaxine, (psychogenic impotence) and premature ejaculation. radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo The model of sexual functioning that is most accepted is biloba), and/or an oxytocin receptor (OXTR) agonist (e.g., one in which sexual desire leads to arousal, and eventually 50 carbetocin, oxytocin, Syntocinon R) and their use to aug orgasm. Even E. D. currently the most treatable of sexual ment sexual desire, arousal, and orgasm. Their ability to help dysfunctions, is unlikely to be aided by pharmacotherapy men feel desire will also aid male sexual performance unless desire can be restored. Thus, loss of desire is of anxiety. These combinations will be particularly effective for primary concern for treating all disorders of sexual function. each of these disorders in men and women because they will The current invention relates to combinations of a 5-HT 55 allow the corrective effects of the individual agents to receptor agonist and/or 5-HT, receptor antagonist (e.g., become manifest without being masked by the side effects of traZodone, nefazodone, mirtazapine, flibanserin), a norepi either drug, and in particular it will allow rapid relief of nephrine-dopamine reuptake inhibitor (e.g., bupropion), symptoms because the effective dose can be given immedi and/or an oxytocin receptor (OXTR) agonist (e.g., carbeto ately due to the low expected side effects, instead of requir cin, oxytocin, Syntocinon R) and their use to augment sexual 60 ing weeks of up-titration to overcome side effects over time. desire, arousal, and orgasm. Their ability to help men feel This makes Lorexys(R), a fixed combination of bupropion desire will also aid male sexual performance anxiety. These and trazodone, of special value for male HSDD and sexual combinations will be particularly effective for each of these performance anxiety as disorders that cause distress and disorders in men and women because they will allow the disrupt quality of life on the days when a man is to have sex corrective effects of the individual agents to become mani 65 with a partner. fest without being masked by the side effects of either drug, Disorders of cognition are also frequent, and are of and in particular it will allow rapid relief of symptoms particular concern because of their high prevalence in older US 9,517,254 B2 5 6 patients (an enlarging segment of the population), the dis DSM-IV-recognized condition of) male sexual performance ability they cause, and their intractability to current treat anxiety; in the female partner, HSDD, FSAD, FOD, and ments. Improvement in cognition as augmentation of cog dyspareunia. It is a novel aspect of the invention that the nition for therapeutic purposes is also of interest, e.g., in the same properties of oxytocin, aiding trust and reducing Social circumstances of subjects whose cognitive skills are limiting anxiety, will aid most of the other subtypes of each of these for tasks that require learning or vigilance. The invention disorders of sexual function, i.e., the subtypes “due to provides a method of treating a subject Suffering from or psychological factors and "due to combined factors.’ “Situ susceptible to a cognitive disorder or otherwise in need of ational is defined in DSM-IV-TR as applying “if the sexual improvement in cognition with a composition comprising a dysfunction is limited to certain types of stimulation, situ 5-HT agonist, a 5-HT, antagonist, a norepinephrine 10 ations, or partners,” which is the opposite of the Generalized dopamine reuptake inhibitor, an oxytocin receptor (OXTR) type. “Due to Psychological Factors' applies “when psy agonist, and a pharmaceutically acceptable carrier. chological factors are judged to have the major role in the Depressive disorders are also frequent (lifetime risk in onset, severity, exacerbation, or maintenance of the Sexual women, 10-25%; in men, 5-12%) and are of particular Dysfunction . . . . “Due to Combined Factors' is defined concern because of the disability they cause, the high 15 as applying “when psychological factors are judged to have likelihood of failure with initial treatment (only about 50% a role in the onset, severity, exacerbation, or maintenance of of patients with Major Depressive Disorder respond to any the Sexual Dysfunction . . . . . one antidepressant, the high frequency of incomplete It is a novel aspect of the invention that oxytocin is useful response to currently available treatments (only about 30% to treat the aforementioned subtypes of every diagnostic of patients achieve full remission with a given antidepres category of sexual dysfunction. Drawing on clinical expe Sant), their increasing frequency of treatment-resistance, and rience in couples having a long-term partnered relationship, especially because they often lead to suicide, in about 15% sexual dysfunction in one partner ordinarily worsens of patients (DSM-IV-TR). The invention provides a method because of the other partner's reaction over time to that of treating a Subject Suffering from or Susceptible to a sexual dysfunction, and can cause sexual dysfunction in the depressive disorder comprising administering to a subject in 25 partner, too. For example, generalized HSDD in a woman is need thereof a therapeutically effective amount of a com likely to lead her to non-receptivity, which may lead her to position comprising a 5-HT agonist, a 5-HTantagonist, a psychosocially destructive pattern of avoidance behavior a norepinephrine-dopamine reuptake inhibitor, an oxytocin regarding potential sexual situations. The male partner receptor (OXTR) agonist, and a pharmaceutically acceptable learns to avoid sexual frustration, anger, arguments etc. by carrier. 30 also practicing avoidance behavior. At first this may simply It is not readily apparent from published literature reports be sublimation, but the likely result over time is atrophy of that oxytocin (OT) can relieve human sexual dysfunction. all sexual aspects of the union, including sexual dysfunction Though a case report of pro-sexual effects of transnasal OT in the male partner performance anxiety likely occurring has been published for each of three very different patients first, then HSDD, ED, and/or PE. That leads to further a postpartum woman without sexual dysfunction: Ander 35 decline in the sexual relationship. The woman's HSDD was son-Hunt and Dennerstein, Brit Med J. 1994; 309:929; an originally, and logically remains, generalized. But both elderly man with orgasmic disorder: Ishak et al., J Sex Med. partners’ sexual disorders may then alternatively be sub 2008; 5:1022-4, and a complex psychiatric patient without typed as situational, due to psychological factors, or due to sexual dysfunction: MacDonald and Feifel, J Sex Med2012: combined factors. 9:1407-1410, the only published placebo-controlled study 40 Similarly, it is another aspect of the invention that oxy showed no significant advantage for oxytocin: 24 Interna tocin specifically aids all additionally proposed DSM-5 tional Units (IU) of intranasal OT failed to increase arousal sexual dysfunction disorders (Male HSDD, Erectile Disor or orgasm in men on the primary outcome scale, the "Acute der, Delayed Ejaculation, Female Sexual Interest/Arousal Sexual Experiences Scale (ASES). The authors concluded Disorder, Genito-Pelvic Pain/Penetration Disorder, Sub that “the effects of OT on sexual behavior were 45 stance/Medication-Induced Sexual Dysfunction, and Sexual equivocal . . . . Burri et al., Psychoneuroendocrinology. Dysfunction Not Elsewhere Classified) with the proposed 2008; 33:591-600. Also, in the most recent review of the Specifiers of Situational, Partner factors (e.g., partner's side effects of transnasal OT, in which almost a thousand sexual problems, partner's health status), and Relationship subjects were treated with OT (Syntocinon(R) in almost all factors (e.g., poor communication, discrepancies in desire studies) in controlled studies to investigate non-sexual 50 for sexual activity). www.dsm5.org, Aug. 2, 2012. effects, no events of any type of increase in sexual function The current invention relates to combinations of a 5-HT were reported MacDonald et al., Psychoneuroendocrinol receptor agonist, 5-HT2 receptor antagonist, 5-HT, recep ogy. 2011 September: 36(8): 1114-26. tor antagonist, or combinations thereof (e.g., traZodone). However, OT mediates pro-social and anti-anxiety The current invention also relates to combinations of a effects, doing so through effects on the amygdala in a 55 5-HT, receptor agonist, 5-HT2 receptor antagonist, placebo-controlled study. Kirsch et al., J. Neuroscience 5-HT, receptor antagonist, or combinations thereof (e.g., 2005; 25(49): 11489-11493. It is a novel aspect of the traZodone), and a norepinephrine-dopamine reuptake inhibi invention that these properties will specifically aid all DSM tor (e.g. bupropion), and/or an oxytocin receptor (OXTR) IV-TR-recognized sexual dysfunction disorders listed as agonist (e.g., carbetocin, oxytocin, Syntocinon R) to aug having the DSM-IV-TR subtype "due to situational factors.” 60 ment cognition, improve failing mental processes in cogni i.e., in men or women who are in a relationship in which tive disorders, and improve mood and the depressive symp sexual activity has deteriorated in frequency and/or satis toms that accompany mood disorders. The current invention faction because of increasing loss of trust and/or anxiety also relates to combinations of a 5-HT, receptor agonist, about performance, avoidance patterns etc., that occur as a 5-HT2 receptor antagonist (e.g., traZodone, nefazodone, consequence of any of the recognized sexual dysfunction 65 mirtazapine, flibanserin), a norepinephrine-dopamine disorders: in the male partner, HSDD, ED, PE, MOD, and reuptake inhibitor (e.g. bupropion), and/or an oxytocin dyspareunia, and in (the epidemiologically frequent but not receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syn US 9,517,254 B2 7 8 tocinon R) to augment cognition, improve failing mental a health provider with less specialized expertise in pharma processes in cognitive disorders, and improve mood and the cologic treatment of neuro-psychiatric disorders. depressive symptoms that accompany mood disorders. The current invention also relates to combinations of a These combinations are particularly effective for each of 5-HT, receptor agonist and/or 5-HT, receptor antagonist these disorders as they allow the corrective effects of the 5 (e.g., traZodone, nefazodone, mirtazapine, flibanserin ketan serin, ritanserin, clozapine, olanzapine, quetiapine, risperi individual agents to become manifest without being masked done, asenapine, MDL-100.907, cyproheptadine, aripipra by the side effects of either drug, and in particular it allow Zole, and the general class of 2-alkyl-4-aryl-tetrahydro rapid relief of symptoms because the effective dose can be pyrimido-azepines), and/or a 5-HT, receptor antagonist, given immediately due to the low expected side effects, and/or a 5HT-2c receptor agonist, (e.g., lorcaserin, vabica instead of requiring weeks of up-titration to overcome side 10 serin, PRX-00933, YM348, and metachlorophenylpipera effects over time. Reduced toxicity is provided by a com zine, mCPP), a norepinephrine-dopamine reuptake inhibitor pound of the invention when administered in vivo, e.g., (e.g., bupropion), and/or other non-abusable agents (agents formulating bupropion, by itself a mild stimulant, with not scheduled by the DEA) that augment dopamine and/or traZodone, by itself a moderate sedative, in the proprietary norepinephrine in the brain, e.g., atomoxetine, reboxetine, ratio of Lorexys, will neutralize the main side effects of each 15 amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, of the two drugs. This makes Lorexys(R), a fixed combination lortalamine, mazindol, nisoxetine, talopram, talsupram, tan of bupropion and traZodone, of special value for treating damine, Viloxazine, maprotiline, ciclazindol, manifaxine, acute symptoms such as Suicidality, disabling symptoms radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo Such as inability to work or otherwise function, especially biloba), and/or an oxytocin receptor (OXTR) agonist (e.g., for older patients who generally are more prone to side carbetocin, oxytocin, Syntocinon R) to augment cognition, effects and for whom adverse effects cause more risk, and improve failing mental processes in cognitive disorders, and especially because Such a combination can be prescribed by improve mood and the depressive symptoms that accom a health provider with less specialized expertise in pharma pany mood disorders. The current invention also relates to cologic treatment of neuro-psychiatric disorders. combinations of a 5-HT, receptor agonist, 5-HT, receptor The current invention relates to combinations of a 5-HT 25 antagonist (e.g., traZodone, nefazodone, mirtazapine, fliban receptor agonist, 5-HT2 receptor antagonist, 5-HT, recep serin), a norepinephrine-dopamine reuptake inhibitor (e.g. tor antagonist, or combinations thereof (e.g., traZodone, bupropion), and/or an oxytocin receptor (OXTR) agonist nefazodone, mirtazapine, flibanserin ketanserin, ritanserin, (e.g., carbetocin, oxytocin, Syntocinon R) to augment cog clozapine, olanzapine, quetiapine, risperidone, asenapine, nition, improve failing mental processes in cognitive disor MDL-100.907, cyproheptadine, aripiprazole, and the gen 30 ders, and improve mood and the depressive symptoms that eral class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). accompany mood disorders. These combinations are par The current invention also relates to combinations of a ticularly effective for each of these disorders as they allow 5-HT, receptor agonist, 5-HT, receptor antagonist, the corrective effects of the individual agents to become 5-HT, receptor antagonist, or combinations thereof (e.g., manifest without being masked by the side effects of either traZodone), and a norepinephrine-dopamine reuptake inhibi 35 drug, and in particular it allow rapid relief of symptoms tor (e.g. bupropion), and/or an oxytocin receptor (OXTR) because the effective dose can be given immediately due to agonist (e.g., carbetocin, oxytocin, Syntocinon R) to aug the low expected side effects, instead of requiring weeks of ment cognition, improve failing mental processes in cogni up-titration to overcome side effects over time. Reduced tive disorders, and improve mood and the depressive symp toxicity is provided by a compound of the invention when toms that accompany mood disorders. The current invention 40 administered in Vivo, e.g., formulating bupropion, by itself also relates to combinations of a 5-HT, receptor agonist, a mild stimulant, with trazodone, by itself a moderate 5-HT, receptor antagonist (e.g., trazodone, nefazodone, sedative, in the proprietary ratio of Lorexys, will neutralize mirtazapine, flibanserin), a norepinephrine-dopamine the main side effects of each of the two drugs. This makes reuptake inhibitor (e.g. bupropion), and/or an oxytocin LorexyS(R), a fixed combination of bupropion and traZodone, receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syn 45 of special value for treating acute symptoms such as Sui tocinon R) to augment cognition, improve failing mental cidality, disabling symptoms such as inability to work or processes in cognitive disorders, and improve mood and the otherwise function, especially for older patients who gen depressive symptoms that accompany mood disorders. erally are more prone to side effects and for whom adverse These combinations are particularly effective for each of effects cause more risk, and especially because such a these disorders as they allow the corrective effects of the 50 combination can be prescribed by a health provider with less individual agents to become manifest without being masked specialized expertise in pharmacologic treatment of neuro by the side effects of either drug, and in particular it allow psychiatric disorders. rapid relief of symptoms because the effective dose can be given immediately due to the low expected side effects, SUMMARY OF THE INVENTION instead of requiring weeks of up-titration to overcome side 55 effects over time. Reduced toxicity is provided by a com In one aspect, the invention provides compositions and pound of the invention when administered in vivo, e.g., methods of treating a Subject Suffering from or Susceptible to formulating bupropion, by itself a mild stimulant, with a sexual disorder or symptom thereof (e.g., HSDD, FSAD, traZodone, by itself a moderate sedative, in the proprietary FOD, erectile disorder, male sexual performance anxiety, ratio of Lorexys, will neutralize the main side effects of each 60 sexual interest-arousal disorder, female sexual dysfunction of the two drugs. This makes Lorexys(R), a fixed combination (FSD), male sexual dysfunction (MSD), and the like) com of bupropion and traZodone, of special value for treating prising administering to a Subject in need thereof a thera acute symptoms such as Suicidality, disabling symptoms peutically effective amount of a composition delineated Such as inability to work or otherwise function, especially herein. for older patients who generally are more prone to side 65 The current invention relates to combinations of a 5-HT effects and for whom adverse effects cause more risk, and receptor agonist, 5-HT2 receptor antagonist, 5-HT, recep especially because Such a combination can be prescribed by tor antagonist, or combinations thereof (e.g., traZodone). US 9,517,254 B2 10 The current invention also relates to combinations of a inhibitor (e.g. bupropion), and/or other non-abusable agents 5-HT, receptor agonist, 5-HT, receptor antagonist, (agents not scheduled by the DEA) that augment dopamine 5-HT, receptor antagonist, or combinations thereof (e.g., and/or norepinephrine in the brain, e.g., atomoxetine, rebox traZodone), and a norepinephrine-dopamine reuptake inhibi etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox tor (e.g. bupropion), and/or an oxytocin receptor (OXTR) etine, lortalamine, mazindol, nisoxetine, talopram, talsu agonist (e.g., carbetocin, oxytocin, SyntocinonR). pram, tandamine, Viloxazine, maprotiline, ciclaZindol, The current invention relates to combinations of a 5-HT manifaxine, radafaxine, tapentadol, teniloxazine, St. John's receptor agonist, 5-HT, receptor antagonist, 5-HT, recep wort, ginkgo biloba), and/or an oxytocin receptor (OXTR) tor antagonist, or combinations thereof (e.g., traZodone, agonist (e.g., carbetocin, oxytocin, SyntocinonR). 10 In one aspect, the invention provides a composition nefazodone, mirtazapine, flibanserin ketanserin, ritanserin, comprising a 5-HT, antagonist, a norepinephrine-dop clozapine, olanzapine, quetiapine, risperidone, asenapine, amine reuptake inhibitor, and a pharmaceutically acceptable MDL-100.907, cyproheptadine, aripiprazole, and the gen carrier. In another aspect the composition is that wherein the eral class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). norepinephrine-dopamine reuptake inhibitor is also an alpha The current invention also relates to combinations of a 15 adrenergic blocker (e.g., bupropion). In another aspect the 5-HT, receptor agonist, 5-HT2 receptor antagonist, composition is that wherein the 5-HT, antagonist is also a 5-HT, receptor antagonist, or combinations thereof (e.g., 5-HT, receptor agonist. In another aspect the composition traZodone, nefazodone, mirtazapine, flibanserin ketanserin, is that wherein the 5-HT2 receptor antagonist is also a ritanserin, clozapine, olanzapine, quetiapine, risperidone, 5-HT, receptor antagonist. In another aspect the composi asenapine, MDL-100.907, cyproheptadine, aripiprazole, and tion is that wherein the 5-HT2 receptor antagonist is also a the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido 5-HT, receptor antagonist and a 5-HT, receptor agonist azepines), and a norepinephrine-dopamine reuptake inhibi (e.g., traZodone). In another aspect the composition is that tor (e.g. bupropion), and/or an oxytocin receptor (OXTR) wherein the 5-HT, receptor antagonist, 5-HT, receptor agonist (e.g., carbetocin, oxytocin, SyntocinonR). agonist, and/or 5-HT, receptor antagonist is also an alpha The current invention relates to combinations of a 5-HT 25 adrenergic blocker (e.g., traZodone). In another aspect the receptor agonist, 5-HT2 receptor antagonist, 5-HT, recep composition is that comprising traZodone and bupropion. In tor antagonist, or combinations thereof (e.g., traZodone, another aspect the composition is that comprising traZodone nefazodone, mirtazapine, flibanserin ketanserin, ritanserin, in a dosage range of 1-450 mg and bupropion in a dosage clozapine, olanzapine, quetiapine, risperidone, asenapine, range of 1-450 mg. MDL-100.907, cyproheptadine, aripiprazole, and the gen 30 In one aspect, the invention provides a composition eral class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). comprising a 5-HT, antagonist, a norepinephrine-dop The current invention also relates to combinations of a amine reuptake inhibitor, other non-abusable agents (agents 5-HT, receptor agonist, 5-HT, receptor antagonist, not scheduled by the DEA) that augment dopamine and/or 5-HT, receptor antagonist, or combinations thereof (e.g., norepinephrine in the brain, e.g., atomoxetine, reboxetine, traZodone, nefazodone, mirtazapine, flibanserin ketanserin, 35 amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, ritanserin, clozapine, olanzapine, quetiapine, risperidone, lortalamine, mazindol, nisoxetine, talopram, talsupram, tan asenapine, MDL-100.907, cyproheptadine, aripiprazole, and damine, Viloxazine, maprotiline, ciclazindol, manifaxine, the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo azepines), and/or a norepinephrine-dopamine reuptake biloba), and a pharmaceutically acceptable carrier. In inhibitor (e.g. bupropion), and/or an oxytocin receptor 40 another aspect the composition is that wherein the norepi (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), nephrine-dopamine reuptake inhibitor is also an alpha adren and/or other non-abusable agents (agents not scheduled by ergic blocker (e.g., bupropion). In another aspect the com the DEA) that augment dopamine and/or norepinephrine in position is that wherein the 5-HT, antagonist is also a the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, 5-HT, receptor agonist. In another aspect the composition 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ 45 is that wherein the 5-HT2 receptor antagonist is also a indol, nisoxetine, talopram, talsupram, tandamine, Vilox 5-HT, receptor antagonist. In another aspect the composi azine, maprotiline, ciclazindol, manifaxine, radafaxine, tion is that wherein the 5-HT, receptor antagonist is also a tapentadol, teniloxazine, St. John’s wort, ginkgo biloba). 5-HT, receptor antagonist and a 5-HT, receptor agonist The current invention relates to combinations of a 5-HT (e.g., traZodone). In another aspect the composition is that receptor agonist, 5-HT2 receptor antagonist, 5-HT, recep 50 wherein the 5-HT2 receptor antagonist, 5-HT, receptor tor antagonist, a 5-HT, receptor agonist (e.g., lorcaserin, agonist, and/or 5-HT, receptor antagonist is also an alpha vabicaserin, PRX-00933, YM348, and metachlorophe adrenergic blocker (e.g., traZodone). In another aspect the nylpiperazine, mCPP) or combinations thereof (e.g., tra composition is that comprising traZodone, bupropion, and at Zodone, nefazodone, mirtazapine, flibanserin ketanserin, least one of the group consisting of atomoxetine, reboxetine, ritanserin, clozapine, olanzapine, quetiapine, risperidone, 55 amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, asenapine, MDL-100.907, cyproheptadine, aripiprazole, and lortalamine, mazindol, nisoxetine, talopram, talsupram, tan the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido damine, Viloxazine, maprotiline, ciclazindol, manifaxine, azepines). The current invention also relates to combinations radafaxine, tapentadol, teniloxazine, St. John's wort, and of a 5-HT, receptor agonist, 5-HT2 receptor antagonist, ginkgo biloba. In another aspect the composition is that 5-HT, receptor antagonist, a 5-HT2 receptor agonist (e.g., 60 comprising traZodone in a dosage range of 1-450 mg and lorcaserin, vabicaserin, PRX-00933, YM348, and metachlo bupropion in a dosage range of 1-450 mg. rophenylpiperazine, mCPP), or combinations thereof (e.g., In one aspect, the invention provides a composition traZodone, nefazodone, mirtazapine, flibanserin ketanserin, comprising a 5-HT, antagonist, a norepinephrine-dop ritanserin, clozapine, olanzapine, quetiapine, risperidone, amine reuptake inhibitor, a 5-HT2, agonist (e.g., lorcaserin, asenapine, MDL-100.907, cyproheptadine, aripiprazole, and 65 vabicaserin, PRX-00933, YM348, and metachlorophe the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido nylpiperazine, mCPP) and a pharmaceutically acceptable azepines), and/or a norepinephrine-dopamine reuptake carrier. In another aspect the composition is that wherein the US 9,517,254 B2 11 12 norepinephrine-dopamine reuptake inhibitor is also an alpha tion is that wherein the 5-HT2 receptor antagonist is also a adrenergic blocker (e.g., bupropion). In another aspect the 5-HT, receptor antagonist and a 5-HT, receptor agonist composition is that wherein the 5-HT, antagonist is also a (e.g., traZodone). In another aspect the composition is that 5-HT, receptor agonist. In another aspect the composition wherein the 5-HT2 receptor antagonist, 5-HT, receptor is that wherein the 5-HT2 receptor antagonist is also a agonist, and/or 5-HT, receptor antagonist is also an alpha 5-HT, receptor antagonist. In another aspect the composi adrenergic blocker (e.g., traZodone). In another aspect the tion is that wherein the 5-HT, receptor antagonist is also a composition is that comprising traZodone, bupropion, and 5-HT, receptor antagonist and a 5-HT, receptor agonist oxytocin (e.g., SyntocinonR). In another aspect the compo (e.g., traZodone). In another aspect the composition is that sition is that comprising traZodone in a dosage range of wherein the 5-HT2 receptor antagonist, 5-HT, receptor 10 1-450 mg, bupropion in a dosage range of 1-450 mg, and agonist, and/or 5-HT, receptor antagonist is also an alpha oxytocin in a dosage range of 4-400 International Units. adrenergic blocker (e.g., traZodone). In another aspect the In one aspect, the invention provides a composition composition is that comprising traZodone, bupropion, and comprising a 5-HT, antagonist, a norepinephrine-dop one or more 5-HT, agonists selected from the group amine reuptake inhibitor, other non-abusable agents (agents consisting of lorcaserin, vabicaserin, PRX-00933, YM348, 15 not scheduled by the DEA) that augment dopamine and/or and metachlorophenylpiperazine, and mCPP. In another norepinephrine in the brain, e.g., atomoxetine, reboxetine, aspect the composition is that comprising traZodone in a amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, dosage range of 1-450 mg and bupropion in a dosage range lortalamine, mazindol, nisoxetine, talopram, talsupram, tan of 1-450 mg. damine, Viloxazine, maprotiline, ciclazindol, manifaxine, In one aspect, the invention provides a composition radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo comprising a 5-HT, antagonist, a norepinephrine-dop biloba), and an oxytocin receptor (OXTR) agonist, and a amine reuptake inhibitor, a 5-HT2, agonist (e.g., lorcaserin, pharmaceutically acceptable carrier. In another aspect the vabicaserin, PRX-00933, YM348, and metachlorophe composition is that wherein the norepinephrine-dopamine nylpiperazine, mCPP), other non-abusable agents (agents reuptake inhibitor is also an alpha adrenergic blocker (e.g., not scheduled by the DEA) that augment dopamine and/or 25 bupropion). In another aspect the composition is that norepinephrine in the brain, e.g., atomoxetine, reboxetine, wherein the 5-HT, antagonist is also a 5-HT, receptor amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, agonist. In another aspect the composition is that wherein lortalamine, mazindol, nisoxetine, talopram, talsupram, tan the 5-HT, receptor antagonist is also a 5-HT, receptor damine, Viloxazine, maprotiline, ciclazindol, manifaxine, antagonist. In another aspect the composition is that wherein radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo 30 the 5-HT, receptor antagonist is also a 5-HT, receptor biloba), and a pharmaceutically acceptable carrier. In antagonist and a 5-HT, receptor agonist (e.g., traZodone). another aspect the composition is that wherein the norepi In another aspect the composition is that wherein the 5-HT, nephrine-dopamine reuptake inhibitor is also an alpha adren receptor antagonist, 5-HT, receptor agonist, and/or 5-HT, ergic blocker (e.g., bupropion). In another aspect the com receptor antagonist is also an alpha adrenergic blocker (e.g., position is that wherein the 5-HT, antagonist is also a 35 traZodone). In another aspect the composition is that com 5-HT, receptor agonist. In another aspect the composition prising traZodone; bupropion; at least one of the group is that wherein the 5-HT2 receptor antagonist is also a consisting of atomoxetine, reboxetine, amedalin, CP-39, 5-HT, receptor antagonist. In another aspect the composi 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ tion is that wherein the 5-HT2 receptor antagonist is also a indol, nisoxetine, talopram, talsupram, tandamine, Vilox 5-HT, receptor antagonist and a 5-HT, receptor agonist 40 azine, maprotiline, ciclazindol, manifaxine, radafaxine, (e.g., traZodone). In another aspect the composition is that tapentadol, teniloxazine, St. John’s wort, and ginkgo biloba; wherein the 5-HT, receptor antagonist, 5-HT, receptor and oxytocin (e.g., SyntocinonR). In another aspect the agonist, and/or 5-HT, receptor antagonist is also an alpha composition is that comprising traZodone in a dosage range adrenergic blocker (e.g., traZodone). In another aspect the of 1-450 mg, bupropion in a dosage range of 1-450 mg, and composition is that comprising traZodone; bupropion; one or 45 oxytocin in a dosage range of 4-400 International Units. more 5-HT2, agonists selected from the group consisting of In one aspect, the invention provides a composition lorcaserin, vabicaserin, PRX-00933, YM348, metachloro comprising a 5-HT, antagonist, a norepinephrine-dop phenylpiperazine, and mCPP, and at least one of the group amine reuptake inhibitor, a 5-HT2, agonist (e.g., lorcaserin, consisting of atomoxetine, reboxetine, amedalin, CP-39, vabicaserin, PRX-00933, YM348, and metachlorophe 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ 50 nylpiperazine, mCPP), an oxytocin receptor (OXTR) ago indol, nisoxetine, talopram, talsupram, tandamine, Vilox nist, and a pharmaceutically acceptable carrier. In another azine, maprotiline, ciclazindol, manifaxine, radafaxine, aspect the composition is that wherein the norepinephrine tapentadol, teniloxazine, St. John’s wort, and ginkgo biloba. dopamine reuptake inhibitor is also an alpha adrenergic In another aspect the composition is that comprising tra blocker (e.g., bupropion). In another aspect the composition Zodone in a dosage range of 1-450 mg and bupropion in a 55 is that wherein the 5-HT, antagonist is also a 5-HT dosage range of 1-450 mg. receptor agonist. In another aspect the composition is that In one aspect, the invention provides a composition wherein the 5-HT2 receptor antagonist is also a 5-HT, comprising a 5-HT, antagonist, a norepinephrine-dop receptor antagonist. In another aspect the composition is that amine reuptake inhibitor, and an oxytocin receptor (OXTR) wherein the 5-HT2 receptor antagonist is also a 5-HT, agonist, and a pharmaceutically acceptable carrier. In 60 receptor antagonist and a 5-HT, receptor agonist (e.g., another aspect the composition is that wherein the norepi traZodone). In another aspect the composition is that nephrine-dopamine reuptake inhibitor is also an alpha adren wherein the 5-HT2 receptor antagonist, 5-HT, receptor ergic blocker (e.g., bupropion). In another aspect the com agonist, and/or 5-HT, receptor antagonist is also an alpha position is that wherein the 5-HT, antagonist is also a adrenergic blocker (e.g., traZodone). In another aspect the 5-HT, receptor agonist. In another aspect the composition 65 composition is that comprising traZodone, bupropion, oxy is that wherein the 5-HT2 receptor antagonist is also a tocin (e.g., SyntocinonR), and one or more 5-HT2, agonists 5-HT, receptor antagonist. In another aspect the composi selected from the group consisting of lorcaserin, vabicaserin, US 9,517,254 B2 13 14 PRX-00933, YM348, metachlorophenylpiperazine, and norepinephrine in the brain, e.g., atomoxetine, reboxetine, mCPP. In another aspect the composition is that comprising amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, traZodone in a dosage range of 1-450 mg, bupropion in a lortalamine, mazindol, nisoxetine, talopram, talsupram, tan dosage range of 1-450 mg, and oxytocin in a dosage range damine, Viloxazine, maprotiline, ciclazindol, manifaxine, of 4-400 International Units. radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo In one aspect, the invention provides a composition biloba), and a pharmaceutically acceptable carrier. In comprising a 5-HT, antagonist, a norepinephrine-dop another aspect the composition is that wherein the 5-HT, amine reuptake inhibitor, a 5-HT2, agonist (e.g., lorcaserin, antagonist is also a 5-HT, receptor agonist. In another vabicaserin, PRX-00933, YM348, and metachlorophe aspect the composition is that wherein the 5-HT, receptor nylpiperazine, mCPP), other non-abusable agents (agents 10 antagonist is also a 5-HT, receptor agonist. In another not scheduled by the DEA) that augment dopamine and/or aspect the composition is that wherein the 5-HT2 receptor norepinephrine in the brain, e.g., atomoxetine, reboxetine, antagonist is also a 5-HT, receptor antagonist. In another amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, aspect the composition is that wherein the 5-HT2 receptor lortalamine, mazindol, nisoxetine, talopram, talsupram, tan antagonist is also a 5-HT, receptor antagonist and a 5-HT damine, Viloxazine, maprotiline, ciclazindol, manifaxine, 15 receptor agonist (e.g., traZodone). In another aspect the radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo composition is that wherein the 5-HT, receptor antagonist, biloba), an oxytocin receptor (OXTR) agonist, and a phar 5-HT, receptor agonist, and/or 5-HT, receptor antagonist maceutically acceptable carrier. In another aspect the com is also an alpha adrenergic blocker (e.g., traZodone). In position is that wherein the norepinephrine-dopamine another aspect the composition is that comprising traZodone; reuptake inhibitor is also an alpha adrenergic blocker (e.g., oxytocin, and at least one of the group consisting of atom bupropion). In another aspect the composition is that oxetine, reboxetine, amedalin, CP-39,332, daledalin, edi wherein the 5-HT, antagonist is also a 5-HT, receptor Voxetine, esreboxetine, lortalamine, mazindol, nisoxetine, agonist. In another aspect the composition is that wherein talopram, talsupram, tandamine, Viloxazine, maprotiline, the 5-HT2 receptor antagonist is also a 5-HT, receptor ciclazindol, manifaxine, radafaxine, tapentadol, tenilox antagonist. In another aspect the composition is that wherein 25 azine, St. John’s wort, and ginkgo biloba. In another aspect the 5-HT2 receptor antagonist is also a 5-HT, receptor the composition is that comprising traZodone in a dosage antagonist and a 5-HT, receptor agonist (e.g., traZodone). range of 25-450 mg and oxytocin in a dosage range of 4-400 In another aspect the composition is that wherein the 5-HT, International Units. receptor antagonist, 5-HT, receptoragonist, and/or 5-HT, In one aspect, the invention provides a composition receptor antagonist is also an alpha adrenergic blocker (e.g., 30 comprising a 5-HT, antagonist, an oxytocin receptor traZodone). In another aspect the composition is that com (OXTR) agonist, a 5-HT, agonist (e.g., lorcaserin, vabica prising trazodone; bupropion; oxytocin (e.g., Syntocinon(R): serin, PRX-00933, YM348, metachlorophenylpiperazine, one or more 5-HT, agonists selected from the group and mOPP) and a pharmaceutically acceptable carrier. In consisting of lorcaserin, vabicaserin, PRX-00933, YM348, another aspect the composition is that wherein the 5-HT metachlorophenylpiperazine, and mOPP; and at least one of 35 antagonist is also a 5-HT, receptor agonist. In another the group consisting of atomoxetine, reboxetine, amedalin, aspect the composition is that wherein the 5-HT2 receptor CP-39,332, daledalin, edivoxetine, esreboxetine, lortala antagonist is also a 5-HT, receptor agonist. In another mine, mazindol, nisoxetine, talopram, talsupram, tandamine, aspect the composition is that wherein the 5-HT2 receptor Viloxazine, maprotiline, ciclaZindol, manifaxine, radafaxine, antagonist is also a 5-HT, receptor antagonist. In another tapentadol, teniloxazine, St. John’s wort, and ginkgo biloba. 40 aspect the composition is that wherein the 5-HT, receptor In another aspect the composition is that comprising tra antagonist is also a 5-HT, receptor antagonist and a 5-HT Zodone in a dosage range of 1-450 mg, bupropion in a receptor agonist (e.g., traZodone). In another aspect the dosage range of 1-450 mg, and oxytocin in a dosage range composition is that wherein the 5-HT2 receptor antagonist, of 4-400 International Units. 5-HT, receptor agonist, and/or 5-HT, receptor antagonist In one aspect, the invention provides a composition 45 is also an alpha adrenergic blocker (e.g., traZodone). In comprising a 5-HT, antagonist, an oxytocin receptor another aspect the composition is that comprising traZodone; (OXTR) agonist, and a pharmaceutically acceptable carrier. oxytocin, and one or more 5-HT, agonists selected from In another aspect the composition is that wherein the 5-HT the group consisting of lorcaserin, vabicaserin, PRX-00933, antagonist is also a 5-HT, receptor agonist. In another YM348, metachlorophenylpiperazine, and mOPP. In another aspect the composition is that wherein the 5-HT2 receptor 50 aspect the composition is that comprising traZodone in a antagonist is also a 5-HT, receptor agonist. In another dosage range of 25-450 mg and oxytocin in a dosage range aspect the composition is that wherein the 5-HT2 receptor of 4-400 International Units. antagonist is also a 5-HT, receptor antagonist. In another In one aspect, the invention provides a composition aspect the composition is that wherein the 5-HT, receptor comprising a 5-HT, antagonist, an oxytocin receptor antagonist is also a 5-HT2 receptor antagonist and a 5-HT 55 (OXTR) agonist, a 5-HT, agonist (e.g., lorcaserin, vabica receptor agonist (e.g., traZodone). In another aspect the serin, PRX-00933, YM348, metachlorophenylpiperazine, composition is that wherein the 5-HT2 receptor antagonist, and mOPP), other non-abusable agents (agents not sched 5-HT, receptor agonist, and/or 5-HT, receptor antagonist uled by the DEA) that augment dopamine and/or norepi is also an alpha adrenergic blocker (e.g., traZodone). In nephrine in the brain, e.g., atomoxetine, reboxetine, ameda another aspect the composition is that comprising traZodone 60 lin, CP-39,332, daledalin, edivoxetine, esreboxetine, and oxytocin. In another aspect the composition is that lortalamine, mazindol, nisoxetine, talopram, talsupram, tan comprising traZodone in a dosage range of 25-450 mg and damine, Viloxazine, maprotiline, ciclazindol, manifaxine, oxytocin in a dosage range of 4-400 International Units. radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo In one aspect, the invention provides a composition biloba), and a pharmaceutically acceptable carrier. In comprising a 5-HT, antagonist, an oxytocin receptor 65 another aspect the composition is that wherein the 5-HT (OXTR) agonist, other non-abusable agents (agents not antagonist is also a 5-HT, receptor agonist. In another scheduled by the DEA) that augment dopamine and/or aspect the composition is that wherein the 5-HT2 receptor US 9,517,254 B2 15 16 antagonist is also a 5-HT, receptor agonist. In another comprising bupropion in a dosage range of 25-450 mg and aspect the composition is that wherein the 5-HT, receptor oxytocin in a dosage range of 4-400 International Units. antagonist is also a 5-HT, receptor antagonist. In another In one aspect, the invention provides a composition aspect the composition is that wherein the 5-HT2 receptor comprising a norepinephrine-dopamine reuptake inhibitor, antagonist is also a 5-HT2 receptor antagonist and a 5-HT an oxytocin receptor (OXTR) agonist, a 5-HT2, agonist receptor agonist (e.g., traZodone). In another aspect the (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, composition is that wherein the 5-HT, receptor antagonist, metachlorophenylpiperazine, and mOPP), other non-abus 5-HT, receptor agonist, and/or 5-HT, receptor antagonist able agents (agents not scheduled by the DEA) that augment is also an alpha adrenergic blocker (e.g., traZodone). In dopamine and/or norepinephrine in the brain, e.g., atomox another aspect the composition is that comprising traZodone; 10 etine, reboxetine, amedalin, CP-39,332, daledalin, edivox oxytocin, one or more 5-HT, agonists selected from the etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo group consisting of lorcaserin, vabicaserin, PRX-00933, pram, talsupram, tandamine, Viloxazine, maprotiline, YM348, metachlorophenylpiperazine, and mCPP, and at ciclazindol, manifaxine, radafaxine, tapentadol, tenilox least one of the group consisting of atomoxetine, reboxetine, azine, St. John’s wort, ginkgo biloba), and a pharmaceuti amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, 15 cally acceptable carrier. In another aspect the composition is lortalamine, mazindol, nisoxetine, talopram, talsupram, tan that comprising bupropion; oxytocin, one or more 5-HT, damine, Viloxazine, maprotiline, ciclazindol, manifaxine, agonists selected from the group consisting of lorcaserin, radafaxine, tapentadol, teniloxazine, St. John's wort, and vabicaserin, PRX-00933, YM348, metachlorophenylpipera ginkgo biloba. In another aspect the composition is that Zine, and mCPP, and at least one of the group consisting of comprising traZodone in a dosage range of 25-450 mg and atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, oxytocin in a dosage range of 4-400 International Units. edivoxetine, esreboxetine, lortalamine, mazindol, nisox In one aspect, the invention provides a composition etine, talopram, talsupram, tandamine, Viloxazine, maproti comprising a norepinephrine-dopamine reuptake inhibitor, line, ciclaZindol, manifaxine, radafaxine, tapentadol, an oxytocin receptor (OXTR) agonist, and a pharmaceuti teniloxazine, St. John's wort, and ginkgo biloba. In another cally acceptable carrier. In another aspect the composition is 25 aspect the composition is that comprising bupropion in a that comprising bupropion and oxytocin. In another aspect dosage range of 200-450 mg and oxytocin in a dosage range the composition is that comprising bupropion in a dosage of 4-400 International Units. In another aspect the compo range of 200-450 mg and oxytocin in a dosage range of sition is that comprising bupropion in a dosage range of 4-400 International Units. In another aspect the composition 25-450 mg and oxytocin in a dosage range of 4-400 Inter is that comprising bupropion in a dosage range of 25-450 mg 30 national Units. and oxytocin in a dosage range of 4-400 International Units. In one aspect, the invention provides a composition In one aspect, the invention provides a composition comprising an oxytocin receptor (OXTR) agonist and a comprising a norepinephrine-dopamine reuptake inhibitor, pharmaceutically acceptable carrier. In another aspect the an oxytocin receptor (OXTR) agonist, other non-abusable composition is that comprising oxytocin. In another aspect agents (agents not scheduled by the DEA) that augment 35 the composition is that comprising oxytocin in a dosage dopamine and/or norepinephrine in the brain, e.g., atomox range of 4-400 International Units. etine, reboxetine, amedalin, CP-39,332, daledalin, edivox In one aspect, the invention provides a composition etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo comprising an oxytocin receptor (OXTR) agonist, other pram, talsupram, tandamine, Viloxazine, maprotiline, non-abusable agents (agents not scheduled by the DEA) that ciclazindol, manifaxine, radafaxine, tapentadol, tenilox 40 augment dopamine and/or norepinephrine in the brain, e.g., azine, St. John’s wort, ginkgo biloba), and a pharmaceuti atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, cally acceptable carrier. In another aspect the composition is edivoxetine, esreboxetine, lortalamine, mazindol, nisox that comprising bupropion; oxytocin, and at least one of the etine, talopram, talsupram, tandamine, Viloxazine, maproti group consisting of atomoxetine, reboxetine, amedalin, line, ciclaZindol, manifaxine, radafaxine, tapentadol, CP-39,332, daledalin, edivoxetine, esreboxetine, lortala 45 teniloxazine, St. John’s wort, ginkgo biloba), and a phar mine, mazindol, nisoxetine, talopram, talsupram, tandamine, maceutically acceptable carrier. In another aspect the com Viloxazine, maprotiline, ciclaZindol, manifaxine, radafaxine, position is that comprising oxytocin and at least one of the tapentadol, teniloxazine, St. John’s wort, and ginkgo biloba. group consisting of atomoxetine, reboxetine, amedalin, In another aspect the composition is that comprising bupro CP-39,332, daledalin, edivoxetine, esreboxetine, lortala pion in a dosage range of 200-450 mg and oxytocin in a 50 mine, mazindol, nisoxetine, talopram, talsupram, tandamine, dosage range of 4-400 International Units. In another aspect Viloxazine, maprotiline, ciclazindol, manifaxine, radafaxine, the composition is that comprising bupropion in a dosage tapentadol, teniloxazine, St. John’s wort, and ginkgo biloba. range of 25-450 mg and oxytocin in a dosage range of 4-400 In another aspect the composition is that comprising oxy International Units. tocin in a dosage range of 4-400 International Units. In one aspect, the invention provides a composition 55 In one aspect, the invention provides a composition comprising a norepinephrine-dopamine reuptake inhibitor, comprising an oxytocin receptor (OXTR) agonist, a 5-HT, an oxytocin receptor (OXTR) agonist, a 5-HT2, agonist agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, metachlorophenylpiperazine, and mCPP), and a pharmaceu metachlorophenylpiperazine, and mCPP), and a pharmaceu tically acceptable carrier. In another aspect the composition tically acceptable carrier. In another aspect the composition 60 is that comprising oxytocin and one or more 5-HT ago is that comprising bupropion; oxytocin, and one or more nists selected from the group consisting of lorcaserin, vabi 5-HT, agonists selected from the group consisting of caserin, PRX-00933, YM348, metachlorophenylpiperazine, lorcaserin, vabicaserin, PRX-00933, YM348, metachloro and mOPP. In another aspect the composition is that com phenylpiperazine, and mCPP. In another aspect the compo prising oxytocin in a dosage range of 4-400 International sition is that comprising bupropion in a dosage range of 65 Units. 200-450 mg and oxytocin in a dosage range of 4-400 In one aspect, the invention provides a composition International Units. In another aspect the composition is that comprising an oxytocin receptor (OXTR) agonist, a 5-HT, US 9,517,254 B2 17 18 agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, norepinephrine in the brain, e.g., atomoxetine, reboxetine, metachlorophenylpiperazine, and mOPP), other non-abus amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, able agents (agents not scheduled by the DEA) that augment lortalamine, mazindol, nisoxetine, talopram, talsupram, tan dopamine and/or norepinephrine in the brain, e.g., atomox damine, Viloxazine, maprotiline, ciclazindol, manifaxine, etine, reboxetine, amedalin, CP-39,332, daledalin, edivox radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo biloba), and a pharmaceutically acceptable carrier. In pram, talsupram, tandamine, Viloxazine, maprotiline, another aspect the composition is that wherein the norepi ciclazindol, manifaxine, radafaxine, tapentadol, tenilox nephrine-dopamine reuptake inhibitor is also an alpha adren azine, St. John’s wort, ginkgo biloba), and a pharmaceuti ergic blocker (e.g., bupropion). In another aspect the com cally acceptable carrier. In another aspect the composition is 10 that comprising oxytocin, one or more 5-HT2, agonists position is that wherein the 5-HT, antagonist is also a selected from the group consisting of lorcaserin, vabicaserin, 5-HT, receptor agonist. In another aspect the composition PRX-00933, YM348, metachlorophenylpiperazine, and is that wherein the 5-HT2 receptor antagonist is also a mCPP, and at least one of the group consisting of atomox 5-HT, receptor antagonist. In another aspect the composi etine, reboxetine, amedalin, CP-39,332, daledalin, edivox 15 tion is that wherein the 5-HT, receptor antagonist is also a etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo 5-HT, receptor antagonist and a 5-HT, receptor agonist pram, talsupram, tandamine, Viloxazine, maprotiline, (e.g., traZodone). In another aspect the composition is that ciclazindol, manifaxine, radafaxine, tapentadol, tenilox wherein the 5-HT, receptor antagonist, 5-HT, receptor azine, St. John’s wort, and ginkgo biloba. In another aspect agonist, and/or 5-HT, receptor antagonist is also an alpha the composition is that comprising oxytocin in a dosage adrenergic blocker (e.g., traZodone). range of 4-400 International Units. In one aspect, the invention provides a method of treating In one embodiment, the composition is that comprising a Subject Suffering from or Susceptible to a sexual disorder bupropion, comprising bupropion in a dosage range of comprising administering to a Subject in need thereof a 200-450 mg; comprising bupropion in a dosage range of therapeutically effective amount of a composition compris 225-300 mg; or comprising bupropion in a dosage range of 25 ing a 5-HT, antagonist, a norepinephrine-dopamine 200-275 mg; comprising bupropion in a dosage range of reuptake inhibitor, a 5-HT2, agonist (e.g., lorcaserin, vabi 100-450 mg; comprising bupropion in a dosage range of caserin, PRX-00933, YM348, metachlorophenylpiperazine, 100-275 mg; comprising bupropion in a dosage range of and mOPP), and a pharmaceutically acceptable carrier. In 25-275 mg, comprising bupropion in a dosage range of another aspect the composition is that wherein the norepi XX-YY mg, wherein XX is an integer between 5 and 400 30 nephrine-dopamine reuptake inhibitor is also an alpha adren and YY is an integer between 50 and 450. ergic blocker (e.g., bupropion). In another aspect the com In one embodiment, the composition is that comprising position is that wherein the 5-HT, antagonist is also a traZodone, comprising traZodone in a dosage range of 5-HT, receptor agonist. In another aspect the composition 25-450 mg; comprising traZodone in a dosage range of is that wherein the 5-HT2 receptor antagonist is also a 75-150 mg; or comprising traZodone in a dosage range of 35 5-HT, receptor antagonist. In another aspect the composi 50-100 mg; comprising traZodone in a dosage range of tion is that wherein the 5-HT2 receptor antagonist is also a XX-YY mg, wherein XX is an integer between 25 and 400 5-HT, receptor antagonist and a 5-HT, receptor agonist and YY is an integer between 50 and 450. (e.g., traZodone). In another aspect the composition is that In one embodiment, the composition is that comprising wherein the 5-HT2 receptor antagonist, 5-HT, receptor oxytocin, comprising oxytocin in a dosage range of 4-400 40 agonist, and/or 5-HT, receptor antagonist is also an alpha International Units. adrenergic blocker (e.g., traZodone). In one aspect, the invention provides a method of treating In one aspect, the invention provides a method of treating a Subject Suffering from or Susceptible to a sexual disorder a Subject Suffering from or Susceptible to a sexual disorder comprising administering to a subject in need thereof a comprising administering to a Subject in need thereof a therapeutically effective amount of a composition compris 45 therapeutically effective amount of a composition compris ing a 5-HT, antagonist, a norepinephrine-dopamine ing a 5-HT, antagonist, a norepinephrine-dopamine reuptake inhibitor, and a pharmaceutically acceptable car reuptake inhibitor, a 5-HT, agonist (e.g., lorcaserin, vabi rier. In another aspect the composition is that wherein the caserin, PRX-00933, YM348, metachlorophenylpiperazine, norepinephrine-dopamine reuptake inhibitor is also an alpha and mOPP), other non-abusable agents (agents not sched adrenergic blocker (e.g., bupropion). In another aspect the 50 uled by the DEA) that augment dopamine and/or norepi composition is that wherein the 5-HT, antagonist is also a nephrine in the brain, e.g., atomoxetine, reboxetine, ameda 5-HT, receptor agonist. In another aspect the composition lin, CP-39,332, daledalin, edivoxetine, esreboxetine, is that wherein the 5-HT2 receptor antagonist is also a lortalamine, mazindol, nisoxetine, talopram, talsupram, tan 5-HT, receptor antagonist. In another aspect the composi damine, Viloxazine, maprotiline, ciclazindol, manifaxine, tion is that wherein the 5-HT2 receptor antagonist is also a 55 radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo 5-HT, receptor antagonist and a 5-HT, receptor agonist biloba), and a pharmaceutically acceptable carrier. In (e.g., traZodone). In another aspect the composition is that another aspect the composition is that wherein the norepi wherein the 5-HT2 receptor antagonist, 5-HT, receptor nephrine-dopamine reuptake inhibitor is also an alpha adren agonist, and/or 5-HT, receptor antagonist is also an alpha ergic blocker (e.g., bupropion). In another aspect the com adrenergic blocker (e.g., traZodone). 