US 2015O150946A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0150946A1 Sitchon et al. (43) Pub. Date: Jun. 4, 2015

(54) TREATMENT REGIMIENS Related U.S. Application Data (60) Provisional application No. 61/679,999, filed on Aug. (71) Applicant: S1 Biopharma, Inc., Jersey City, NJ 6, 2012. (US) Publication Classification (72) Inventors: Nicolas G. Sitchon, Jersey City, NJ (51) Int. Cl. (US); Robert E. Pyke, New Fairfield, A638/22 (2006.01) CT (US); John F. Kaufmann, Beltsville, A613 L/496 (2006.01) MD (US) A63/37 (2006.01) (52) U.S. Cl. (21) Appl. No.: 14/420,112 CPC ...... A61K 38/22 (2013.01); A61 K3I/I37 (2013.01); A61 K3I/496 (2013.01) (22) PCT Fled: Aug. 6, 2013 (57) ABSTRACT (86) PCT NO.: PCT/US2O13/O53843 The invention further relates to compounds, pharmaceutical compositions and methods for treating all disorders of human S371 (c)(1), sexual function including hypoactive sexual desire disorder (2) Date: Feb. 6, 2015 (HSDD) in a subject. US 2015/O150946 A1 Jun. 4, 2015

TREATMENT REGIMENS mic Disorder (MOD; delayed ejaculation). Male dysfunc tionally premature ejaculation (PE) is much more frequent CROSS REFERENCE TO RELATED than any of these problems, occurring in up to 30% of younger APPLICATIONS men (Laumann et al., Sexual dysfunction in the United States: 0001. This application claims the benefit of U.S. Provi Prevalence and predictors, JAMA, 1999; 281:537–44). sional Application No. 61/679,999 filed on Aug. 6, 2012, the 0007 Sexual dysfunction may also be manifested as a entire disclosure of which is hereby incorporated in its significant burden in the course of physical diseases. Sexual entirety. dysfunction is frequent in women with chronic, fatiguing medical illness, especially Female HSDD or FSAD due to breast cancer, diabetes mellitus, or irritable bowel syndrome BACKGROUND OF THE INVENTION or due to combined factors including one of these medical 0002 Sexual Dysfunction (SD) is described as a disorder diseases. These conditions occur mainly in middle-aged to of or an interruption in sexual functioning. In women, the older patients. Collectively, these conditions cause sexual most 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 orgynecologic cancer, 1.5 Edition, Text Revision (American Psychiatric Association, million; diabetes, at least 3.4 million; irritable bowel, at least 2000; DSM-IV-TR) as: “The persistent lack (or absence) of 2.9 million). SD in Men with chronic diseases is little studied sexual fantasies or desire for any form of sexual activity but can be presumed from the ample evidence on women to be marked by distress or interpersonal difficulty and not better another large set of clinically and epidemiologically signifi accounted for by another disorder (except another sexual cant health problems. The most authoritative arbiter of diag dysfunction) direct physiological effects of a substance (in nostic names and criteria on sexual dysfunction, the DSM cluding medications) or a general medical condition.” The IV-TR, recognizes eight kinds of sexual disorders due to presence of distress or interpersonal difficulty is an integral chronic physical disease: Sexual Dysfunction due to General part of sexual disorders and is central to the diagnosis of the Medical Conditions (e.g., irritable bowel syndrome, diabetes, condition. Approximately 1 in 10 women reported low sexual cancer); Female HSDD due to General Medical Conditions desire with associated distress, which may be HSDD. (e.g., irritable bowel syndrome, diabetes, cancer); Male 0003 Synonyms for HSDD include sexual aversion, i.e., HSDD due to General Medical Conditions (e.g., irritable extreme aversion to, absence of, and avoidance of all, or bowel syndrome, diabetes, cancer); Male Erectile Disorder almost all, sexual contact with a partner; inhibited sexual due to General Medical Conditions (e.g., irritable bowel syn desire; sexual apathy; loss of libido; decreased sexual desire: drome, diabetes, cancer): Female Dyspareunia due to General distressing loss of sexual desire; and sexual anorexia. HSDD Medical Conditions (e.g., irritable bowel syndrome, diabetes, occurs in both sexes. It is considered to be the most common cancer); Male Dyspareunia due to General Medical Condi of all female sexual disorders, possibly occurring in as many tions (e.g., irritable bowel syndrome, diabetes, cancer); Other as 10% of women in the United States. Female Sexual Dysfunction due to General Medical Condi 0004. In women, a majority of HSDD cases are general tions (e.g., irritable bowel syndrome, diabetes, cancer) if ized in subtype, though a substantial minority of cases may Some other feature is predominant (e.g., Orgasmic Disorder) relate to dissatisfaction or loss of interest in the sexual partner. or no feature predominates; and Other Male Sexual Dysfunc Either subtype of HSDD can lead to general feelings of dis tion due to General Medical Conditions (e.g., irritable bowel satisfaction in the person and/or discord in their personal syndrome, diabetes, cancer) if some other feature is predomi relationships, including for example marital discord. Sexual nant (e.g., Orgasmic Disorder) or no feature predominates. disorders, whether generalized or situational, often do not 0008 Collectively, in this document, all of the sexual dys respond to counseling therapy, and frequently culminate in functions and disorders described above are called sexual separation, finding a new sexual partner, and divorce. dysfunctions, sexual disorders, or SD. 0005. The other phases of sexual function, sexual arousal 0009. As there is no currently approved treatment for and orgasm, are also subject to impairment. In women, dys HSDD or any other sexual disorder except (male) erectile functions in these sexual phases, if sufficiently distressing, dysfunction in the United States, a therapeutic composition are known, respectively, as Female Sexual Arousal Disorder and methods for ameliorating sexual disorders is an unmet (FSAD) and Female Orgasmic Disorder (FOD) in DSM-IV need for a significant portion of the population and their TR. Collectively, they impair sexual function in almost as quality of life. Delineated herein are compositions and meth many women as does HSDD (Shifren J Letal, Sexual prob ods of treatment that may be useful to address this unmet need lems and distress in United States women: prevalence and based on heretofore unexpected properties possessed by the correlates. ObstetGynecol. 2008 November; 112(5):970-81. subject compositions. Women in the peri- and post-menopause are the most affected I0010 Erectile Dysfunction (ED) is the only