60 position is that wherein the 5-HT, antagonist is also a In one aspect, the invention provides a method of treating 5-HT, receptor agonist. In another aspect the composition a Subject Suffering from or Susceptible to a sexual disorder is that wherein the 5-HT2 receptor antagonist is also a comprising administering to a subject in need thereof a 5-HT, receptor antagonist. In another aspect the composi therapeutically effective amount of a composition compris tion is that wherein the 5-HT2 receptor antagonist is also a ing a 5-HT, antagonist, a norepinephrine-dopamine 65 5-HT, receptor antagonist and a 5-HT, receptor agonist reuptake inhibitor, other non-abusable agents (agents not (e.g., traZodone). In another aspect the composition is that scheduled by the DEA) that augment dopamine and/or wherein the 5-HT2 receptor antagonist, 5-HT, receptor US 9,517,254 B2 19 20 agonist, and/or 5-HT, receptor antagonist is also an alpha In another aspect the composition is that wherein the 5-HT adrenergic blocker (e.g., traZodone). receptor antagonist is also a 5-HT, receptor antagonist and In one aspect, the invention provides a method of treating a 5-HT, receptor agonist. (e.g., traZodone) In another a Subject Suffering from or Susceptible to a sexual disorder aspect, the norepinephrine-dopamine reuptake inhibitor is comprising administering to a subject in need thereof a also an alpha adrenergic blocker (e.g., bupropion). In therapeutically effective amount of a composition compris another aspect, the alpha adrenergic blocker is also a 5-HT ing a 5-HT, antagonist, a norepinephrine-dopamine antagonist, a 5-HT, receptor agonist, and/or 5-HT, recep reuptake inhibitor, an oxytocin receptor (OXTR) agonist tor antagonist (e.g., traZodone). (e.g., carbetocin, oxytocin, Syntocinon R.), and a pharma In one aspect, the invention provides a method of treating ceutically acceptable carrier. In one aspect, one compound is 10 a Subject Suffering from or Susceptible to a sexual disorder both a 5-HT, antagonist and a 5-HT, receptor agonist comprising administering to a Subject in need thereof a (e.g., traZodone, nefazodone, mirtazapine, flibanserin). In therapeutically effective amount of a composition compris another aspect the composition is that wherein the 5-HT ing a 5-HT, antagonist, a norepinephrine-dopamine antagonist is also a 5-HT, receptor antagonist. In another reuptake inhibitor, an oxytocin receptor (OXTR) agonist aspect the composition is that wherein the 5-HT2 receptor 15 (e.g., carbetocin, oxytocin, Syntocinon R.), a 5-HT2, agonist antagonist is also a 5-HT, receptor antagonist and a 5-HT (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, receptor agonist. (e.g., traZodone) In another aspect, the metachlorophenylpiperazine, and mCPP), and a pharmaceu norepinephrine-dopamine reuptake inhibitor is also an alpha tically acceptable carrier. In one aspect, one compound is adrenergic blocker (e.g., bupropion). In another aspect, the both a 5-HT, antagonist and a 5-HT, receptor agonist alpha adrenergic blocker is also a 5-HT, antagonist, a (e.g., traZodone, nefazodone, mirtazapine, flibanserin, 5-HT, receptor agonist, and/or 5-HT, receptor antagonist ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris (e.g., traZodone). peridone, asenapine, MDL-100.907, cyproheptadine, arip In one aspect, the invention provides a method of treating iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro a Subject Suffering from or Susceptible to a sexual disorder pyrimido-azepines). In another aspect the composition is comprising administering to a subject in need thereof a 25 that wherein the 5-HT, antagonist is also a 5-HT, receptor therapeutically effective amount of a composition compris antagonist. In another aspect the composition is that wherein ing a 5-HT, antagonist, a norepinephrine-dopamine the 5-HT2 receptor antagonist is also a 5-HT, receptor reuptake inhibitor, an oxytocin receptor (OXTR) agonist antagonist and a 5-HT, receptor agonist. (e.g., trazodone) (e.g., carbetocin, oxytocin, Syntocinon R.), and a pharma In another aspect, the norepinephrine-dopamine reuptake ceutically acceptable carrier. In one aspect, one compound is 30 inhibitor is also an alpha adrenergic blocker (e.g., bupro both a 5-HT, antagonist and a 5-HT, receptor agonist pion). In another aspect, the alpha adrenergic blocker is also (e.g., trazodone, nefazodone, mirtazapine, flibanserin, a 5-HT, antagonist, a 5-HT, receptor agonist, and/or ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris 5-HT, receptor antagonist (e.g., trazodone). peridone, asenapine, MDL-100.907, cyproheptadine, arip In one aspect, the invention provides a method of treating iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro 35 a Subject Suffering from or Susceptible to a sexual disorder pyrimido-azepines). In another aspect the composition is comprising administering to a Subject in need thereof a that wherein the 5-HT, antagonist is also a 5-HT, receptor therapeutically effective amount of a composition compris antagonist. In another aspect the composition is that wherein ing a 5-HT, antagonist, a norepinephrine-dopamine the 5-HT2 receptor antagonist is also a 5-HT, receptor reuptake inhibitor, an oxytocin receptor (OXTR) agonist antagonist and a 5-HT, receptor agonist. (e.g., trazodone) 40 (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, agonist In another aspect, the norepinephrine-dopamine reuptake (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, inhibitor is also an alpha adrenergic blocker (e.g., bupro metachlorophenylpiperazine, and mOPP), other non-abus pion). In another aspect, the alpha adrenergic blocker is also able agents (agents not scheduled by the DEA) that augment a 5-HT, antagonist, a 5-HT, receptor agonist, and/or dopamine and/or norepinephrine in the brain, e.g., atomox 5-HT, receptor antagonist (e.g., traZodone). 45 etine, reboxetine, amedalin, CP-39,332, daledalin, edivox In one aspect, the invention provides a method of treating etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo a Subject Suffering from or Susceptible to a sexual disorder pram, talsupram, tandamine, Viloxazine, maprotiline, comprising administering to a subject in need thereof a ciclazindol, manifaxine, radafaxine, tapentadol, tenilox therapeutically effective amount of a composition compris azine, St. John’s wort, ginkgo biloba), and a pharmaceuti ing a 5-HT, antagonist, a norepinephrine-dopamine 50 cally acceptable carrier. In one aspect, one compound is both reuptake inhibitor, an oxytocin receptor (OXTR) agonist a 5-HT, antagonist and a 5-HT, receptor agonist (e.g., (e.g., carbetocin, oxytocin, Syntocinon R.), other non-abus traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, able agents (agents not scheduled by the DEA) that augment ritanserin, clozapine, olanzapine, quetiapine, risperidone, dopamine and/or norepinephrine in the brain, e.g., atomox asenapine, MDL-100.907, cyproheptadine, aripiprazole, and etine, reboxetine, amedalin, CP-39,332, daledalin, edivox 55 the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo azepines). In another aspect the composition is that wherein pram, talsupram, tandamine, Viloxazine, maprotiline, the 5-HT2, antagonist is also a 5-HT, receptor antagonist. ciclazindol, manifaxine, radafaxine, tapentadol, tenilox In another aspect the composition is that wherein the 5-HT azine, St. John’s wort, ginkgo biloba), and a pharmaceuti receptor antagonist is also a 5-HT, receptor antagonist and cally acceptable carrier. In one aspect, one compound is both 60 a 5-HT, receptor agonist. (e.g., traZodone) In another a 5-HT, antagonist and a 5-HT, receptor agonist (e.g., aspect, the norepinephrine-dopamine reuptake inhibitor is traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, also an alpha adrenergic blocker (e.g., bupropion). In ritanserin, clozapine, olanzapine, quetiapine, risperidone, another aspect, the alpha adrenergic blocker is also a 5-HT, asenapine, MDL-100.907, cyproheptadine, aripiprazole, and antagonist, a 5-HT, receptor agonist, and/or 5-HT, recep the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido 65 tor antagonist (e.g., traZodone). azepines). In another aspect the composition is that wherein In one aspect, the invention provides a method of treating the 5-HT2, antagonist is also a 5-HT, receptor antagonist. a Subject Suffering from or Susceptible to a sexual disorder US 9,517,254 B2 21 22 comprising administering to a subject in need thereof a In one aspect, the invention provides a method of treating therapeutically effective amount of a composition compris a Subject Suffering from or Susceptible to a sexual disorder ing a 5-HT, receptor agonist, a 5-HT, antagonist, and a comprising administering to a Subject in need thereof a pharmaceutically acceptable carrier. In one aspect, one com therapeutically effective amount of a composition compris pound is the 5-HT, receptoragonist and the 5-HT, antago ing a 5-HT, receptor agonist, a 5-HT, antagonist, a nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin). 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, In another aspect the composition is that wherein the 5-HT, YM348, metachlorophenylpiperazine, and mOPP), and a receptor antagonist is also a 5-HT, receptor agonist. In pharmaceutically acceptable carrier. In one aspect, one com another aspect the composition is that wherein the 5-HT pound is the 5-HT, receptoragonist and the 5-HT, antago antagonist is also a 5-HT, receptor antagonist. In another 10 nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, aspect the composition is that wherein the 5-HT2 receptor ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris antagonist is also a 5-HT2 receptor antagonist and a 5-HT peridone, asenapine, MDL-100.907, cyproheptadine, arip receptor agonist (e.g., traZodone). In another aspect the iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro composition is that wherein the 5-HT, antagonist, 5-HT pyrimido-azepines). In another aspect the composition is receptor agonist, and/or 5-HT, receptor antagonist is also 15 that wherein the 5-HT2 receptor antagonist is also a 5-HT an alpha adrenergic blocker (e.g., traZodone). receptor agonist. In another aspect the composition is that In one aspect, the invention provides a method of treating wherein the 5-HT, antagonist is also a 5-HT, receptor a Subject Suffering from or Susceptible to a sexual disorder antagonist. In another aspect the composition is that wherein comprising administering to a subject in need thereof a the 5-HT2 receptor antagonist is also a 5-HT, receptor therapeutically effective amount of a composition compris antagonist and a 5-HT, receptor agonist (e.g., traZodone). ing a 5-HT, receptor agonist, a 5-HT, antagonist, and a In another aspect the composition is that wherein the 5-HT, pharmaceutically acceptable carrier. In one aspect, one com antagonist, 5-HT, receptoragonist, and/or 5-HT, receptor pound is the 5-HT, receptoragonist and the 5-HT, antago antagonist is also an alpha adrenergic blocker (e.g., tra nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, Zodone). ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris 25 In one aspect, the invention provides a method of treating peridone, asenapine, MDL-100.907, cyproheptadine, arip a Subject Suffering from or Susceptible to a sexual disorder iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro comprising administering to a Subject in need thereof a pyrimido-azepines). In another aspect the composition is therapeutically effective amount of a composition compris that wherein the 5-HT2 receptor antagonist is also a 5-HT ing a 5-HT, receptor agonist, a 5-HT, antagonist, a receptor agonist. In another aspect the composition is that 30 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, wherein the 5-HT, antagonist is also a 5-HT, receptor YM348, metachlorophenylpiperazine, and mCPP), other antagonist. In another aspect the composition is that wherein non-abusable agents (agents not scheduled by the DEA) that the 5-HT, receptor antagonist is also a 5-HT, receptor augment dopamine and/or norepinephrine in the brain, e.g., antagonist and a 5-HT, receptor agonist (e.g., traZodone). atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, In another aspect the composition is that wherein the 35 edivoxetine, esreboxetine, lortalamine, mazindol, nisox 5-HTantagonist, 5-HT, receptor agonist, and/or 5-HT, etine, talopram, talsupram, tandamine, Viloxazine, maproti receptor antagonist is also an alpha adrenergic blocker (e.g., line, ciclaZindol, manifaxine, radafaxine, tapentadol, traZodone). teniloxazine, St. John’s wort, ginkgo biloba), and a phar In one aspect, the invention provides a method of treating maceutically acceptable carrier. In one aspect, one com a Subject Suffering from or Susceptible to a sexual disorder 40 pound is the 5-HT, receptoragonist and the 5-HT, antago comprising administering to a subject in need thereof a nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, therapeutically effective amount of a composition compris ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris ing a 5-HT, receptor agonist, a 5-HT, antagonist, other peridone, asenapine, MDL-100.907, cyproheptadine, arip non-abusable agents (agents not scheduled by the DEA) that iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro augment dopamine and/or norepinephrine in the brain, e.g., 45 pyrimido-azepines). In another aspect the composition is atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, that wherein the 5-HT2 receptor antagonist is also a 5-HT edivoxetine, esreboxetine, lortalamine, mazindol, nisox receptor agonist. In another aspect the composition is that etine, talopram, talsupram, tandamine, Viloxazine, maproti wherein the 5-HT, antagonist is also a 5-HT, receptor line, ciclaZindol, manifaxine, radafaxine, tapentadol, antagonist. In another aspect the composition is that wherein teniloxazine, St. John’s wort, ginkgo biloba), and a phar 50 the 5-HT2 receptor antagonist is also a 5-HT, receptor maceutically acceptable carrier. In one aspect, one com antagonist and a 5-HT, receptor agonist (e.g., traZodone). pound is the 5-HT, receptoragonist and the 5-HT, antago In another aspect the composition is that wherein the 5-HT nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, antagonist, 5-HT, receptoragonist, and/or 5-HT, receptor ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris antagonist is also an alpha adrenergic blocker (e.g., tra peridone, asenapine, MDL-100.907, cyproheptadine, arip 55 Zodone). iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro In one aspect, the invention provides a method of treating pyrimido-azepines). In another aspect the composition is a Subject Suffering from or Susceptible to a sexual disorder that wherein the 5-HT2 receptor antagonist is also a 5-HT comprising administering to a Subject in need thereof a receptor agonist. In another aspect the composition is that therapeutically effective amount of a composition compris wherein the 5-HT, antagonist is also a 5-HT, receptor 60 ing a 5-HT, receptor agonist, a 5-HT, antagonist, an antagonist. In another aspect the composition is that wherein oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto the 5-HT2 receptor antagonist is also a 5-HT, receptor cin, SyntocinonR), and a pharmaceutically acceptable car antagonist and a 5-HT, receptor agonist (e.g., trazodone). rier. In one aspect, one compound is the 5-HT, receptor In another aspect the composition is that wherein the 5-HT agonist and the 5-HT, antagonist (e.g., traZodone, nefa antagonist, 5-HT, receptoragonist, and/or 5-HT, receptor 65 Zodone, mirtazapine, flibanserin). In another aspect the antagonist is also an alpha adrenergic blocker (e.g., tra composition is that wherein the 5-HT, receptor antagonist Zodone). is also a 5-HT, receptor agonist. In another aspect the US 9,517,254 B2 23 24 composition is that wherein the 5-HT, antagonist is also a cin, Syntocinon R.), a 5-HT, agonist (e.g., lorcaserin, vabi 5-HT, receptor antagonist. In another aspect the composi caserin, PRX-00933, YM348, metachlorophenylpiperazine, tion is that wherein the 5-HT2 receptor antagonist is also a and mOPP), and a pharmaceutically acceptable carrier. In 5-HT, receptor antagonist and a 5-HT, receptor agonist one aspect, one compound is the 5-HT, receptor agonist (e.g., traZodone). In another aspect the composition is that and the 5-HT, antagonist (e.g., traZodone, nefazodone, wherein the 5-HT2 receptor antagonist, 5-HT, receptor mirtazapine, flibanserin, ketanserin, ritanserin, clozapine, agonist, and/or 5-HT, receptor antagonist is also an alpha olanzapine, quetiapine, risperidone, asenapine, MDL-100, adrenergic blocker (e.g., traZodone). 907, cyproheptadine, aripiprazole, and the general class of In one aspect, the invention provides a method of treating 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another a Subject Suffering from or Susceptible to a sexual disorder 10 aspect the composition is that wherein the 5-HT2 receptor comprising administering to a subject in need thereof a antagonist is also a 5-HT, receptor agonist. In another therapeutically effective amount of a composition compris aspect the composition is that wherein the 5-HT, antagonist ing a 5-HT, receptor agonist, a 5-HT, antagonist, an is also a 5-HT, receptor antagonist. In another aspect the oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto composition is that wherein the 5-HT, receptor antagonist cin, SyntocinonR), and a pharmaceutically acceptable car 15 is also a 5-HT, receptor antagonist and a 5-HT, receptor rier. In one aspect, one compound is the 5-HT, receptor agonist (e.g., traZodone). In another aspect the composition agonist and the 5-HT, antagonist (e.g., traZodone, nefa is that wherein the 5-HT2 receptor antagonist, 5-HT Zodone, mirtazapine, flibanserin, ketanserin, ritanserin, clo receptor agonist, and/or 5-HT, receptor antagonist is also Zapine, olanzapine, quetiapine, risperidone, asenapine, an alpha adrenergic blocker (e.g., traZodone). MDL-100.907, cyproheptadine, aripiprazole, and the gen In one aspect, the invention provides a method of treating eral class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). a Subject Suffering from or Susceptible to a sexual disorder In another aspect the composition is that wherein the 5-HT comprising administering to a Subject in need thereof a receptor antagonist is also a 5-HT, receptor agonist. In therapeutically effective amount of a composition compris another aspect the composition is that wherein the 5-HT ing a 5-HT, receptor agonist, a 5-HT, antagonist, an antagonist is also a 5-HT, receptor antagonist. In another 25 oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto aspect the composition is that wherein the 5-HT2 receptor cin, Syntocinon R.), a 5-HT, agonist (e.g., lorcaserin, vabi antagonist is also a 5-HT2 receptor antagonist and a 5-HT caserin, PRX-00933, YM348, metachlorophenylpiperazine, receptor agonist (e.g., traZodone). In another aspect the and mOPP), other non-abusable agents (agents not sched composition is that wherein the 5-HT2 receptor antagonist, uled by the DEA) that augment dopamine and/or norepi 5-HT, receptor agonist, and/or 5-HT, receptor antagonist 30 nephrine in the brain, e.g., atomoxetine, reboxetine, ameda is also an alpha adrenergic blocker (e.g., traZodone). lin, CP-39,332, daledalin, edivoxetine, esreboxetine, In one aspect, the invention provides a method of treating lortalamine, mazindol, nisoxetine, talopram, talsupram, tan a Subject Suffering from or Susceptible to a sexual disorder damine, Viloxazine, maprotiline, ciclazindol, manifaxine, comprising administering to a subject in need thereof a radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo therapeutically effective amount of a composition compris 35 biloba), and a pharmaceutically acceptable carrier. In one ing a 5-HT, receptor agonist, a 5-HT, antagonist, an aspect, one compound is the 5-HT, receptoragonist and the oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto 5-HT, antagonist (e.g., traZodone, nefazodone, mirtazap cin, Syntocinon R.), other non-abusable agents (agents not ine, flibanserin, ketanserin, ritanserin, clozapine, olanzapine, scheduled by the DEA) that augment dopamine and/or quetiapine, risperidone, asenapine, MDL-100.907, cypro norepinephrine in the brain, e.g., atomoxetine, reboxetine, 40 heptadine, aripiprazole, and the general class of 2-alkyl-4- amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, aryl-tetrahydro-pyrimido-azepines). In another aspect the lortalamine, mazindol, nisoxetine, talopram, talsupram, tan composition is that wherein the 5-HT, receptor antagonist damine, Viloxazine, maprotiline, ciclazindol, manifaxine, is also a 5-HT, receptor agonist. In another aspect the radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo composition is that wherein the 5-HT, antagonist is also a biloba), and a pharmaceutically acceptable carrier. In one 45 5-HT, receptor antagonist. In another aspect the composi aspect, one compound is the 5-HT, receptoragonist and the tion is that wherein the 5-HT2 receptor antagonist is also a 5-HT, antagonist (e.g., trazodone, nefazodone, mirtazap 5-HT, receptor antagonist and a 5-HT, receptor agonist ine, flibanserin, ketanserin, ritanserin, clozapine, olanzapine, (e.g., traZodone). In another aspect the composition is that quetiapine, risperidone, asenapine, MDL-100.907, cypro wherein the 5-HT, receptor antagonist, 5-HT, receptor heptadine, aripiprazole, and the general class of 2-alkyl-4- 50 agonist, and/or 5-HT, receptor antagonist is also an alpha aryl-tetrahydro-pyrimido-azepines). In another aspect the adrenergic blocker (e.g., traZodone). composition is that wherein the 5-HT, receptor antagonist In one aspect, the invention provides a method of treating is also a 5-HT, receptor agonist. In another aspect the a Subject Suffering from or Susceptible to a sexual disorder composition is that wherein the 5-HT, antagonist is also a comprising administering to a Subject in need thereof a 5-HT, receptor antagonist. In another aspect the composi 55 therapeutically effective amount of a composition compris tion is that wherein the 5-HT, receptor antagonist is also a ing a norepinephrine-dopamine reuptake inhibitor, an oxy 5-HT, receptor antagonist and a 5-HT, receptor agonist tocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, (e.g., traZodone). In another aspect the composition is that Syntocinon R.), and a pharmaceutically acceptable carrier. In wherein the 5-HT2 receptor antagonist, 5-HT, receptor another aspect, the composition also includes an alpha agonist, and/or 5-HT, receptor antagonist is also an alpha 60 adrenergic blocker (e.g., traZodone). adrenergic blocker (e.g., traZodone). In one aspect, the invention provides a method of treating In one aspect, the invention provides a method of treating a Subject Suffering from or Susceptible to a sexual disorder a Subject Suffering from or Susceptible to a sexual disorder comprising administering to a Subject in need thereof a comprising administering to a subject in need thereof a therapeutically effective amount of a composition compris therapeutically effective amount of a composition compris 65 ing a norepinephrine-dopamine reuptake inhibitor, an oxy ing a 5-HT, receptor agonist, a 5-HT, antagonist, an tocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto Syntocinon R.), other non-abusable agents (agents not sched US 9,517,254 B2 25 26 uled by the DEA) that augment dopamine and/or norepi male sexual disorder (MSD). In aspects, the method is that nephrine in the brain, e.g., atomoxetine, reboxetine, ameda wherein the sexual disorder is male Hypoactive Sexual lin, CP-39,332, daledalin, edivoxetine, esreboxetine, Desire Disorder (HSDD); wherein the sexual disorder is lortalamine, mazindol, nisoxetine, talopram, talsupram, tan male sexual arousal disorder (FSAD); wherein the sexual damine, Viloxazine, maprotiline, ciclazindol, manifaxine, disorder is male orgasmic disorder (MOD; delayed ejacula radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo tion); wherein the sexual disorder is premature ejaculation biloba), and a pharmaceutically acceptable carrier. In (PE); wherein the sexual dysfunction is sexual performance another aspect, the composition also includes an alpha anxiety; or wherein the sexual disorder is sexual pain adrenergic blocker (e.g., traZodone). disorder or dysfunction. In aspects, the method is that In one aspect, the invention provides a method of treating 10 wherein the MSD includes one or more simultaneous dys a Subject Suffering from or Susceptible to a sexual disorder functions of sexual desire, arousal, orgasm, and/or pain. comprising administering to a subject in need thereof a In one aspect, the invention provides a method of treating therapeutically effective amount of a composition compris a Subject suffering from or Susceptible to a cognitive disor ing a norepinephrine-dopamine reuptake inhibitor, an oxy der comprising administering to a subject in need thereof a tocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, 15 therapeutically effective amount of a composition compris SyntocinonR), a 5-HT, agonist (e.g., lorcaserin, vabica ing a 5-HT, antagonist, a norepinephrine-dopamine serin, PRX-00933, YM348, metachlorophenylpiperazine, reuptake inhibitor, an oxytocin receptor (OXTR) agonist and mOPP), and a pharmaceutically acceptable carrier. In (e.g., carbetocin, oxytocin, Syntocinon R.), and a pharma another aspect, the composition also includes an alpha ceutically acceptable carrier. In one aspect, one compound is adrenergic blocker (e.g., traZodone). both a 5-HT, antagonist and a 5-HT, receptor agonist In one aspect, the invention provides a method of treating (e.g., traZodone, nefazodone, mirtazapine, flibanserin). In a Subject Suffering from or Susceptible to a sexual disorder another aspect the composition is that wherein the norepi comprising administering to a subject in need thereof a nephrine-dopamine reuptake inhibitor is also an alpha adren therapeutically effective amount of a composition compris ergic blocker (e.g., bupropion). In another aspect the com ing a norepinephrine-dopamine reuptake inhibitor, an oxy 25 position is that wherein the 5-HT2 receptor antagonist is tocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, also a 5-HT, receptor agonist. In another aspect the com Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, vabica position is that wherein the 5-HT2 receptor antagonist is serin, PRX-00933, YM348, metachlorophenylpiperazine, also a 5-HT, receptor antagonist. In another aspect the and mCPP), other non-abusable agents (agents not sched composition is that wherein the 5-HT, receptor antagonist uled by the DEA) that augment dopamine and/or norepi 30 is also a 5-HT, receptor antagonist and a 5-HT, receptor nephrine in the brain, e.g., atomoxetine, reboxetine, ameda agonist (e.g., traZodone). In another aspect the composition lin, CP-39,332, daledalin, edivoxetine, esreboxetine, is that wherein the 5-HT, receptor antagonist, 5-HT lortalamine, mazindol, nisoxetine, talopram, talsupram, tan receptor agonist, and/or 5-HT, receptor antagonist is also damine, Viloxazine, maprotiline, ciclazindol, manifaxine, an alpha adrenergic blocker (e.g., traZodone). radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo 35 In one aspect, the invention provides a method of treating biloba), and a pharmaceutically acceptable carrier. In a Subject suffering from or Susceptible to a cognitive disor another aspect, the composition also includes an alpha der comprising administering to a subject in need thereof a adrenergic blocker (e.g., traZodone). therapeutically effective amount of a composition compris In one aspect, the invention provides a method of treating ing a 5-HT, antagonist, a norepinephrine-dopamine a Subject Suffering from or Susceptible to a sexual disorder 40 reuptake inhibitor, an oxytocin receptor (OXTR) agonist comprising administering to a subject in need thereof a (e.g., carbetocin, oxytocin, Syntocinon R.), and a pharma therapeutically effective amount of a composition compris ceutically acceptable carrier. In one aspect, one compound is ing an oxytocin receptor (OXTR) agonist (e.g., carbetocin, both a 5-HT, antagonist and a 5-HT, receptor agonist oxytocin, Syntocinon R) and a pharmaceutically acceptable (e.g., traZodone, nefazodone, mirtazapine, flibanserin, carrier. 45 ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris In one aspect, the invention provides a method of treating peridone, asenapine, MDL-100.907, cyproheptadine, arip a Subject Suffering from or Susceptible to a sexual disorder iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro comprising administering to a subject in need thereof a pyrimido-azepines). In another aspect the composition is therapeutically effective amount of a composition compris that wherein the norepinephrine-dopamine reuptake inhibi ing an oxytocin receptor (OXTR) agonist (e.g., carbetocin, 50 tor is also an alpha adrenergic blocker (e.g., bupropion). In oxytocin, Syntocinon R.), other non-abusable agents (agents another aspect the composition is that wherein the 5-HT not scheduled by the DEA) that augment dopamine and/or receptor antagonist is also a 5-HT, receptor agonist. In norepinephrine in the brain, e.g., atomoxetine, reboxetine, another aspect the composition is that wherein the 5-HT amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, receptor antagonist is also a 5-HT, receptor antagonist. In lortalamine, mazindol, nisoxetine, talopram, talsupram, tan 55 another aspect the composition is that wherein the 5-HT damine, Viloxazine, maprotiline, ciclazindol, manifaxine, receptor antagonist is also a 5-HT, receptor antagonist and radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo a 5-HT, receptor agonist (e.g., traZodone). In another biloba), and a pharmaceutically acceptable carrier. aspect the composition is that wherein the 5-HT2 receptor In aspects, the method is that wherein the sexual disorder antagonist, 5-HT, receptoragonist, and/or 5-HT, receptor is female sexual disorder (FSD). In aspects, the method is 60 antagonist is also an alpha adrenergic blocker (e.g., tra that wherein the sexual disorder is female orgasmic disorder Zodone). (FOD); wherein the sexual disorder is female sexual arousal In one aspect, the invention provides a method of treating disorder (FSAD); or wherein the sexual disorder is sexual a Subject suffering from or Susceptible to a cognitive disor pain disorder or dysfunction. In aspects, the method is that der comprising administering to a subject in need thereof a wherein the FSD includes one or more simultaneous dys 65 therapeutically effective amount of a composition compris functions of sexual desire, arousal, orgasm, and/or pain. In ing a 5-HT, antagonist, a norepinephrine-dopamine aspects, the method is that wherein the sexual disorder is reuptake inhibitor, an oxytocin receptor (OXTR) agonist US 9,517,254 B2 27 28 (e.g., carbetocin, oxytocin, Syntocinon R.), other non-abus reuptake inhibitor, an oxytocin receptor (OXTR) agonist able agents (agents not scheduled by the DEA) that augment (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, agonist dopamine and/or norepinephrine in the brain, e.g., atomox (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, etine, reboxetine, amedalin, CP-39,332, daledalin, edivox metachlorophenylpiperazine, and mOPP), other non-abus etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo able agents (agents not scheduled by the DEA) that augment pram, talsupram, tandamine, Viloxazine, maprotiline, dopamine and/or norepinephrine in the brain, e.g., atomox ciclazindol, manifaxine, radafaxine, tapentadol, tenilox etine, reboxetine, amedalin, CP-39,332, daledalin, edivox azine, St. John’s wort, ginkgo biloba), and a pharmaceuti etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo cally acceptable carrier. In one aspect, one compound is both pram, talsupram, tandamine, Viloxazine, maprotiline, a 5-HT, antagonist and a 5-HT, receptor agonist (e.g., 10 ciclazindol, manifaxine, radafaxine, tapentadol, tenilox traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, azine, St. John’s wort, ginkgo biloba), other non-abusable ritanserin, clozapine, olanzapine, quetiapine, risperidone, agents (agents not scheduled by the DEA) that augment asenapine, MDL-100.907, cyproheptadine, aripiprazole, and dopamine and/or norepinephrine in the brain, e.g., atomox the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido etine, reboxetine, amedalin, CP-39,332, daledalin, edivox azepines). In another aspect the composition is that wherein 15 etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo the norepinephrine-dopamine reuptake inhibitor is also an pram, talsupram, tandamine, Viloxazine, maprotiline, alpha adrenergic blocker (e.g., bupropion). In another aspect ciclazindol, manifaxine, radafaxine, tapentadol, tenilox the composition is that wherein the 5-HT2 receptor antago azine, St. John’s wort, ginkgo biloba), and a pharmaceuti nist is also a 5-HT, receptor agonist. In another aspect the cally acceptable carrier. In one aspect, one compound is both composition is that wherein the 5-HT, receptor antagonist a 5-HT, antagonist and a 5-HT, receptor agonist (e.g., is also a 5-HT, receptor antagonist. In another aspect the traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, composition is that wherein the 5-HT, receptor antagonist ritanserin, clozapine, olanzapine, quetiapine, risperidone, is also a 5-HT, receptor antagonist and a 5-HT, receptor asenapine, MDL-100.907, cyproheptadine, aripiprazole, and agonist (e.g., traZodone). In another aspect the composition the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido is that wherein the 5-HT2 receptor antagonist, 5-HT 25 azepines). In another aspect the composition is that wherein receptor agonist, and/or 5-HT, receptor antagonist is also the norepinephrine-dopamine reuptake inhibitor is also an an alpha adrenergic blocker (e.g., traZodone). alpha adrenergic blocker (e.g., bupropion). In another aspect In one aspect, the invention provides a method of treating the composition is that wherein the 5-HT, receptor antago a subject suffering from or Susceptible to a cognitive disor nist is also a 5-HT, receptor agonist. In another aspect the der comprising administering to a Subject in need thereof a 30 composition is that wherein the 5-HT, receptor antagonist therapeutically effective amount of a composition compris is also a 5-HT, receptor antagonist. In another aspect the ing a 5-HT, antagonist, a norepinephrine-dopamine composition is that wherein the 5-HT, receptor antagonist reuptake inhibitor, an oxytocin receptor (OXTR) agonist is also a 5-HT, receptor antagonist and a 5-HT, receptor (e.g., carbetocin, oxytocin, Syntocinon R.), a 5-HT2, agonist agonist (e.g., traZodone). In another aspect the composition (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, 35 is that wherein the 5-HT, receptor antagonist, 5-HT metachlorophenylpiperazine, and mOPP), other non-abus receptor agonist, and/or 5-HT, receptor antagonist is also able agents (agents not scheduled by the DEA) that augment an alpha adrenergic blocker (e.g., traZodone). dopamine and/or norepinephrine in the brain, e.g., atomox In one aspect, the invention provides a method of treating etine, reboxetine, amedalin, CP-39,332, daledalin, edivox a Subject suffering from or Susceptible to a cognitive disor etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo 40 der comprising administering to a subject in need thereof a pram, talsupram, tandamine, Viloxazine, maprotiline, therapeutically effective amount of a composition compris ciclazindol, manifaxine, radafaxine, tapentadol, tenilox ing a 5-HT, antagonist, a norepinephrine-dopamine azine, St. John’s wort, ginkgo biloba), and a pharmaceuti reuptake inhibitor, and a pharmaceutically acceptable car cally acceptable carrier. In one aspect, one compound is both rier. In one aspect, one compound is both a 5-HT, antago a 5-HT, antagonist and a 5-HT, receptor agonist (e.g., 45 nist and a 5-HT, receptor agonist (e.g., traZodone, nefa traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, Zodone, mirtazapine, flibanserin). In another aspect the ritanserin, clozapine, olanzapine, quetiapine, risperidone, composition is that wherein the norepinephrine-dopamine asenapine, MDL-100.907, cyproheptadine, aripiprazole, and reuptake inhibitor is also an alpha adrenergic blocker (e.g., the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido bupropion). In another aspect the composition is that azepines). In another aspect the composition is that wherein 50 wherein the 5-HT2 receptor antagonist is also a 5-HT the norepinephrine-dopamine reuptake inhibitor is also an receptor agonist. In another aspect the composition is that alpha adrenergic blocker (e.g., bupropion). In another aspect wherein the 5-HT2 receptor antagonist is also a 5-HT, the composition is that wherein the 5-HT2 receptor antago receptor antagonist. In another aspect the composition is that nist is also a 5-HT, receptor agonist. In another aspect the wherein the 5-HT, receptor antagonist is also a 5-HT, composition is that wherein the 5-HT, receptor antagonist 55 receptor antagonist and a 5-HT, receptor agonist (e.g., is also a 5-HT, receptor antagonist. In another aspect the traZodone). In another aspect the composition is that composition is that wherein the 5-HT, receptor antagonist wherein the 5-HT2 receptor antagonist, 5-HT, receptor is also a 5-HT, receptor antagonist and a 5-HT, receptor agonist, and/or 5-HT, receptor antagonist is also an alpha agonist (e.g., traZodone). In another aspect the composition adrenergic blocker (e.g., traZodone). is that wherein the 5-HT2 receptor antagonist, 5-HT 60 In one aspect, the invention provides a method of treating receptor agonist, and/or 5-HT, receptor antagonist is also a Subject suffering from or Susceptible to a cognitive disor an alpha adrenergic blocker (e.g., traZodone). der comprising administering to a subject in need thereof a In one aspect, the invention provides a method of treating therapeutically effective amount of a composition compris a subject suffering from or Susceptible to a cognitive disor ing a 5-HT, antagonist, a norepinephrine-dopamine der comprising administering to a Subject in need thereof a 65 reuptake inhibitor, and a pharmaceutically acceptable car therapeutically effective amount of a composition compris rier. In one aspect, one compound is both a 5-HT, antago ing a 5-HT, antagonist, a norepinephrine-dopamine nist and a 5-HT, receptor agonist (e.g., traZodone, nefa US 9,517,254 B2 29 30 Zodone, mirtazapine, flibanserin, ketanserin, ritanserin, 5-HT, receptor agonist. In another aspect the composition clozapine, olanzapine, quetiapine, risperidone, asenapine, is that wherein the 5-HT, receptor antagonist is also a MDL-100.907, cyproheptadine, aripiprazole, and the gen 5-HT, receptor antagonist. In another aspect the composi eral class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). tion is that wherein the 5-HT2 receptor antagonist is also a In another aspect the composition is that wherein the nor 5-HT, receptor antagonist and a 5-HT, receptor agonist epinephrine-dopamine reuptake inhibitor is also an alpha (e.g., traZodone). In another aspect the composition is that adrenergic blocker (e.g., bupropion). In another aspect the wherein the 5-HT, receptor antagonist, 5-HT, receptor composition is that wherein the 5-HT, receptor antagonist agonist, and/or 5-HT, receptor antagonist is also an alpha is also a 5-HT, receptor agonist. In another aspect the adrenergic blocker (e.g., traZodone). composition is that wherein the 5-HT, receptor antagonist 10 In one aspect, the invention provides a method of treating is also a 5-HT, receptor antagonist. In another aspect the a Subject suffering from or Susceptible to a cognitive disor composition is that wherein the 5-HT, receptor antagonist der comprising administering to a subject in need thereof a is also a 5-HT, receptor antagonist and a 5-HT, receptor therapeutically effective amount of a composition compris agonist (e.g., traZodone). In another aspect the composition ing a 5-HT, antagonist, a norepinephrine-dopamine is that wherein the 5-HT2 receptor antagonist, 5-HT 15 reuptake inhibitor, a 5-HT2, agonist (e.g., lorcaserin, vabi receptor agonist, and/or 5-HT, receptor antagonist is also caserin, PRX-00933, YM348, metachlorophenylpiperazine, an alpha adrenergic blocker (e.g., traZodone). and mOPP), other non-abusable agents (agents not sched In one aspect, the invention provides a method of treating uled by the DEA) that augment dopamine and/or norepi a subject suffering from or Susceptible to a cognitive disor nephrine in the brain, e.g., atomoxetine, reboxetine, ameda der comprising administering to a Subject in need thereof a lin, CP-39,332, daledalin, edivoxetine, esreboxetine, therapeutically effective amount of a composition compris lortalamine, mazindol, nisoxetine, talopram, talsupram, tan ing a 5-HT, antagonist, a norepinephrine-dopamine damine, Viloxazine, maprotiline, ciclazindol, manifaxine, reuptake inhibitor, other non-abusable agents (agents not radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo scheduled by the DEA) that augment dopamine and/or biloba), and a pharmaceutically acceptable carrier. In one norepinephrine in the brain, e.g., atomoxetine, reboxetine, 25 aspect, one compound is both a 5-HT, antagonist and a amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, 5-HT, receptor agonist (e.g., traZodone, nefazodone, mir lortalamine, mazindol, nisoxetine, talopram, talsupram, tan tazapine, flibanserin, ketanserin, ritanserin, clozapine, olan damine, Viloxazine, maprotiline, ciclazindol, manifaxine, Zapine, quetiapine, risperidone, asenapine, MDL-100.907. radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo cyproheptadine, aripiprazole, and the general class of biloba), and a pharmaceutically acceptable carrier. In one 30 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another aspect, one compound is both a 5-HT, antagonist and a aspect the composition is that wherein the norepinephrine 5-HT, receptor agonist (e.g., trazodone, nefazodone, mir dopamine reuptake inhibitor is also an alpha adrenergic tazapine, flibanserin, ketanserin, ritanserin, clozapine, olan blocker (e.g., bupropion). In another aspect the composition Zapine, quetiapine, risperidone, asenapine, MDL-100.907. is that wherein the 5-HT2 receptor antagonist is also a cyproheptadine, aripiprazole, and the general class of 35 5-HT, receptor agonist. In another aspect the composition 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another is that wherein the 5-HT2 receptor antagonist is also a aspect the composition is that wherein the norepinephrine 5-HT, receptor antagonist. In another aspect the composi dopamine reuptake inhibitor is also an alpha adrenergic tion is that wherein the 5-HT2 receptor antagonist is also a blocker (e.g., bupropion). In another aspect the composition 5-HT, receptor antagonist and a 5-HT, receptor agonist is that wherein the 5-HT, receptor antagonist is also a 40 (e.g., traZodone). In another aspect the composition is that 5-HT, receptor agonist. In another aspect the composition wherein the 5-HT2 receptor antagonist, 5-HT, receptor is that wherein the 5-HT, receptor antagonist is also a agonist, and/or 5-HT, receptor antagonist is also an alpha 5-HT, receptor antagonist. In another aspect the composi adrenergic blocker (e.g., traZodone). tion is that wherein the 5-HT2 receptor antagonist is also a In one aspect, the invention provides a method of treating 5-HT, receptor antagonist and a 5-HT, receptor agonist 45 a Subject suffering from or Susceptible to a cognitive disor (e.g., traZodone). In another aspect the composition is that der comprising administering to a subject in need thereof a wherein the 5-HT, receptor antagonist, 5-HT, receptor therapeutically effective amount of a composition compris agonist, and/or 5-HT, receptor antagonist is also an alpha ing a 5-HT, receptor agonist, a 5-HT, antagonist, and a adrenergic blocker (e.g., traZodone). pharmaceutically acceptable carrier. In one aspect, one com In one aspect, the invention provides a method of treating 50 pound is the 5-HT, receptoragonist and the 5-HT, antago a subject suffering from or Susceptible to a cognitive disor nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin). der comprising administering to a Subject in need thereof a In another aspect the composition is that wherein the 5-HT therapeutically effective amount of a composition compris receptor antagonist is also a 5-HT, receptor agonist. In ing a 5-HT, antagonist, a norepinephrine-dopamine another aspect the composition is that wherein the 5-HT, reuptake inhibitor, a 5-HT2, agonist (e.g., lorcaserin, vabi 55 receptor antagonist is also a 5-HT, receptor antagonist. In caserin, PRX-00933, YM348, metachlorophenylpiperazine, another aspect the composition is that wherein the 5-HT, and mOPP), and a pharmaceutically acceptable carrier. In receptor antagonist is also a 5-HT, receptor antagonist and one aspect, one compound is both a 5-HT, antagonist and a 5-HT, receptor agonist (e.g., traZodone). In another a 5-HT, receptor agonist (e.g., traZodone, nefazodone, aspect the composition is that wherein the 5-HT2 receptor mirtazapine, flibanserin, ketanserin, ritanserin, clozapine, 60 antagonist, 5-HT, receptoragonist, and/or 5-HT, receptor olanzapine, quetiapine, risperidone, asenapine, MDL-100, antagonist is also an alpha adrenergic blocker (e.g., tra 907, cyproheptadine, aripiprazole, and the general class of Zodone). 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another In one aspect, the invention provides a method of treating aspect the composition is that wherein the norepinephrine a Subject suffering from or Susceptible to a cognitive disor dopamine reuptake inhibitor is also an alpha adrenergic 65 der comprising administering to a subject in need thereof a blocker (e.g., bupropion). In another aspect the composition therapeutically effective amount of a composition compris is that wherein the 5-HT2 receptor antagonist is also a ing a 5-HT, receptor agonist, a 5-HT, antagonist, and a US 9,517,254 B2 31 32 pharmaceutically acceptable carrier. In one aspect, one com that wherein the 5-HT2 receptor antagonist is also a 5-HT pound is the 5-HT, receptoragonist and the 5-HT, antago receptor agonist. In another aspect the composition is that nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, wherein the 5-HT2 receptor antagonist is also a 5-HT, ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris receptor antagonist. In another aspect the composition is that peridone, asenapine, MDL-100.907, cyproheptadine, arip wherein the 5-HT, receptor antagonist is also a 5-HT, iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro receptor antagonist and a 5-HT, receptor agonist (e.g., pyrimido-azepines). In another aspect the composition is traZodone). In another aspect the composition is that that wherein the 5-HT2 receptor antagonist is also a 5-HT wherein the 5-HT, receptor antagonist, 5-HT, receptor receptor agonist. In another aspect the composition is that agonist, and/or 5-HT, receptor antagonist is also an alpha wherein the 5-HT2 receptor antagonist is also a 5-HT, 10 receptor antagonist. In another aspect the composition is that adrenergic blocker (e.g., traZodone). wherein the 5-HT2 receptor antagonist is also a 5-HT, In one aspect, the invention provides a method of treating receptor antagonist and a 5-HT, receptor agonist (e.g., a Subject suffering from or Susceptible to a cognitive disor traZodone). In another aspect the composition is that der comprising administering to a subject in need thereof a wherein the 5-HT2 receptor antagonist, 5-HT, receptor 15 therapeutically effective amount of a composition compris agonist, and/or 5-HT, receptor antagonist is also an alpha ing a 5-HT, receptor agonist, a 5-HT, antagonist, a adrenergic blocker (e.g., traZodone). 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, In one aspect, the invention provides a method of treating YM348, metachlorophenylpiperazine, and mCPP), other a subject suffering from or Susceptible to a cognitive disor non-abusable agents (agents not scheduled by the DEA) that der comprising administering to a Subject in need thereof a augment dopamine and/or norepinephrine in the brain, e.g., therapeutically effective amount of a composition compris atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, ing a 5-HT, receptor agonist, a 5-HT, antagonist, other edivoxetine, esreboxetine, lortalamine, mazindol, nisox non-abusable agents (agents not scheduled by the DEA) that etine, talopram, talsupram, tandamine, Viloxazine, maproti augment dopamine and/or norepinephrine in the brain, e.g., line, ciclaZindol, manifaxine, radafaxine, tapentadol, atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, 25 teniloxazine, St. John's wort, ginkgo biloba), other non edivoxetine, esreboxetine, lortalamine, mazindol, nisox abusable agents (agents not scheduled by the DEA) that etine, talopram, talsupram, tandamine, Viloxazine, maproti augment dopamine and/or norepinephrine in the brain, e.g., line, ciclaZindol, manifaxine, radafaxine, tapentadol, atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, teniloxazine, St. John’s wort, ginkgo biloba), and a phar edivoxetine, esreboxetine, lortalamine, mazindol, nisox maceutically acceptable carrier. In one aspect, one com 30 etine, talopram, talsupram, tandamine, Viloxazine, maproti pound is the 5-HT, receptoragonist and the 5-HT, antago line, ciclaZindol, manifaxine, radafaxine, tapentadol, nist (e.g., trazodone, nefazodone, mirtazapine, flibanserin, teniloxazine, St. John’s wort, ginkgo biloba), and a phar ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris maceutically acceptable carrier. In one aspect, one com peridone, asenapine, MDL-100.907, cyproheptadine, arip pound is the 5-HT, receptoragonist and the 5-HT, antago iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro 35 nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, pyrimido-azepines). In another aspect the composition is ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris that wherein the 5-HT2 receptor antagonist is also a 5-HT peridone, asenapine, MDL-100.907, cyproheptadine, arip receptor agonist. In another aspect the composition is that iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro wherein the 5-HT2 receptor antagonist is also a 5-HT, pyrimido-azepines). In another aspect the composition is receptor antagonist. In another aspect the composition is that 40 that wherein the 5-HT, receptor antagonist is also a 5-HT wherein the 5-HT2 receptor antagonist is also a 5-HT, receptor agonist. In another aspect the composition is that receptor antagonist and a 5-HT, receptor agonist (e.g., wherein the 5-HT, receptor antagonist is also a 5-HT, traZodone). In another aspect the composition is that receptor antagonist. In another aspect the composition is that wherein the 5-HT2 receptor antagonist, 5-HT, receptor wherein the 5-HT2 receptor antagonist is also a 5-HT, agonist, and/or 5-HT, receptor antagonist is also an alpha 45 receptor antagonist and a 5-HT, receptor agonist (e.g., adrenergic blocker (e.g., traZodone). traZodone). In another aspect the composition is that In one aspect, the invention provides a method of treating wherein the 5-HT, receptor antagonist, 5-HT, receptor a subject suffering from or Susceptible to a cognitive disor agonist, and/or 5-HT, receptor antagonist is also an alpha der comprising administering to a Subject in need thereof a adrenergic blocker (e.g., traZodone). therapeutically effective amount of a composition compris 50 In one aspect, the invention provides a method of treating ing a 5-HT, receptor agonist, a 5-HT, antagonist, a a Subject suffering from or Susceptible to a cognitive disor 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, der comprising administering to a subject in need thereof a YM348, metachlorophenylpiperazine, and mCPP), other therapeutically effective amount of a composition compris non-abusable agents (agents not scheduled by the DEA) that ing a 5-HT, receptor agonist, a 5-HT, antagonist, an augment dopamine and/or norepinephrine in the brain, e.g., 55 oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, cin, SyntocinonR), and a pharmaceutically acceptable car edivoxetine, esreboxetine, lortalamine, mazindol, nisox rier. In one aspect, one compound is the 5-HT, receptor etine, talopram, talsupram, tandamine, Viloxazine, maproti agonist and the 5-HT, antagonist (e.g., traZodone, nefa line, ciclaZindol, manifaxine, radafaxine, tapentadol, Zodone, mirtazapine, flibanserin). In another aspect the teniloxazine, St. John’s wort, ginkgo biloba), and a phar 60 composition is that wherein the 5-HT, receptor antagonist maceutically acceptable carrier. In one aspect, one com is also a 5-HT, receptor agonist. In another aspect the pound is the 5-HT, receptoragonist and the 5-HT, antago composition is that wherein the 5-HT, receptor antagonist nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, is also a 5-HT, receptor antagonist. In another aspect the ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris composition is that wherein the 5-HT, receptor antagonist peridone, asenapine, MDL-100.907, cyproheptadine, arip 65 is also a 5-HT, receptor antagonist and a 5-HT, receptor iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro agonist (e.g., traZodone). In another aspect the composition pyrimido-azepines). In another aspect the composition is is that wherein the 5-HT2 receptor antagonist, 5-HT US 9,517,254 B2 33 34 receptor agonist, and/or 5-HT, receptor antagonist is also mirtazapine, flibanserin, ketanserin, ritanserin, clozapine, an alpha adrenergic blocker (e.g., traZodone). olanzapine, quetiapine, risperidone, asenapine, MDL-100, In one aspect, the invention provides a method of treating 907, cyproheptadine, aripiprazole, and the general class of a subject suffering from or Susceptible to a cognitive disor 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another der comprising administering to a Subject in need thereof a aspect the composition is that wherein the 5-HT2 receptor therapeutically effective amount of a composition compris antagonist is also a 5-HT, receptor agonist. In another ing a 5-HT, receptor agonist, a 5-HT, antagonist, an aspect the composition is that wherein the 5-HT, receptor oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto antagonist is also a 5-HT, receptor antagonist. In another cin, SyntocinonR), and a pharmaceutically acceptable car aspect the composition is that wherein the 5-HT, receptor rier. In one aspect, one compound is the 5-HT, receptor 10 antagonist is also a 5-HT, receptor antagonist and a 5-HT agonist and the 5-HT, antagonist (e.g., traZodone, nefa receptor agonist (e.g., traZodone). In another aspect the Zodone, mirtazapine, flibanserin, ketanserin, ritanserin, clo composition is that wherein the 5-HT2 receptor antagonist, Zapine, olanzapine, quetiapine, risperidone, asenapine, 5-HT, receptor agonist, and/or 5-HT, receptor antagonist MDL-100.907, cyproheptadine, aripiprazole, and the gen is also an alpha adrenergic blocker (e.g., traZodone). eral class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). 15 In one aspect, the invention provides a method of treating In another aspect the composition is that wherein the 5-HT, a Subject suffering from or Susceptible to a cognitive disor receptor antagonist is also a 5-HT, receptor agonist. In der comprising administering to a subject in need thereof a another aspect the composition is that wherein the 5-HT therapeutically effective amount of a composition compris receptor antagonist is also a 5-HT, receptor antagonist. In ing a 5-HT, receptor agonist, a 5-HT, antagonist, an another aspect the composition is that wherein the 5-HT oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto receptor antagonist is also a 5-HT, receptor antagonist and cin, SyntocinonR), a 5-HT, agonist (e.g., lorcaserin, vabi a 5-HT, receptor agonist (e.g., traZodone). In another caserin, PRX-00933, YM348, metachlorophenylpiperazine, aspect the composition is that wherein the 5-HT, receptor and mOPP), other non-abusable agents (agents not sched antagonist, 5-HT, receptoragonist, and/or 5-HT, receptor uled by the DEA) that augment dopamine and/or norepi antagonist is also an alpha adrenergic blocker (e.g., tra 25 nephrine in the brain, e.g., atomoxetine, reboxetine, ameda Zodone). lin, CP-39,332, daledalin, edivoxetine, esreboxetine, In one aspect, the invention provides a method of treating lortalamine, mazindol, nisoxetine, talopram, talsupram, tan a subject suffering from or Susceptible to a cognitive disor damine, Viloxazine, maprotiline, ciclazindol, manifaxine, der comprising administering to a Subject in need thereof a radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo therapeutically effective amount of a composition compris 30 biloba), and a pharmaceutically acceptable carrier. In one ing a 5-HT, receptor agonist, a 5-HT, antagonist, an aspect, one compound is the 5-HT, receptoragonist and the oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto 5-HT, antagonist (e.g., traZodone, nefazodone, mirtazap cin, Syntocinon R.), other non-abusable agents (agents not ine, flibanserin, ketanserin, ritanserin, clozapine, olanzapine, scheduled by the DEA) that augment dopamine and/or quetiapine, risperidone, asenapine, MDL-100.907, cypro norepinephrine in the brain, e.g., atomoxetine, reboxetine, 35 heptadine, aripiprazole, and the general class of 2-alkyl-4- amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, aryl-tetrahydro-pyrimido-azepines). In another aspect the lortalamine, mazindol, nisoxetine, talopram, talsupram, tan composition is that wherein the 5-HT, receptor antagonist damine, Viloxazine, maprotiline, ciclazindol, manifaxine, is also a 5-HT, receptor agonist. In another aspect the radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo composition is that wherein the 5-HT, receptor antagonist biloba), and a pharmaceutically acceptable carrier. In one 40 is also a 5-HT, receptor antagonist. In another aspect the aspect, one compound is the 5-HT, receptoragonist and the composition is that wherein the 5-HT, receptor antagonist 5-HT, antagonist (e.g., trazodone, nefazodone, mirtazap is also a 5-HT, receptor antagonist and a 5-HT, receptor ine, flibanserin, ketanserin, ritanserin, clozapine, olanzapine, agonist (e.g., traZodone). In another aspect the composition quetiapine, risperidone, asenapine, MDL-100.907, cypro is that wherein the 5-HT2 receptor antagonist, 5-HT heptadine, aripiprazole, and the general class of 2-alkyl-4- 45 receptor agonist, and/or 5-HT, receptor antagonist is also aryl-tetrahydro-pyrimido-azepines). In another aspect the an alpha adrenergic blocker (e.g., traZodone). composition is that wherein the 5-HT, receptor antagonist In one aspect, the invention provides a method of treating is also a 5-HT, receptor agonist. In another aspect the a Subject suffering from or Susceptible to a cognitive disor composition is that wherein the 5-HT, receptor antagonist der comprising administering to a subject in need thereof a is also a 5-HT, receptor antagonist. In another aspect the 50 therapeutically effective amount of a composition compris composition is that wherein the 5-HT, receptor antagonist ing a norepinephrine-dopamine reuptake inhibitor, an oxy is also a 5-HT, receptor antagonist and a 5-HT, receptor tocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, agonist (e.g., traZodone). In another aspect the composition Syntocinon R.), and a pharmaceutically acceptable carrier. In is that wherein the 5-HT, receptor antagonist, 5-HT another aspect the composition is that wherein the norepi receptor agonist, and/or 5-HT, receptor antagonist is also 55 nephrine-dopamine reuptake inhibitor is also an alpha adren an alpha adrenergic blocker (e.g., traZodone). ergic blocker (e.g., bupropion). In one aspect, the invention provides a method of treating In one aspect, the invention provides a method of treating a subject suffering from or Susceptible to a cognitive disor a Subject suffering from or Susceptible to a cognitive disor der comprising administering to a Subject in need thereof a der comprising administering to a subject in need thereof a therapeutically effective amount of a composition compris 60 therapeutically effective amount of a composition compris ing a 5-HT, receptor agonist, a 5-HT, antagonist, an ing a norepinephrine-dopamine reuptake inhibitor, an oxy oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto tocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, cin, SyntocinonR), a 5-HT, agonist (e.g., lorcaserin, vabi Syntocinon R.), other non-abusable agents (agents not sched caserin, PRX-00933, YM348, metachlorophenylpiperazine, uled by the DEA) that augment dopamine and/or norepi and mOPP), and a pharmaceutically acceptable carrier. In 65 nephrine in the brain, e.g., atomoxetine, reboxetine, ameda one aspect, one compound is the 5-HT, receptor agonist lin, CP-39,332, daledalin, edivoxetine, esreboxetine, and the 5-HT, antagonist (e.g., traZodone, nefazodone, lortalamine, mazindol, nisoxetine, talopram, talsupram, tan US 9,517,254 B2 35 36 damine, Viloxazine, maprotiline, ciclazindol, manifaxine, der comprising administering to a subject in need thereof a radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo therapeutically effective amount of a composition compris biloba), and a pharmaceutically acceptable carrier. In ing an oxytocin receptor (OXTR) agonist (e.g., carbetocin, another aspect the composition is that wherein the norepi oxytocin, Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, nephrine-dopamine reuptake inhibitor is also an alpha adren vabicaserin, PRX-00933, YM348, metachlorophenylpipera ergic blocker (e.g., bupropion). Zine, and mCPP), other non-abusable agents (agents not In one aspect, the invention provides a method of treating scheduled by the DEA) that augment dopamine and/or a subject suffering from or Susceptible to a cognitive disor norepinephrine in the brain, e.g., atomoxetine, reboxetine, der comprising administering to a Subject in need thereof a amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, therapeutically effective amount of a composition compris 10 lortalamine, mazindol, nisoxetine, talopram, talsupram, tan ing a norepinephrine-dopamine reuptake inhibitor, an oxy damine, Viloxazine, maprotiline, ciclazindol, manifaxine, tocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, vabica biloba), and a pharmaceutically acceptable carrier. serin, PRX-00933, YM348, metachlorophenylpiperazine, In aspects, the method is that wherein the cognitive and mOPP), and a pharmaceutically acceptable carrier. In 15 disorder is dementia, where dementia can refer to Alzheim another aspect the composition is that wherein the norepi er's disease, frontotemporal lobar degeneration, dementia nephrine-dopamine reuptake inhibitor is also an alpha adren with Lewy bodies, Parkinson's disease, Huntington's dis ergic blocker (e.g., bupropion). ease, multi-infarct dementia, dementia resulting from infec In one aspect, the invention provides a method of treating tions affecting the central nervous system, dementia result a subject suffering from or Susceptible to a cognitive disor ing from chronic drug use, dementia resulting from der comprising administering to a Subject in need thereof a hydrocephalus, dementia resulting from brain injury, or therapeutically effective amount of a composition compris dementia resulting from a brain tumor. ing a norepinephrine-dopamine reuptake inhibitor, an oxy In aspects, the method is that wherein the cognitive tocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, disorder is cognitive disability, where cognitive disability Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, vabica 25 can refer to schizophrenia, schizoaffective disorder, bipolar serin, PRX-00933, YM348, metachlorophenylpiperazine, disorder, or major depression. and mCPP), other non-abusable agents (agents not sched In aspects, the method is that wherein the cognitive uled by the DEA) that augment dopamine and/or norepi disorder is cognitive disability, where cognitive disability nephrine in the brain, e.g., atomoxetine, reboxetine, ameda can refer to schizophrenia, schizoaffective disorder, bipolar lin, CP-39,332, daledalin, edivoxetine, esreboxetine, 30 disorder, Social anxiety disorder, or major depression. lortalamine, mazindol, nisoxetine, talopram, talsupram, tan In aspects, the method is that wherein the cognitive damine, viloxazine, maprotiline, ciclazindol, manifaxine, disorder is developmental cognitive impairment, where cog radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo nitive impairment can refer to Autism, Asperger's syndrome, biloba), and a pharmaceutically acceptable carrier. In or pervasive developmental disorder. another aspect the composition is that wherein the norepi 35 In aspects, the method is that wherein the cognitive nephrine-dopamine reuptake inhibitor is also an alpha adren disorder is mild cognitive decline. ergic blocker (e.g., bupropion). In one aspect, the invention provides a method of enhanc In one aspect, the invention provides a method of treating ing cognition comprising administering to a Subject in need a subject suffering from or Susceptible to a cognitive disor thereof a therapeutically effective amount of a composition der comprising administering to a Subject in need thereof a 40 comprising a 5-HT, antagonist, a norepinephrine-dop therapeutically effective amount of a composition compris amine reuptake inhibitor, an oxytocin receptor (OXTR) ing an oxytocin receptor (OXTR) agonist (e.g., carbetocin, agonist (e.g., carbetocin, oxytocin, SyntocinonR), and a oxytocin, Syntocinon R) and a pharmaceutically acceptable pharmaceutically acceptable carrier. In one aspect, one com carrier. pound is both a 5-HT, antagonist and a 5-HT, receptor In one aspect, the invention provides a method of treating 45 agonist (e.g., traZodone, nefazodone, mirtazapine, fliban a subject suffering from or Susceptible to a cognitive disor serin). In another aspect the composition is that wherein the der comprising administering to a Subject in need thereof a norepinephrine-dopamine reuptake inhibitor is also an alpha therapeutically effective amount of a composition compris adrenergic blocker (e.g., bupropion). In another aspect the ing an oxytocin receptor (OXTR) agonist (e.g., carbetocin, composition is that wherein the 5-HT, receptor antagonist oxytocin, Syntocinon R.), other non-abusable agents (agents 50 is also a 5-HT, receptor agonist. In another aspect the not scheduled by the DEA) that augment dopamine and/or composition is that wherein the 5-HT, receptor antagonist norepinephrine in the brain, e.g., atomoxetine, reboxetine, is also a 5-HT, receptor antagonist. In another aspect the amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, composition is that wherein the 5-HT, receptor antagonist lortalamine, mazindol, nisoxetine, talopram, talsupram, tan is also a 5-HT, receptor antagonist and a 5-HT, receptor damine, Viloxazine, maprotiline, ciclazindol, manifaxine, 55 agonist (e.g., traZodone). In another aspect the composition radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo is that wherein the 5-HT, receptor antagonist, 5-HT biloba), and a pharmaceutically acceptable carrier. receptor agonist, and/or 5-HT, receptor antagonist is also In one aspect, the invention provides a method of treating an alpha adrenergic blocker (e.g., traZodone). a subject suffering from or Susceptible to a cognitive disor In one aspect, the invention provides a method of enhanc der comprising administering to a Subject in need thereof a 60 ing cognition comprising administering to a Subject in need therapeutically effective amount of a composition compris thereof a therapeutically effective amount of a composition ing an oxytocin receptor (OXTR) agonist (e.g., carbetocin, comprising a 5-HT, antagonist, a norepinephrine-dop oxytocin, SyntocinonR), a 5-HT, agonist (e.g., lorcaserin, amine reuptake inhibitor, an oxytocin receptor (OXTR) vabicaserin, PRX-00933, YM348, metachlorophenylpipera agonist (e.g., carbetocin, oxytocin, SyntocinonR), and a Zine, and mCPP), and a pharmaceutically acceptable carrier. 65 pharmaceutically acceptable carrier. In one aspect, one com In one aspect, the invention provides a method of treating pound is both a 5-HT, antagonist and a 5-HT, receptor a subject suffering from or Susceptible to a cognitive disor agonist (e.g., traZodone, nefazodone, mirtazapine, fliban US 9,517,254 B2 37 38 serin, ketanserin, ritanserin, clozapine, olanzapine, quetiap another aspect the composition is that wherein the 5-HT ine, risperidone, asenapine, MDL-100.907, cyproheptadine, receptor antagonist is also a 5-HT, receptor agonist. In aripiprazole, and the general class of 2-alkyl-4-aryl-tetra another aspect the composition is that wherein the 5-HT hydro-pyrimido-azepines). In another aspect the composi receptor antagonist is also a 5-HT, receptor antagonist. In tion is that wherein the norepinephrine-dopamine reuptake another aspect the composition is that wherein the 5-HT, inhibitor is also an alpha adrenergic blocker (e.g., bupro receptor antagonist is also a 5-HT, receptor antagonist and pion). In another aspect the composition is that wherein the a 5-HT, receptor agonist (e.g., traZodone). In another 5-HT2 receptor antagonist is also a 5-HT, receptor ago aspect the composition is that wherein the 5-HT, receptor nist. In another aspect the composition is that wherein the antagonist, 5-HT, receptoragonist, and/or 5-HT, receptor 5-HT2 receptor antagonist is also a 5-HT, receptor antago 10 nist. In another aspect the composition is that wherein the antagonist is also an alpha adrenergic blocker (e.g., tra 5-HT2 receptor antagonist is also a 5-HT, receptor antago Zodone). nist and a 5-HT, receptor agonist (e.g., traZodone). In In one aspect, the invention provides a method of enhanc another aspect the composition is that wherein the 5-HT ing cognition comprising administering to a Subject in need receptor antagonist, 5-HT, receptoragonist, and/or 5-HT, 15 thereof a therapeutically effective amount of a composition receptor antagonist is also an alpha adrenergic blocker (e.g., comprising a 5-HT, antagonist, a norepinephrine-dop traZodone). amine reuptake inhibitor, an oxytocin receptor (OXTR) In one aspect, the invention provides a method of enhanc agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, ing cognition comprising administering to a Subject in need agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, thereof a therapeutically effective amount of a composition metachlorophenylpiperazine, and mOPP), other non-abus comprising a 5-HT, antagonist, a norepinephrine-dop able agents (agents not scheduled by the DEA) that augment amine reuptake inhibitor, an oxytocin receptor (OXTR) dopamine and/or norepinephrine in the brain, e.g., atomox agonist (e.g., carbetocin, oxytocin, Syntocinon R.), other etine, reboxetine, amedalin, CP-39,332, daledalin, edivox non-abusable agents (agents not scheduled by the DEA) that etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo augment dopamine and/or norepinephrine in the brain, e.g., 25 pram, talsupram, tandamine, Viloxazine, maprotiline, atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, ciclazindol, manifaxine, radafaxine, tapentadol, tenilox edivoxetine, esreboxetine, lortalamine, mazindol, nisox azine, St. John’s wort, ginkgo biloba), and a pharmaceuti etine, talopram, talsupram, tandamine, Viloxazine, maproti cally acceptable carrier. In one aspect, one compound is both line, ciclaZindol, manifaxine, radafaxine, tapentadol, a 5-HT, antagonist and a 5-HT, receptor agonist (e.g., teniloxazine, St. John’s wort, ginkgo biloba), and a phar 30 traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, maceutically acceptable carrier. In one aspect, one com ritanserin, clozapine, olanzapine, quetiapine, risperidone, pound is both a 5-HT, antagonist and a 5-HT, receptor asenapine, MDL-100.907, cyproheptadine, aripiprazole, and agonist (e.g., traZodone, nefazodone, mirtazapine, fliban the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido serin, ketanserin, ritanserin, clozapine, olanzapine, quetiap azepines). In another aspect the composition is that wherein ine, risperidone, asenapine, MDL-100.907, cyproheptadine, 35 the norepinephrine-dopamine reuptake inhibitor is also an aripiprazole, and the general class of 2-alkyl-4-aryl-tetra alpha adrenergic blocker (e.g., bupropion). In another aspect hydro-pyrimido-azepines). In another aspect the composi the composition is that wherein the 5-HT2 receptor antago tion is that wherein the norepinephrine-dopamine reuptake nist is also a 5-HT, receptor agonist. In another aspect the inhibitor is also an alpha adrenergic blocker (e.g., bupro composition is that wherein the 5-HT, receptor antagonist pion). In another aspect the composition is that wherein the 40 is also a 5-HT, receptor antagonist. In another aspect the 5-HT2 receptor antagonist is also a 5-HT, receptor ago composition is that wherein the 5-HT, receptor antagonist nist. In another aspect the composition is that wherein the is also a 5-HT, receptor antagonist and a 5-HT, receptor 5-HT2 receptor antagonist is also a 5-HT, receptor antago agonist (e.g., traZodone). In another aspect the composition nist. In another aspect the composition is that wherein the is that wherein the 5-HT2 receptor antagonist, 5-HT 5-HT2 receptor antagonist is also a 5-HT, receptor antago 45 receptor agonist, and/or 5-HT, receptor antagonist is also nist and a 5-HT, receptor agonist (e.g., traZodone). In an alpha adrenergic blocker (e.g., traZodone). another aspect the composition is that wherein the 5-HT In one aspect, the invention provides a method of enhanc receptor antagonist, 5-HT, receptoragonist, and/or 5-HT, ing cognition comprising administering to a Subject in need receptor antagonist is also an alpha adrenergic blocker (e.g., thereof a therapeutically effective amount of a composition traZodone). 50 comprising a 5-HT, antagonist, a norepinephrine-dop In one aspect, the invention provides a method of enhanc amine reuptake inhibitor, and a pharmaceutically acceptable ing cognition comprising administering to a Subject in need carrier. In one aspect, one compound is both a 5-HT thereof a therapeutically effective amount of a composition antagonist and a 5-HT, receptor agonist (e.g., traZodone, comprising a 5-HT, antagonist, a norepinephrine-dop nefazodone, mirtazapine, flibanserin). In another aspect the amine reuptake inhibitor, an oxytocin receptor (OXTR) 55 composition is that wherein the norepinephrine-dopamine agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, reuptake inhibitor is also an alpha adrenergic blocker (e.g., agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, bupropion). In another aspect the composition is that metachlorophenylpiperazine, and mCPP), and a pharmaceu wherein the 5-HT2 receptor antagonist is also a 5-HT tically acceptable carrier. In one aspect, one compound is receptor agonist. In another aspect the composition is that both a 5-HT, antagonist and a 5-HT, receptor agonist 60 wherein the 5-HT2 receptor antagonist is also a 5-HT, (e.g., traZodone, nefazodone, mirtazapine, flibanserin, receptor antagonist. In another aspect the composition is that ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris wherein the 5-HT2 receptor antagonist is also a 5-HT, peridone, asenapine, MDL-100.907, cyproheptadine, arip receptor antagonist and a 5-HT, receptor agonist (e.g., iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro traZodone). In another aspect the composition is that pyrimido-azepines). In another aspect the composition is 65 wherein the 5-HT2 receptor antagonist, 5-HT, receptor that wherein the norepinephrine-dopamine reuptake inhibi agonist, and/or 5-HT, receptor antagonist is also an alpha tor is also an alpha adrenergic blocker (e.g., bupropion). In adrenergic blocker (e.g., traZodone). US 9,517,254 B2 39 40 In one aspect, the invention provides a method of enhanc radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo ing cognition comprising administering to a Subject in need biloba), and a pharmaceutically acceptable carrier. In one thereof a therapeutically effective amount of a composition aspect, one compound is both a 5-HT, antagonist and a comprising a 5-HT, antagonist, a norepinephrine-dop 5-HT, receptor agonist (e.g., traZodone, nefazodone, mir amine reuptake inhibitor, and a pharmaceutically acceptable tazapine, flibanserin, ketanserin, ritanserin, clozapine, olan carrier. In one aspect, one compound is both a 5-HT Zapine, quetiapine, risperidone, asenapine, MDL-100.907. antagonist and a 5-HT, receptor agonist (e.g., trazodone, cyproheptadine, aripiprazole, and the general class of nefazodone, mirtazapine, flibanserin, ketanserin, ritanserin, 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another clozapine, olanzapine, quetiapine, risperidone, asenapine, aspect the composition is that wherein the norepinephrine MDL-100.907, cyproheptadine, aripiprazole, and the gen 10 dopamine reuptake inhibitor is also an alpha adrenergic eral class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). blocker (e.g., bupropion). In another aspect the composition In another aspect the composition is that wherein the nor is that wherein the 5-HT2 receptor antagonist is also a epinephrine-dopamine reuptake inhibitor is also an alpha 5-HT, receptor agonist. In another aspect the composition adrenergic blocker (e.g., bupropion). In another aspect the is that wherein the 5-HT, receptor antagonist is also a composition is that wherein the 5-HT, receptor antagonist 15 5-HT, receptor antagonist. In another aspect the composi is also a 5-HT, receptor agonist. In another aspect the tion is that wherein the 5-HT, receptor antagonist is also a composition is that wherein the 5-HT, receptor antagonist 5-HT, receptor antagonist and a 5-HT, receptor agonist is also a 5-HT, receptor antagonist. In another aspect the (e.g., traZodone). In another aspect the composition is that composition is that wherein the 5-HT, receptor antagonist wherein the 5-HT2 receptor antagonist, 5-HT, receptor is also a 5-HT, receptor antagonist and a 5-HT, receptor agonist, and/or 5-HT, receptor antagonist is also an alpha agonist (e.g., traZodone). In another aspect the composition adrenergic blocker (e.g., traZodone). is that wherein the 5-HT2 receptor antagonist, 5-HT In one aspect, the invention provides a method of enhanc receptor agonist, and/or 5-HT, receptor antagonist is also ing cognition comprising administering to a Subject in need an alpha adrenergic blocker (e.g., traZodone). thereof a therapeutically effective amount of a composition In one aspect, the invention provides a method of enhanc 25 comprising a 5-HT, antagonist, a norepinephrine-dop ing cognition comprising administering to a Subject in need amine reuptake inhibitor, a 5-HT2, agonist (e.g., lorcaserin, thereof a therapeutically effective amount of a composition vabicaserin, PRX-00933, YM348, metachlorophenylpipera comprising a 5-HT, antagonist, a norepinephrine-dop Zine, and mCPP), other non-abusable agents (agents not amine reuptake inhibitor, other non-abusable agents (agents scheduled by the DEA) that augment dopamine and/or not scheduled by the DEA) that augment dopamine and/or 30 norepinephrine in the brain, e.g., atomoxetine, reboxetine, norepinephrine in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, talopram, talsupram, tan lortalamine, mazindol, nisoxetine, talopram, talsupram, tan damine, Viloxazine, maprotiline, ciclazindol, manifaxine, damine, Viloxazine, maprotiline, ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo 35 biloba), and a pharmaceutically acceptable carrier. In one biloba), and a pharmaceutically acceptable carrier. In one aspect, one compound is both a 5-HT, antagonist and a aspect, one compound is both a 5-HT, antagonist and a 5-HT, receptor agonist (e.g., traZodone, nefazodone, mir 5-HT, receptor agonist (e.g., traZodone, nefazodone, mir tazapine, flibanserin, ketanserin, ritanserin, clozapine, olan tazapine, flibanserin, ketanserin, ritanserin, clozapine, olan Zapine, quetiapine, risperidone, asenapine, MDL-100.907. Zapine, quetiapine, risperidone, asenapine, MDL-100.907. 40 cyproheptadine, aripiprazole, and the general class of cyproheptadine, aripiprazole, and the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another aspect the composition is that wherein the norepinephrine aspect the composition is that wherein the norepinephrine dopamine reuptake inhibitor is also an alpha adrenergic dopamine reuptake inhibitor is also an alpha adrenergic blocker (e.g., bupropion). In another aspect the composition blocker (e.g., bupropion). In another aspect the composition 45 is that wherein the 5-HT2 receptor antagonist is also a is that wherein the 5-HT2 receptor antagonist is also a 5-HT, receptor agonist. In another aspect the composition 5-HT, receptor agonist. In another aspect the composition is that wherein the 5-HT, receptor antagonist is also a is that wherein the 5-HT2 receptor antagonist is also a 5-HT, receptor antagonist. In another aspect the composi 5-HT, receptor antagonist. In another aspect the composi tion is that wherein the 5-HT, receptor antagonist is also a tion is that wherein the 5-HT2 receptor antagonist is also a 50 5-HT, receptor antagonist and a 5-HT, receptor agonist 5-HT, receptor antagonist and a 5-HT, receptor agonist (e.g., traZodone). In another aspect the composition is that (e.g., traZodone). In another aspect the composition is that wherein the 5-HT2 receptor antagonist, 5-HT, receptor wherein the 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or 5-HT, receptor antagonist is also an alpha agonist, and/or 5-HT, receptor antagonist is also an alpha adrenergic blocker (e.g., traZodone). adrenergic blocker (e.g., traZodone). 55 In one aspect, the invention provides a method of enhanc In one aspect, the invention provides a method of enhanc ing cognition comprising administering to a Subject in need ing cognition comprising administering to a Subject in need thereof a therapeutically effective amount of a composition thereof a therapeutically effective amount of a composition comprising a 5-HT, receptor agonist, a 5-HT, antagonist, comprising a 5-HT, antagonist, a norepinephrine-dop and a pharmaceutically acceptable carrier. In one aspect, one amine reuptake inhibitor, a 5-HT2, agonist (e.g., lorcaserin, 60 compound is the 5-HT, receptor agonist and the 5-HT vabicaserin, PRX-00933, YM348, metachlorophenylpipera antagonist (e.g., traZodone, nefazodone, mirtazapine, fliban Zine, and mCPP), other non-abusable agents (agents not serin). In another aspect the composition is that wherein the scheduled by the DEA) that augment dopamine and/or 5-HT, receptor antagonist is also a 5-HT, receptor ago norepinephrine in the brain, e.g., atomoxetine, reboxetine, nist. In another aspect the composition is that wherein the amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, 65 5-HT2 receptor antagonist is also a 5-HT, receptor antago lortalamine, mazindol, nisoxetine, talopram, talsupram, tan nist. In another aspect the composition is that wherein the damine, Viloxazine, maprotiline, ciclazindol, manifaxine, 5-HT2 receptor antagonist is also a 5-HT, receptor antago US 9,517,254 B2 41 42 nist and a 5-HT, receptor agonist (e.g., traZodone). In that wherein the 5-HT2 receptor antagonist is also a 5-HT another aspect the composition is that wherein the 5-HT receptor agonist. In another aspect the composition is that receptor antagonist, 5-HT, receptoragonist, and/or 5-HT, wherein the 5-HT2 receptor antagonist is also a 5-HT, receptor antagonist is also an alpha adrenergic blocker (e.g., receptor antagonist. In another aspect the composition is that traZodone). wherein the 5-HT2 receptor antagonist is also a 5-HT, In one aspect, the invention provides a method of enhanc receptor antagonist and a 5-HT, receptor agonist (e.g., ing cognition comprising administering to a Subject in need traZodone). In another aspect the composition is that thereof a therapeutically effective amount of a composition wherein the 5-HT2 receptor antagonist, 5-HT, receptor comprising a 5-HT, receptor agonist, a 5-HT, antagonist, agonist, and/or 5-HT, receptor antagonist is also an alpha and a pharmaceutically acceptable carrier. In one aspect, one 10 adrenergic blocker (e.g., traZodone). compound is the 5-HT, receptor agonist and the 5-HT In one aspect, the invention provides a method of enhanc antagonist (e.g., traZodone, nefazodone, mirtazapine, fliban ing cognition comprising administering to a Subject in need serin, ketanserin, ritanserin, clozapine, olanzapine, quetiap thereof a therapeutically effective amount of a composition ine, risperidone, asenapine, MDL-100.907, cyproheptadine, comprising a 5-HT, receptor agonist, a 5-HT, antagonist, aripiprazole, and the general class of 2-alkyl-4-aryl-tetra 15 a 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, hydro-pyrimido-azepines). In another aspect the composi YM348, metachlorophenylpiperazine, and mCPP), other tion is that wherein the 5-HT2 receptor antagonist is also a non-abusable agents (agents not scheduled by the DEA) that 5-HT, receptor agonist. In another aspect the composition augment dopamine and/or norepinephrine in the brain, e.g., is that wherein the 5-HT2 receptor antagonist is also a atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, 5-HT, receptor antagonist. In another aspect the composi edivoxetine, esreboxetine, lortalamine, mazindol, nisox tion is that wherein the 5-HT, receptor antagonist is also a etine, talopram, talsupram, tandamine, Viloxazine, maproti 5-HT, receptor antagonist and a 5-HT, receptor agonist line, ciclaZindol, manifaxine, radafaxine, tapentadol, (e.g., traZodone). In another aspect the composition is that teniloxazine, St. John’s wort, ginkgo biloba), and a phar wherein the 5-HT2 receptor antagonist, 5-HT, receptor maceutically acceptable carrier. In one aspect, one com agonist, and/or 5-HT, receptor antagonist is also an alpha 25 pound is the 5-HT, receptoragonist and the 5-HT, antago adrenergic blocker (e.g., traZodone). nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, In one aspect, the invention provides a method of enhanc ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris ing cognition comprising administering to a Subject in need peridone, asenapine, MDL-100.907, cyproheptadine, arip thereof a therapeutically effective amount of a composition iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro comprising a 5-HT, receptor agonist, a 5-HT, antagonist, 30 pyrimido-azepines). In another aspect the composition is other non-abusable agents (agents not scheduled by the that wherein the 5-HT2 receptor antagonist is also a 5-HT DEA) that augment dopamine and/or norepinephrine in the receptor agonist. In another aspect the composition is that brain, e.g., atomoxetine, reboxetine, amedalin, CP-39,332, wherein the 5-HT, receptor antagonist is also a 5-HT, daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, receptor antagonist. In another aspect the composition is that nisoxetine, talopram, talSupram, tandamine, Viloxazine, 35 wherein the 5-HT, receptor antagonist is also a 5-HT, maprotiline, ciclazindol, manifaxine, radafaxine, tapentadol, receptor antagonist and a 5-HT, receptor agonist (e.g., teniloxazine, St. John’s wort, ginkgo biloba), and a phar traZodone). In another aspect the composition is that maceutically acceptable carrier. In one aspect, one com wherein the 5-HT2 receptor antagonist, 5-HT, receptor pound is the 5-HT, receptoragonist and the 5-HT, antago agonist, and/or 5-HT, receptor antagonist is also an alpha nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, 40 adrenergic blocker (e.g., traZodone). ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris In one aspect, the invention provides a method of enhanc peridone, asenapine, MDL-100.907, cyproheptadine, arip ing cognition comprising administering to a Subject in need iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro thereof a therapeutically effective amount of a composition pyrimido-azepines). In another aspect the composition is comprising a 5-HT, receptor agonist, a 5-HT, antagonist, that wherein the 5-HT2 receptor antagonist is also a 5-HT 45 an oxytocin receptor (OXTR) agonist (e.g., carbetocin, receptor agonist. In another aspect the composition is that oxytocin, Syntocinon R.), and a pharmaceutically acceptable wherein the 5-HT, receptor antagonist is also a 5-HT, carrier. In one aspect, one compound is the 5-HT, receptor receptor antagonist. In another aspect the composition is that agonist and the 5-HT, antagonist (e.g., traZodone, nefa wherein the 5-HT, receptor antagonist is also a 5-HT, Zodone, mirtazapine, flibanserin). In another aspect the receptor antagonist and a 5-HT, receptor agonist (e.g., 50 composition is that wherein the 5-HT, receptor antagonist traZodone). In another aspect the composition is that is also a 5-HT, receptor agonist. In another aspect the wherein the 5-HT2 receptor antagonist, 5-HT, receptor composition is that wherein the 5-HT, receptor antagonist agonist, and/or 5-HT, receptor antagonist is also an alpha is also a 5-HT, receptor antagonist. In another aspect the adrenergic blocker (e.g., traZodone). composition is that wherein the 5-HT, receptor antagonist In one aspect, the invention provides a method of enhanc 55 is also a 5-HT, receptor antagonist and a 5-HT, receptor ing cognition comprising administering to a Subject in need agonist (e.g., traZodone). In another aspect the composition thereof a therapeutically effective amount of a composition is that wherein the 5-HT2 receptor antagonist, 5-HT comprising a 5-HT, receptor agonist, a 5-HT, antagonist, receptor agonist, and/or 5-HT, receptor antagonist is also a 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, an alpha adrenergic blocker (e.g., traZodone). YM348, metachlorophenylpiperazine, and mOPP), and a 60 In one aspect, the invention provides a method of enhanc pharmaceutically acceptable carrier. In one aspect, one com ing cognition comprising administering to a Subject in need pound is the 5-HT, receptoragonist and the 5-HT, antago thereof a therapeutically effective amount of a composition nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, comprising a 5-HT, receptor agonist, a 5-HT, antagonist, ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris an oxytocin receptor (OXTR) agonist (e.g., carbetocin, peridone, asenapine, MDL-100.907, cyproheptadine, arip 65 oxytocin, Syntocinon R.), and a pharmaceutically acceptable iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro carrier. In one aspect, one compound is the 5-HT, receptor pyrimido-azepines). In another aspect the composition is agonist and the 5-HT, antagonist (e.g., traZodone, nefa US 9,517,254 B2 43 44 Zodone, mirtazapine, flibanserin, ketanserin, ritanserin, clo 5-HT, receptor agonist, and/or 5-HT, receptor antagonist Zapine, olanzapine, quetiapine, risperidone, asenapine, is also an alpha adrenergic blocker (e.g., traZodone). MDL-100.907, cyproheptadine, aripiprazole, and the gen In one aspect, the invention provides a method of enhanc eral class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). ing cognition comprising administering to a Subject in need In another aspect the composition is that wherein the 5-HT, 5 thereof a therapeutically effective amount of a composition receptor antagonist is also a 5-HT, receptor agonist. In comprising a 5-HT, receptor agonist, a 5-HT, antagonist, another aspect the composition is that wherein the 5-HT an oxytocin receptor (OXTR) agonist (e.g., carbetocin, receptor antagonist is also a 5-HT, receptor antagonist. In oxytocin, Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, another aspect the composition is that wherein the 5-HT vabicaserin, PRX-00933, YM348, metachlorophenylpipera 10 Zine, and mCPP), other non-abusable agents (agents not receptor antagonist is also a 5-HT, receptor antagonist and scheduled by the DEA) that augment dopamine and/or a 5-HT, receptor agonist (e.g., trazodone). In another norepinephrine in the brain, e.g., atomoxetine, reboxetine, aspect the composition is that wherein the 5-HT2 receptor amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, antagonist, 5-HT, receptoragonist, and/or 5-HT, receptor lortalamine, mazindol, nisoxetine, talopram, talsupram, tan antagonist is also an alpha adrenergic blocker (e.g., tra 15 damine, Viloxazine, maprotiline, ciclazindol, manifaxine, Zodone). radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo In one aspect, the invention provides a method of enhanc biloba), and a pharmaceutically acceptable carrier. In one ing cognition comprising administering to a Subject in need aspect, one compound is the 5-HT, receptoragonist and the thereof a therapeutically effective amount of a composition 5-HT, antagonist (e.g., traZodone, nefazodone, mirtazap comprising a 5-HT, receptor agonist, a 5-HT, antagonist, ine, flibanserin, ketanserin, ritanserin, clozapine, olanzapine, an oxytocin receptor (OXTR) agonist (e.g., carbetocin, quetiapine, risperidone, asenapine, MDL-100.907, cypro oxytocin, Syntocinon R.), other non-abusable agents (agents heptadine, aripiprazole, and the general class of 2-alkyl-4- not scheduled by the DEA) that augment dopamine and/or aryl-tetrahydro-pyrimido-azepines). In another aspect the norepinephrine in the brain, e.g., atomoxetine, reboxetine, composition is that wherein the 5-HT, receptor antagonist amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, 25 is also a 5-HT, receptor agonist. In another aspect the lortalamine, mazindol, nisoxetine, talopram, talsupram, tan composition is that wherein the 5-HT, receptor antagonist damine, Viloxazine, maprotiline, ciclazindol, manifaxine, is also a 5-HT, receptor antagonist. In another aspect the radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo composition is that wherein the 5-HT, receptor antagonist biloba), and a pharmaceutically acceptable carrier. In one is also a 5-HT, receptor antagonist and a 5-HT, receptor aspect, one compound is the 5-HT, receptoragonist and the 30 agonist (e.g., traZodone). In another aspect the composition 5-HT, antagonist (e.g., traZodone, nefazodone, mirtazap is that wherein the 5-HT2 receptor antagonist, 5-HT ine, flibanserin, ketanserin, ritanserin, clozapine, olanzapine, receptor agonist, and/or 5-HT, receptor antagonist is also quetiapine, risperidone, asenapine, MDL-100.907, cypro an alpha adrenergic blocker (e.g., traZodone). heptadine, aripiprazole, and the general class of 2-alkyl-4- In one aspect, the invention provides a method of enhanc aryl-tetrahydro-pyrimido-azepines). In another aspect the 35 ing cognition comprising administering to a Subject in need composition is that wherein the 5-HT, receptor antagonist thereof a therapeutically effective amount of a composition is also a 5-HT, receptor agonist. In another aspect the comprising a norepinephrine-dopamine reuptake inhibitor, composition is that wherein the 5-HT, receptor antagonist an oxytocin receptor (OXTR) agonist (e.g., carbetocin, is also a 5-HT, receptor antagonist. In another aspect the oxytocin, Syntocinon R.), and a pharmaceutically acceptable composition is that wherein the 5-HT, receptor antagonist 40 carrier. In another aspect, the norepinephrine-dopamine is also a 5-HT, receptor antagonist and a 5-HT, receptor reuptake inhibitor is also a alpha adrenergic blocker (e.g., agonist (e.g., traZodone). In another aspect the composition bupropion). is that wherein the 5-HT2 receptor antagonist, 5-HT In one aspect, the invention provides a method of enhanc receptor agonist, and/or 5-HT, receptor antagonist is also ing cognition comprising administering to a Subject in need an alpha adrenergic blocker (e.g., traZodone). 45 thereof a therapeutically effective amount of a composition In one aspect, the invention provides a method of enhanc comprising a norepinephrine-dopamine reuptake inhibitor, ing cognition comprising administering to a Subject in need an oxytocin receptor (OXTR) agonist (e.g., carbetocin, thereof a therapeutically effective amount of a composition oxytocin, Syntocinon R.), other non-abusable agents (agents comprising a 5-HT, receptor agonist, a 5-HT, antagonist, not scheduled by the DEA) that augment dopamine and/or an oxytocin receptor (OXTR) agonist (e.g., carbetocin, 50 norepinephrine in the brain, e.g., atomoxetine, reboxetine, oxytocin, Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, vabicaserin, PRX-00933, YM348, metachlorophenylpipera lortalamine, mazindol, nisoxetine, talopram, talsupram, tan Zine, and mCPP), and a pharmaceutically acceptable carrier. damine, Viloxazine, maprotiline, ciclazindol, manifaxine, In one aspect, one compound is the 5-HT, receptor agonist radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo and the 5-HT, antagonist (e.g., traZodone, nefazodone, 55 biloba), and a pharmaceutically acceptable carrier. In mirtazapine, flibanserin, ketanserin, ritanserin, clozapine, another aspect, the norepinephrine-dopamine reuptake olanzapine, quetiapine, risperidone, asenapine, MDL-100, inhibitor is also a alpha adrenergic blocker (e.g., bupropion). 907, cyproheptadine, aripiprazole, and the general class of In one aspect, the invention provides a method of enhanc 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another ing cognition comprising administering to a Subject in need aspect the composition is that wherein the 5-HT2 receptor 60 thereof a therapeutically effective amount of a composition antagonist is also a 5-HT, receptor agonist. In another comprising a norepinephrine-dopamine reuptake inhibitor, aspect the composition is that wherein the 5-HT2 receptor an oxytocin receptor (OXTR) agonist (e.g., carbetocin, antagonist is also a 5-HT, receptor antagonist. In another oxytocin, SyntocinonR), a 5-HT, agonist (e.g., lorcaserin, aspect the composition is that wherein the 5-HT2 receptor vabicaserin, PRX-00933, YM348, metachlorophenylpipera antagonist is also a 5-HT2 receptor antagonist and a 5-HT 65 Zine, and mCPP), and a pharmaceutically acceptable carrier. receptor agonist (e.g., traZodone). In another aspect the In another aspect, the norepinephrine-dopamine reuptake composition is that wherein the 5-HT2 receptor antagonist, inhibitor is also a alpha adrenergic blocker (e.g., bupropion). US 9,517,254 B2 45 46 In one aspect, the invention provides a method of enhanc Another aspect is a method of treating a disease, disorder ing cognition comprising administering to a Subject in need or symptom thereof described in the Diagnostic and Statis thereof a therapeutically effective amount of a composition tical Manual of Mental Disorders (DSM-IV-TR) in a subject comprising a norepinephrine-dopamine reuptake inhibitor, comprising administering to the Subject a compound or an oxytocin receptor (OXTR) agonist (e.g., carbetocin, composition herein. oxytocin, Syntocinon R.), other non-abusable agents (agents Another aspect is a method of treating erectile dysfunc not scheduled by the DEA) that augment dopamine and/or tion (ED) in a Subject comprising administering to the norepinephrine in the brain, e.g., atomoxetine, reboxetine, Subject a compound or composition herein. amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, Another aspect is a method of treating male HSDD in a lortalamine, mazindol, nisoxetine, talopram, talsupram, tan 10 Subject comprising administering to the Subject a compound damine, Viloxazine, maprotiline, ciclazindol, manifaxine, or composition herein. radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo Another aspect is a method of treating male sexual biloba), a 5-HT2, agonist (e.g., lorcaserin, vabicaserin, disorders in a Subject comprising administering to the Sub PRX-00933, YM348, metachlorophenylpiperazine, and ject a compound or composition herein. mCPP), and a pharmaceutically acceptable carrier. In 15 Another aspect is a method of treating depressive disor another aspect, the norepinephrine-dopamine reuptake ders in a Subject comprising administering to the Subject a inhibitor is also a alpha adrenergic blocker (e.g., bupropion). compound or composition herein. Depressive disorders and In one aspect, the invention provides a method of enhanc “depression” as used in this document includes each of the ing cognition comprising administering to a Subject in need depressive disorder recognized and defined by the DSM-IV thereof a therapeutically effective amount of a composition TR: Major Depressive Disorder and Major Depressive Epi comprising an oxytocin receptor (OXTR) agonist (e.g., sode (MDD/MDE: at least five major symptoms such as carbetocin, oxytocin, Syntocinon R) and a pharmaceutically impairment of ability to work and suicidality nearly every acceptable carrier. day for at least two weeks), Mood Disorder due to a General In one aspect, the invention provides a method of enhanc Medical Condition, Substance-Induced Mood Disorder, and ing cognition comprising administering to a Subject in need 25 Depressive Disorder Not Otherwise Specified. Each of these thereof a therapeutically effective amount of a composition disorders includes specifiers of With or Without Psychotic comprising an oxytocin receptor (OXTR) agonist (e.g., Features. With Catatonic Features (or without). With Mel carbetocin, oxytocin, Syntocinon R.), other non-abusable ancholic Features (or without). With Atypical Features (or agents (agents not scheduled by the DEA) that augment without), and With Postpartum Onset. Lesser depressive dopamine and/or norepinephrine in the brain, e.g., atomox 30 disorders, but still associated with significant disability, etine, reboxetine, amedalin, CP-39,332, daledalin, edivox include Dysthymic Disorder (lesser symptoms Such as low etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo energy but not loss of pleasure in all activities; feelings of pram, talsupram, tandamine, Viloxazine, maprotiline, hopeless but not suicidality, on a majority of days for at least ciclazindol, manifaxine, radafaxine, tapentadol, tenilox two years) and Depressive Disorder Not Otherwise Speci azine, St. John’s wort, ginkgo biloba), and a pharmaceuti 35 fied (too few symptoms or too little constancy to meet cally acceptable carrier. criteria for MDD/MDE but still causing disability, including In one aspect, the invention provides a method of enhanc premenstrual dysphoric disorder, minor depressive disorder ing cognition comprising administering to a Subject in need (less than 5 depressive symptoms), recurrent brief depres thereof a therapeutically effective amount of a composition sive disorder (episodes lasting less than 2 weeks), post comprising an oxytocin receptor (OXTR) agonist (e.g., 40 psychotic depressive disorder of Schizophrenia. carbetocin, oxytocin, Syntocinon R, a 5-HT, agonist (e.g., Another aspect is an extended release composition com lorcaserin, vabicaserin, PRX-00933, YM348, metachloro prising a 5-HT, antagonist, a norepinephrine-dopamine phenylpiperazine, and mCPP), and a pharmaceutically reuptake inhibitor (e.g., bupropion), and a pharmaceutically acceptable carrier. acceptable carrier. In one aspect, the invention provides a method of enhanc 45 Another aspect is an extended release composition com ing cognition comprising administering to a Subject in need prising a 5-HT, antagonist, a norepinephrine-dopamine thereof a therapeutically effective amount of a composition reuptake inhibitor (e.g., bupropion), other non-abusable comprising an oxytocin receptor (OXTR) agonist (e.g., agents (agents not scheduled by the DEA) that augment carbetocin, oxytocin, Syntocinon R.), other non-abusable dopamine and/or norepinephrine in the brain, e.g., atomox agents (agents not scheduled by the DEA) that augment 50 etine, reboxetine, amedalin, CP-39,332, daledalin, edivox dopamine and/or norepinephrine in the brain, e.g., atomox etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo etine, reboxetine, amedalin, CP-39,332, daledalin, edivox pram, talsupram, tandamine, Viloxazine, maprotiline, etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo ciclazindol, manifaxine, radafaxine, tapentadol, tenilox pram, talsupram, tandamine, Viloxazine, maprotiline, azine, St. John’s wort, ginkgo biloba), and a pharmaceuti ciclazindol, manifaxine, radafaxine, tapentadol, tenilox 55 cally acceptable carrier. azine, St. John’s wort, ginkgo biloba), a 5-HT, agonist Another aspect is an extended release composition com (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, prising a 5-HT, antagonist, a norepinephrine-dopamine metachlorophenylpiperazine, and mCPP), and a pharmaceu reuptake inhibitor (e.g., bupropion), a 5-HT, agonist (e.g., tically acceptable carrier. lorcaserin, vabicaserin, PRX-00933, YM348, metachloro In aspects, the method is that wherein the cognition 60 phenylpiperazine, and mCPP), and a pharmaceutically enhancement is improving mental activities such as atten acceptable carrier. tion, perception, learning, memory, language, planning, Another aspect is an extended release composition com decision-making, organization, conceptualization, reorgani prising a 5-HT, antagonist, a norepinephrine-dopamine Zation, synthesis of facts, synthesis of data, recall, calcula reuptake inhibitor (e.g., bupropion), a 5-HT, agonist (e.g., tion, spatiotemporal visualization, mental flexibility, creativ 65 lorcaserin, vabicaserin, PRX-00933, YM348, metachloro ity, or the ability to accept challenging intellectual or cultural phenylpiperazine, and mCPP), other non-abusable agents pursuits. (agents not scheduled by the DEA) that augment dopamine US 9,517,254 B2 47 48 and/or norepinephrine in the brain, e.g., atomoxetine, rebox Another aspect is an extended release composition com etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox prising a 5-HT, antagonist, an oxytocin receptor (OXTR) etine, lortalamine, mazindol, nisoxetine, talopram, talsu agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, pram, tandamine, Viloxazine, maprotiline, ciclaZindol, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, manifaxine, radafaxine, tapentadol, teniloxazine, St. John's metachlorophenylpiperazine, and mOPP), other non-abus wort, ginkgo biloba), and a pharmaceutically acceptable able agents (agents not scheduled by the DEA) that augment carrier. dopamine and/or norepinephrine in the brain, e.g., atomox Another aspect is an extended release composition com etine, reboxetine, amedalin, CP-39,332, daledalin, edivox prising a 5-HT, antagonist, a norepinephrine-dopamine etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo reuptake inhibitor (e.g., bupropion), an oxytocin receptor 10 pram, talsupram, tandamine, Viloxazine, maprotiline, (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), ciclazindol, manifaxine, radafaxine, tapentadol, tenilox and a pharmaceutically acceptable carrier. azine, St. John’s wort, ginkgo biloba), and a pharmaceuti Another aspect is an extended release composition com cally acceptable carrier. prising a 5-HT, antagonist, a norepinephrine-dopamine Another aspect is an extended release composition com reuptake inhibitor (e.g., bupropion), an oxytocin receptor 15 prising a norepinephrine-dopamine reuptake inhibitor (e.g., (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), bupropion), an oxytocin receptor (OXTR) agonist (e.g., other non-abusable agents (agents not scheduled by the carbetocin, oxytocin, Syntocinon R.), and a pharmaceutically DEA) that augment dopamine and/or norepinephrine in the acceptable carrier. brain, e.g., atomoxetine, reboxetine, amedalin, CP-39,332, Another aspect is an extended release composition com daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, prising a norepinephrine-dopamine reuptake inhibitor (e.g., nisoxetine, talopram, talSupram, tandamine, Viloxazine, bupropion), an oxytocin receptor (OXTR) agonist (e.g., maprotiline, ciclazindol, manifaxine, radafaxine, tapentadol, carbetocin, oxytocin, Syntocinon R.), other non-abusable teniloxazine, St. John’s wort, ginkgo biloba), and a phar agents (agents not scheduled by the DEA) that augment maceutically acceptable carrier. 25 dopamine and/or norepinephrine in the brain, e.g., atomox Another aspect is an extended release composition com etine, reboxetine, amedalin, CP-39,332, daledalin, edivox prising a 5-HT, antagonist, a norepinephrine-dopamine etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo reuptake inhibitor (e.g., bupropion), an oxytocin receptor pram, talsupram, tandamine, Viloxazine, maprotiline, (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), ciclazindol, manifaxine, radafaxine, tapentadol, tenilox a 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, 30 azine, St. John’s wort, ginkgo biloba), and a pharmaceuti YM348, metachlorophenylpiperazine, and mOPP), and a cally acceptable carrier. pharmaceutically acceptable carrier. Another aspect is an extended release composition com Another aspect is an extended release composition com prising a norepinephrine-dopamine reuptake inhibitor (e.g., prising a 5-HT, antagonist, a norepinephrine-dopamine bupropion), an oxytocin receptor (OXTR) agonist (e.g., reuptake inhibitor (e.g., bupropion), an oxytocin receptor 35 carbetocin, oxytocin, SyntocinonR), a 5-HT, agonist (e.g., (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), lorcaserin, vabicaserin, PRX-00933, YM348, metachloro a 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, phenylpiperazine, and mCPP), and a pharmaceutically YM348, metachlorophenylpiperazine, and mCPP), other acceptable carrier. non-abusable agents (agents not scheduled by the DEA) that Another aspect is an extended release composition com augment dopamine and/or norepinephrine in the brain, e.g., 40 prising a norepinephrine-dopamine reuptake inhibitor (e.g., atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, bupropion), an oxytocin receptor (OXTR) agonist (e.g., edivoxetine, esreboxetine, lortalamine, mazindol, nisox carbetocin, oxytocin, SyntocinonR), a 5-HT, agonist (e.g., etine, talopram, talsupram, tandamine, Viloxazine, maproti lorcaserin, vabicaserin, PRX-00933, YM348, metachloro line, ciclaZindol, manifaxine, radafaxine, tapentadol, phenylpiperazine, and mCPP), other non-abusable agents teniloxazine, St. John’s wort, ginkgo biloba), and a phar 45 (agents not scheduled by the DEA) that augment dopamine maceutically acceptable carrier. and/or norepinephrine in the brain, e.g., atomoxetine, rebox Another aspect is an extended release composition com etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox prising a 5-HT, antagonist, an oxytocin receptor (OXTR) etine, lortalamine, mazindol, nisoxetine, talopram, talsu agonist (e.g., carbetocin, oxytocin, SyntocinonR), and a pram, tandamine, Viloxazine, maprotiline, ciclaZindol, pharmaceutically acceptable carrier. 50 manifaxine, radafaxine, tapentadol, teniloxazine, St. John's Another aspect is an extended release composition com wort, ginkgo biloba), and a pharmaceutically acceptable prising a 5-HT, antagonist, an oxytocin receptor (OXTR) carrier. agonist (e.g., carbetocin, oxytocin, Syntocinon R.), other Another aspect is an extended release composition com non-abusable agents (agents not scheduled by the DEA) that prising an oxytocin receptor (OXTR) agonist (e.g., carbe augment dopamine and/or norepinephrine in the brain, e.g., 55 tocin, oxytocin, Syntocinon R) and a pharmaceutically atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, acceptable carrier. edivoxetine, esreboxetine, lortalamine, mazindol, nisox Another aspect is an extended release composition com etine, talopram, talsupram, tandamine, Viloxazine, maproti prising an oxytocin receptor (OXTR) agonist (e.g., carbe line, ciclaZindol, manifaxine, radafaxine, tapentadol, tocin, oxytocin, Syntocinon R.), other non-abusable agents teniloxazine, St. John’s wort, ginkgo biloba), and a phar 60 (agents not scheduled by the DEA) that augment dopamine maceutically acceptable carrier. and/or norepinephrine in the brain, e.g., atomoxetine, rebox Another aspect is an extended release composition com etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox prising a 5-HT, antagonist, an oxytocin receptor (OXTR) etine, lortalamine, mazindol, nisoxetine, talopram, talsu agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, pram, tandamine, Viloxazine, maprotiline, ciclaZindol, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, 65 manifaxine, radafaxine, tapentadol, teniloxazine, St. John's metachlorophenylpiperazine, and mCPP), and a pharmaceu wort, ginkgo biloba), and a pharmaceutically acceptable tically acceptable carrier. carrier. US 9,517,254 B2 49 50 Another aspect is an extended release composition com In one aspect, the invention provides a composition prising an oxytocin receptor (OXTR) agonist (e.g., carbe comprising the 5-HT, receptor agonist and 5-HT, antago tocin, oxytocin, SyntocinonR), a 5-HT2, agonist (e.g., lor nist mirtazapine, a 5-HT2, agonist (e.g., lorcaserin, vabica caserin, vabicaserin, PRX-00933, YM348, serin, PRX-00933, YM348, metachlorophenylpiperazine, metachlorophenylpiperazine, and mCPP), and a pharmaceu and mCPP), ther non-abusable agents (agents not scheduled tically acceptable carrier. by the DEA) that augment dopamine and/or norepinephrine Another aspect is an extended release composition com in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, prising an oxytocin receptor (OXTR) agonist (e.g., carbe 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ tocin, oxytocin, SyntocinonR), a 5-HT, agonist (e.g., lor indol, nisoxetine, talopram, talsupram, tandamine, Vilox caserin, vabicaserin, PRX-00933, YM348, 10 azine, maprotiline, ciclazindol, manifaxine, radafaxine, metachlorophenylpiperazine, and mOPP), other non-abus tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), able agents (agents not scheduled by the DEA) that augment and a pharmaceutically acceptable carrier. dopamine and/or norepinephrine in the brain, e.g., atomox In one aspect, the invention provides a composition etine, reboxetine, amedalin, CP-39,332, daledalin, edivox comprising the 5-HT, receptor agonist and 5-HT, antago etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo 15 nist flibanserin and a pharmaceutically acceptable carrier. pram, talsupram, tandamine, Viloxazine, maprotiline, In one aspect, the invention provides a composition ciclazindol, manifaxine, radafaxine, tapentadol, tenilox comprising the 5-HT, receptoragonist, and 5-HT, antago azine, St. John’s wort, ginkgo biloba), and a pharmaceuti nist flibanserin, other non-abusable agents (agents not cally acceptable carrier. scheduled by the DEA) that augment dopamine and/or In one aspect, the invention provides a composition norepinephrine in the brain, e.g., atomoxetine, reboxetine, comprising the 5-HT, receptor agonist and 5-HT, antago amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, nist nefazodone and a pharmaceutically acceptable carrier. lortalamine, mazindol, nisoxetine, talopram, talsupram, tan In one aspect, the invention provides a composition damine, Viloxazine, maprotiline, ciclazindol, manifaxine, comprising the 5-HT, receptoragonist, and 5-HT, antago radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo nist nefazodone, other non-abusable agents (agents not 25 biloba), and a pharmaceutically acceptable carrier. scheduled by the DEA) that augment dopamine and/or In one aspect, the invention provides a composition norepinephrine in the brain, e.g., atomoxetine, reboxetine, comprising the 5-HT, receptor agonist and 5-HT2, antago amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, nist flibanserin, a 5-HT, agonist (e.g., lorcaserin, vabica lortalamine, mazindol, nisoxetine, talopram, talsupram, tan serin, PRX-00933, YM348, metachlorophenylpiperazine, damine, Viloxazine, maprotiline, ciclazindol, manifaxine, 30 and mOPP), and a pharmaceutically acceptable carrier. radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo In one aspect, the invention provides a composition biloba), and a pharmaceutically acceptable carrier. comprising the 5-HT, receptor agonist and 5-HT, antago In one aspect, the invention provides a composition nist flibanserin, a 5-HT, agonist (e.g., lorcaserin, vabica comprising the 5-HT, receptor agonist and 5-HT2, antago serin, PRX-00933, YM348, metachlorophenylpiperazine, nist nefazodone, a 5-HT, agonist (e.g., lorcaserin, vabica 35 and mCPP), ther non-abusable agents (agents not scheduled serin, PRX-00933, YM348, metachlorophenylpiperazine, by the DEA) that augment dopamine and/or norepinephrine and mOPP), and a pharmaceutically acceptable carrier. in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, In one aspect, the invention provides a composition 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ comprising the 5-HT, receptor agonist and 5-HT2, antago indol, nisoxetine, talopram, talsupram, tandamine, Vilox nist nefazodone, a 5-HT, agonist (e.g., lorcaserin, vabica 40 azine, maprotiline, ciclazindol, manifaxine, radafaxine, serin, PRX-00933, YM348, metachlorophenylpiperazine, tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), and mCPP), ther non-abusable agents (agents not scheduled and a pharmaceutically acceptable carrier. by the DEA) that augment dopamine and/or norepinephrine In one aspect, the invention provides a composition in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, comprising the 5-HT, receptor agonist, 5-HT, receptor 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ 45 antagonist, and/or 5-HT, receptor antagonist traZodone and indol, nisoxetine, talopram, talsupram, tandamine, Vilox a pharmaceutically acceptable carrier. azine, maprotiline, ciclazindol, manifaxine, radafaxine, In one aspect, the invention provides a composition tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), comprising the 5-HT, receptoragonist, and 5-HT, antago and a pharmaceutically acceptable carrier. nist traZodone, other non-abusable agents (agents not sched In one aspect, the invention provides a composition 50 uled by the DEA) that augment dopamine and/or norepi comprising the 5-HT, receptor agonist and 5-HT2, antago nephrine in the brain, e.g., atomoxetine, reboxetine, nist mirtazapine and a pharmaceutically acceptable carrier. amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, In one aspect, the invention provides a composition lortalamine, mazindol, nisoxetine, talopram, talsupram, tan comprising the 5-HT, receptoragonist, and 5-HT, antago damine, Viloxazine, maprotiline, ciclazindol, manifaxine, nist mirtazapine, other non-abusable agents (agents not 55 radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo scheduled by the DEA) that augment dopamine and/or biloba), and a pharmaceutically acceptable carrier. norepinephrine in the brain, e.g., atomoxetine, reboxetine, In one aspect, the invention provides a composition amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, comprising the 5-HT, receptor agonist and 5-HT2, antago lortalamine, mazindol, nisoxetine, talopram, talsupram, tan nist traZodone, a 5-HT, agonist (e.g., lorcaserin, vabica damine, Viloxazine, maprotiline, ciclazindol, manifaxine, 60 serin, PRX-00933, YM348, metachlorophenylpiperazine, radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo and mOPP), and a pharmaceutically acceptable carrier. biloba), and a pharmaceutically acceptable carrier. In one aspect, the invention provides a composition In one aspect, the invention provides a composition comprising the 5-HT, receptor agonist and 5-HT, antago comprising the 5-HT, receptor agonist and 5-HT2, antago nist traZodone, a 5-HT, agonist (e.g., lorcaserin, vabica nist mirtazapine, a 5-HT2, agonist (e.g., lorcaserin, vabica 65 serin, PRX-00933, YM348, metachlorophenylpiperazine, serin, PRX-00933, YM348, metachlorophenylpiperazine, and mCPP), ther non-abusable agents (agents not scheduled and mOPP), and a pharmaceutically acceptable carrier. by the DEA) that augment dopamine and/or norepinephrine US 9,517,254 B2 51 52 in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, In another aspect of the invention, a formulation of 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ bupropion and traZodone to treat sexual disorders has an indol, nisoxetine, talopram, talsupram, tandamine, Vilox outer layer that releases a nontoxic dye in water or water azine, maprotiline, ciclazindol, manifaxine, radafaxine, alcohol solutions (alcoholic drinks) sufficient in color to tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), show that the drink has been tampered with. and a pharmaceutically acceptable carrier. In another aspect of the invention, a formulation of Other aspects include those, wherein the composition is bupropion and traZodone to treat sexual disorders has an administered orally; wherein the composition is adminis outer layer that releases a nontoxic gelling agent in water or tered topically; wherein the Subject is diagnosed and being water-alcohol solutions sufficient to thicken or solidify the treated for depression; wherein the Subject is not undergoing 10 drink to show it has been tampered with. treatment for depression; wherein the Subject is concurrently In one aspect, the invention provides a composition prescribed an additional therapeutic agent; or wherein the comprising the 5-HT, receptor agonist and 5-HT2, antago Subject is concurrently not prescribed an additional thera nist nefazodone and a pharmaceutically acceptable carrier. peutic agent; wherein the Subject is concurrently adminis In one aspect, the invention provides a composition tered an additional therapeutic agent; or wherein the Subject 15 comprising the 5-HT, receptoragonist, and 5-HT, antago is concurrently not administered an additional therapeutic nist nefazodone, other non-abusable agents (agents not agent. scheduled by the DEA) that augment dopamine and/or In one aspect, the invention provides a composition norepinephrine in the brain, e.g., atomoxetine, reboxetine, comprising a 5-HT, receptor agonist, a 5-HT, antagonist, amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, and a pharmaceutically acceptable carrier. lortalamine, mazindol, nisoxetine, talopram, talsupram, tan In one aspect, the invention provides a composition damine, Viloxazine, maprotiline, ciclazindol, manifaxine, comprising the 5-HT, receptoragonist, and 5-HT, antago radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo nist, other non-abusable agents (agents not scheduled by the biloba), and a pharmaceutically acceptable carrier. DEA) that augment dopamine and/or norepinephrine in the In one aspect, the invention provides a composition brain, e.g., atomoxetine, reboxetine, amedalin, CP-39,332, 25 comprising the 5-HT, receptor agonist and 5-HT2, antago daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, nist nefazodone, a 5-HT2, agonist (e.g., lorcaserin, vabica nisoxetine, talopram, talSupram, tandamine, Viloxazine, serin, PRX-00933, YM348, metachlorophenylpiperazine, maprotiline, ciclazindol, manifaxine, radafaxine, tapentadol, and mOPP), and a pharmaceutically acceptable carrier. teniloxazine, St. John’s wort, ginkgo biloba), and a phar In one aspect, the invention provides a composition maceutically acceptable carrier. 30 comprising the 5-HT, receptor agonist and 5-HT, antago In one aspect, the invention provides a composition nist nefazodone, a 5-HT2, agonist (e.g., lorcaserin, vabica comprising the 5-HT, receptor agonist and 5-HT, antago serin, PRX-00933, YM348, metachlorophenylpiperazine, nist, a 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX and mCPP), ther non-abusable agents (agents not scheduled 00933, YM348, metachlorophenylpiperazine, and mCPP), by the DEA) that augment dopamine and/or norepinephrine and a pharmaceutically acceptable carrier. 35 in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, In one aspect, the invention provides a composition 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ comprising the 5-HT, receptor agonist and 5-HT2, antago indol, nisoxetine, talopram, talsupram, tandamine, Vilox nist, a 5-HT agonist (e.g., lorcaserin, vabicaserin, PRX azine, maprotiline, ciclazindol, manifaxine, radafaxine, 00933, YM348, metachlorophenylpiperazine, and mCPP), tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), other non-abusable agents (agents not scheduled by the 40 and a pharmaceutically acceptable carrier. DEA) that augment dopamine and/or norepinephrine in the In one aspect, the invention provides a composition brain, e.g., atomoxetine, reboxetine, amedalin, CP-39,332, comprising the 5-HT, receptor agonist and 5-HT, antago daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, nist mirtazapine and a pharmaceutically acceptable carrier. nisoxetine, talopram, talSupram, tandamine, Viloxazine, In one aspect, the invention provides a composition maprotiline, ciclazindol, manifaxine, radafaxine, tapentadol, 45 comprising the 5-HT, receptoragonist, and 5-HT, antago teniloxazine, St. John’s wort, ginkgo biloba), and a phar nist mirtazapine, other non-abusable agents (agents not maceutically acceptable carrier. scheduled by the DEA) that augment dopamine and/or In another aspect of the invention, a formulation of norepinephrine in the brain, e.g., atomoxetine, reboxetine, bupropion and traZodone to treat sexual disorders meets the amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, specific concerns of men including onset of action within an 50 lortalamine, mazindol, nisoxetine, talopram, talsupram, tan hour and continuation of efficacy overnight after a dose. damine, Viloxazine, maprotiline, ciclazindol, manifaxine, In another aspect of the invention, a formulation of radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo bupropion and traZodone to treat sexual disorders has a dose biloba), and a pharmaceutically acceptable carrier. up to 50% larger of the two components compared to a In one aspect, the invention provides a composition formulation for women. 55 comprising the 5-HT, receptor agonist and 5-HT2, antago In another aspect of the invention, a formulation of nist mirtazapine, a 5-HT, agonist (e.g., lorcaserin, vabica bupropion and traZodone to treat sexual disorders has an serin, PRX-00933, YM348, metachlorophenylpiperazine, outer layer with rapid release of an effective but well and mOPP), and a pharmaceutically acceptable carrier. tolerated amount of traZodone and bupropion, and an inner In one aspect, the invention provides a composition core with a sustained release of an effective and well 60 comprising the 5-HT, receptor agonist and 5-HT2, antago tolerated amount of traZodone and bupropion. nist mirtazapine, a 5-HT, agonist (e.g., lorcaserin, vabica In another aspect of the invention, a formulation of serin, PRX-00933, YM348, metachlorophenylpiperazine, bupropion and traZodone to treat sexual disorders has a and mCPP), ther non-abusable agents (agents not scheduled highly soluble outer layer and a matrix inner layer that by the DEA) that augment dopamine and/or norepinephrine remains insoluble in water or water-alcohol Solutions (alco 65 in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, holic drinks) and is large enough to be easily visible and 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ show that the drink has been tampered with. indol, nisoxetine, talopram, talsupram, tandamine, Vilox US 9,517,254 B2 53 54 azine, maprotiline, ciclazindol, manifaxine, radafaxine, tolerated amount of bupropion, traZodone, and oxytocin, and tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), an inner core with a Sustained release of an effective and and a pharmaceutically acceptable carrier. well tolerated amount of bupropion, traZodone, and oxyto In one aspect, the invention provides a composition cin. comprising the 5-HT, receptor agonist and 5-HT2, antago In another aspect of the invention, a formulation of nist flibanserin and a pharmaceutically acceptable carrier. bupropion, traZodone, and oxytocin to treat sexual disorders In one aspect, the invention provides a composition has a highly soluble outer layer and a matrix inner layer that comprising the 5-HT, receptoragonist, and 5-HT, antago remains insoluble in water or water-alcohol Solutions (alco nist flibanserin, other non-abusable agents (agents not holic drinks) and is large enough to be easily visible and scheduled by the DEA) that augment dopamine and/or 10 show that the drink has been tampered with. norepinephrine in the brain, e.g., atomoxetine, reboxetine, In another aspect of the invention, a formulation of amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, bupropion, traZodone, and oxytocin to treat sexual disorders lortalamine, mazindol, nisoxetine, talopram, talsupram, tan has an outer layer that releases a nontoxic dye in water or damine, Viloxazine, maprotiline, ciclazindol, manifaxine, water-alcohol solutions (alcoholic drinks) sufficient in color radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo 15 to show that the drink has been tampered with. biloba), and a pharmaceutically acceptable carrier. In another aspect of the invention, a formulation of In one aspect, the invention provides a composition bupropion, traZodone, and oxytocin to treat sexual disorders comprising the 5-HT, receptor agonist and 5-HT2, antago has an outer layer that releases a nontoxic gelling agent in nist flibanserin, a 5-HT2, agonist (e.g., lorcaserin, vabica water or water-alcohol solutions sufficient to thicken or serin, PRX-00933, YM348, metachlorophenylpiperazine, solidify the drink to show it has been tampered with. and mOPP), and a pharmaceutically acceptable carrier. In another aspect of the invention, a formulation of In one aspect, the invention provides a composition bupropion and oxytocinto treat sexual disorders has an outer comprising the 5-HT, receptor agonist and 5-HT, antago layer with rapid release of an effective but well tolerated nist flibanserin, a 5-HT2, agonist (e.g., lorcaserin, vabica amount of bupropion and oxytocin, and an inner core with serin, PRX-00933, YM348, metachlorophenylpiperazine, 25 a sustained release of an effective and well tolerated amount and mCPP), ther non-abusable agents (agents not scheduled of bupropion and oxytocin. by the DEA) that augment dopamine and/or norepinephrine In another aspect of the invention, a formulation of in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, bupropion and oxytocinto treat sexual disorders has a highly 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ soluble outer layer and a matrix inner layer that remains indol, nisoxetine, talopram, talsupram, tandamine, Vilox 30 insoluble in water or water-alcohol solutions (alcoholic azine, maprotiline, ciclazindol, manifaxine, radafaxine, drinks) and is large enough to be easily visible and show that tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), the drink has been tampered with. and a pharmaceutically acceptable carrier. In another aspect of the invention, a formulation of In one aspect, the invention provides a composition bupropion and oxytocinto treat sexual disorders has an outer comprising the 5-HT, receptor agonist, 5-HT, receptor 35 layer that releases a nontoxic dye in water or water-alcohol antagonist, and/or 5-HT, receptor antagonist traZodone and solutions (alcoholic drinks) sufficient in color to show that a pharmaceutically acceptable carrier. the drink has been tampered with. In one aspect, the invention provides a composition In another aspect of the invention, a formulation of comprising the 5-HT, receptoragonist, and 5-HT, antago bupropion and oxytocinto treat sexual disorders has an outer nist traZodone, other non-abusable agents (agents not sched 40 layer that releases a nontoxic gelling agent in water or uled by the DEA) that augment dopamine and/or norepi water-alcohol solutions sufficient to thicken or solidify the nephrine in the brain, e.g., atomoxetine, reboxetine, drink to show it has been tampered with. amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, In another aspect of the invention, a formulation of lortalamine, mazindol, nisoxetine, talopram, talsupram, tan traZodone and oxytocinto treat sexual disorders has an outer damine, Viloxazine, maprotiline, ciclazindol, manifaxine, 45 layer with rapid release of an effective but well tolerated radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo amount of traZodone and oxytocin, and an inner core with a biloba), and a pharmaceutically acceptable carrier. sustained release of an effective and well tolerated amount In one aspect, the invention provides a composition of traZodone and oxytocin. comprising the 5-HT, receptor agonist and 5-HT, antago In another aspect of the invention, a formulation of nist traZodone, a 5-HT2, agonist (e.g., lorcaserin, vabica 50 traZodone and oxytocinto treat sexual disorders has a highly serin, PRX-00933, YM348, metachlorophenylpiperazine, soluble outer layer and a matrix inner layer that remains and mOPP), and a pharmaceutically acceptable carrier. insoluble in water or water-alcohol solutions (alcoholic In one aspect, the invention provides a composition drinks) and is large enough to be easily visible and show that comprising the 5-HT, receptor agonist and 5-HT, antago the drink has been tampered with. nist traZodone, a 5-HT2, agonist (e.g., lorcaserin, vabica 55 In another aspect of the invention, a formulation of serin, PRX-00933, YM348, metachlorophenylpiperazine, traZodone and oxytocinto treat sexual disorders has an outer and mCPP), ther non-abusable agents (agents not scheduled layer that releases a nontoxic dye in water or water-alcohol by the DEA) that augment dopamine and/or norepinephrine solutions (alcoholic drinks) sufficient in color to show that in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, the drink has been tampered with. 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ 60 In another aspect of the invention, a formulation of indol, nisoxetine, talopram, talsupram, tandamine, Vilox traZodone and oxytocinto treat sexual disorders has an outer azine, maprotiline, ciclazindol, manifaxine, radafaxine, layer that releases a nontoxic gelling agent in water or tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), water-alcohol solutions sufficient to thicken or solidify the and a pharmaceutically acceptable carrier. drink to show it has been tampered with. In another aspect of the invention, a formulation of 65 In another aspect of the invention, a formulation of bupropion, traZodone, and oxytocin to treat sexual disorders oxytocin to treat sexual disorders has an outer layer with has an outer layer with rapid release of an effective but well rapid release of an effective but well tolerated amount of US 9,517,254 B2 55 56 oxytocin, and an inner core with a Sustained release of an azine, maprotiline, ciclazindol, manifaxine, radafaxine, effective and well tolerated amount of oxytocin. tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), In another aspect of the invention, a formulation of and a pharmaceutically acceptable carrier. oxytocin to treat sexual disorders has a highly soluble outer In one aspect, the invention provides a composition layer and a matrix inner layer that remains insoluble in water comprising the 5-HT, receptor agonist and 5-HT2, antago or water-alcohol solutions (alcoholic drinks) and is large nist mirtazapine and a pharmaceutically acceptable carrier. enough to be easily visible and show that the drink has been In one aspect, the invention provides a composition tampered with. comprising the 5-HT, receptoragonist, and 5-HT, antago In another aspect of the invention, a formulation of nist mirtazapine, other non-abusable agents (agents not oxytocin to treat sexual disorders has an outer layer that 10 scheduled by the DEA) that augment dopamine and/or releases a nontoxic dye in water or water-alcohol Solutions norepinephrine in the brain, e.g., atomoxetine, reboxetine, (alcoholic drinks) sufficient in color to show that the drink amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, has been tampered with. lortalamine, mazindol, nisoxetine, talopram, talsupram, tan In another aspect of the invention, a formulation of damine, Viloxazine, maprotiline, ciclazindol, manifaxine, oxytocin to treat sexual disorders has an outer layer that 15 radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo releases a nontoxic gelling agent in water or water-alcohol biloba), and a pharmaceutically acceptable carrier. solutions sufficient to thicken or solidify the drink to show In one aspect, the invention provides a composition it has been tampered with. comprising the 5-HT, receptor agonist and 5-HT2, antago In another aspect of the invention, a formulation of nist mirtazapine, a 5-HT2, agonist (e.g., lorcaserin, vabica bupropion and traZodone to treat cognitive disorders has an serin, PRX-00933, YM348, metachlorophenylpiperazine, outer layer with rapid release of an effective but well and mOPP), and a pharmaceutically acceptable carrier. tolerated amount of traZodone and bupropion, and an inner In one aspect, the invention provides a composition core with a sustained release of an effective and well comprising the 5-HT, receptor agonist and 5-HT, antago tolerated amount of traZodone and bupropion. nist mirtazapine, a 5-HT2, agonist (e.g., lorcaserin, vabica In another aspect of the invention, a formulation of 25 serin, PRX-00933, YM348, metachlorophenylpiperazine, bupropion and trazodone to treat cognitive disorders has a and mCPP), ther non-abusable agents (agents not scheduled highly soluble outer layer and a matrix inner layer that by the DEA) that augment dopamine and/or norepinephrine remains insoluble in water or water-alcohol Solutions (alco in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, holic drinks) and is large enough to be easily visible and 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ show that the drink has been tampered with. 30 indol, nisoxetine, talopram, talsupram, tandamine, Vilox In another aspect of the invention, a formulation of azine, maprotiline, ciclazindol, manifaxine, radafaxine, bupropion and trazodone to treat cognitive disorders has an tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), outer layer that releases a nontoxic dye in water or water and a pharmaceutically acceptable carrier. alcohol solutions (alcoholic drinks) sufficient in color to In one aspect, the invention provides a composition show that the drink has been tampered with. 35 comprising the 5-HT, receptor agonist and 5-HT, antago In another aspect of the invention, a formulation of nist flibanserin and a pharmaceutically acceptable carrier. bupropion and traZodone to treat cognitive disorders has an In one aspect, the invention provides a composition outer layer that releases a nontoxic gelling agent in water or comprising the 5-HT, receptoragonist, and 5-HT, antago water-alcohol solutions sufficient to thicken or solidify the nist flibanserin, other non-abusable agents (agents not drink to show it has been tampered with. 40 scheduled by the DEA) that augment dopamine and/or In one aspect, the invention provides a composition norepinephrine in the brain, e.g., atomoxetine, reboxetine, comprising the 5-HT, receptor agonist and 5-HT, antago amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, nist nefazodone and a pharmaceutically acceptable carrier. lortalamine, mazindol, nisoxetine, talopram, talsupram, tan In one aspect, the invention provides a composition damine, Viloxazine, maprotiline, ciclazindol, manifaxine, comprising the 5-HT, receptoragonist, and 5-HT, antago 45 radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo nist nefazodone, other non-abusable agents (agents not biloba), and a pharmaceutically acceptable carrier. scheduled by the DEA) that augment dopamine and/or In one aspect, the invention provides a composition norepinephrine in the brain, e.g., atomoxetine, reboxetine, comprising the 5-HT, receptor agonist and 5-HT2, antago amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, nist flibanserin, a 5-HT, agonist (e.g., lorcaserin, vabica lortalamine, mazindol, nisoxetine, talopram, talsupram, tan 50 serin, PRX-00933, YM348, metachlorophenylpiperazine, damine, Viloxazine, maprotiline, ciclazindol, manifaxine, and mOPP), and a pharmaceutically acceptable carrier. radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo In one aspect, the invention provides a composition biloba), and a pharmaceutically acceptable carrier. comprising the 5-HT, receptor agonist and 5-HT2, antago In one aspect, the invention provides a composition nist flibanserin, a 5-HT, agonist (e.g., lorcaserin, vabica comprising the 5-HT, receptor agonist and 5-HT2, antago 55 serin, PRX-00933, YM348, metachlorophenylpiperazine, nist nefazodone, a 5-HT, agonist (e.g., lorcaserin, vabica and mCPP), ther non-abusable agents (agents not scheduled serin, PRX-00933, YM348, metachlorophenylpiperazine, by the DEA) that augment dopamine and/or norepinephrine and mOPP), and a pharmaceutically acceptable carrier. in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, In one aspect, the invention provides a composition 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ comprising the 5-HT, receptor agonist and 5-HT2, antago 60 indol, nisoxetine, talopram, talsupram, tandamine, Vilox nist nefazodone, a 5-HT, agonist (e.g., lorcaserin, vabica azine, maprotiline, ciclazindol, manifaxine, radafaxine, serin, PRX-00933, YM348, metachlorophenylpiperazine, tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), and mCPP), ther non-abusable agents (agents not scheduled and a pharmaceutically acceptable carrier. by the DEA) that augment dopamine and/or norepinephrine In one aspect, the invention provides a composition in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, 65 comprising a 5-HT, receptor agonist, 5-HT2 receptor 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ antagonist, and/or 5-HT, receptor antagonist traZodone and indol, nisoxetine, talopram, talsupram, tandamine, Vilox a pharmaceutically acceptable carrier. US 9,517,254 B2 57 58 In one aspect, the invention provides a composition alcohol solutions (alcoholic drinks) sufficient in color to comprising the 5-HT, receptoragonist, and 5-HT, antago show that the drink has been tampered with. nist traZodone, other non-abusable agents (agents not sched In another aspect of the invention, a formulation of uled by the DEA) that augment dopamine and/or norepi bupropion and oxytocin to treat cognitive disorders has an nephrine in the brain, e.g., atomoxetine, reboxetine, outer layer that releases a nontoxic gelling agent in water or amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, water-alcohol solutions sufficient to thicken or solidify the lortalamine, mazindol, nisoxetine, talopram, talsupram, tan drink to show it has been tampered with. damine, Viloxazine, maprotiline, ciclazindol, manifaxine, In another aspect of the invention, a formulation of radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo traZodone and oxytocin to treat cognitive disorders has an biloba), and a pharmaceutically acceptable carrier. 10 outer layer with rapid release of an effective but well tolerated amount of traZodone and oxytocin, and an inner In one aspect, the invention provides a composition core with a sustained release of an effective and well comprising the 5-HT, receptor agonist and 5-HT2, antago tolerated amount of traZodone and oxytocin. nist traZodone, a 5-HT2, agonist (e.g., lorcaserin, vabica In another aspect of the invention, a formulation of serin, PRX-00933, YM348, metachlorophenylpiperazine, 15 traZodone and oxytocin to treat cognitive disorders has a and mOPP), and a pharmaceutically acceptable carrier. highly soluble outer layer and a matrix inner layer that In one aspect, the invention provides a composition remains insoluble in water or water-alcohol Solutions (alco comprising the 5-HT, receptor agonist and 5-HT, antago holic drinks) and is large enough to be easily visible and nist traZodone, a 5-HT2, agonist (e.g., lorcaserin, vabica show that the drink has been tampered with. serin, PRX-00933, YM348, metachlorophenylpiperazine, In another aspect of the invention, a formulation of and mCPP), ther non-abusable agents (agents not scheduled traZodone and oxytocin to treat cognitive disorders has an by the DEA) that augment dopamine and/or norepinephrine outer layer that releases a nontoxic dye in water or water in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, alcohol solutions (alcoholic drinks) sufficient in color to 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ show that the drink has been tampered with. indol, nisoxetine, talopram, talsupram, tandamine, Vilox 25 In another aspect of the invention, a formulation of azine, maprotiline, ciclazindol, manifaxine, radafaxine, traZodone and oxytocin to treat cognitive disorders has an tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), outer layer that releases a nontoxic gelling agent in water or and a pharmaceutically acceptable carrier. water-alcohol solutions sufficient to thicken or solidify the In another aspect of the invention, a formulation of drink to show it has been tampered with. bupropion, traZodone, and oxytocin to treat cognitive dis 30 In another aspect of the invention, a formulation of orders has an outer layer with rapid release of an effective oxytocin to treat cognitive disorders has an outer layer with but well tolerated amount of bupropion, trazodone, and rapid release of an effective but well tolerated amount of oxytocin, and an inner core with a Sustained release of an oxytocin, and an inner core with a Sustained release of an effective and well tolerated amount of bupropion, trazodone, effective and well tolerated amount of oxytocin. and oxytocin. 35 In another aspect of the invention, a formulation of In another aspect of the invention, a formulation of oxytocin to treat cognitive disorders has a highly soluble bupropion, traZodone, and oxytocin to treat cognitive dis outer layer and a matrix inner layer that remains insoluble in orders has a highly soluble outer layer and a matrix inner water or water-alcohol Solutions (alcoholic drinks) and is layer that remains insoluble in water or water-alcohol solu large enough to be easily visible and show that the drink has tions (alcoholic drinks) and is large enough to be easily 40 been tampered with. visible and show that the drink has been tampered with. In another aspect of the invention, a formulation of In another aspect of the invention, a formulation of oxytocin to treat cognitive disorders has an outer layer that bupropion, traZodone, and oxytocin to treat cognitive dis releases a nontoxic dye in water or water-alcohol Solutions orders has an outer layer that releases a nontoxic dye in (alcoholic drinks) sufficient in color to show that the drink water or water-alcohol solutions (alcoholic drinks) sufficient 45 has been tampered with. in color to show that the drink has been tampered with. In another aspect of the invention, a formulation of In another aspect of the invention, a formulation of oxytocin to treat cognitive disorders has an outer layer that bupropion, traZodone, and oxytocin to treat cognitive dis releases a nontoxic gelling agent in water or water-alcohol orders has an outer layer that releases a nontoxic gelling solutions sufficient to thicken or solidify the drink to show agent in water or water-alcohol Solutions Sufficient to 50 it has been tampered with. thicken or solidify the drink to show it has been tampered In another aspect of the invention, a formulation of with. bupropion and traZodone to enhance cognition has an outer In another aspect of the invention, a formulation of layer with rapid release of an effective but well tolerated bupropion and oxytocin to treat cognitive disorders has an amount of traZodone and bupropion, and an inner core with outer layer with rapid release of an effective but well 55 a sustained release of an effective and well tolerated amount tolerated amount of bupropion and oxytocin, and an inner of traZodone and bupropion. core with a sustained release of an effective and well In another aspect of the invention, a formulation of tolerated amount of bupropion and oxytocin. bupropion and traZodone to enhance cognition has a highly In another aspect of the invention, a formulation of soluble outer layer and a matrix inner layer that remains bupropion and oxytocin to treat cognitive disorders has a 60 insoluble in water or water-alcohol solutions (alcoholic highly soluble outer layer and a matrix inner layer that drinks) and is large enough to be easily visible and show that remains insoluble in water or water-alcohol Solutions (alco the drink has been tampered with. holic drinks) and is large enough to be easily visible and In another aspect of the invention, a formulation of show that the drink has been tampered with. bupropion and traZodone to enhance cognition has an outer In another aspect of the invention, a formulation of 65 layer that releases a nontoxic dye in water or water-alcohol bupropion and oxytocin to treat cognitive disorders has an solutions (alcoholic drinks) sufficient in color to show that outer layer that releases a nontoxic dye in water or water the drink has been tampered with. US 9,517,254 B2 59 60 In another aspect of the invention, a formulation of In one aspect, the invention provides a composition bupropion and traZodone to enhance cognition has an outer comprising the 5-HT, receptor agonist and 5-HT, antago layer that releases a nontoxic gelling agent in water or nist flibanserin and a pharmaceutically acceptable carrier. water-alcohol solutions sufficient to thicken or solidify the In one aspect, the invention provides a composition drink to show it has been tampered with. comprising the 5-HT, receptoragonist, and 5-HT, antago In one aspect, the invention provides a composition nist flibanserin, other non-abusable agents (agents not comprising the 5-HT, receptor agonist and 5-HT2, antago scheduled by the DEA) that augment dopamine and/or nist nefazodone and a pharmaceutically acceptable carrier. norepinephrine in the brain, e.g., atomoxetine, reboxetine, In one aspect, the invention provides a composition amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, comprising the 5-HT, receptoragonist, and 5-HT, antago 10 lortalamine, mazindol, nisoxetine, talopram, talsupram, tan nist nefazodone, other non-abusable agents (agents not damine, Viloxazine, maprotiline, ciclazindol, manifaxine, scheduled by the DEA) that augment dopamine and/or radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo norepinephrine in the brain, e.g., atomoxetine, reboxetine, biloba), and a pharmaceutically acceptable carrier. amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, 15 In one aspect, the invention provides a composition lortalamine, mazindol, nisoxetine, talopram, talsupram, tan comprising the 5-HT, receptor agonist and 5-HT2, antago damine, Viloxazine, maprotiline, ciclazindol, manifaxine, nist flibanserin, a 5-HT, agonist (e.g., lorcaserin, vabica radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo serin, PRX-00933, YM348, metachlorophenylpiperazine, biloba), and a pharmaceutically acceptable carrier. and mOPP), and a pharmaceutically acceptable carrier. In one aspect, the invention provides a composition In one aspect, the invention provides a composition comprising the 5-HT, receptor agonist and 5-HT, antago comprising the 5-HT, receptor agonist and 5-HT, antago nist nefazodone, a 5-HT2, agonist (e.g., lorcaserin, vabica nist flibanserin, a 5-HT, agonist (e.g., lorcaserin, vabica serin, PRX-00933, YM348, metachlorophenylpiperazine, serin, PRX-00933, YM348, metachlorophenylpiperazine, and mOPP), and a pharmaceutically acceptable carrier. and mCPP), ther non-abusable agents (agents not scheduled In one aspect, the invention provides a composition 25 by the DEA) that augment dopamine and/or norepinephrine comprising the 5-HT, receptor agonist and 5-HT, antago in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, nist nefazodone, a 5-HT2, agonist (e.g., lorcaserin, vabica 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ serin, PRX-00933, YM348, metachlorophenylpiperazine, indol, nisoxetine, talopram, talsupram, tandamine, Vilox and mCPP), ther non-abusable agents (agents not scheduled azine, maprotiline, ciclazindol, manifaxine, radafaxine, by the DEA) that augment dopamine and/or norepinephrine 30 tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, and a pharmaceutically acceptable carrier. 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ In one aspect, the invention provides a composition indol, nisoxetine, talopram, talsupram, tandamine, Vilox comprising a 5-HT, receptor agonist, 5-HT2 receptor azine, maprotiline, ciclazindol, manifaxine, radafaxine, antagonist, and/or 5-HT, receptor antagonist traZodone and tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), 35 a pharmaceutically acceptable carrier. and a pharmaceutically acceptable carrier. In one aspect, the invention provides a composition In one aspect, the invention provides a composition comprising the 5-HT, receptoragonist, and 5-HT, antago comprising the 5-HT, receptor agonist and 5-HT, antago nist traZodone, other non-abusable agents (agents not sched nist mirtazapine and a pharmaceutically acceptable carrier. 40 uled by the DEA) that augment dopamine and/or norepi In one aspect, the invention provides a composition nephrine in the brain, e.g., atomoxetine, reboxetine, comprising the 5-HT, receptoragonist, and 5-HT, antago amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, nist mirtazapine, other non-abusable agents (agents not lortalamine, mazindol, nisoxetine, talopram, talsupram, tan scheduled by the DEA) that augment dopamine and/or damine, Viloxazine, maprotiline, ciclazindol, manifaxine, norepinephrine in the brain, e.g., atomoxetine, reboxetine, 45 radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, biloba), and a pharmaceutically acceptable carrier. lortalamine, mazindol, nisoxetine, talopram, talsupram, tan In one aspect, the invention provides a composition damine, Viloxazine, maprotiline, ciclazindol, manifaxine, comprising the 5-HT, receptor agonist and 5-HT2, antago radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo nist trazodone, a 5-HT, agonist (e.g., lorcaserin, vabica biloba), and a pharmaceutically acceptable carrier. 50 serin, PRX-00933, YM348, metachlorophenylpiperazine, In one aspect, the invention provides a composition and mOPP), and a pharmaceutically acceptable carrier. comprising the 5-HT, receptor agonist and 5-HT2, antago In one aspect, the invention provides a composition nist mirtazapine, a 5-HT2, agonist (e.g., lorcaserin, vabica comprising the 5-HT, receptor agonist and 5-HT2, antago serin, PRX-00933, YM348, metachlorophenylpiperazine, nist trazodone, a 5-HT, agonist (e.g., lorcaserin, vabica and mOPP), and a pharmaceutically acceptable carrier. 55 serin, PRX-00933, YM348, metachlorophenylpiperazine, In one aspect, the invention provides a composition and mCPP), ther non-abusable agents (agents not scheduled comprising the 5-HT, receptor agonist and 5-HT2, antago by the DEA) that augment dopamine and/or norepinephrine nist mirtazapine, a 5-HT2, agonist (e.g., lorcaserin, vabica in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, serin, PRX-00933, YM348, metachlorophenylpiperazine, 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ and mCPP), ther non-abusable agents (agents not scheduled 60 indol, nisoxetine, talopram, talsupram, tandamine, Vilox by the DEA) that augment dopamine and/or norepinephrine azine, maprotiline, ciclazindol, manifaxine, radafaxine, in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ and a pharmaceutically acceptable carrier. indol, nisoxetine, talopram, talsupram, tandamine, Vilox In another aspect of the invention, a formulation of azine, maprotiline, ciclazindol, manifaxine, radafaxine, 65 bupropion, traZodone, and oxytocin to enhance cognition tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), has an outer layer with rapid release of an effective but well and a pharmaceutically acceptable carrier. tolerated amount of bupropion, traZodone, and oxytocin, and US 9,517,254 B2 61 62 an inner core with a sustained release of an effective and and an inner core with a Sustained release of an effective and well tolerated amount of bupropion, traZodone, and oxyto well tolerated amount of oxytocin. cin. In another aspect of the invention, a formulation of In another aspect of the invention, a formulation of oxytocin to enhance cognition has a highly soluble outer bupropion, traZodone, and oxytocin to enhance cognition layer and a matrix inner layer that remains insoluble in water has a highly soluble outer layer and a matrix inner layer that or water-alcohol Solutions (alcoholic drinks) and is large remains insoluble in water or water-alcohol Solutions (alco enough to be easily visible and show that the drink has been holic drinks) and is large enough to be easily visible and tampered with. show that the drink has been tampered with. In another aspect of the invention, a formulation of 10 oxytocin to enhance cognition has an outer layer that In another aspect of the invention, a formulation of releases a nontoxic dye in water or water-alcohol Solutions bupropion, traZodone, and oxytocin to enhance cognition (alcoholic drinks) sufficient in color to show that the drink has an outer layer that releases a nontoxic dye in water or has been tampered with. water-alcohol solutions (alcoholic drinks) sufficient in color In another aspect of the invention, a formulation of to show that the drink has been tampered with. 15 oxytocin to enhance cognition has an outer layer that In another aspect of the invention, a formulation of releases a nontoxic gelling agent in water or water-alcohol bupropion, traZodone, and oxytocin to enhance cognition solutions sufficient to thicken or solidify the drink to show has an outer layer that releases a nontoxic gelling agent in it has been tampered with. water or water-alcohol solutions sufficient to thicken or In one embodiment, the composition is that comprising solidify the drink to show it has been tampered with. bupropion, comprising bupropion in a dosage range of In another aspect of the invention, a formulation of 100-450 mg qd; comprising bupropion in a dosage range of bupropion and oxytocin to enhance cognition has an outer 200-450 mg qd; comprising bupropion in a dosage range of layer with rapid release of an effective but well tolerated 100-300 mg qd; comprising bupropion in a dosage range of amount of bupropion and oxytocin, and an inner core with 225-300 mg qd; comprising bupropion in a dosage range of a sustained release of an effective and well tolerated amount 25 100-275 mg qd; or comprising bupropion in a dosage range of bupropion and oxytocin. of 200-275 mg qd; comprising bupropion in a dosage range In another aspect of the invention, a formulation of of XX-YY mg qd, wherein XX is an integer between 5 and bupropion and oxytocin to enhance cognition has a highly 400 and YY is an integer between 50 and 450. soluble outer layer and a matrix inner layer that remains In one embodiment, the composition is that comprising insoluble in water or water-alcohol solutions (alcoholic 30 traZodone, comprising traZodone in a dosage range of drinks) and is large enough to be easily visible and show that 25-450 mg qd; comprising traZodone in a dosage range of the drink has been tampered with. 75-150 mg qd; or comprising trazodone in a dosage range of In another aspect of the invention, a formulation of 50-100 mg qd; comprising traZodone in a dosage range of bupropion and oxytocin to enhance cognition has an outer XX-YY mg qd, wherein XX is an integer between 25 and layer that releases a nontoxic dye in water or water-alcohol 35 400 and YY is an integer between 50 and 450. solutions (alcoholic drinks) sufficient in color to show that In one embodiment, the composition is that comprising the drink has been tampered with. oxytocin, comprising oxytocin in a dosage range of 4-400 In another aspect of the invention, a formulation of International Units. bupropion and oxytocin to enhance cognition has an outer In one embodiment, the composition is that comprising layer that releases a nontoxic gelling agent in water or 40 bupropion and traZodone, comprising bupropion in a dosage water-alcohol solutions sufficient to thicken or solidify the range of 50-450 mg and traZodone in a dosage range of drink to show it has been tampered with. 25-450 mg, comprising bupropion in a dosage range of In another aspect of the invention, a formulation of 200-450 mg and traZodone in a dosage range of 25-450 mg: traZodone and oxytocin to enhance cognition has an outer comprising bupropion in a dosage range of 100-300 mg qd layer with rapid release of an effective but well tolerated 45 and comprising traZodone in a dosage range of 75-150 mg amount of traZodone and oxytocin, and an inner core with a qd; comprising bupropion in a dosage range of 225-300 mg sustained release of an effective and well tolerated amount qd and comprising traZodone in a dosage range of 75-150 of traZodone and oxytocin. mg qd; comprising bupropion in a dosage range of 100-275 In another aspect of the invention, a formulation of mg qd and comprising traZodone in a dosage range of traZodone and oxytocin to enhance cognition has a highly 50 50-100 mg qd; or comprising bupropion in a dosage range soluble outer layer and a matrix inner layer that remains of 200-275 mg qd and comprising traZodone in a dosage insoluble in water or water-alcohol solutions (alcoholic range of 50-100 mg qd. drinks) and is large enough to be easily visible and show that In one embodiment, the composition is that comprising the drink has been tampered with. bupropion, traZodone, and oxytocin, comprising bupropion In another aspect of the invention, a formulation of 55 in a dosage range of 50-450 mg. traZodone in a dosage range traZodone and oxytocin to enhance cognition has an outer of 25-450 mg, and oxytocin in a dose range of 4-400 layer that releases a nontoxic dye in water or water-alcohol International Units; comprising bupropion in a dosage range solutions (alcoholic drinks) sufficient in color to show that of 200-450 mg. trazodone in a dosage range of 25-450 mg. the drink has been tampered with. and oxytocin in a dose range of 4-400 International Units: In another aspect of the invention, a formulation of 60 comprising bupropion in a dosage range of 100-300 mg qd, traZodone and oxytocin to enhance cognition has an outer comprising trazodone in a dosage range of 75-150 mg qd, layer that releases a nontoxic gelling agent in water or and oxytocin in a dose range of 4-400 International Units qd; water-alcohol solutions sufficient to thicken or solidify the comprising bupropion in a dosage range of 225-300 mg qd, drink to show it has been tampered with. comprising trazodone in a dosage range of 75-150 mg qd, In another aspect of the invention, a formulation of 65 and oxytocin in a dose range of 4-400 International Units qd; oxytocin to enhance cognition has an outer layer with rapid comprising bupropion in a dosage range of 100-275 mg qd, release of an effective but well tolerated amount of oxytocin, comprising trazodone in a dosage range of 50-100 mg qd, US 9,517,254 B2 63 64 and comprising oxytocin in a dose range of 4-400 Interna PRX-00933, YM348, metachlorophenylpiperazine, and tional Units qd; or comprising bupropion in a dosage range mCPP), and a pharmaceutically acceptable carrier. In one of 200-275 mg qd, comprising traZodone in a dosage range aspect, the invention provides a method of making a com of 50-100 mg qd, and comprising oxytocin in a dose range position comprising combining a 5-HT, receptoragonist, a of 4-400 International Units. 5-HT, antagonist, and a pharmaceutically acceptable car In one embodiment, the composition is that comprising rier. In one aspect, the invention provides a method of bupropion and oxytocin, comprising bupropion in a dosage making a composition comprising combining a 5-HT range of 50-450 mg and oxytocin in a dosage range of 4-400 receptor agonist, and a pharmaceutically acceptable carrier. International Units; comprising bupropion in a dosage range In one aspect, the invention provides a method of making a of 200-450 mg and oxytocin in a dosage range of 4-400 10 International Units; comprising bupropion in a dosage range composition comprising combining a 5-HT, receptor ago of 100-300 mg qd and comprising oxytocin in a dosage nist, 5-HT, receptor antagonist, and/or 5-HT, receptor range of 4-400 International Units qd; comprising bupropion antagonist, and a pharmaceutically acceptable carrier. in a dosage range of 225-300 mg qd and comprising oxy In one aspect, the invention provides a method of making tocin in a dosage range of 4-400 International Units qd; 15 a composition comprising combining a 5-HT agonist/5- comprising bupropion in a dosage range of 100-275 mg qd HT, antagonist, a norepinephrine-dopamine reuptake and comprising oxytocin in a dosage range of 4-400 Inter inhibitor, a 5-HT, agonist (e.g., lorcaserin, vabicaserin, national Units qd; or comprising bupropion in a dosage PRX-00933, YM348, metachlorophenylpiperazine, and range of 200-275 mg qd and comprising oxytocin in a mCPP), other non-abusable agents (agents not scheduled by dosage range of 4-400 International Units qd. the DEA) that augment dopamine and/or norepinephrine in In one embodiment, the composition is that comprising the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, oxytocin and traZodone, comprising oxytocin in a dosage 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ range of 4-400 International Units and traZodone in a dosage indol, nisoxetine, talopram, talsupram, tandamine, Vilox range of 25-450 mg, comprising oxytocin in a dosage range azine, maprotiline, ciclazindol, manifaxine, radafaxine, of 4-400 International Units qd and comprising traZodone in 25 tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), a dosage range of 75-150 mg qd; or comprising oxytocin in and a pharmaceutically acceptable carrier. In one aspect, the a dosage range of 4-400 International Units qd and com invention provides a method of making a composition prising traZodone in a dosage range of 50-100 mg qd. comprising combining a 5-HT, receptor agonist, a 5-HT, In one aspect, the invention provides a method of making antagonist, and a pharmaceutically acceptable carrier. In one a composition comprising combining a 5-HT agonist/5- 30 aspect, the invention provides a method of making a com HT antagonist, a norepinephrine-dopamine reuptake position comprising combining a 5-HT, receptor agonist, inhibitor, and a pharmaceutically acceptable carrier. In one and a pharmaceutically acceptable carrier. In one aspect, the aspect, the invention provides a method of making a com invention provides a method of making a composition position comprising combining a 5-HT, receptoragonist, a comprising combining a 5-HT, receptor agonist, 5-HT 5-HT, antagonist, and a pharmaceutically acceptable car 35 receptor antagonist, and/or 5-HT, receptor antagonist, and rier. In one aspect, the invention provides a method of a pharmaceutically acceptable carrier. making a composition comprising combining a 5-HT In one aspect, the method of making a composition receptor agonist, and a pharmaceutically acceptable carrier. comprises combining a 5-HT, receptor agonist, a norepi In one aspect, the invention provides a method of making a nephrine-dopamine reuptake inhibitor and a pharmaceuti composition comprising combining a 5-HT, receptor ago 40 cally acceptable carrier Such that the composition comprises nist, 5-HT, receptor antagonist, and/or 5-HT, receptor a range of 25-450 mg of a 5-HT, receptor agonist. In antagonist, and a pharmaceutically acceptable carrier. another aspect, the invention provides a method of making In one aspect, the invention provides a method of making a composition comprising combining a 5-HT, receptor a composition comprising combining a 5-HT agonist/5- agonist, 5-HT2 receptor antagonist, and/or 5-HT, receptor HT antagonist, a norepinephrine-dopamine reuptake 45 antagonist and a pharmaceutically acceptable carrier Such inhibitor, other non-abusable agents (agents not scheduled that the composition comprises a range of 25-450 mg of a by the DEA) that augment dopamine and/or norepinephrine 5-HT, antagonist and a norepinephrine-dopamine reuptake in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, inhibitor. 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ In one aspect, the method of making a composition indol, nisoxetine, talopram, talsupram, tandamine, Vilox 50 comprises combining a 5-HT, receptor agonist, a norepi azine, maprotiline, ciclazindol, manifaxine, radafaxine, nephrine-dopamine reuptake inhibitor, other non-abusable tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), agents (agents not scheduled by the DEA) that augment and a pharmaceutically acceptable carrier. In one aspect, the dopamine and/or norepinephrine in the brain, e.g., atomox invention provides a method of making a composition etine, reboxetine, amedalin, CP-39,332, daledalin, edivox comprising combining a 5-HT, receptor agonist, a 5-HT 55 etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo antagonist, and a pharmaceutically acceptable carrier. In one pram, talsupram, tandamine, Viloxazine, maprotiline, aspect, the invention provides a method of making a com ciclazindol, manifaxine, radafaxine, tapentadol, tenilox position comprising combining a 5-HT, receptor agonist, azine, St. John’s wort, ginkgo biloba), and a pharmaceuti and a pharmaceutically acceptable carrier. In one aspect, the cally acceptable carrier Such that the composition comprises invention provides a method of making a composition 60 a range of 25-450 mg of a 5-HT, receptor agonist. In comprising combining a 5-HT, receptor agonist, 5-HT another aspect, the invention provides a method of making receptor antagonist, and/or 5-HT, receptor antagonist, and a composition comprising combining a 5-HT, receptor a pharmaceutically acceptable carrier. agonist, 5-HT, receptor antagonist, and/or 5-HT, receptor In one aspect, the invention provides a method of making antagonist and a pharmaceutically acceptable carrier Such a composition comprising combining a 5-HT agonist/5- 65 that the composition comprises a range of 25-450 mg of a HT antagonist, a norepinephrine-dopamine reuptake 5-HT, antagonist and a norepinephrine-dopamine reuptake inhibitor, a 5-HT, agonist (e.g., lorcaserin, vabicaserin, inhibitor. US 9,517,254 B2 65 66 In one aspect, the method of making a composition rier Such that the composition comprises a range of 25-450 comprises combining a 5-HT, receptor agonist, a norepi mg of a 5-HT, receptor agonist. In another aspect, the nephrine-dopamine reuptake inhibitor, a 5-HT2, agonist method of making comprises combining a 5-HT agonist/ (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, 5-HT, antagonist (e.g., traZodone, nefazodone, mirtazap metachlorophenylpiperazine, and mCPP), and a pharmaceu ine, flibanserin) and a pharmaceutically acceptable carrier tically acceptable carrier Such that the composition com Such that the composition comprises a range of 25-450 mg prises a range of 25-450 mg of a 5-HT, receptor agonist. In of a 5-HT, antagonist, a norepinephrine-dopamine another aspect, the invention provides a method of making reuptake inhibitor (e.g., bupropion), and an oxytocin recep a composition comprising combining a 5-HT, receptor tor (OXTR) agonist (e.g., carbetocin, oxytocin, Syntoci agonist, 5-HT2 receptor antagonist, and/or 5-HT, receptor 10 non(R). antagonist and a pharmaceutically acceptable carrier Such In one aspect, the method of making a composition that the composition comprises a range of 25-450 mg of a comprises combining a 5-HT, receptor agonist, a norepi 5-HT, antagonist and a norepinephrine-dopamine reuptake nephrine-dopamine reuptake inhibitor (e.g., bupropion), an inhibitor. oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto In one aspect, the method of making a composition 15 cin, SyntocinonR), and a pharmaceutically acceptable car comprises combining a 5-HT, receptor agonist, a norepi rier Such that the composition comprises a range of 25-450 nephrine-dopamine reuptake inhibitor, a 5-HT2, agonist mg of a 5-HT, receptor agonist. In another aspect, the (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, method of making comprises combining a 5-HT agonist/ metachlorophenylpiperazine, and mOPP), other non-abus 5-HT, antagonist (e.g., traZodone, nefazodone, mirtazap able agents (agents not scheduled by the DEA) that augment ine, flibanserin, ketanserin, ritanserin, clozapine, olanzapine, dopamine and/or norepinephrine in the brain, e.g., atomox quetiapine, risperidone, asenapine, MDL-100.907, cypro etine, reboxetine, amedalin, CP-39,332, daledalin, edivox heptadine, aripiprazole, and the general class of 2-alkyl-4- etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo aryl-tetrahydro-pyrimido-azepines) and a pharmaceutically pram, talsupram, tandamine, Viloxazine, maprotiline, acceptable carrier Such that the composition comprises a ciclazindol, manifaxine, radafaxine, tapentadol, tenilox 25 range of 25-450 mg of a 5-HT, antagonist, a norepineph azine, St. John’s wort, ginkgo biloba), and a pharmaceuti rine-dopamine reuptake inhibitor (e.g., bupropion), and an cally acceptable carrier Such that the composition comprises oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto a range of 25-450 mg of a 5-HT, receptor agonist. In cin, SyntocinonR). another aspect, the invention provides a method of making In one aspect, the method of making a composition a composition comprising combining a 5-HT, receptor 30 comprises combining a 5-HT, receptor agonist, a norepi agonist, 5-HT2 receptor antagonist, and/or 5-HT, receptor nephrine-dopamine reuptake inhibitor (e.g., bupropion), an antagonist and a pharmaceutically acceptable carrier such oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto that the composition comprises a range of 25-450 mg of a cin, Syntocinon R.), other non-abusable agents (agents not 5-HT, antagonist and a norepinephrine-dopamine reuptake scheduled by the DEA) that augment dopamine and/or inhibitor. 35 norepinephrine in the brain, e.g., atomoxetine, reboxetine, In one embodiment, the method comprises combining amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, bupropion, traZodone, and a pharmaceutically acceptable lortalamine, mazindol, nisoxetine, talopram, talsupram, tan carrier. damine, Viloxazine, maprotiline, ciclazindol, manifaxine, In one embodiment, the method comprises combining radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo bupropion, traZodone, other non-abusable agents (agents not 40 biloba), and a pharmaceutically acceptable carrier Such that scheduled by the DEA) that augment dopamine and/or the composition comprises a range of 25-450 mg of a norepinephrine in the brain, e.g., atomoxetine, reboxetine, 5-HT, receptor agonist. In another aspect, the method of amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, making comprises combining a 5-HT agonist/5-HT lortalamine, mazindol, nisoxetine, talopram, talsupram, tan antagonist (e.g., traZodone, nefazodone, mirtazapine, fliban damine, Viloxazine, maprotiline, ciclazindol, manifaxine, 45 serin, ketanserin, ritanserin, clozapine, olanzapine, quetiap radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo ine, risperidone, asenapine, MDL-100.907, cyproheptadine, biloba), and a pharmaceutically acceptable carrier. aripiprazole, and the general class of 2-alkyl-4-aryl-tetra In one embodiment, the method comprises combining hydro-pyrimido-azepines) and a pharmaceutically accept bupropion, trazodone, a 5-HT, agonist (e.g., lorcaserin, able carrier Such that the composition comprises a range of vabicaserin, PRX-00933, YM348, metachlorophenylpipera 50 25-450 mg of a 5-HT, antagonist, a norepinephrine-dop Zine, and mCPP), and a pharmaceutically acceptable carrier. amine reuptake inhibitor (e.g., bupropion), and an oxytocin In one embodiment, the method comprises combining receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syn bupropion, traZodone, a 5-HT, agonist (e.g., lorcaserin, tocinonR). vabicaserin, PRX-00933, YM348, metachlorophenylpipera In one aspect, the method of making a composition Zine, other non-abusable agents (agents not scheduled by the 55 comprises combining a 5-HT, receptor agonist, a norepi DEA) that augment dopamine and/or norepinephrine in the nephrine-dopamine reuptake inhibitor (e.g., bupropion), an brain, e.g., atomoxetine, reboxetine, amedalin, CP-39,332, oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, cin, Syntocinon R.), a 5-HT, agonist (e.g., lorcaserin, vabi nisoxetine, talopram, talSupram, tandamine, Viloxazine, caserin, PRX-00933, YM348, metachlorophenylpiperazine), maprotiline, ciclazindol, manifaxine, radafaxine, tapentadol, 60 and a pharmaceutically acceptable carrier Such that the teniloxazine, St. John’s wort, ginkgo biloba), and mOPP), composition comprises a range of 25-450 mg of a 5-HT and a pharmaceutically acceptable carrier. receptor agonist. In another aspect, the method of making In one aspect, the method of making a composition comprises combining a 5-HT agonist/5-HT, antagonist comprises combining a 5-HT, receptor agonist, a norepi (e.g., traZodone, nefazodone, mirtazapine, flibanserin, nephrine-dopamine reuptake inhibitor (e.g., bupropion), an 65 ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto peridone, asenapine, MDL-100.907, cyproheptadine, arip cin, SyntocinonR), and a pharmaceutically acceptable car iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro US 9,517,254 B2 67 68 pyrimido-azepines) and a pharmaceutically acceptable able agents (agents not scheduled by the DEA) that augment carrier Such that the composition comprises a range of dopamine and/or norepinephrine in the brain, e.g., atomox 25-450 mg of a 5-HT, antagonist, a norepinephrine-dop etine, reboxetine, amedalin, CP-39,332, daledalin, edivox amine reuptake inhibitor (e.g., bupropion), and an oxytocin etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syn pram, talsupram, tandamine, Viloxazine, maprotiline, tocinonR). ciclazindol, manifaxine, radafaxine, tapentadol, tenilox In one aspect, the method of making a composition azine, St. John’s wort, ginkgo biloba), and a pharmaceuti comprises combining a 5-HT, receptor agonist, a norepi cally acceptable carrier Such that the composition comprises nephrine-dopamine reuptake inhibitor (e.g., bupropion), an a range of 50-450 mg of a norepinephrine-dopamine oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto 10 reuptake inhibitor, a 5-HT, antagonist, and an oxytocin cin, Syntocinon R.), a 5-HT, agonist (e.g., lorcaserin, vabi receptor (OXTR) agonist. caserin, PRX-00933, YM348, metachlorophenylpiperazine), In one aspect, the method of making a composition other non-abusable agents (agents not scheduled by the comprises combining a 5-HT2 receptor antagonist (e.g., DEA) that augment dopamine and/or norepinephrine in the traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, brain, e.g., atomoxetine, reboxetine, amedalin, CP-39,332, 15 ritanserin, clozapine, olanzapine, quetiapine, risperidone, daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, asenapine, MDL-100.907, cyproheptadine, aripiprazole, and nisoxetine, talopram, talSupram, tandamine, Viloxazine, the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido maprotiline, ciclazindol, manifaxine, radafaxine, tapentadol, azepines), a norepinephrine-dopamine reuptake inhibitor teniloxazine, St. John’s wort, ginkgo biloba), and a phar (e.g., bupropion), an oxytocin receptor (OXTR) agonist maceutically acceptable carrier Such that the composition (e.g., carbetocin, oxytocin, Syntocinon R.), a 5-HT2, agonist comprises a range of 25-450 mg of a 5-HT, receptor (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, agonist. In another aspect, the method of making comprises metachlorophenylpiperazine), and a pharmaceutically combining a 5-HT agonist/5-HT, antagonist (e.g., tra acceptable carrier Such that the composition comprises a Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, range of 50-450 mg of a norepinephrine-dopamine reuptake ritanserin, clozapine, olanzapine, quetiapine, risperidone, 25 inhibitor, a 5-HT, antagonist, and an oxytocin receptor asenapine, MDL-100.907, cyproheptadine, aripiprazole, and (OXTR) agonist. the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido In one aspect, the method of making a composition azepines) and a pharmaceutically acceptable carrier Such comprises combining a 5-HT, receptor antagonist (e.g., that the composition comprises a range of 25-450 mg of a traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, 5-HT, antagonist, a norepinephrine-dopamine reuptake 30 ritanserin, clozapine, olanzapine, quetiapine, risperidone, inhibitor (e.g., bupropion), and an oxytocin receptor asenapine, MDL-100.907, cyproheptadine, aripiprazole, and (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon R). the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido In one embodiment, the method comprises combining azepines), a norepinephrine-dopamine reuptake inhibitor bupropion, traZodone, oxytocin (Syntocinon R.), and a phar (e.g., bupropion), an oxytocin receptor (OXTR) agonist maceutically acceptable carrier. 35 (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, agonist In one aspect, the method of making a composition (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, comprises combining a 5-HT2 receptor antagonist (e.g., metachlorophenylpiperazine), other non-abusable agents traZodone, nefazodone, mirtazapine, flibanserin), a norepi (agents not scheduled by the DEA) that augment dopamine nephrine-dopamine reuptake inhibitor (e.g., bupropion), an and/or norepinephrine in the brain, e.g., atomoxetine, rebox oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto 40 etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox cin, SyntocinonR), and a pharmaceutically acceptable car etine, lortalamine, mazindol, nisoxetine, talopram, talsu rier such that the composition comprises a range of 50-450 pram, tandamine, Viloxazine, maprotiline, ciclaZindol, mg of a norepinephrine-dopamine reuptake inhibitor, a manifaxine, radafaxine, tapentadol, teniloxazine, St. John's 5-HT, antagonist, and an oxytocin receptor (OXTR) ago wort, ginkgo biloba), and a pharmaceutically acceptable nist. 45 carrier Such that the composition comprises a range of In one aspect, the method of making a composition 50-450 mg of a norepinephrine-dopamine reuptake inhibi comprises combining a 5-HT, receptor antagonist (e.g., tor, a 5-HT, antagonist, and an oxytocin receptor (OXTR) traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, agonist. ritanserin, clozapine, olanzapine, quetiapine, risperidone, In one embodiment, the method comprises combining asenapine, MDL-100.907, cyproheptadine, aripiprazole, and 50 bupropion, traZodone, oxytocin, and a pharmaceutically the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido acceptable carrier. azepines), a norepinephrine-dopamine reuptake inhibitor In one aspect, the method of making a composition (e.g., bupropion), an oxytocin receptor (OXTR) agonist comprises combining a 5-HT2 receptor antagonist (e.g., (e.g., carbetocin, oxytocin, Syntocinon R.), and a pharma traZodone, nefazodone, mirtazapine, flibanserin), a norepi ceutically acceptable carrier Such that the composition com 55 nephrine-dopamine reuptake inhibitor (e.g., bupropion), an prises a range of 50-450 mg of a norepinephrine-dopamine oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto reuptake inhibitor, a 5-HT, antagonist, and an oxytocin cin, SyntocinonR), and a pharmaceutically acceptable car receptor (OXTR) agonist. rier Such that the composition comprises a range of 4-400 In one aspect, the method of making a composition International Units of an oxytocin receptor (OXTR) agonist, comprises combining a 5-HT2 receptor antagonist (e.g., 60 a norepinephrine-dopamine reuptake inhibitor, and a 5-HT traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, antagonist. ritanserin, clozapine, olanzapine, quetiapine, risperidone, In one aspect, the method of making a composition asenapine, MDL-100.907, cyproheptadine, aripiprazole, and comprises combining a 5-HT, receptor antagonist (e.g., the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, azepines), a norepinephrine-dopamine reuptake inhibitor 65 ritanserin, clozapine, olanzapine, quetiapine, risperidone, (e.g., bupropion), an oxytocin receptor (OXTR) agonist asenapine, MDL-100.907, cyproheptadine, aripiprazole, and (e.g., carbetocin, oxytocin, Syntocinon R.), other non-abus the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido US 9,517,254 B2 69 70 azepines), a norepinephrine-dopamine reuptake inhibitor In one aspect, the method of making a composition (e.g., bupropion), an oxytocin receptor (OXTR) agonist comprises combining a 5-HT, receptor agonist (e.g., tra (e.g., carbetocin, oxytocin, Syntocinon R.), and a pharma Zodone, nefazodone, mirtazapine, flibanserin), an oxytocin ceutically acceptable carrier Such that the composition com receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syn prises a range of 4-400 International Units of an oxytocin 5 tocinon R.), and a pharmaceutically acceptable carrier Such receptor (OXTR) agonist, a norepinephrine-dopamine that the composition comprises a range of 25-450 mg of a reuptake inhibitor, and a 5-HT, antagonist. 5-HT, receptor agonist. In another aspect, the method of In one aspect, the method of making a composition making comprises combining a 5-HT agonist/5-HT, comprises combining a 5-HT, receptor antagonist (e.g., antagonist and a pharmaceutically acceptable carrier Such traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, 10 ritanserin, clozapine, olanzapine, quetiapine, risperidone, that the composition comprises a range of 25-450 mg of a asenapine, MDL-100.907, cyproheptadine, aripiprazole, and 5-HT, antagonist and an oxytocin receptor (OXTR) ago the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido nist. azepines), a norepinephrine-dopamine reuptake inhibitor In one aspect, the method of making a composition (e.g., bupropion), an oxytocin receptor (OXTR) agonist 15 comprises combining a 5-HT, receptor agonist (e.g., tra (e.g., carbetocin, oxytocin, Syntocinon R.), other non-abus Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, able agents (agents not scheduled by the DEA) that augment ritanserin, clozapine, olanzapine, quetiapine, risperidone, dopamine and/or norepinephrine in the brain, e.g., atomox asenapine, MDL-100.907, cyproheptadine, aripiprazole, and etine, reboxetine, amedalin, CP-39,332, daledalin, edivox the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo azepines), an oxytocin receptor (OXTR) agonist (e.g., car pram, talsupram, tandamine, Viloxazine, maprotiline, betocin, oxytocin, Syntocinon R.), and a pharmaceutically ciclazindol, manifaxine, radafaxine, tapentadol, tenilox acceptable carrier Such that the composition comprises a azine, St. John’s wort, ginkgo biloba), and a pharmaceuti range of 25-450 mg of a 5-HT, receptor agonist. In another cally acceptable carrier Such that the composition comprises aspect, the method of making comprises combining a a range of 4-400 International Units of an oxytocin receptor 25 5-HT agonist/5-HT, antagonist and a pharmaceutically (OXTR) agonist, a norepinephrine-dopamine reuptake acceptable carrier Such that the composition comprises a inhibitor, and a 5-HT, antagonist. range of 25-450 mg of a 5-HT, antagonist and an oxytocin In one aspect, the method of making a composition receptor (OXTR) agonist. comprises combining a 5-HT2 receptor antagonist (e.g., In one aspect, the method of making a composition traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, 30 comprises combining a 5-HT, receptor agonist (e.g., tra ritanserin, clozapine, olanzapine, quetiapine, risperidone, Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, asenapine, MDL-100.907, cyproheptadine, aripiprazole, and ritanserin, clozapine, olanzapine, quetiapine, risperidone, the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido asenapine, MDL-100.907, cyproheptadine, aripiprazole, and azepines), a norepinephrine-dopamine reuptake inhibitor the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido (e.g., bupropion), an oxytocin receptor (OXTR) agonist 35 azepines), an oxytocin receptor (OXTR) agonist (e.g., car (e.g., carbetocin, oxytocin, Syntocinon R.), a 5-HT2, agonist betocin, oxytocin, Syntocinon R.), other non-abusable agents (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, (agents not scheduled by the DEA) that augment dopamine metachlorophenylpiperazine), and a pharmaceutically and/or norepinephrine in the brain, e.g., atomoxetine, rebox acceptable carrier Such that the composition comprises a etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox range of 4-400 International Units of an oxytocin receptor 40 etine, lortalamine, mazindol, nisoxetine, talopram, talsu (OXTR) agonist, a norepinephrine-dopamine reuptake pram, tandamine, Viloxazine, maprotiline, ciclaZindol, inhibitor, and a 5-HT, antagonist. manifaxine, radafaxine, tapentadol, teniloxazine, St. John's In one aspect, the method of making a composition wort, ginkgo biloba), and a pharmaceutically acceptable comprises combining a 5-HT2 receptor antagonist (e.g., carrier Such that the composition comprises a range of traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, 45 25-450 mg of a 5-HT, receptor agonist. In another aspect, ritanserin, clozapine, olanzapine, quetiapine, risperidone, the method of making comprises combining a 5-HT asenapine, MDL-100.907, cyproheptadine, aripiprazole, and agonist/5-HT, antagonist and a pharmaceutically accept the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido able carrier Such that the composition comprises a range of azepines), a norepinephrine-dopamine reuptake inhibitor 25-450 mg of a 5-HT, antagonist and an oxytocin receptor (e.g., bupropion), an oxytocin receptor (OXTR) agonist 50 (OXTR) agonist. (e.g., carbetocin, oxytocin, Syntocinon R.), a 5-HT2, agonist In one aspect, the method of making a composition (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, comprises combining a 5-HT, receptor agonist (e.g., tra metachlorophenylpiperazine), other non-abusable agents Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, (agents not scheduled by the DEA) that augment dopamine ritanserin, clozapine, olanzapine, quetiapine, risperidone, and/or norepinephrine in the brain, e.g., atomoxetine, rebox 55 asenapine, MDL-100.907, cyproheptadine, aripiprazole, and etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido etine, lortalamine, mazindol, nisoxetine, talopram, talsu azepines), an oxytocin receptor (OXTR) agonist (e.g., car pram, tandamine, Viloxazine, maprotiline, ciclaZindol, betocin, oxytocin, Syntocinon R.), a 5-HT, agonist (e.g., manifaxine, radafaxine, tapentadol, teniloxazine, St. John's lorcaserin, vabicaserin, PRX-00933, YM348, metachloro wort, ginkgo biloba), and a pharmaceutically acceptable 60 phenylpiperazine), and a pharmaceutically acceptable car carrier Such that the composition comprises a range of 4-400 rier Such that the composition comprises a range of 25-450 International Units of an oxytocin receptor (OXTR) agonist, mg of a 5-HT, receptor agonist. In another aspect, the a norepinephrine-dopamine reuptake inhibitor, and a 5-HT method of making comprises combining a 5-HT agonist/ antagonist. 5-HT, antagonist and a pharmaceutically acceptable carrier In one embodiment, the method comprises combining 65 Such that the composition comprises a range of 25-450 mg bupropion, traZodone, oxytocin, and a pharmaceutically of a 5-HT, antagonist and an oxytocin receptor (OXTR) acceptable carrier. agonist. US 9,517,254 B2 71 72 In one aspect, the method of making a composition ritanserin, clozapine, olanzapine, quetiapine, risperidone, comprises combining a 5-HT, receptor agonist (e.g., tra asenapine, MDL-100.907, cyproheptadine, aripiprazole, and Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido ritanserin, clozapine, olanzapine, quetiapine, risperidone, azepines), an oxytocin receptor (OXTR) agonist (e.g., car asenapine, MDL-100.907, cyproheptadine, aripiprazole, and betocin, oxytocin, Syntocinon R.), a 5-HT, agonist (e.g., the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido lorcaserin, vabicaserin, PRX-00933, YM348, metachloro azepines), an oxytocin receptor (OXTR) agonist (e.g., car phenylpiperazine), and a pharmaceutically acceptable car betocin, oxytocin, Syntocinon R.), a 5-HT, agonist (e.g., rier Such that the composition comprises a range of 4-400 lorcaserin, vabicaserin, PRX-00933, YM348, metachloro International Units of an oxytocin receptor (OXTR) agonist phenylpiperazine), other non-abusable agents (agents not 10 and a 5-HT, antagonist. scheduled by the DEA) that augment dopamine and/or In one aspect, the method of making a composition norepinephrine in the brain, e.g., atomoxetine, reboxetine, comprises combining a 5-HT2 receptor antagonist (e.g., amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, lortalamine, mazindol, nisoxetine, talopram, talsupram, tan ritanserin, clozapine, olanzapine, quetiapine, risperidone, damine, Viloxazine, maprotiline, ciclazindol, manifaxine, 15 asenapine, MDL-100.907, cyproheptadine, aripiprazole, and radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido biloba), and a pharmaceutically acceptable carrier Such that azepines), an oxytocin receptor (OXTR) agonist (e.g., car the composition comprises a range of 25-450 mg of a betocin, oxytocin, Syntocinon R.), a 5-HT, agonist (e.g., 5-HT, receptor agonist. In another aspect, the method of lorcaserin, vabicaserin, PRX-00933, YM348, metachloro making comprises combining a 5-HT agonist/5-HT phenylpiperazine), other non-abusable agents (agents not antagonist and a pharmaceutically acceptable carrier Such scheduled by the DEA) that augment dopamine and/or that the composition comprises a range of 25-450 mg of a norepinephrine in the brain, e.g., atomoxetine, reboxetine, 5-HT, antagonist and an oxytocin receptor (OXTR) ago amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, nist. lortalamine, mazindol, nisoxetine, talopram, talsupram, tan In one embodiment, the method comprises combining 25 damine, Viloxazine, maprotiline, ciclazindol, manifaxine, traZodone, oxytocin, and a pharmaceutically acceptable car radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo rier. biloba), and a pharmaceutically acceptable carrier Such that In one aspect, the method of making a composition the composition comprises a range of 4-400 International comprises combining a 5-HT2 receptor antagonist (e.g., Units of an oxytocin receptor (OXTR) agonist and a 5-HT, traZodone, nefazodone, mirtazapine, flibanserin), an oxyto 30 antagonist. cin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, In one embodiment, the method comprises combining Syntocinon R.), and a pharmaceutically acceptable carrier trazodone, oxytocin, and a pharmaceutically acceptable car Such that the composition comprises a range of 4-400 1. International Units of an oxytocin receptor (OXTR) agonist In one aspect, the method of making a composition and a 5-HT, antagonist. 35 comprises combining a norepinephrine-dopamine reuptake In one aspect, the method of making a composition inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) comprises combining a 5-HT2 receptor antagonist (e.g., agonist (e.g., carbetocin, oxytocin, SyntocinonR), and a traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, pharmaceutically acceptable carrier Such that the composi ritanserin, clozapine, olanzapine, quetiapine, risperidone, tion comprises a range of 50-450 mg of a norepinephrine asenapine, MDL-100.907, cyproheptadine, aripiprazole, and 40 dopamine reuptake inhibitor and an oxytocin receptor the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido (OXTR) agonist. azepines), an oxytocin receptor (OXTR) agonist (e.g., car In one aspect, the method of making a composition betocin, oxytocin, Syntocinon R.), and a pharmaceutically comprises combining a norepinephrine-dopamine reuptake acceptable carrier Such that the composition comprises a inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) range of 4-400 International Units of an oxytocin receptor 45 agonist (e.g., carbetocin, oxytocin, Syntocinon R.), other (OXTR) agonist and a 5-HT, antagonist. non-abusable agents (agents not scheduled by the DEA) that In one aspect, the method of making a composition augment dopamine and/or norepinephrine in the brain, e.g., comprises combining a 5-HT2 receptor antagonist (e.g., atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, edivoxetine, esreboxetine, lortalamine, mazindol, nisox ritanserin, clozapine, olanzapine, quetiapine, risperidone, 50 etine, talopram, talsupram, tandamine, Viloxazine, maproti asenapine, MDL-100.907, cyproheptadine, aripiprazole, and line, ciclaZindol, manifaxine, radafaxine, tapentadol, the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido teniloxazine, St. John’s wort, ginkgo biloba), and a phar azepines), an oxytocin receptor (OXTR) agonist (e.g., car maceutically acceptable carrier Such that the composition betocin, oxytocin, Syntocinon R.), other non-abusable agents comprises a range of 50-450 mg of a norepinephrine (agents not scheduled by the DEA) that augment dopamine 55 dopamine reuptake inhibitor and an oxytocin receptor and/or norepinephrine in the brain, e.g., atomoxetine, rebox (OXTR) agonist. etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox In one aspect, the method of making a composition etine, lortalamine, mazindol, nisoxetine, talopram, talsu comprises combining a norepinephrine-dopamine reuptake pram, tandamine, Viloxazine, maprotiline, ciclaZindol, inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) manifaxine, radafaxine, tapentadol, teniloxazine, St. John's 60 agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, wort, ginkgo biloba), and a pharmaceutically acceptable agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, carrier Such that the composition comprises a range of 4-400 metachlorophenylpiperazine), and a pharmaceutically International Units of an oxytocin receptor (OXTR) agonist acceptable carrier Such that the composition comprises a and a 5-HT, antagonist. range of 50-450 mg of a norepinephrine-dopamine reuptake In one aspect, the method of making a composition 65 inhibitor and an oxytocin receptor (OXTR) agonist. comprises combining a 5-HT2 receptor antagonist (e.g., In one aspect, the method of making a composition traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, comprises combining a norepinephrine-dopamine reuptake US 9,517,254 B2 73 74 inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) In one embodiment, the method comprises combining agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, bupropion, oxytocin, and a pharmaceutically acceptable agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, carrier. metachlorophenylpiperazine), other non-abusable agents In one aspect, the invention provides a kit comprising a (agents not scheduled by the DEA) that augment dopamine composition delineated herein and a label providing instruc and/or norepinephrine in the brain, e.g., atomoxetine, rebox tions for administration of the composition to a subject for etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox treating or ameliorating sexual disorders or symptoms etine, lortalamine, mazindol, nisoxetine, talopram, talsu thereof in the subject. pram, tandamine, Viloxazine, maprotiline, ciclaZindol, In one aspect, the invention provides a kit comprising a 10 composition delineated herein and a label providing instruc manifaxine, radafaxine, tapentadol, teniloxazine, St. John's tions for administration of the composition to a subject for wort, ginkgo biloba), and a pharmaceutically acceptable treating or ameliorating cognitive disorders or symptoms carrier Such that the composition comprises a range of thereof in the subject. 50-450 mg of a norepinephrine-dopamine reuptake inhibitor In one aspect, the invention provides a kit comprising a and an oxytocin receptor (OXTR) agonist. 15 composition delineated herein and a label providing instruc In one embodiment, the method comprises combining tions for administration of the composition to a subject for bupropion, oxytocin, and a pharmaceutically acceptable enhancing cognition in the Subject. carrier. In another aspect, the invention provides a method of In one aspect, the method of making a composition treating sexual disorders in a subject comprising adminis comprises combining a norepinephrine-dopamine reuptake tering to the Subject a 5-HT, receptoragonist, and a 5-HT inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) antagonist. The methods herein can further comprise those agonist (e.g., carbetocin, oxytocin, SyntocinonR), and a wherein the subject is identified as in need of such treatment, pharmaceutically acceptable carrier Such that the composi and those wherein the Subject is treated upon administration tion comprises a range of 4-400 International Units of an of the compounds and/or compositions herein. The methods oxytocin receptor (OXTR) agonist and a norepinephrine 25 can include those wherein the Subject has not previously dopamine reuptake inhibitor. been administered the compounds and/or compositions In one aspect, the method of making a composition herein, or wherein the subject has not previously been comprises combining a norepinephrine-dopamine reuptake administered the compounds and/or compositions herein at inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) the stated dosage levels or administration regimens. agonist (e.g., carbetocin, oxytocin, Syntocinon R.), other 30 In another aspect, the invention provides a method of non-abusable agents (agents not scheduled by the DEA) that treating sexual disorders in a subject comprising adminis augment dopamine and/or norepinephrine in the brain, e.g., tering to the subject a 5-HT, receptor agonist, a 5-HT, atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, antagonist, and ther non-abusable agents (agents not sched edivoxetine, esreboxetine, lortalamine, mazindol, nisox uled by the DEA) that augment dopamine and/or norepi etine, talopram, talsupram, tandamine, Viloxazine, maproti 35 nephrine in the brain, e.g., atomoxetine, reboxetine, ameda line, ciclaZindol, manifaxine, radafaxine, tapentadol, lin, CP-39,332, daledalin, edivoxetine, esreboxetine, teniloxazine, St. John’s wort, ginkgo biloba), and a phar lortalamine, mazindol, nisoxetine, talopram, talsupram, tan maceutically acceptable carrier Such that the composition damine, Viloxazine, maprotiline, ciclazindol, manifaxine, comprises a range of 4-400 International Units of an oxy radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo tocin receptor (OXTR) agonist and a norepinephrine-dop 40 biloba). The methods herein can further comprise those amine reuptake inhibitor. wherein the subject is identified as in need of such treatment, In one aspect, the method of making a composition and those wherein the Subject is treated upon administration comprises combining a norepinephrine-dopamine reuptake of the compounds and/or compositions herein. The methods inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) can include those wherein the Subject has not previously agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, 45 been administered the compounds and/or compositions agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, herein, or wherein the subject has not previously been metachlorophenylpiperazine), and a pharmaceutically administered the compounds and/or compositions herein at acceptable carrier Such that the composition comprises a the stated dosage levels or administration regimens. range of 4-400 International Units of an oxytocin receptor In another aspect, the invention provides a method of (OXTR) agonist and a norepinephrine-dopamine reuptake 50 treating sexual disorders in a subject comprising adminis inhibitor. tering to the Subject a 5-HT, receptor agonist, a 5-HT In one aspect, the method of making a composition antagonist, and a 5-HT2, agonist (e.g., lorcaserin, vabica comprises combining a norepinephrine-dopamine reuptake serin, PRX-00933, YM348, metachlorophenylpiperazine). inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) The methods herein can further comprise those wherein the agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, 55 Subject is identified as in need of Such treatment, and those agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, wherein the subject is treated upon administration of the metachlorophenylpiperazine), other non-abusable agents compounds and/or compositions herein. The methods can (agents not scheduled by the DEA) that augment dopamine include those wherein the subject has not previously been and/or norepinephrine in the brain, e.g., atomoxetine, rebox administered the compounds and/or compositions herein, or etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox 60 wherein the subject has not previously been administered the etine, lortalamine, mazindol, nisoxetine, talopram, talsu compounds and/or compositions herein at the Stated dosage pram, tandamine, Viloxazine, maprotiline, ciclaZindol, levels or administration regimens. manifaxine, radafaxine, tapentadol, teniloxazine, St. John's In another aspect, the invention provides a method of wort, ginkgo biloba), and a pharmaceutically acceptable treating sexual disorders in a subject comprising adminis carrier Such that the composition comprises a range of 4-400 65 tering to the Subject a 5-HT, receptor agonist, a 5-HT International Units of an oxytocin receptor (OXTR) agonist antagonist, other non-abusable agents (agents not scheduled and a norepinephrine-dopamine reuptake inhibitor. by the DEA) that augment dopamine and/or norepinephrine US 9,517,254 B2 75 76 in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, PRX-00933, YM348, metachlorophenylpiperazine), an 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ endocrine active agent, or any combination thereof. indol, nisoxetine, talopram, talsupram, tandamine, Vilox In another aspect, the invention provides a method of azine, maprotiline, ciclazindol, manifaxine, radafaxine, treating cognitive disorders in a Subject comprising admin tapentadol, teniloxazine, St. John’s wort, ginkgo biloba), istering to the subject a 5-HT, receptor agonist, and a and a 5-HT2, agonist (e.g., lorcaserin, vabicaserin, PRX 5-HT, antagonist. The methods herein can further comprise 00933, YM348, metachlorophenylpiperazine). The methods those wherein the subject is identified as in need of such herein can further comprise those wherein the subject is treatment, and those wherein the Subject is treated upon identified as in need of such treatment, and those wherein the administration of the compounds and/or compositions Subject is treated upon administration of the compounds 10 and/or compositions herein. The methods can include those herein. The methods can include those wherein the subject wherein the subject has not previously been administered the has not previously been administered the compounds and/or compounds and/or compositions herein, or wherein the compositions herein, or wherein the Subject has not previ Subject has not previously been administered the compounds ously been administered the compounds and/or composi and/or compositions herein at the stated dosage levels or 15 tions herein at the stated dosage levels or administration administration regimens. regimens. In another embodiment, the invention provides a method In another aspect, the invention provides a method of of treating a subject Suffering from or Susceptible to a sexual treating cognitive disorders in a Subject comprising admin disorder comprising administering to a Subject in need istering to the Subject a 5-HT, receptor agonist, other thereof a therapeutically effective amount of a composition non-abusable agents (agents not scheduled by the DEA) that comprising any one of a 5-HT, antagonist, a norepineph augment dopamine and/or norepinephrine in the brain, e.g., rine-dopamine reuptake inhibitor (e.g., bupropion), a atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, 5-HT, receptor agonist, an oxytocin receptor (OXTR) edivoxetine, esreboxetine, lortalamine, mazindol, nisox agonist (e.g., carbetocin, oxytocin, Syntocinon R.), an endo etine, talopram, talsupram, tandamine, Viloxazine, maproti crine active agent, or any combination thereof and a phar 25 line, ciclaZindol, manifaxine, radafaxine, tapentadol, maceutically acceptable carrier. teniloxazine, St. John's wort, ginkgo biloba), and a 5-HT In another embodiment, the invention provides a method antagonist. The methods herein can further comprise those of treating a subject Suffering from or Susceptible to a sexual wherein the subject is identified as in need of such treatment, disorder comprising administering to a Subject in need and those wherein the Subject is treated upon administration thereof a therapeutically effective amount of a composition 30 of the compounds and/or compositions herein. The methods comprising any one of a 5-HT, antagonist, a norepineph can include those wherein the Subject has not previously rine-dopamine reuptake inhibitor (e.g., bupropion), a been administered the compounds and/or compositions 5-HT, receptor agonist, an oxytocin receptor (OXTR) herein, or wherein the subject has not previously been agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, administered the compounds and/or compositions herein at agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, 35 the stated dosage levels or administration regimens. metachlorophenylpiperazine), other non-abusable agents In another aspect, the invention provides a method of (agents not scheduled by the DEA) that augment dopamine treating cognitive disorders in a Subject comprising admin and/or norepinephrine in the brain, e.g., atomoxetine, rebox istering to the Subject a 5-HT, receptor agonist, a 5-HT, etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, etine, lortalamine, mazindol, nisoxetine, talopram, talsu 40 metachlorophenylpiperazine), and a 5-HT, antagonist. The pram, tandamine, Viloxazine, maprotiline, ciclaZindol, methods herein can further comprise those wherein the manifaxine, radafaxine, tapentadol, teniloxazine, St. John's Subject is identified as in need of Such treatment, and those wort, ginkgo biloba), an endocrine active agent, or any wherein the subject is treated upon administration of the combination thereof and a pharmaceutically acceptable car compounds and/or compositions herein. The methods can rier. 45 include those wherein the subject has not previously been In another aspect, the invention provides a method of administered the compounds and/or compositions herein, or treating sexual disorders in a subject comprising adminis wherein the subject has not previously been administered the tering to the subject a therapeutically effective amount of compounds and/or compositions herein at the Stated dosage any one of a 5-HT, antagonist, a norepinephrine-dopamine levels or administration regimens. reuptake inhibitor (e.g., bupropion), a 5-HT, receptor ago 50 In another aspect, the invention provides a method of nist, an oxytocin receptor (OXTR) agonist (e.g., carbetocin, treating cognitive disorders in a Subject comprising admin oxytocin, Syntocinon R.), an endocrine active agent, or any istering to the Subject a 5-HT, receptor agonist, a 5-HT, combination thereof. agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, In another aspect, the invention provides a method of metachlorophenylpiperazine), other non-abusable agents treating sexual disorders in a subject comprising adminis 55 (agents not scheduled by the DEA) that augment dopamine tering to the subject a therapeutically effective amount of and/or norepinephrine in the brain, e.g., atomoxetine, rebox any one of a 5-HT, antagonist, a norepinephrine-dopamine etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox reuptake inhibitor (e.g., bupropion), a 5-HT, receptor ago etine, lortalamine, mazindol, nisoxetine, talopram, talsu nist, an oxytocin receptor (OXTR) agonist (e.g., carbetocin, pram, tandamine, Viloxazine, maprotiline, ciclaZindol, oxytocin, Syntocinon R.), other non-abusable agents (agents 60 manifaxine, radafaxine, tapentadol, teniloxazine, St. John's not scheduled by the DEA) that augment dopamine and/or wort, ginkgo biloba), and a 5-HT, antagonist. The methods norepinephrine in the brain, e.g., atomoxetine, reboxetine, herein can further comprise those wherein the subject is amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, identified as in need of such treatment, and those wherein the lortalamine, mazindol, nisoxetine, talopram, talsupram, tan Subject is treated upon administration of the compounds damine, Viloxazine, maprotiline, ciclazindol, manifaxine, 65 and/or compositions herein. The methods can include those radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo wherein the subject has not previously been administered the biloba), a 5-HT2, agonist (e.g., lorcaserin, vabicaserin, compounds and/or compositions herein, or wherein the US 9,517,254 B2 77 78 Subject has not previously been administered the compounds administered the compounds and/or compositions herein at and/or compositions herein at the stated dosage levels or the stated dosage levels or administration regimens. administration regimens. In another aspect, the invention provides a method of In another embodiment, the invention provides a method enhancing cognition in a subject comprising administering of treating a Subject Suffering from or Susceptible to a to the Subject a 5-HT, receptor agonist, other non-abusable cognitive disorder comprising administering to a Subject in agents (agents not scheduled by the DEA) that augment need thereof a therapeutically effective amount of a com dopamine and/or norepinephrine in the brain, e.g., atomox position comprising any one of a 5-HT, antagonist, a etine, reboxetine, amedalin, CP-39,332, daledalin, edivox norepinephrine-dopamine reuptake inhibitor (e.g., bupro etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo pion), a 5-HT, receptor agonist, an oxytocin receptor 10 pram, talsupram, tandamine, Viloxazine, maprotiline, ciclazindol, manifaxine, radafaxine, tapentadol, tenilox (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), azine, St. John's wort, ginkgo biloba), and a 5-HT, antago an endocrine active agent, or any combination thereof and a nist. The methods herein can further comprise those wherein pharmaceutically acceptable carrier. the Subject is identified as in need of Such treatment, and In another embodiment, the invention provides a method 15 those wherein the subject is treated upon administration of of treating a Subject Suffering from or Susceptible to a the compounds and/or compositions herein. The methods cognitive disorder comprising administering to a Subject in can include those wherein the Subject has not previously need thereof a therapeutically effective amount of a com been administered the compounds and/or compositions position comprising any one of a 5-HT, antagonist, a herein, or wherein the subject has not previously been norepinephrine-dopamine reuptake inhibitor (e.g., bupro administered the compounds and/or compositions herein at pion), a 5-HT, receptor agonist, an oxytocin receptor the stated dosage levels or administration regimens. (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), In another aspect, the invention provides a method of a 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, enhancing cognition in a subject comprising administering YM348, metachlorophenylpiperazine), other non-abusable to the Subject a 5-HT, receptor agonist, a 5-HT2, agonist agents (agents not scheduled by the DEA) that augment 25 (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, dopamine and/or norepinephrine in the brain, e.g., atomox metachlorophenylpiperazine), and a 5-HT, antagonist. The etine, reboxetine, amedalin, CP-39,332, daledalin, edivox methods herein can further comprise those wherein the etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo Subject is identified as in need of Such treatment, and those pram, talsupram, tandamine, Viloxazine, maprotiline, wherein the subject is treated upon administration of the ciclazindol, manifaxine, radafaxine, tapentadol, tenilox 30 compounds and/or compositions herein. The methods can azine, St. John’s wort, ginkgo biloba), an endocrine active include those wherein the subject has not previously been agent, or any combination thereof and a pharmaceutically administered the compounds and/or compositions herein, or acceptable carrier. wherein the subject has not previously been administered the In another aspect, the invention provides a method of compounds and/or compositions herein at the Stated dosage treating cognitive disorders in a Subject comprising admin 35 levels or administration regimens. istering to the subject a therapeutically effective amount of In another aspect, the invention provides a method of any one of a 5-HT, antagonist, a norepinephrine-dopamine enhancing cognition in a subject comprising administering reuptake inhibitor (e.g., bupropion), a 5-HT, receptor ago to the Subject a 5-HT, receptor agonist, a 5-HT2, agonist nist, an oxytocin receptor (OXTR) agonist (e.g., carbetocin, (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, oxytocin, Syntocinon R.), an endocrine active agent, or any 40 metachlorophenylpiperazine), other non-abusable agents combination thereof. (agents not scheduled by the DEA) that augment dopamine In another aspect, the invention provides a method of and/or norepinephrine in the brain, e.g., atomoxetine, rebox treating cognitive disorders in a Subject comprising admin etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox istering to the subject a therapeutically effective amount of etine, lortalamine, mazindol, nisoxetine, talopram, talsu any one of a 5-HT, antagonist, a norepinephrine-dopamine 45 pram, tandamine, Viloxazine, maprotiline, ciclaZindol, reuptake inhibitor (e.g., bupropion), a 5-HT, receptor ago manifaxine, radafaxine, tapentadol, teniloxazine, St. John's nist, an oxytocin receptor (OXTR) agonist (e.g., carbetocin, wort, ginkgo biloba), and a 5-HT, antagonist. The methods oxytocin, Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, herein can further comprise those wherein the subject is vabicaserin, PRX-00933, YM348, metachlorophenylpipera identified as in need of such treatment, and those wherein the Zine), other non-abusable agents (agents not scheduled by 50 Subject is treated upon administration of the compounds the DEA) that augment dopamine and/or norepinephrine in and/or compositions herein. The methods can include those the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, wherein the subject has not previously been administered the 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ compounds and/or compositions herein, or wherein the indol, nisoxetine, talopram, talsupram, tandamine, Vilox Subject has not previously been administered the compounds azine, maprotiline, ciclazindol, manifaxine, radafaxine, 55 and/or compositions herein at the stated dosage levels or tapentadol, teniloxazine, St. John's wort, ginkgo biloba), an administration regimens. endocrine active agent, or any combination thereof. In another embodiment, the invention provides a method In another aspect, the invention provides a method of of enhancing cognition comprising administering to a Sub enhancing cognition in a subject comprising administering ject in need thereof a therapeutically effective amount of a to the Subject a 5-HT, receptor agonist, and a 5-HT 60 composition comprising any one of a 5-HT, antagonist, a antagonist. The methods herein can further comprise those norepinephrine-dopamine reuptake inhibitor (e.g., bupro wherein the subject is identified as in need of such treatment, pion), a 5-HT, receptor agonist, an oxytocin receptor and those wherein the Subject is treated upon administration (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), of the compounds and/or compositions herein. The methods an endocrine active agent, or any combination thereof and a can include those wherein the Subject has not previously 65 pharmaceutically acceptable carrier. been administered the compounds and/or compositions In another embodiment, the invention provides a method herein, or wherein the subject has not previously been of enhancing cognition comprising administering to a Sub US 9,517,254 B2 79 80 ject in need thereof a therapeutically effective amount of a been administered the compounds and/or compositions composition comprising any one of a 5-HT, antagonist, a herein, or wherein the subject has not previously been norepinephrine-dopamine reuptake inhibitor (e.g., bupro administered the compounds and/or compositions herein at pion), a 5-HT, receptor agonist, an oxytocin receptor the stated dosage levels or administration regimens. (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon R.), 5 In another aspect, the invention provides a method of a 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, relieving depression in a Subject comprising administering YM348, metachlorophenylpiperazine), other non-abusable to the Subject a 5-HT, receptor agonist, a 5-HT2, agonist agents (agents not scheduled by the DEA) that augment (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, dopamine and/or norepinephrine in the brain, e.g., atomox metachlorophenylpiperazine), and a 5-HTantagonist. The etine, reboxetine, amedalin, CP-39,332, daledalin, edivox 10 etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo methods herein can further comprise those wherein the pram, talsupram, tandamine, Viloxazine, maprotiline, Subject is identified as in need of Such treatment, and those ciclazindol, manifaxine, radafaxine, tapentadol, tenilox wherein the subject is treated upon administration of the azine, St. John’s wort, ginkgo biloba), an endocrine active compounds and/or compositions herein. The methods can agent, or any combination thereof and a pharmaceutically 15 include those wherein the subject has not previously been acceptable carrier. administered the compounds and/or compositions herein, or In another aspect, the invention provides a method of wherein the subject has not previously been administered the enhancing cognition in a subject comprising administering compounds and/or compositions herein at the Stated dosage to the subject a therapeutically effective amount of any one levels or administration regimens. of a 5-HT, antagonist, a norepinephrine-dopamine In another aspect, the invention provides a method of reuptake inhibitor (e.g., bupropion), a 5-HT, receptor ago relieving depression in a Subject comprising administering nist, an oxytocin receptor (OXTR) agonist (e.g., carbetocin, to the Subject a 5-HT, receptor agonist, a 5-HT2, agonist oxytocin, Syntocinon R.), an endocrine active agent, or any (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, combination thereof. metachlorophenylpiperazine), other non-abusable agents In another aspect, the invention provides a method of 25 (agents not scheduled by the DEA) that augment dopamine enhancing cognition in a subject comprising administering and/or norepinephrine in the brain, e.g., atomoxetine, rebox to the subject a therapeutically effective amount of any one etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox of a 5-HT, antagonist, a norepinephrine-dopamine etine, lortalamine, mazindol, nisoxetine, talopram, talsu reuptake inhibitor (e.g., bupropion), a 5-HT, receptor ago pram, tandamine, Viloxazine, maprotiline, ciclaZindol, nist, an oxytocin receptor (OXTR) agonist (e.g., carbetocin, 30 manifaxine, radafaxine, tapentadol, teniloxazine, St. John's oxytocin, Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, wort, ginkgo biloba), and a 5-HT, antagonist. The methods vabicaserin, PRX-00933, YM348, metachlorophenylpipera herein can further comprise those wherein the subject is Zine), other non-abusable agents (agents not scheduled by identified as in need of such treatment, and those wherein the the DEA) that augment dopamine and/or norepinephrine in Subject is treated upon administration of the compounds the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, 35 and/or compositions herein. The methods can include those 332, daledalin, edivoxetine, esreboxetine, lortalamine, maZ wherein the subject has not previously been administered the indol, nisoxetine, talopram, talsupram, tandamine, Vilox compounds and/or compositions herein, or wherein the azine, maprotiline, ciclazindol, manifaxine, radafaxine, Subject has not previously been administered the compounds tapentadol, teniloxazine, St. John's wort, ginkgo biloba), an and/or compositions herein at the stated dosage levels or endocrine active agent, or any combination thereof. 40 administration regimens. In another aspect, the invention provides a method of In another embodiment, the invention provides a method relieving depression in a Subject comprising administering of relieving depression comprising administering to a Sub to the Subject a 5-HT, receptor agonist, and a 5-HT ject in need thereof a therapeutically effective amount of a antagonist. The methods herein can further comprise those composition comprising any one of a 5-HT, antagonist, a wherein the subject is identified as in need of such treatment, 45 norepinephrine-dopamine reuptake inhibitor (e.g., bupro and those wherein the Subject is treated upon administration pion), a 5-HT, receptor agonist, an oxytocin receptor of the compounds and/or compositions herein. The methods (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), can include those wherein the Subject has not previously an endocrine active agent, or any combination thereof and a been administered the compounds and/or compositions pharmaceutically acceptable carrier. herein, or wherein the subject has not previously been 50 In another embodiment, the invention provides a method administered the compounds and/or compositions herein at of relieving depression comprising administering to a Sub the stated dosage levels or administration regimens. ject in need thereof a therapeutically effective amount of a In another aspect, the invention provides a method of composition comprising any one of a 5-HT, antagonist, a relieving depression in a Subject comprising administering norepinephrine-dopamine reuptake inhibitor (e.g., bupro to the Subject a 5-HT, receptor agonist, other non-abusable 55 pion), a 5-HT, receptor agonist, an oxytocin receptor agents (agents not scheduled by the DEA) that augment (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), dopamine and/or norepinephrine in the brain, e.g., atomox a 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, etine, reboxetine, amedalin, CP-39,332, daledalin, edivox YM348, metachlorophenylpiperazine), other non-abusable etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo agents (agents not scheduled by the DEA) that augment pram, talsupram, tandamine, Viloxazine, maprotiline, 60 dopamine and/or norepinephrine in the brain, e.g., atomox ciclazindol, manifaxine, radafaxine, tapentadol, tenilox etine, reboxetine, amedalin, CP-39,332, daledalin, edivox azine, St. John's wort, ginkgo biloba), and a 5-HT2, antago etine, esreboxetine, lortalamine, mazindol, nisoxetine, talo nist. The methods herein can further comprise those wherein pram, talsupram, tandamine, Viloxazine, maprotiline, the Subject is identified as in need of Such treatment, and ciclazindol, manifaxine, radafaxine, tapentadol, tenilox those wherein the subject is treated upon administration of 65 azine, St. John’s wort, ginkgo biloba), an endocrine active the compounds and/or compositions herein. The methods agent, or any combination thereof and a pharmaceutically can include those wherein the Subject has not previously acceptable carrier. US 9,517,254 B2 81 82 In another aspect, the invention provides a method of pamine reuptake inhibitor (e.g., bupropion), and oxytocin relieving depression in a Subject comprising administering receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syn to the subject a therapeutically effective amount of any one tocinonR), (and optionally an endocrine active agent) pro of a 5-HT, antagonist, a norepinephrine-dopamine vides unexpected Superior and synergistic results in address reuptake inhibitor, a 5-HT, receptor agonist, an oxytocin ing sexual disorders, cognitive disorders, or offers cognition receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syn enhancement in a subject. tocinon R.), an endocrine active agent, or any combination thereof. 1. Definitions In another aspect, the invention provides a method of relieving depression in a Subject comprising administering 10 Before further description of the present invention, and in to the subject a therapeutically effective amount of any one order that the invention may be more readily understood, of a 5-HT, antagonist, a norepinephrine-dopamine certain terms are first defined and collected here for conve reuptake inhibitor, a 5-HT, receptor agonist, an oxytocin nience. receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syn The term “administration” or “administering includes tocinon R.), a 5-HT2, agonist (e.g., lorcaserin, vabicaserin, 15 routes of introducing the compound of the invention(s) to a PRX-00933, YM348, metachlorophenylpiperazine), other subject to perform their intended function. Examples of non-abusable agents (agents not scheduled by the DEA) that routes of administration that may be used include injection augment dopamine and/or norepinephrine in the brain, e.g., (Subcutaneous, intravenous, parenterally, intraperitoneally, atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, intrathecal), oral, buccal, Sublingual, inhalation, rectal and edivoxetine, esreboxetine, lortalamine, mazindol, nisox transdermal. The pharmaceutical preparations may be given etine, talopram, talsupram, tandamine, Viloxazine, maproti by forms suitable for each administration route. For line, ciclaZindol, manifaxine, radafaxine, tapentadol, example, these preparations are administered in tablets or teniloxazine, St. John’s wort, ginkgo biloba), an endocrine capsule form, by injection, inhalation, eye lotion, ointment, active agent, or any combination thereof. Suppository, etc. administration by injection, infusion or In aspects the endocrine agent is testosterone, which can 25 inhalation; topical by lotion or ointment; and rectal by be in an amount of a dosage range of 25 to 1000 mg per day Suppositories. Oral administration is preferred. The injection in men or 150 to 300 micrograms per day in women. can be bolus or can be continuous infusion. Depending on In aspects, the Subject is that wherein the Subject is not the route of administration, the compound of the invention being treated with a selective serotonin reuptake inhibitor can be coated with or disposed in a selected material to (SSRI) agent. 30 protect it from natural conditions which may detrimentally In aspects, the Subject is that wherein the Subject is being effect its ability to perform its intended function. The treated with a selective serotonin reuptake inhibitor (SSRI) compound of the invention can be administered alone, or in agent. conjunction with either another agent as described above or In aspects, the Subject is that wherein the Subject is with a pharmaceutically-acceptable carrier, or both. The identified as having selective serotonin reuptake inhibitor 35 compound of the invention can be administered prior to the (SSRI) agent induced sexual disorders. administration of the other agent, simultaneously with the In aspects, the Subject is that wherein the Subject is being agent, or after the administration of the agent. Furthermore, treated with a PDE-5 inhibitor compound (i.e., sildenafil. the compound of the invention can also be administered in tadalafil, and the like). a pro-drug form which is converted into its active metabo In aspects, the Subject is that wherein the Subject is not 40 lite, or more active metabolite in vivo. concurrently being treated with a PDE-5 inhibitor compound The term “alkyl refers to the radical of saturated aliphatic (i.e., sildenafil, tadalafil, and the like). groups, including straight-chain alkyl groups, branched In aspects, the Subject is that wherein the Subject is being chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl Sub treated with an endocrine agent (e.g., testosterone). stituted cycloalkyl groups, and cycloalkyl Substituted alkyl In aspects, the Subject is that wherein the Subject is not 45 groups. The term alkyl further includes alkyl groups, which concurrently being treated with an endocrine agent (e.g., can further include oxygen, nitrogen, Sulfur or phosphorous testosterone). atoms replacing one or more carbons of the hydrocarbon In another aspect, the methods herein comprise taking a backbone, e.g., oxygen, nitrogen, Sulfur or phosphorous sample (i.e., fluid, blood, urine, saliva, tissue, etc.) and atoms. In preferred embodiments, a straight chain or assessing a biological marker (i.e., liver enzymes, CYP3A4, 50 branched chain alkyl has 30 or fewer carbon atoms in its and/or a genetic marker of the transport, receptor type, backbone (e.g., C1-C30 for straight chain, C-Clso for receptor density, receptor affinity, metabolism, or activity of branched chain), preferably 26 or fewer, and more prefer serotonin, serotonin 1A or 2A Subtype, dopamine, or a ably 20 or fewer, and still more preferably 4 or fewer. receptor Subtype of dopamine) to measure health status of Likewise, preferred cycloalkyls have from 3-10 carbon the subject either prior to, during or after administration of 55 atoms in their ring structure, and more preferably have 3, 4, the compositions herein. 5, 6 or 7 carbons in the ring structure. Moreover, the term alkyl as used throughout the specifi DETAILED DESCRIPTION OF THE cation and sentences is intended to include both “unsubsti INVENTION tuted alkyls' and “substituted alkyls, the latter of which 60 refers to alkyl moieties having Substituents replacing a The present inventors have now discovered a therapeutic hydrogen on one or more carbons of the hydrocarbon strategy that addresses sexual disorders, cognitive disorders, backbone. Such substituents can include, for example, halo or offers cognition enhancement in a subject. gen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy The present invention relates, at least in part, to the carbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbo discovery that a combination of a 5-HT, antagonist (which 65 nyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, is optionally a 5-HT, receptor agonist) (e.g., traZodone, alkoxyl, phosphate, phosphonato, phosphinato, cyano, nefazodone, mirtazapine, flibanserin), a norepinephrine-do amino (including alkyl amino, dialkylamino, arylamino, US 9,517,254 B2 83 84 diarylamino, and alkylarylamino), acylamino (including juxtaposition is energetically favored by hydrogen bonding alkylcarbonylamino, arylcarbonylamino, carbamoyl and or van der Waals or electrostatic interactions) or it may be ureido), amidino, imino, Sulfhydryl, alkylthio, arylthio, thio covalent. carboxylate, Sulfates, Sulfonato, Sulfamoyl, Sulfonamido, The language “biological activities of a compound of the nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, invention includes all activities elicited by compound of the or an aromatic or heteroaromatic moiety. It will be under inventions in a responsive cell. It includes genomic and stood by those skilled in the art that the moieties substituted non-genomic activities elicited by these compounds. on the hydrocarbon chain can themselves be substituted, if “Biological composition' or “biological sample” refers to appropriate. Cycloalkyls can be further substituted, e.g., a composition containing or derived from cells or biopoly with the substituents described above. An “alkylaryl moiety 10 mers. Cell-containing compositions include, for example, is an alkyl Substituted with an aryl (e.g., phenylmethyl mammalian blood, red cell concentrates, platelet concen (benzyl)). The term “alkyl also includes unsaturated ali trates, leukocyte concentrates, blood cell proteins, blood phatic groups analogous in length and possible Substitution plasma, platelet-rich plasma, a plasma concentrate, a pre to the alkyls described above, but that contain at least one 15 cipitate from any fractionation of the plasma, a Supernatant double or triple bond respectively. from any fractionation of the plasma, blood plasma protein Unless the number of carbons is otherwise specified, fractions, purified or partially purified blood proteins or “lower alkyl as used herein means an alkyl group, as other components, serum, semen, mammalian colostrum, defined above, but having from one to ten carbons, more milk, saliva, placental extracts, a cryoprecipitate, a cryosu preferably from one to six, and still more preferably from pernatant, a cell lysate, mammalian cell culture or culture one to four carbon atoms in its backbone structure, which medium, products of fermentation, ascites fluid, proteins may be straight or branched-chain. Examples of lower alkyl induced in blood cells, and products produced in cell culture groups include methyl, ethyl, n-propyl, i-propyl, tert-butyl, by normal or transformed cells (e.g., via recombinant DNA hexyl, heptyl, octyl and so forth. In preferred embodiment, or monoclonal antibody technology). Biological composi the term “lower alkyl includes a straight chain alkyl having 25 tions can be cell-free. In a preferred embodiment, a suitable 4 or fewer carbon atoms in its backbone, e.g., C1-C4 alkyl. biological composition or biological sample is a red blood The terms “alkoxyalkyl,” “polyaminoalkyl and “thio cell Suspension. In some embodiments, the blood cell Sus alkoxyalkyl refer to alkyl groups, as described above, pension includes mammalian blood cells. Preferably, the which further include oxygen, nitrogen or Sulfur atoms blood cells are obtained from a human, a non-human pri 30 mate, a dog, a cat, a horse, a cow, a goat, a sheep or a pig. replacing one or more carbons of the hydrocarbon backbone, In preferred embodiments, the blood cell suspension e.g., oxygen, nitrogen or Sulfur atoms. includes red blood cells and/or platelets and/or leukocytes The terms “alkenyl and “alkynyl refer to unsaturated and/or bone marrow cells. aliphatic groups analogous in length and possible Substitu The term "chiral' refers to molecules which have the tion to the alkyls described above, but that contain at least 35 property of non-Superimposability of the mirror image part one double or triple bond, respectively. For example, the ner, while the term “achiral' refers to molecules which are invention contemplates cyano and propargyl groups. Superimposable on their minor image partner. The term “aryl as used herein, refers to the radical of aryl The term "diastereomers' refers to stereoisomers with groups, including 5- and 6-membered single-ring aromatic two or more centers of dissymmetry and whose molecules groups that may include from Zero to four heteroatoms, for 40 are not minor images of one another. example, benzene, pyrrole, furan, thiophene, imidazole, The term “effective amount includes an amount effec benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, tive, at dosages and for periods of time necessary, to achieve pyridine, pyrazine, pyridazine and pyrimidine, and the like. the desired result, e.g., Sufficient to treat a sexual disorder or Aryl groups also include polycyclic fused aromatic groups hypoactive sexual desire disorder in a subject. An effective Such as naphthyl, quinolyl, indolyl, and the like. Those aryl 45 amount of compound of the invention may vary according to groups having heteroatoms in the ring structure may also be factors such as the disease state, age, and weight of the referred to as “aryl heterocycles,” “heteroaryls' or “het subject, and the ability of the compound of the invention to eroaromatics.” The aromatic ring can be substituted at one or elicit a desired response in the Subject. Dosage regimens more ring positions with Such substituents as described may be adjusted to provide the optimum therapeutic above, as for example, halogen, hydroxyl, alkoxy, alkylcar 50 response. An effective amount is also one in which any toxic bonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycar or detrimental effects (e.g., side effects) of the compound of bonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, the invention are outweighed by the therapeutically benefi aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, cial effects. phosphinato, cyano, amino (including alkyl amino, dialky A therapeutically effective amount of compound of the lamino, arylamino, diarylamino, and alkylarylamino), acy 55 invention (i.e., an effective dosage) may range from about lamino (including alkylcarbonylamino, arylcarbonylamino, 0.001 to 30 mg/kg body weight, preferably about 0.01 to 25 carbamoyl and ureido), amidino, imino, Sulfhydryl, alkyl mg/kg body weight, more preferably about 0.1 to 20 mg/kg thio, arylthio, thiocarboxylate, Sulfates, Sulfonato, Sulfa body weight, and even more preferably about 1 to 10 mg/kg, moyl, Sulfonamido, nitro, trifluoromethyl, cyano, azido, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg heterocyclyl, alkylaryl, or an aromatic or heteroaromatic 60 body weight. The skilled artisan will appreciate that certain moiety. Aryl groups can also be fused or bridged with factors may influence the dosage required to effectively treat alicyclic or heterocyclic rings which are not aromatic So as a subject, including but not limited to the severity of the to form a polycycle (e.g., tetralin). disease or disorder, previous treatments, the general health The term “associating with refers to a condition of and/or age of the Subject, and other diseases present. More proximity between a chemical entity or compound, or por 65 over, treatment of a subject with a therapeutically effective tions thereof, and a binding pocket or binding site on a amount of a compound of the invention can include a single protein. The association may be non-covalent (wherein the treatment or, preferably, can include a series of treatments. US 9,517,254 B2 85 86 In one example, a Subject is treated with a compound of the The term "isomers' or “stereoisomers' refers to com invention in the range of between about 0.1 to 20 mg/kg pounds which have identical chemical constitution, but body weight, one time per week for between about 1 to 10 differ with regard to the arrangement of the atoms or groups weeks, preferably between 2 to 8 weeks, more preferably in space. between about 3 to 7 weeks, and even more preferably for The term “modulate” refers to an increase or decrease, about 4, 5, or 6 weeks. It will also be appreciated that the e.g., the alteration in sexual disorder or hypoactive sexual effective dosage of a compound of the invention used for desire disorder and/or symptoms thereof in a Subject Such treatment may increase or decrease over the course of a that a desired end result is achieved, e.g., a therapeutic particular treatment. Administration regimens herein where result. designated are in accordance with the following abbrevia 10 The term “obtaining as in “obtaining a compound useful tions: SID or QD-Once a day; BID=Twice a day, in treating sexual disorder or hypoactive sexual desire TID=Three times a day; QID=Four times a day; qh.s-every disorder is intended to include purchasing, synthesizing or night. otherwise acquiring the compound. The term “enantiomers' refers to two stereoisomers of a 15 The phrases “parenteral administration” and “adminis compound which are non-Superimposable minor images of tered parenterally as used herein means modes of admin one another. An equimolar mixture of two enantiomers is istration other than enteral and topical administration, usu called a “racemic mixture' or a “racemate.” The compounds ally by injection, and includes, without limitation, of this invention may contain one or more asymmetric intravenous, intramuscular, intraarterial, intrathecal, intraca centers and thus occur as racemates and racemic mixtures, psular, intraorbital, intracardiac, intradermal, intraperito single enantiomers, individual diastereomers and diastereo neal, transtracheal, Subcutaneous, Subcuticular, intraarticu meric mixtures. All Such isomeric forms of these compounds lare, Subcapsular, Subarachnoid, intraspinal and intrasternal are expressly included in the present invention. The com injection and infusion. pounds of this invention may also be represented in multiple The terms “polycyclyl or “polycyclic radical refer to the tautomeric forms, in Such instances, the invention expressly 25 radical of two or more cyclic rings (e.g., cycloalkyls, includes all tautomeric forms of the compounds described cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in herein. All Such isomeric forms of Such compounds are which two or more carbons are common to two adjoining expressly included in the present invention. All crystal forms rings, e.g., the rings are “fused rings'. Rings that are joined of the compounds described herein are expressly included in through non-adjacent atoms are termed "bridged rings. the present invention. 30 Each of the rings of the polycycle can be substituted with The term “haloalkyl is intended to include alkyl groups Such substituents as described above, as for example, halo as defined above that are mono-, di- or polysubstituted by gen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxy halogen, e.g., fluoromethyl and trifluoromethyl. carbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbo The term “halogen designates —F. —Cl, —Br or —I. nyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, The term “hydroxyl means —OH. 35 alkoxyl, phosphate, phosphonato, phosphinato, cyano, The term "heteroatom' as used herein means an atom of amino (including alkyl amino, dialkylamino, arylamino, any element other than carbon or hydrogen. Preferred het diarylamino, and alkylarylamino), acylamino (including eroatoms are nitrogen, oxygen, Sulfur and phosphorus. alkylcarbonylamino, arylcarbonylamino, carbamoyl and The term "homeostasis is art-recognized to mean main ureido), amidino, imino, Sulfhydryl, alkylthio, arylthio, thio tenance of static, or constant, conditions in an internal 40 carboxylate, Sulfates, Sulfonato, Sulfamoyl, Sulfonamido, environment. nitro, trifluoromethyl, cyano, azido, heterocyclyl alkyl, The language “improved biological properties' refers to alkylaryl, or an aromatic or heteroaromatic moiety. any activity inherent in a compound of the invention that The term “prodrug or “pro-drug includes compounds enhances its effectiveness in vivo. In a preferred embodi with moieties that can be metabolized in vivo. Generally, the ment, this term refers to any qualitative or quantitative 45 prodrugs are metabolized in vivo by esterases or by other improved therapeutic property of a compound of the inven mechanisms to active drugs. Examples of prodrugs and their tion, such as reduced toxicity. uses are well known in the art (See, e.g., Berge et al. (1977) The term “optionally substituted' is intended to encom “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19). The prod pass groups that are unsubstituted or are Substituted by other rugs can be prepared in situ during the final isolation and than hydrogen at one or more available positions, typically 50 purification of the compounds, or by separately reacting the 1, 2, 3, 4 or 5 positions, by one or more Suitable groups purified compound in its free acid form or hydroxyl with a (which may be the same or different). Such optional sub Suitable esterifying agent. Hydroxyl groups can be con stituents include, for example, hydroxy, halogen, cyano, verted into esters via treatment with a carboxylic acid. nitro, C-Calkyl, C-C alkenyl, C-Calkynyl. Examples of prodrug moieties include Substituted and C-Csalkoxy, C-Csalkyl ether, Cs-Csalkanone, 55 unsubstituted, branch or unbranched lower alkyl ester moi C-Calkylthio, amino, mono- or di-(C1-Calkyl)amino, eties, (e.g., propionoic acid esters), lower alkenyl esters, haloC-Csalkyl, haloC-Csalkoxy, C-Csalkanoyl, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylam C-Csalkanoyloxy, C-Csalkoxycarbonyl, -COOH, inoethyl ester), acylamino lower alkyl esters (e.g., acety —CONH2 mono- or di-(C-Csalkyl)aminocarbonyl, loxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloy —SONH2, and/or mono or di(C-Calkyl)sulfonamido, as 60 loxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl well as carbocyclic and heterocyclic groups. Optional Sub esters (e.g., benzyl ester), Substituted (e.g., with methyl, stitution is also indicated by the phrase “substituted with halo, or methoxy substituents) aryl and aryl-lower alkyl from 0 to X substituents, where X is the maximum number esters, amides, lower-alkyl amides, di-lower alkyl amides, of possible substituents. Certain optionally substituted and hydroxy amides. Preferred prodrug moieties are propi groups are substituted with from 0 to 2, 3 or 4 independently 65 onoic acid esters and acyl esters. Prodrugs which are con selected substituents (i.e., are unsubstituted or substituted verted to active forms through other mechanisms in vivo are with up to the recited maximum number of substituents). also included. US 9,517,254 B2 87 88 The language “a prophylactically effective amount of a In one aspect, the invention provides compounds capable compound refers to an amount of a compound of the of modulating sexual disorder or hypoactive sexual desire invention any formula herein or otherwise described herein disorder in a Subject. Such compounds include a 5-HT which is effective, upon single or multiple dose administra antagonist (e.g., traZodone, nefazodone, mirtazapine, fliban tion to the patient, in preventing or treating a sexual disorder. serin), a 5-HT, receptor agonist (e.g., traZodone, nefa The language “reduced toxicity' is intended to include a Zodone, mirtazapine, flibanserin), a norepinephrine-dop reduction in any undesired side effect elicited by a com amine reuptake inhibitor (e.g., bupropion), an oxytocin pound of the invention when administered in vivo e.g., receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syn formulating bupropion, by itself a mild stimulant, with tocinon R.), a 5-HT, agonist (e.g., lorcaserin, vabicaserin, 10 PRX-00933, YM348, metachlorophenylpiperazine), other traZodone, by itself a moderate sedative, in the proprietary non-abusable agents (agents not scheduled by the DEA) that ratio of Lorexys will neutralize the main side effects of each augment dopamine and/or norepinephrine in the brain, e.g., of the two drugs. atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, The term “subject' includes organisms which are capable edivoxetine, esreboxetine, lortalamine, mazindol, nisox of suffering from a sexual disorder or who could otherwise 15 etine, talopram, talsupram, tandamine, Viloxazine, maproti benefit from the administration of a compound or compo line, ciclaZindol, manifaxine, radafaxine, tapentadol, sition of the invention, such as human (male or female) and teniloxazine, St. John’s wort, ginkgo biloba), and an endo non-human animals (male or female). Preferred humans crine active agent. Compositions of the invention further include human patients Suffering from or prone to Suffering include a pharmaceutically acceptable carrier. from sexual disorder or hypoactive sexual desire disorder or The compounds delineated herein include a 5-HT, associated State, as described herein. The term “non-human antagonist (e.g., traZodone, nefazodone, mirtazapine, fliban animals' of the invention includes all vertebrates, e.g., serin), that is a compound that demonstrates antagonistic mammals, e.g., rodents, e.g., mice, and non-mammals. Such activity against the 5-HT, receptor, a norepinephrine-dop as non-human primates, e.g., sheep, dog, cow, chickens, amine reuptake inhibitor (e.g., bupropion); that is a com amphibians, reptiles, etc. 25 pound that exhibits inhibition activity in norepinephrine The term “susceptible to a sexual disorder or hypoactive dopamine reuptake; a 5-HT, receptor agonist (e.g., sexual desire disorder is meant to include subjects at risk of traZodone, nefazodone, mirtazapine, flibanserin), that is a developing sexual disorder or hypoactive sexual desire compound that demonstrates agonist activity against the disorder, e.g., Subjects previously diagnosed as having or 5-HT, receptor, an oxytocin receptor (OXTR) agonist (e.g., having a family or medical history of sexual disorder or 30 carbetocin, oxytocin, Syntocinon R.), that is a compound that hypoactive sexual desire disorder, and the like. demonstrates agonistic activity against the oxytocin recep The phrases “systemic administration, “administered sys tor; and an endocrine active agent, that is an agent that is temically”, “peripheral administration' and “administered active in modulating the endocrine system. peripherally as used herein mean the administration of a The compounds delineated herein include a 5-HT, compound of the invention(s), drug or other material. Such 35 antagonist (e.g., traZodone, nefazodone, mirtazapine, fliban that it enters the patient's system and, thus, is subject to serin, ketanserin, ritanserin, clozapine, olanzapine, quetiap metabolism and other like processes, for example, Subcuta ine, risperidone, asenapine, MDL-100.907, cyproheptadine, neous administration. aripiprazole, and the general class of 2-alkyl-4-aryl-tetra The language “therapeutically effective amount of a hydro-pyrimido-azepines), that is a compound that demon compound of the invention of the invention refers to an 40 strates antagonistic activity against the 5-HT, receptor; a amount of an agent which is effective, upon single or norepinephrine-dopamine reuptake inhibitor (e.g., bupro multiple dose administration to the patient, in modulating pion); that is a compound that exhibits inhibition activity in sexual disorder or hypoactive sexual desire disorder and/or norepinephrine-dopamine reuptake; a 5-HT, receptor ago symptoms of sexual disorder or hypoactive sexual desire nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, disorder, or in improving the patient (either objectively or 45 ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris Subjectively according to the patient or health care provider) peridone, asenapine, MDL-100.907, cyproheptadine, arip beyond that expected in the absence of such treatment. iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro With respect to the nomenclature of a chiral center, terms pyrimido-azepines), that is a compound that demonstrates “d” and “1” configuration are as defined by the IUPAC agonist activity against the 5-HT, receptor, an oxytocin Recommendations. As to the use of the terms, diastereomer, 50 receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syn racemate, epimer and enantiomer will be used in their tocinon R.), that is a compound that demonstrates agonistic normal context to describe the Stereochemistry of prepara activity against the oxytocin receptor, and an endocrine tions. active agent, that is an agent that is active in modulating the endocrine system. 2. Compounds of the Invention 55 In one embodiment, the invention provides a compound (e.g., a compound herein) capable of modulating sexual In one aspect, the invention provides compounds capable disorder or hypoactive sexual desire disorder, and pharma of modulating sexual disorder or hypoactive sexual desire ceutically acceptable esters, salts, isomers and prodrugs disorder in a subject. Such compounds include a 5-HT thereof. antagonist (e.g., traZodone, nefazodone, mirtazapine, fliban 60 In another embodiment, the invention provides a com serin), a 5-HT, receptor agonist (e.g., trazodone, nefa pound (e.g., a compound herein) capable of modulating Zodone, mirtazapine, flibanserin), a norepinephrine-dop cognition disorder; and pharmaceutically acceptable esters, amine reuptake inhibitor (e.g., bupropion), an oxytocin salts, isomers and prodrugs thereof. receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syn In another embodiment, the invention provides a com tocinon R.), and an endocrine active agent. Compositions of 65 pound (e.g., a compound herein) capable of enhancing the invention further include a pharmaceutically acceptable cognition; and pharmaceutically acceptable esters, salts, Ca1. isomers and prodrugs thereof. US 9,517,254 B2 89 90 Naturally occurring or synthetic isomers can be separated by the attending clinician, including, but not limited to: the in several ways known in the art. Methods for separating a specific sexual disorder or hypoactive sexual desire disorder racemic mixture of two enantiomers include chromatogra involved; pharmacodynamic characteristics of the particular phy using a chiral stationary phase (see, e.g., “Chiral Liquid agent and its mode and route of administration; the desired Chromatography.’ W. J. Lough, Ed. Chapman and Hall, 5 time course of treatment; the species of mammal; its size, New York (1989)). Enantiomers can also be separated by age, and general health; the specific disease involved; the classical resolution techniques. For example, formation of degree of or involvement or the severity of the disease; the diastereomeric salts and fractional crystallization can be response of the individual patient; the particular compound used to separate enantiomers. For the separation of administered; the mode of administration; the bioavailability enantiomers of carboxylic acids, the diastereomeric salts can 10 characteristics of the preparation administered; the dose be formed by addition of enantiomerically pure chiral bases regimen selected; the kind of concurrent treatment (i.e., the Such as brucine, quinine, ephedrine, Strychnine, and the like. interaction of the compound of the invention with other Alternatively, diastereomeric esters can be formed with co-administered therapeutics); and other relevant circum enantiomerically pure chiral alcohols such as menthol, fol StanceS. lowed by separation of the diastereomeric esters and hydro 15 lysis to yield the free, enantiomerically enriched carboxylic The dosage administration can be in a single dosage form acid. For separation of the optical isomers of amino com or multiple dosage forms. The dosages can be administered pounds, addition of chiral carboxylic or Sulfonic acids. Such concurrently, simultaneously, or sequentially. The dosages as camphorsulfonic acid, tartaric acid, mandelic acid, or can be a single dosage immediately prior to sexual activity, lactic acid can result in formation of the diastereomeric salts. or can be one or more doses daily without regard to timing prior to sexual activity. Treatment can be initiated with 3. Uses of the Compounds of the Invention Smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by In one embodiment, the invention provides methods of Small increments until the optimum effect under the circum treating a disease or disorder in a Subject comprising admin 25 stances is reached. For convenience, the total daily dosage istering to the Subject a composition delineated herein. In may be divided and administered in portions during the day one embodiment, the invention provides methods of treating if desired. A therapeutically effective amount and a prophy sexual disorder in a Subject comprising administering to the lactically effective amount of a compound of the invention Subject a composition delineated herein. In certain embodi of the invention is expected to vary from about 0.1 milligram ments, the Subject is a mammal, e.g., a primate, e.g., a 30 per kilogram of body weight per day (mg/kg/day) to about human. In aspect, the disease, disorder or symptom thereof 100 mg/kg/day. in which the compounds, compositions, and methods of The identification of those patients who are in need of treatment relate to is one described in the Diagnostic and prophylactic treatment for sexual disorder or hypoactive Statistical Manual of Mental Disorders 4" edition Text sexual desire disorder is well within the ability and knowl Revision, (DSM-I-TRV), American Psychiatric Association. 35 edge of one skilled in the art. Certain of the methods for In certain embodiments, the methods of the invention identification of patients which are at risk of developing include administering to a Subject a therapeutically effective sexual disorder or hypoactive sexual desire disorder which amount of a compound of the invention in combination with can be treated by the subject method are appreciated in the another pharmaceutically active compound. Examples of medical arts, such as family history, and the presence of risk pharmaceutically active compounds include compounds 40 factors associated with the development of that disease state known to treat sexual disorder in a subject. Other pharma in the Subject patient (e.g., use of antidepressant drugs, ceutically active compounds that may be used can be found hormonal contraceptives, antihormonal and/or cytotoxic in Harrison's Principles of Internal Medicine, Thirteenth chemotherapies, sedatives, antipsychotic drugs, antiepileptic Edition, Eds. T. R. Harrison et al. McGraw-Hill N.Y., NY: drugs, mood stabilizer drugs, opioid drugs, alcohol, or and the Physicians Desk Reference 50th Edition 1997, 45 narcotic drugs). A clinician skilled in the art can readily Oradell New Jersey, Medical Economics Co., the complete identify such candidate patients, by the use of for example, contents of which are expressly incorporated herein by clinical tests, physical examination and medical/family his reference. The compound of the invention and the pharma tory. ceutically active compound may be administered to the As used herein, "obtaining a biological sample from a Subject in the same pharmaceutical composition or in dif 50 Subject, includes obtaining a sample for use in the methods ferent pharmaceutical compositions (at the same time or at described herein. A biological sample is described above. different times). In another aspect, a compound of the invention is pack Determination of a therapeutically effective sexual disor aged in a therapeutically effective amount with a pharma der effective amount, a prophylactically effective sexual ceutically acceptable carrier or diluent. The composition disorder or hypoactive sexual desire disorder amount of the 55 may be formulated for treating a Subject Suffering from or compound of the invention, can be readily made by the Susceptible to a sexual disorder or hypoactive sexual desire physician or veterinarian (the "attending clinician'), as one disorder, and packaged with instructions to treat a subject skilled in the art, by the use of known techniques and by Suffering from or Susceptible to a sexual disorder or hypo observing results obtained under analogous circumstances. active sexual desire disorder. The dosages may be varied depending upon the require 60 The subject may be at risk of a sexual disorder or ments of the patient in the judgment of the attending hypoactive sexual desire disorder, may be exhibiting Symp clinician; the severity of the condition being treated and the toms of a sexual disorder or hypoactive sexual desire particular compound being employed. In determining the disorder, may be susceptible to a sexual disorder or hypo therapeutically effective sexual disorder or hypoactive active sexual desire disorder and/or may have been diag sexual desire disorder amount or dose, and the prophylac 65 nosed with a sexual desire disorder. tically effective sexual disorder or hypoactive sexual desire If the modulation of the status indicates that the subject disorder amount or dose, a number of factors are considered may have a favorable clinical response to the treatment, the US 9,517,254 B2 91 92 subject may be treated with the compound. For example, the the individual patient; the particular compound adminis subject can be administered therapeutically effective dose or tered; the mode of administration; the bioavailability char doses of the compound. acteristics of the preparation administered; the dose regimen Kits of the invention include kits for treating a sexual selected; the kind of concurrent treatment (i.e., the interac disorder or hypoactive sexual desire disorder in a subject. tion of the compound of the invention with other co The kit may include a compound of the invention, for administered therapeutics); and other relevant circum example, a compound described herein, pharmaceutically StanceS. acceptable esters, salts, and prodrugs thereof, and instruc The dosage administration can be in a single dosage form tions for use. The instructions for use may include informa or multiple dosage forms. The dosages can be administered tion on dosage, method of delivery, storage of the kit, etc. In 10 concurrently, simultaneously, or sequentially. The dosages aspects, the kits (and methods of using them) comprise instructions indicating that the compositions and/or treat can be a single dosage, or can be one or more doses daily. ment methods are contraindicated for (or not to be admin Treatment can be initiated with Smaller dosages, which are istered to) Subjects that: (i) require and/or are taking less than the optimum dose of the compound. Thereafter, the CYP3A4, CYP2B6-, or CYP2D6-metabolized drugs; (ii) 15 dosage may be increased by Small increments until the take any sex hormone other than an approved hormonal optimum effect under the circumstances is reached. For contraceptive; (iii) drink more than one alcoholic drink per convenience, the total daily dosage may be divided and day (e.g., 12-OZ beer, 4-OZ wine, etc). administered in portions during the day if desired. A thera Alternatively, the effects of compound of the invention peutically effective amount and a prophylactically effective can be characterized in vivo using animals models. amount of a compound of the invention of the invention is In another embodiment, the invention provides methods expected to vary from about 0.1 milligram per kilogram of of treating cognitive disorder in a Subject comprising admin body weight per day (mg/kg/day) to about 100 mg/kg/day. istering to the Subject a composition delineated herein. In The identification of those patients who are in need of certain embodiments, the Subject is a mammal, e.g., a prophylactic treatment for cognitive disorder is well within primate, e.g., a human. In aspect, the disease, disorder or 25 the ability and knowledge of one skilled in the art. Certain symptom thereof in which the compounds, compositions, of the methods for identification of patients which are at risk and methods of treatment relate to is one described in the of developing cognitive disorder which can be treated by the Diagnostic and Statistical Manual of Mental Disorders 4" Subject method are appreciated in the medical arts, such as edition Text Revision, (DSM-I-TRV), American Psychiat family history, and the presence of risk factors associated ric Association. 30 with the development of that disease state in the subject In certain embodiments, the methods of the invention patient. A clinician skilled in the art can readily identify Such include administering to a subject a therapeutically effective candidate patients, by the use of, for example, clinical tests, amount of a compound of the invention in combination with physical examination and medical/family history. another pharmaceutically active compound. Examples of As used herein, "obtaining a biological sample from a pharmaceutically active compounds include compounds 35 Subject, includes obtaining a sample for use in the methods known to treat cognitive disorder in a subject. Other phar described herein. A biological sample is described above. maceutically active compounds that may be used can be In another aspect, a compound of the invention is pack found in Harrison's Principles of Internal Medicine. Thir aged in a therapeutically effective amount with a pharma teenth Edition, Eds. T. R. Harrison et al. McGraw-Hill N.Y., ceutically acceptable carrier or diluent. The composition NY; and the Physicians Desk Reference 50th Edition 1997, 40 may be formulated for treating a Subject Suffering from or Oradell New Jersey, Medical Economics Co., the complete Susceptible to a cognition disorder, and packaged with contents of which are expressly incorporated herein by instructions to treat a subject Suffering from or Susceptible to reference. The compound of the invention and the pharma a cognition disorder. ceutically active compound may be administered to the The Subject may be at risk of a cognition disorder, may be Subject in the same pharmaceutical composition or in dif 45 exhibiting symptoms of a cognition disorder, may be sus ferent pharmaceutical compositions (at the same time or at ceptible to a cognitive disorder and/or may have been different times). diagnosed with a cognition disorder. Determination of a therapeutically effective cognitive If the modulation of the status indicates that the subject disorder effective amount, a prophylactically effective cog may have a favorable clinical response to the treatment, the nitive disorder amount of the compound of the invention, 50 subject may be treated with the compound. For example, the can be readily made by the physician or veterinarian (the subject can be administered therapeutically effective dose or “attending clinician'), as one skilled in the art, by the use of doses of the compound. known techniques and by observing results obtained under Kits of the invention include kits for treating a cognitive analogous circumstances. The dosages may be varied disorder in a subject. The kit may include a compound of the depending upon the requirements of the patient in the 55 invention, for example, a compound described herein, phar judgment of the attending clinician; the severity of the maceutically acceptable esters, salts, and prodrugs thereof, condition being treated and the particular compound being and instructions for use. The instructions for use may employed. In determining the therapeutically effective cog include information on dosage, method of delivery, storage nitive disorder amount or dose, and the prophylactically of the kit, etc. In aspects, the kits (and methods of using effective cognitive disorder amount or dose, a number of 60 them) comprise instructions indicating that the compositions factors are considered by the attending clinician, including, and/or treatment methods are contraindicated for (or not to but not limited to: the specific cognitive disorder involved; be administered to) Subjects that: (i) require and/or are pharmacodynamic characteristics of the particular agent and taking CYP3A4, CYP 2B6-, or CYP 2D6-metabolized its mode and route of administration; the desired time course drugs; (ii) drink more than one alcoholic drink per day (e.g., of treatment; the species of mammal; its size, age, and 65 12-OZ beer, 4-OZ wine, etc). general health; the specific disease involved; the degree of or Alternatively, the effects of compound of the invention involvement or the severity of the disease; the response of can be characterized in vivo using animals models. US 9,517,254 B2 93 94 In another embodiment, the invention provides methods The identification of those patients who are in need of of enhancing cognition in a Subject comprising administer prophylactic treatment for cognition enhancement is well ing to the Subject a composition delineated herein. In certain within the ability and knowledge of one skilled in the art. embodiments, the Subject is a mammal, e.g., a primate, e.g., Certain of the methods for identification of patients which a human. In aspect, the disease, disorder or symptom thereof 5 are at risk of needing cognition enhancement which can be in which the compounds, compositions, and methods of treated by the subject method are appreciated in the medical treatment relate to is one described in the Diagnostic and arts, such as family history, and the presence of risk factors Statistical Manual of Mental Disorders 4" edition Text associated with the development of that disease state in the Revision, (DSM-I-TRV), American Psychiatric Association. Subject patient. A clinician skilled in the art can readily In certain embodiments, the methods of the invention 10 identify such candidate patients, by the use of for example, include administering to a Subject a therapeutically effective clinical tests, physical examination and medical/family his amount of a compound of the invention in combination with tory. another pharmaceutically active compound. Examples of As used herein, "obtaining a biological sample from a pharmaceutically active compounds include compounds Subject, includes obtaining a sample for use in the methods 15 described herein. A biological sample is described above. known to enhance cognition in a Subject. Other pharmaceu In another aspect, a compound of the invention is pack tically active compounds that may be used can be found in aged in a therapeutically effective amount with a pharma Harrison's Principles of Internal Medicine. Thirteenth Edi ceutically acceptable carrier or diluent. The composition tion, Eds. T. R. Harrison et al. McGraw-Hill N.Y., NY; and may be formulated for treating a Subject requiring or Sus the Physicians Desk Reference 50th Edition 1997, Oradell ceptible to requiring cognition enhancement, and packaged New Jersey, Medical Economics Co., the complete contents with instructions to treat a subject requiring or Susceptible to of which are expressly incorporated herein by reference. The requiring cognition enhancement. compound of the invention and the pharmaceutically active The Subject may be at risk requiring cognition enhance compound may be administered to the Subject in the same ment, may be exhibiting symptoms of requiring cognition pharmaceutical composition or in different pharmaceutical 25 enhancement, may be susceptible to requiring cognition compositions (at the same time or at different times). enhancement and/or may have been diagnosed with requir Determination of a therapeutically effective cognition ing cognition enhancement. enhancing effective amount, a prophylactically effective If the modulation of the status indicates that the subject cognition enhancement amount of the compound of the may have a favorable clinical response to the treatment, the invention, can be readily made by the physician or veteri 30 subject may be treated with the compound. For example, the narian (the “attending clinician'), as one skilled in the art, by subject can be administered therapeutically effective dose or the use of known techniques and by observing results doses of the compound. obtained under analogous circumstances. The dosages may Kits of the invention include kits for enhancing cognition be varied depending upon the requirements of the patient in in a Subject. The kit may include a compound of the the judgment of the attending clinician; the severity of the 35 invention, for example, a compound described herein, phar condition being treated and the particular compound being maceutically acceptable esters, salts, and prodrugs thereof, employed. In determining the therapeutically effective cog and instructions for use. The instructions for use may nition enhancement amount or dose, and the prophylacti include information on dosage, method of delivery, storage cally effective cognition enhancing amount or dose, a num of the kit, etc. In aspects, the kits (and methods of using ber of factors are considered by the attending clinician, 40 them) comprise instructions indicating that the compositions including, but not limited to: the specific cognition enhance and/or treatment methods are contraindicated for (or not to ment needed; pharmacodynamic characteristics of the par be administered to) Subjects that: (i) require and/or are ticular agent and its mode and route of administration; the taking CYP3A4, CYP 2B6-, or CYP 2D6-metabolized desired time course of treatment; the species of mammal; its drugs; (ii) drink more than one alcoholic drink per day (e.g., size, age, and general health; the specific disease involved; 45 12-OZ beer, 4-OZ wine, etc). the degree of or involvement or the severity of the disease: Alternatively, the effects of compound of the invention the response of the individual patient; the particular com can be characterized in vivo using animals models. pound administered; the mode of administration; the bio availability characteristics of the preparation administered; 4. Pharmaceutical Compositions the dose regimen selected; the kind of concurrent treatment 50 (i.e., the interaction of the compound of the invention with The invention also provides a pharmaceutical composi other co-administered therapeutics); and other relevant cir tion, comprising an effective amount of a compound Cum Stances. described herein and a pharmaceutically acceptable carrier. The dosage administration can be in a single dosage form In a further embodiment, the effective amount is effective to or multiple dosage forms. The dosages can be administered 55 treat a sexual disorder or hypoactive sexual desire disorder, concurrently, simultaneously, or sequentially. The dosages as described previously. can be a single dosage, or can be one or more doses daily. In an embodiment, the compound of the invention is Treatment can be initiated with Smaller dosages, which are administered to the Subject using a pharmaceutically-accept less than the optimum dose of the compound. Thereafter, the able formulation, e.g., a pharmaceutically-acceptable for dosage may be increased by Small increments until the 60 mulation that provides Sustained delivery of the compound optimum effect under the circumstances is reached. For of the invention to a subject for at least 12 hours, 24 hours, convenience, the total daily dosage may be divided and 36 hours, 48 hours, one week, two weeks, three weeks, or administered in portions during the day if desired. A thera four weeks after the pharmaceutically-acceptable formula peutically effective amount and a prophylactically effective tion is administered to the Subject. amount of a compound of the invention of the invention is 65 In certain embodiments, these pharmaceutical composi expected to vary from about 0.1 milligram per kilogram of tions are suitable for topical or oral, buccal or Sublingual body weight per day (mg/kg/day) to about 100 mg/kg/day. administration to a subject. In other embodiments, as US 9,517,254 B2 95 96 described in detail below, the pharmaceutical compositions be presented in unit dosage form and may be prepared by of the present invention may be specially formulated for any methods well known in the art of pharmacy. The amount administration in Solid or liquid form, including those of active ingredient which can be combined with a carrier adapted for the following: (1) oral administration, for material to produce a single dosage form will vary depend example, drenches (aqueous or non-aqueous solutions or 5 ing upon the host being treated, the particular mode of Suspensions), tablets, boluses, powders, granules, pastes; (2) administration. The amount of active ingredient which can parenteral administration, for example, by Subcutaneous, be combined with a carrier material to produce a single intramuscular or intravenous injection as, for example, a dosage form will generally be that amount of the compound sterile solution or Suspension; (3) topical application, for which produces a therapeutic effect. Generally, out of one example, as a cream, ointment or spray applied to the skin; 10 (4) intravaginally or intrarectally, for example, as a pessary, hundred percent, this amount will range from about 1 cream or foam; or (5) aerosol, for example, as an aqueous percent to about ninety-nine percent of active ingredient, aerosol, liposomal preparation or Solid particles containing preferably from about 5 percent to about 70 percent, more the compound or composition herein. preferably from about 10 percent to about 30 percent. The phrase “pharmaceutically acceptable' refers to those 15 Methods of preparing these compositions include the step compound of the inventions of the present invention, com of bringing into association a compound of the invention(s) positions containing Such compounds, and/or dosage forms with the carrier and, optionally, one or more accessory which are, within the scope of Sound medical judgment, ingredients. In general, the formulations are prepared by Suitable for use in contact with the tissues of human beings uniformly and intimately bringing into association a com and animals without excessive toxicity, irritation, allergic pound of the invention with liquid carriers, or finely divided response, or other problem or complication, commensurate Solid carriers, or both, and then, if necessary, shaping the with a reasonable benefit/risk ratio. product. The phrase “pharmaceutically-acceptable carrier' Compositions of the invention suitable for oral adminis includes pharmaceutically-acceptable material, composition tration may be in the form of capsules, cachets, pills, tablets, or vehicle. Such as a liquid or Solid filler, diluent, excipient, 25 lozenges (using a flavored basis, usually Sucrose and acacia Solvent or encapsulating material, involved in carrying or or tragacanth), powders, granules, or as a solution or a transporting the Subject chemical from one organ, or portion Suspension in an aqueous or non-aqueous liquid, or as an of the body, to another organ, or portion of the body. Each oil-in-water or water-in-oil liquid emulsion, or as an elixir or carrier is “acceptable' in the sense of being compatible with syrup, or as pastilles (using an inert base, such as gelatin and the other ingredients of the formulation and not injurious to 30 glycerin, or Sucrose and acacia) and/or as mouth washes and the patient. Some examples of materials which can serve as the like, each containing a predetermined amount of a pharmaceutically-acceptable carriers include: (1) sugars, compound of the invention(s) as an active ingredient. A Such as lactose, glucose and Sucrose; (2) starches, such as compound may also be administered as a bolus, electuary or corn starch and potato starch; (3) cellulose, and its deriva paste. tives, such as Sodium carboxymethyl cellulose, ethyl cellu 35 lose and cellulose acetate; (4) powdered tragacanth; (5) In solid dosage forms of the invention for oral adminis malt; (6) gelatin; (7) talc.; (8) excipients, such as cocoa butter tration (capsules, tablets, pills, dragees, powders, granules and Suppository waxes; (9) oils, such as peanut oil, cotton and the like), the active ingredient is mixed with one or more seed oil, safflower oil, sesame oil, olive oil, corn oil and pharmaceutically-acceptable carriers, such as Sodium citrate Soybean oil: (10) glycols, such as propylene glycol; (11) 40 or dicalcium phosphate, and/or any of the following: (1) polyols, such as glycerin, Sorbitol, mannitol and polyethyl fillers or extenders, such as starches, lactose, Sucrose, glu ene glycol, (12) esters, such as ethyl oleate and ethyl laurate; cose, mannitol, and/or silicic acid; (2) binders. Such as, for (13) agar, (14) buffering agents, such as magnesium hydrox example, carboxymethylcellulose, alginates, gelatin, poly ide and aluminum hydroxide; (15) alginic acid, (16) pyro vinyl pyrrolidone. Sucrose and/or acacia; (3) humectants, gen-free water, (17) isotonic saline; (18) Ringer's solution; 45 Such as glycerol; (4) disintegrating agents, such as agar-agar, (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) calcium carbonate, potato or tapioca starch, alginic acid, other non-toxic compatible Substances employed in phar certain silicates, and sodium carbonate; (5) Solution retard maceutical formulations. ing agents. Such as paraffin; (6) absorption accelerators, such Wetting agents, emulsifiers and lubricants, such as Sodium as quaternary ammonium compounds; (7) wetting agents, lauryl Sulfate and magnesium Stearate, as well as coloring 50 Such as, for example, acetyl alcohol and glycerol monoste agents, release agents, coating agents, Sweetening, flavoring arate; (8) absorbents, such as kaolin and bentonite clay; (9) and perfuming agents, preservatives and antioxidants can lubricants. Such a talc, calcium Stearate, magnesium Stearate, also be present in the compositions. Solid polyethylene glycols, sodium lauryl Sulfate, and mix Examples of pharmaceutically-acceptable antioxidants tures thereof, and (10) coloring agents. In the case of include: (1) water soluble antioxidants. Such as ascorbic 55 capsules, tablets and pills, the pharmaceutical compositions acid, cysteine hydrochloride, Sodium bisulfate, sodium may also comprise buffering agents. Solid compositions of metabisulfite, sodium sulfite and the like; (2) oil-soluble a similar type may also be employed as fillers in Soft and antioxidants, such as ascorbyl palmitate, butylated hydroxy hard-filled gelatin capsules using Such excipients as lactose anisole (BHA), butylated hydroxytoluene (BHT), lecithin, or milk Sugars, as well as high molecular weight polyeth propyl gallate, alpha-tocopherol, and the like; and (3) metal 60 ylene glycols and the like. chelating agents, such as citric acid, ethylenediamine tet A tablet may be made by compression or molding, option raacetic acid (EDTA), sorbitol, tartaric acid, phosphoric ally with one or more accessory ingredients. Compressed acid, and the like. tablets may be prepared using binder (for example, gelatin Compositions containing a compound of the invention(s) or hydroxypropylmethyl cellulose), lubricant, inert diluent, include those Suitable for oral, nasal, topical (including 65 preservative, disintegrant (for example, Sodium starch gly buccal and Sublingual), rectal, vaginal, aerosol and/or par colate or cross-linked sodium carboxymethyl cellulose), enteral administration. The compositions may conveniently Surface-active or dispersing agent. Molded tablets may be US 9,517,254 B2 97 98 made by molding in a suitable machine a mixture of the pharmaceutically-acceptable carrier, and with any preserva powdered active ingredient moistened with an inert liquid tives, buffers, or propellants which may be required. diluent. The ointments, pastes, creams and gels may contain, in The tablets, and other solid dosage forms of the pharma addition to compound of the invention(s) of the present ceutical compositions of the present invention, Such as invention, excipients. Such as animal and vegetable fats, oils, dragees, capsules, pills and granules, may optionally be waxes, paraffins, starch, tragacanth, cellulose derivatives, scored or prepared with coatings and shells, such as enteric polyethylene glycols, silicones, bentonites, silicic acid, talc coatings and other coatings well known in the pharmaceu and Zinc oxide, or mixtures thereof. tical-formulating art. They may also be formulated so as to Powders and sprays can contain, in addition to a com provide slow or controlled release of the active ingredient 10 pound of the invention(s), excipients such as lactose, talc, therein using, for example, hydroxypropylmethyl cellulose silicic acid, aluminum hydroxide, calcium silicates and in varying proportions to provide the desired release profile, polyamide powder, or mixtures of these Substances. Sprays other polymer matrices, liposomes and/or microspheres. can additionally contain customary propellants, such as They may be sterilized by, for example, filtration through a chlorofluorohydrocarbons and volatile unsubstituted hydro bacteria-retaining filter, or by incorporating sterilizing 15 carbons, such as butane and propane. agents in the form of sterile Solid compositions which can be The compound of the invention(s) can be alternatively dissolved in sterile water, or some other sterile injectable administered by aerosol. This is accomplished by preparing medium immediately before use. These compositions may an aqueous aerosol, liposomal preparation or solid particles also optionally contain opacifying agents and may be of a containing the compound. A nonaqueous (e.g., fluorocarbon composition that they release the active ingredient(s) only, propellant) Suspension could be used. Sonic nebulizers are or preferentially, in a certain portion of the gastrointestinal preferred because they minimize exposing the agent to tract, optionally, in a delayed manner. Examples of embed shear, which can result in degradation of the compound. ding compositions which can be used include polymeric Ordinarily, an aqueous aerosol is made by formulating an Substances and waxes. The active ingredient can also be in aqueous Solution or Suspension of the agent together with micro-encapsulated form, if appropriate, with one or more of 25 conventional pharmaceutically-acceptable carriers and sta the above-described excipients. bilizers. The carriers and stabilizers vary with the require Liquid dosage forms for oral administration of the com ments of the particular compound, but typically include pound of the invention(s) include pharmaceutically-accept nonionic Surfactants (Tweens, Pluronics, or polyethylene able emulsions, microemulsions, solutions, Suspensions, glycol), innocuous proteins like serum albumin, Sorbitan syrups and elixirs. In addition to the active ingredient, the 30 esters, oleic acid, lecithin, amino acids such as glycine, liquid dosage forms may contain inert diluents commonly buffers, salts, Sugars or Sugar alcohols. Aerosols generally used in the art, such as, for example, water or other solvents, are prepared from isotonic solutions. solubilizing agents and emulsifiers, such as ethyl alcohol, Transdermal patches have the added advantage of pro isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl viding controlled delivery of a compound of the invention(s) alcohol, benzyl benzoate, propylene glycol, 1,3-butylene 35 to the body. Such dosage forms can be made by dissolving glycol, oils (in particular, cottonseed, groundnut, corn, germ, or dispersing the agent in the proper medium. Absorption olive, castor and sesame oils), glycerol, tetrahydrofuryl enhancers can also be used to increase the flux of the active alcohol, polyethylene glycols and fatty acid esters of Sorbi ingredient across the skin. The rate of Such flux can be tan, and mixtures thereof. controlled by either providing a rate controlling membrane In addition to inert diluents, the oral compositions can 40 or dispersing the active ingredient in a polymer matrix or include adjuvants such as wetting agents, emulsifying and gel. Suspending agents, Sweetening, flavoring, coloring, perfum Ophthalmic formulations, eye ointments, powders, solu ing and preservative agents. tions and the like, are also contemplated as being within the Suspensions, in addition to the active compound of the Scope of the invention. invention(s) may contain Suspending agents as, for example, 45 Pharmaceutical compositions of the invention suitable for ethoxylated isostearyl alcohols, polyoxyethylene sorbitol parenteral administration comprise one or more compound and Sorbitan esters, microcrystalline cellulose, aluminum of the invention(s) in combination with one or more phar metahydroxide, bentonite, agar-agar and tragacanth, and maceutically-acceptable sterile isotonic aqueous or non mixtures thereof. aqueous solutions, dispersions, Suspensions or emulsions, or Pharmaceutical compositions of the invention for rectal or 50 sterile powders which may be reconstituted into sterile vaginal administration may be presented as a Suppository, injectable solutions or dispersions just prior to use, which which may be prepared by mixing one or more compound of may contain antioxidants, buffers, bacteriostats, solutes the invention(s) with one or more Suitable nonirritating which render the formulation isotonic with the blood of the excipients or carriers comprising, for example, cocoa butter, intended recipient or Suspending or thickening agents. polyethylene glycol, a Suppository wax or a salicylate, and 55 Examples of Suitable aqueous and nonaqueous carriers, which is solid at room temperature, but liquid at body which may be employed in the pharmaceutical compositions temperature and, therefore, will melt in the rectum or of the invention include water, ethanol, polyols (such as vaginal cavity and release the active agent. glycerol, propylene glycol, polyethylene glycol, and the Compositions of the present invention which are suitable like), and Suitable mixtures thereof, vegetable oils, such as for vaginal administration also include pessaries, tampons, 60 olive oil, and injectable organic esters, such as ethyl oleate. creams, gels, pastes, foams or spray formulations containing Proper fluidity can be maintained, for example, by the use of Such carriers as are known in the art to be appropriate. coating materials, such as lecithin, by the maintenance of the Dosage forms for the topical or transdermal administra required particle size in the case of dispersions, and by the tion of a compound of the invention(s) include powders, use of Surfactants. sprays, ointments, pastes, creams, lotions, gels, Solutions, 65 These compositions may also contain adjuvants such as patches and inhalants. The active compound of the preservatives, wetting agents, emulsifying agents and dis invention(s) may be mixed under sterile conditions with a persing agents. Prevention of the action of microorganisms US 9,517,254 B2 99 100 may be ensured by the inclusion of various antibacterial and riomers, racemates; all of which are included herein) are antifungal agents, for example, paraben, chlorobutanol, phe available from commercial sources and/or readily synthe nol sorbic acid, and the like. It may also be desirable to sized using methods and reagents know in the art. Bupropion include isotonic agents. Such as Sugars, sodium chloride, and is also known as, i.e., f-Keto-3-chloro-N-tert-butylamphet the like into the compositions. In addition, prolonged 5 amine, i.e., (E)-2-(tert-Butylamino)-1-(3-chlorophenyl)pro absorption of the injectable pharmaceutical form may be pan-1-one; trazodone is also known as, i.e., 2-3-4-(3- brought about by the inclusion of agents which delay chlorophenyl)piperazin-1-yl)propyl-1,2,4-triazolo 4.3-al absorption Such as aluminum monostearate and gelatin. pyridin-3(2H)-one; oxytocin is also known as, i.e., 1-((4R, In some cases, in order to prolong the effect of a drug, it 7S,10S,13S, 16S, 19R)-19-amino-7-(2-amino-2-oxoethyl)- is desirable to slow the absorption of the drug from subcu- 10 10-(3-amino-3-oxopropyl)-16-(4-hydroxybenzoyl)-13 taneous or intramuscular injection. This may be accom (1S)-1-methylpropyl-6,9,12,15, 18-pentaoxo-1,2-dithia-5, plished by the use of a liquid Suspension of crystalline or 8, 11.14.17-pentaazacycloicosan-4-yl)carbonyl)-L-prolyl-L- amorphous material having poor water Solubility. The rate of leucylglycinamide. absorption of the drug then depends upon its rate of disso lution which, in turn, may depend upon crystal size and 15 Example 1 crystalline form. Alternatively, delayed absorption of a par enterally-administered drug form is accomplished by dis Clinical Protocol Solving or Suspending the drug in an oil vehicle. Subjects in a single blind, sequential study are adminis Injectable depot forms are made by forming microencap tered bupropion and traZodone in increasing dosages (a 3-4 Sule matrices of compound of the invention(s) in biodegrad- 20 weeks each, that is, from a 3 (or 4)-week placebo baseline, able polymers such as polylactide-polyglycolide. Depending to an intermediate dose ((a) another 3-4 weeks), to a maxi on the ratio of drug to polymer, and the nature of the mum dose ((a) a final 3-4 weeks). The subjects feedback/ particular polymer employed, the rate of drug release can be reports on Subjective (e.g., feelings, sensations, general controlled. Examples of other biodegradable polymers response) and objective (e.g., response time, performance include poly(orthoesters) and poly(anhydrides). Depot 25 measures, partner response) is collated and analyzed against injectable formulations are also prepared by entrapping the dosage. Each study also includes one or more patient(s) drug in liposomes or microemulsions which are compatible serving as a control (in demonstrating the Synergistic effect with body tissue. between the two actives) would receive only bupropion, When the compound of the invention(s) are administered while the second and third will each be given a different as pharmaceuticals, to humans and animals, they can be 30 fixed dose combination products having a defined ratio of given perse or as a pharmaceutical composition containing, active ingredients (e.g., bupropion and traZodone). for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically Example 2 acceptable carrier. Regardless of the route of administration selected, the 35 Method. compound of the invention(s), which may be used in a A 36 year-old healthy male volunteer in a stable marital Suitable hydrated form, and/or the pharmaceutical compo relationship for two years with no current sexual disorders, sitions of the present invention, are formulated into phar exposed himself sequentially to four treatments, each for 4 maceutically-acceptable dosage forms by conventional weeks: (1) Treatment B: Instant-release (IR) Bupropion methods known to those of skill in the art. 40 (Bup) 150 mg in the morning and 100 mg in the evening; (2) Actual dosage levels and time course of administration of Treatment T: IR trazodone (Trz) 50 mg. t.i.d.; (3) Treatment the active ingredients in the pharmaceutical compositions of L. IRTrz 25 mg b.i.d. plus IRBup 150 mg in the morning the invention may be varied so as to obtain an amount of the and 100 mg in the evening; and (4) Treatment L. IR Trz active ingredient which is effective to achieve the desired 50 mg. t.i.d. plus IRBup 75 mg. t.i.d. A washout of 1-4 weeks therapeutic response for a particular patient, composition, 45 occurred between each treatment. Level and frequency of and mode of administration, without being toxic to the sexual desire was scored daily, as not improved (0), some patient. An exemplary dose range is from 0.1 to 10 mg per what improved (1), or markedly improved (2). Sexual events day. were counted, and three domains (sexual arousal, orgasm, A preferred dose of the compound of the invention for the and overall satisfaction with the event) were scored. Each of present invention is the maximum that a patient can tolerate 50 the sexual event variables was converted to a simple and not develop serious side effects. Preferably, the com patient’s global impression of improvement (PGI; improved pound of the invention of the present invention is adminis or not improved today compared to pre-treatment baseline). tered at a concentration of about 0.001 mg to about 100 mg The 3 domains of sexual event improvements were summed per kilogram of body weight, about 0.001-about 10 mg/kg or for analysis. Bup is already recommended as a treatment for about 0.001 mg-about 100 mg/kg of body weight. Ranges 55 HSDD; Trz is not. Thus, Fisher's exact test was applied intermediate to the above-recited values are also intended to post-hoc to the PGIs for Treatment B vs. Treatment L io be part of the invention. (Lou) and VS. Treatment Li, (L). Results. EXAMPLES For sexual desire, the mean score with Li and Li, was 60 about twice that with Treatment B (two-tailed paired t-test, The invention is further illustrated by the following p-0.0001), and Treatment B was superior to Treatment T. examples which are intended to illustrate but not limit the For arousal, orgasm, and overall satisfaction with a sexual Scope of the invention. event, Li was associated with somewhat more improve Materials ments than with Treatment B in the third and fourth weeks Small-Molecule Compounds— 65 of use. Li, was associated with significantly more bupropion, traZodone, oxytocin, and testosterone (and improvements than with Treatment B in the third and fourth their salt, Solvates, hydrates, isomers, enantiomers, diaste weeks of use and in the total for all four weeks. Fisher's US 9,517,254 B2 101 102 exact test, two-tailed, showed the combination of bupropion TABLE-continued plus trazodone superior, p<0.05, for the 3-domain sum of sexual event improvement. This study conducted with the Scores of desire, and counts of sexual combination of bupropion plus traZodone showed increased event domain improved per treatment benefits in sexual arousal, orgasm, and event satisfaction, 5 after exposure for 4 weeks, compared to either bupropion alone or trazodone alone. The effects occurred at or below 0-2 Daily Desire Score, PGI Improved for Sexual the target dosage of bupropion or traZodone in their current total, % of max. (max. = 28), Events, Sum of 3 domains 3 (antidepressant) labeling. 10 An independent researcher then scored the desire results mean it SD, p-value n/N, 9% p-value as unimproved=0, somewhat improved=1, and markedly Treatment vs. Bup' improved vs. Bup? improved=2. Upon the advice of the independent researcher the Subject dichotomized his sexual event results in a simple I-high 20, 71% 1.43 + 0.94 6/15, 40% l.S. daily patient’s global impression of improvement: improved 15 wks 1-2 p = 0.021 or not improved today (compared to pre-treatment baseline). high 28, 100% 13/18, 72% The independent researcher, when told that the results were positive for the subject but before seeing any of the data, wks 3-4 decided to apply categorical tests to the most obvious comparisons between treatments: for the first two weeks, the List, total 1.71 + 0.71, 20/33, 61% O.OO19 second two weeks, and for all four weeks of treatment, p < 0.0001 low-dose combination of bupropion plus traZodone vs. cor responding dose of bupropion; and high-dose the combina 'P-values vs. corresponding treatment Bup, paired ttest, two-tailed tion of bupropion plus traZodone vs. same dose of traZodone. *P-values vs. corresponding treatment Bup, two-tailed Fisher's exact test The test used for the desire score was a two-tailed paired t 25 test, using all scores within a given treatment as repeated Sum of n improved in arousal, orgasm, and overall satisfaction measures. The test used for the two-category variables was Note: an online two-tailed Fisher's exact test using all scores P-values larger than 0.1 are omitted from the table. B or Bup is bupropion alone, Tor Trz is trazodone alone, Li is the lower dose of BupTrz within a given treatment as repeated measures. Both were combination, Li, is the higher dose of Bup/Trz combination. from the website graphpad.com.* 30 *http://graphpad.com quickcalcSchiscuared1.cfm For sexual desire, the response to T (Treatment T) was low, to B (Treatment B) was intermediate, and to L, and TABLE L., was sometimes strong in the first two weeks and uniformly strong (improvement rated as marked every day) Scores of desire, and counts of sexual 35 in the second two weeks of treatment. The differences event domain improved per treatment between each dose of L vs. B were highly statistically significant, p<0.0001. 0-2 Daily Desire Score, PGI Improved for Sexual B was markedly superior to T, p<0.05 for all comparisons. total, 9% of max. (max. = 28), Events, Sum of 3 domains 40 For the sum of improvements in arousal, orgasm, and mean it SD, p-value n/N, 9% p-value overall satisfaction with a sexual event, L showed sig Treatment vs. Bup' improved vs. Bup? nificantly more improvements than with B in the third and fourth weeks of use, 52% vs. 20%, p<0.05. L., was Bup 9, 32% 0.65 + 0.74 4/15, 27% 45 associated with significantly more improvements than with wks 1-2 B in the third and fourth weeks of use (72% vs. 13%) and Bup 14, 50% 2/15, 13% in the total for all four weeks (61% vs. 20%). Fisher's exact wks 3-4 test, two-tailed, showed the combination of bupropion plus Bup total O.82 - 0.55 6/30, 20% 50 trazodone superior, p<0.05, for each of these 3-domain sums wks 1-2 2, 7% 0.14 + 0.53 3/12, 25% l.S. of sexual event improvement. p = 0.051 For improvements in orgasm or overall satisfaction for a Trz O, 0% 3/18, 17% sexual event, the numbers appeared too small and the wks 3-4 55 numerical trends were generally too weak to show statisti cally significant differences. For arousal, however, L, was Trz total 2, 4% 0.07 + 0.38 6/30, 20% l.S. associated with significantly more improvements than with B in the third and fourth weeks of use (100% vs. 0%) and p < 0.0001 in the total for all four weeks (91% vs. 20%). Fisher's exact Lloy 14, 50% 0.64 + 0.74, n.s. 3/15, 20% l.S. test, two-tailed, showed the combination of bupropion plus wks 1-2 60 trazodone superior, p<0.05, for each of these 3-domain sums Lllow 28, 100% 11/21, 52% of sexual event improvement. A numerical trend also wks 3-4 favored L, in weeks 1-2 by % vs. 2/s (80% vs. 40%). The applicability of these male results to female subjects Lia total 1.50 - 0.88 14/36, 39% l.S. 65 with HSDD is possible given the similarities of desire P< O.OOO1 dysfunction in men and women Laumann 1999, and is to be tested next. US 9,517,254 B2 103 104 Example 3 Week 0: Informed consent, screening evaluations Medi cal, psychiatric, social/relationship, and sexual history; diag Additional Study Design. nostics, measures of sexual dysfunction, and safety evalu Further study is conducted as delineated in the Schematic ations physical examination, ECG, standard laboratory below. safety analytes

Schematic of Study Design Week

O 1 2 3 4 5

Day 1-7 8-15 15-21 22-29 29-35 36 Period Screening First Washout Second Washout Final Dosing Dosing Evaluations Group X Low dose drug B + X High dose X One Low dose drug T drug B + High dose drug T Group X High dose drug B X High dose X Two drug T B or BUP = SR bupropion T or TRZ = SR trazodone

Week 1: Treatment #1 Flow Chart of Study Data Collection Group 1 25 Low Dose combination of bupropion plus trazodone: 250 Period mg BUP+75 mg TRZ/day, given as 150 mg SR BUP in the First and 8th morning and 100 mg SR BUP in the evening and 75 mg SR day of each Final Screening Treatment Evaluation trazodone q.d.; and test battery. The test battery includes 30 single-dose PK, steady-state PK and pharmacodynamics. Note: each subject undergoes 2 Final Pharmacodynamics includes a cognitive test battery and treatments, for 1 week each Evaluation ollowed by a 1-week washout numeric rating scales (NRS) of feeling states, which will be informed consent X done in the morning of the first and last day of dosing, at FSFI-1 wk recall; FSDS-R-1 X X X pre-dose and at 1, 2, 4 and 8 hours post-dose. The cognitive wk recall 35 testing battery includes choice reaction time, word recall, Both are self-rated (s) Psychiatric history picture recognition, numeric and spatial working memory. clinician-rated (c) The self-rated NRS offeeling states for sedation/activation Relational/marital history (c) includes drowsy, dizzy, nervous, agitated, and hyper. Cog PHQ-9 self-rated (s) Beck Anxiety Inventory (s) nitive testing will be done within -20 minutes before the Sexual Interest and Desire 40 hour, blood sampling will be done exactly on the hour, and nventory - F (c) VAS will be done within +15 minutes after the hour. Or Checklist for DSM-IV & DSM Group 2 5 female sexual disorders: 150 mg SR BUP in the morning and 100 mg SR BUP in FSD diagnoses (c) the evening Marital Adjustment Test X X 45 Week 2: washout #1 (MAT) (s) Week 3: Treatment #2: Physical examination Prin. Only Laboratory analytes Group 1 ECG, 12-lead High Dose combination of bupropion plus trazodone (250 Sexual Activity Log (s) mg BUP+150 mg TRZ/day, given as 150 mg SR BUP in the Sexual Desire Relationship 50 morning and 100 mg SR BUP in the evening and 150 mg SR Distress Scale (SDRDS) (s) if traZodone q.d.) and test battery or available from authors Group 2 Vital signs (supine and X Pre-dose & 1, X standing b.p., pulse)2 2, 4, 8 & 24 hr 150 mg SR trazodone q.d. post-dose Week 4: Washout H2 AE inquiry and checklist2 55 Drug blood levels Pre-dose and 1, Example 4 2, 4, 6, 8, 12, 24 hr post-dose Cognitive test battery Pre-dose and 1, Compositions of the invention can be made by combining 2, and 4 hours the active agents (i.e., bupropion and traZodone) with one or post-dose 60 more of the following excipients: Verbal Numeric Rating Scales X CARNAUBA WAX, CYSTEINE HYDROCHLORIDE, of 6 feeling states (s) HYPROMELLOSES, MAGNESIUM STEARATE, CEL Partner's tests (may do at IIEF IIEF home LULOSE, MICROCRYSTALLINE, POLYETHYLENE, if use HTS) MAT (p) MAT (p) GLYCOL, POLYSORBATE 80, TITANIUM DIOXIDE, SDRDS (p) SDRDS (p) 65 FD&C BLUE NO. 1; Hydroxypropyl distarch phosphate (Contramid(R), Hypromellose, Sodium stearyl fumarate, Colloidal silicon US 9,517,254 B2 105 106 dioxide, Iron Oxide Yellow, Iron Oxide Red, Talc, Polyeth thereof. The recitation of an embodiment herein includes ylene Glycol 3350. Titanium Dioxide, Polyvinyl Alcohol, that embodiment as any single embodiment or in combina Black ink (food grade). tion with any other embodiments or portions thereof. The disclosures of each and every patent, patent applica Although the invention has been disclosed with reference tion and publication cited herein are hereby incorporated to specific embodiments, it is apparent that other embodi herein by reference in their entirety. ments and variations of the invention may be devised by The recitation of a listing of chemical groups in any others skilled in the art without departing from the true spirit definition of a variable herein includes definitions of that and scope of the invention. The claims are intended to be variable as any single group or combination of listed groups. 10 construed to include all Such embodiments and equivalent The recitation of an embodiment for a variable herein variations. includes that embodiment as any single embodiment or in combination with any other embodiments or portions Example 5

Schematic of Study Design for a clinical trial of transnasal oxytocin

Treatment Week

O 1-4 5 6-9 10 11-14 14.1

Day 1-71 8-36 36-42 43-71 71-77 78-106 1062 Period Screening Control Washout Low-Dose Washout Moderate- Final treatinent #1 oxytocin #2 Dose Evaluations oxytocin Dosing None Placebo None Oxytocin 12 None Oxytocin 24 None IU/day IU/day Alternative Moderate- High Dose Dosing Dose Oxytocin Oxytocin 24 IU/day 40 IU/day Oxytocin oxytocin

May shorten to 3 days if all screening requirements are met, *Prolong to repeat any final evaluations needed because of clinical abnormalities, *If efficacy and the maximumwell tolerated dose are not found after 5-15 patients have been treated with the “Moderate Dose oxytocin,” doses will be increased, and the “High Dose oxytocin' will be implemented for subsequent patients.

Flow Chart Control Low-dose Mod/High-dose Final Screening (placebo) OXYTOCIN OXYTOCIN Visit Study Day 1 8 36 43 71 78 106 106 Informed consent X Psychiatric history (c’ X Relational/marital history (c) X PHQ-9 self-rated (s) X X C-SSRS Screen Version (c) X X FSFI with 4-week recall (s) X FSFI with 1-week recall (s) X X X X X X FSDS-R" w/30-day recall (s) X FSDS-R with 7-day recall X X X X X X FSFI-6 with 1-wk recall (s) Via web on Via web on Via web on FSDS-R' item 13 (s) days 15, 22, 29 days 50, 57, 64 days 85,92, 99 Pt's Global Impression of Via web on Via web on Via web on Improvement (s) d 15, 22, 29, 36 d 50, 57, 64, 71 d 85,92, 99, 106 Sexual function interview, X Checklist for DSM-IVFSD diagnoses (c) Marital Adjustment Test (s) X

Physical, pelvic examinations' s Prin Prin Pap test (c) Dosing None Start End Start End Start End Supine & standing b.p., pulse' O X XX X XX X XX X X US 9,517,254 B2 107 108 -continued

Flow Chart Control Low-dose Mod/High-dose Final Screening (placebo) OXYTOCIN OXYTOCIN Visit AE inquiry & checklist'' (s, c) X XX X XX X XX X CBC, ALT, AST (others prin?) X X Treatments may start any day of the week, provided the first day's dose is taken in the clinic. Each dosing period must last 28 days 1 and 29 day clinic visits are on same day of week), C = clinician-rated PHQ-9 = Patient Health questionnaire, 9-item depression module S = Self-rated by female subject C-SSRS = Columbia Suicide Severity Rating Scale, 6-item Screening Triage version FSFI = Female Sexual Function Inventory. FSFI-6 = 6-item version of the FSFI "FSDS-R = Female Sexual Distress Scale - Revised, Each DSM-IV-TR sexual symptom to be rated as present or not, and causing distress or not. To be performed as needed to investigate any symptoms that began within the prior 3 months, 'On the first day of each treatment, Supine and standing BP and pulse pre-dose and 3:30 hours post-dose, and p.r.n, palpitations, faintness, or other CV-referable symptoms. 'On the first day of each treatment, AE general inquiry and 16-item Side Effects Checklist pre-dose and 3:50 hours post-dose. Patient completes form; clinician checks it to confirm type and severity of AE. If new findings occur & persist until the final visit, perform relevant laboratory analytes,

Example 6

Schematic of Study Design for a clinical trial of oxytocin plus bupropion

Treatment Week

O 1-4 5 6-9 10 11-14 14.1

Day 1-71 8-36 36-42 43-71 71-77 78-106 106? Period Screening Control Washout Low-Dose Washout Moderate- Final treatment #1 OXYTOCIN H2 Dose Evaluations OXYTOCIN* Dosing None BUP 150 mg None BUP 150 mg None BUP 150 mg None q.a.m. and q.d b.i.d. and OT increasing on plus OT 12 24 IU b.i.d.* day 4 to 150 IU q.d.* Alternative mg b.i.d. Moderate- High-Dose Dosing Dose Oxytocin Oxytocin BUP 150 mg BUP 200 mg b.i.d. and b.i.d. and OT OT 24 IU 40 IU b.i.d.* b.i.d.*

May shorten to 3 days if all screening requirements are met, Prolong to repeat any final evaluations needed because of clinical abnormalities, 5. BUP = SR bupropion 6, OT = oxytocin *If efficacy and the maximum well tolerated dose are not found after 5-15 patients have been treated with the “Moderate Dose Oxytocin,” doses will be increased, and the “High Dose Oxytocin' will be implemented for subsequent patients.

Flow Chart Control Lower-dose Higher-dose Final Screening (BUP) OT - BUP OT - BUP Visit Study Day 1 8 36 43 71 78 106 106 Informed consent X Psychiatric history (c. X Relational/marital history (c) X PHQ-9 self-rated (s) X X C-SSRS Screen Version (c) X X FSFI with 4-week recall (s) X FSFI with 1-week recall (s) X X X X X X FSDS-R" w/30-day recall (s) X FSDS-R with 7-day recall X X X X X X FSFI-6 with 1-wk recall (s) Via web on Via web on Via web on FSDS-R' item 13 (s) days 15, 22, 29 days 50, 57, 64 days 85,92, 99 Pt's Global Impression of Via web on Via web on Via web on Improvement (s) d 15, 22, 29, 36 d 50, 57, 64, 71 d 85,92, 99, 106 US 9,517,254 B2 109 110 -continued

Flow Chart Control Lower-dose Higher-dose Final Screening (BUP) OT - BUP OT - BUP Visit Sexual function interview, X Checklist for DSM-IVFSD diagnoses (c) Marital Adjustment Test (s) X Physical, pelvic examinations', Prin Prin Pap test (c) Dosing None Start End Start End Start End Supine & standing b.p., pulse' X XX X XX X XX X X AE inquiry & checklist'' (s, c) X XX X XX X XX X CBC, ALT, AST (others prin?) X X Treatments may start any day of the week, provided the first day's dose is taken in the clinic. Each dosing period must last 28 days 1 and 29 day clinic visits are on same day of week), C = clinician-rated PHQ-9 = Patient Health questionnaire, 9-item depression module S = Self-rated by female subject C-SSRS = Columbia Suicide Severity Rating Scale, 6-item Screening Triage version FSFI = Female Sexual Function Inventory. FSFI-6 = 6-item version of the FSFI "FSDS-R = Female Sexual Distress Scale - Revised, Each sexual symptom in DSM-IV-TR to be rated as present or not, causing distress or not. To be performed as needed to investigate any symptoms that began within the prior 3 months, 'On the first day of each treatment, Supine and standing BP and pulse pre-dose and 3:30 hours post-dose, and p.r.n, palpitations, faintness, or other CV-referable symptoms. 'On the first day of each treatment, AE general inquiry and 16-item Side Effects Checklist pre-dose and 3:50 hours post-dose. Patient completes form; clinician checks it to confirm type and severity of AE, 'If new findings occur & persist until the final visit, perform relevant laboratory analytes,

Example 7

Schematic of Study Design for a clinical trial of oxytocin (OT) and Sustained release (SR) trazodone (TRZ

Treatment Week

O 1-4 5 6-9 10 11-14 14.1 Day 1-71 8-36 36-42 43-71 71-77 78-106 106? Period Screening Control Washout Low-Dose Washout Moderate- Final treatinent #1 OT - TRZ. #2 Dose Evaluations OT TRZ: Dosing None SR TRZ 150 None OT 12 IU None OT 12 IU None mg q.a.m. and q.d. b.i.d. and increasing on plus TRZ' TRZ 75 mg day 4 to 150 75 mg q.d b.i.d.* Alternative mg b.i.d. Moderate- High-Dose Dosing Dose OT + OT - TRZ. TRZ. OT 12 IU OT 4.0 IU q.d. b.i.d. and and TRZ 150 TRZ 75 mg mg b.i.d.* b.i.d.* May shorten to 3 days if all screening requirements are met, *Prolong to repeat any final evaluations needed because of clinical abnormalities, OT = transnasal or SR oral oxytocin TRZ = SR trazodone *If efficacy and the maximum well tolerated dose are not found after 5-15 patients have been treated with the “Moderate Dose OT + TRZ.” doses will be increased, and a “High Dose OT + TRZ” of 40 IU OT and 150 mg TRZ b.i.d. will be implemented for subsequent patients,

Flow Chart Control Lower-dose Higher-dose Final Screening (BUP) OT + TRZ' OT + TRZ Visit Study Day 8 36 43 71 78 106 106 Informed consent Psychiatric history (c. Relational/marital history (c) PHQ-9 self-rated (s) C-SSRS Screen Version (c) X US 9,517,254 B2 111 112 -continued

Flow Chart Control Lower-dose Higher-dose Final Screening (BUP) OT + TRZ' OT + TRZ Visit FSFI with 4-week recall (s) X FSFI with 1-week recall (s) X X X X X X FSDS-R" w/30-day recall (s) X FSDS-R with 7-day recall X X X X X X FSFI-6 with 1-wk recall (s) Via web on Via web on Via web on FSDS-R7 item 13 (s) days 15, 22, 29 days 50, 57, 64 days 85,92, 99 Pt's Global Impression of Via web on Via web on Via web on Improvement (s) d 15, 22, 29, 36 d 50, 57, 64, 71 d 85,92, 99, 106 Sexual function interview, X Checklist for DSM-IVFSD diagnoses (c) Marital Adjustment Test (s) X Physical, pelvic examinations', Prin Prin Pap test (c) Dosing None Start End Start End Start End Supine & standing b.p., pulse' X XX X XX X XX X X AE inquiry & checklist'' (s, c) X XX X XX X XX X CBC, ALT, AST (others prin?) X X Treatments may start any day of the week, provided the first day's dose is taken in the clinic. Each dosing period must last 28 days 1 and 29 day clinic visits are on same day of week), C = clinician-rated PHQ-9 = Patient Health questionnaire, 9-item depression module S = Self-rated by female subject C-SSRS = Columbia Suicide Severity Rating Scale, 6-item Screening Triage version FSFI = Female Sexual Function Inventory. FSFI-6 = 6-item version of the FSFI "FSDS-R = Female Sexual Distress Scale - Revised, Each symptom as in the DSM-IV-TR, to be rated as present or not, causing distress or not. To be performed as needed to investigate any symptoms that began within the prior 3 months, 'On the first day of each treatment, Supine and standing BP and pulse pre-dose and 3:30 hours post-dose, and p.r.n, palpitations, faintness, or other CV-referable symptoms. 'On the first day of each treatment, AE general inquiry and 16-item Side Effects Checklist pre-dose and 3:50 hours post-dose. Patient completes form; clinician checks it to confirm type and severity of AE, 'If new findings occur & persist until the final visit, perform relevant laboratory analytes.

Example 8

Schematic of Study Design for a clinical trial of oxytocin (OT), bupropion (BUP or B), and trazodone (TRZ or T)

Treatment Week

O 1-4 5 6-9 10 11-14 14.1

Day 1-71 8-36 36-42 43-71 71-77 78-106 1062 Period Screening Control Washout Low-Dose Washout Moderate- Final treatinent #1 OT - B -- T #2 Dose Evaluations OT - B -- T. Dosing None BUP 150 mg None BUP 150 mg None BUP 150 mg None q.a.m. and q.d. + b.i.d. + 12 IU increasing on 12 IU OT - Ot- TRZ 75 day 4 to 150 TRZ 75 mg b.i.d.* mg b.i.d. mg q.d.* Alternative Moderate- High-dose Dosing Dose OT - B - T OT - B -- T BUP 150 mg BUP 200 mg b.i.d. 24 IU b.i.d. + 40 IU OT - TRZ. OT - TRZ. 75 mg b.i.d.* 150 mg b.i.d.*

May shorten to 3 days if all screening requirements are met, *Prolong to repeat any final evaluations needed because of clinical abnormalities BLIP = SR bupropion TRZ = SR trazodone *If efficacy and the maximum well tolerated dose are not found after 5-15 patients have been treated with the “Moderate Dose OT +B+ T.” doses will be increased, and a “High Dose OT +B+ T will be implemented for subsequent patients, US 9,517,254 B2 113 114

Flow Chart Control Low-dose Mod/High-dose Final Screening (BUP) OT + B + T OT + B + T Visit Study Day 1 8 36 43 71 78 106 106 Informed consent X Psychiatric history (c. X Relational/marital history (c) X PHQ-9 self-rated (s) X X C-SSRS Screen Version (c) X X FSFI with 4-week recall (s) X FSFI with 1-week recall (s) X X X X X X FSDS-R" w/30-day recall (s) X FSDS-R with 7-day recall X X X X X X FSFI-6 with 1-wk recall (s) Via web on Via web on Via web on FSDS-R7 item 13 (s) days 15, 22, 29 days 50, 57, 64 days 85,92, 99 Pt's Global Impression of Via web on Via web on Via web on Improvement (s) d 15, 22, 29, 36 d 50, 57, 64, 71 d 85,92, 99, 106 Sexual function interview, X Checklist for DSM-IVFSD diagnoses (c) Marital Adjustment Test (s) X Physical, pelvic examinations', Prin Prin Pap test (c) Dosing None Start End Start End Start End Supine & standing b.p., pulse' X XX X XX X XX X X AE inquiry & checklist'' (s, c) X XX X XX X XX X CBC, ALT, AST (others prin?) X X Treatments may start any day of the week, provided the first day's dose is taken in the clinic. Each dosing period must last 28 days 1 and 29 day clinic visits are on same day of week), C = clinician-rated PHQ-9 = Patient Health questionnaire, 9-item depression module S = Self-rated by female subject C-SSRS = Columbia Suicide Severity Rating Scale, 6-item Screening Triage version FSFI = Female Sexual Function Inventory. FSFI-6 = 6-item version of the FSFI "FSDS-R = Female Sexual Distress Scale - Revised, The 16 most common AE with either BUP or TRZ as in US labeling of these drugs, plus sexual desire and sexual arousal. To be performed as needed to investigate any symptoms that began within the prior 3 months, 'On the first day of each treatment, Supine and standing BP and pulse pre-dose and 3:30 hours post-dose, and p.r.n, palpitations, faintness, or other CV-referable symptoms. 'On the first day of each treatment, AE general inquiry and 16-item Side Effects Checklist pre-dose and 3:50 hours post-dose. Patient completes form; clinician checks it to confirm type and severity of AE. See Appendix H. 'If new findings occur & persist until the final visit, perform relevant laboratory analytes,

What is claimed is: 11. The method of claim 10, wherein the sexual disorder 1. A composition comprising a 5-HT, antagonist, a is hypoactive sexual desire disorder (HSDD). norepinephrine-dopamine reuptake inhibitor, an oxytocin 12. The method of claim 10, wherein the sexual disorder receptor (OXTR) agonist, and a pharmaceutically acceptable is female orgasm disorder (FOD). carrier. 13. The method of claim 10, wherein the sexual disorder 2. The composition of claim 1, wherein the 5-HT is female sexual arousal disorder (FSAD). antagonist is also a 5-HT, receptor agonist. 14. The method of claim 10, wherein the sexual disorder 3. The composition of claim 1, comprising traZodone, 45 is sexual pain dysfunction. bupropion, and oxytocin. 15. The method of claim 10, wherein the sexual disorder 4. The composition of claim 1, comprising bupropion in is male HSDD. a dosage range of 200-450 mg. 16. A method of treating a cognitive disorder in a subject 5. The composition of claim 1, comprising traZodone in a comprising administering to the Subject a composition dosage range of 25-450 mg. 50 according to claim 1. 6. The composition of claim 1, comprising oxytocin in a 17. The method in claim 16, wherein the cognitive dis dosage range of 4-400 International Units. order is dementia. 7. The composition of claim 1, comprising traZodone in a 18. The method in claim 17, wherein the dementia is dosage range of 1-450 mg, bupropion in a dosage range of Alzheimer's disease, frontotemporal lobar degeneration, 1-450 mg, and oxytocin in a dosage range of 4-400 Inter 55 dementia with Lewy bodies, Parkinson's disease, Hunting national Units. ton's disease, multi-infarct dementia, dementia resulting 8. A method of making a composition comprising com from infections affecting the central nervous system, demen bining a 5-HT agonist, a 5-HT, antagonist, a norepineph tia resulting from chronic drug use, dementia resulting from rine-dopamine reuptake inhibitor, an oxytocin receptor hydrocephalus, dementia resulting from brain injury, or (OXTR) agonist, and a pharmaceutically acceptable carrier. 60 dementia resulting from a brain tumor. 9. The method of claim 8, comprising combining bupro 19. The method in claim 16, wherein the cognitive dis pion, traZodone, oxytocin, and a pharmaceutically accept order is cognitive disability. able carrier. 20. The method in claim 19, wherein the cognitive dis 10. A method of treating a sexual disorder in a subject ability is schizophrenia, schizoaffective disorder, bipolar comprising administering to the Subject a composition 65 disorder, or major depression. according to claim 1. k k k k k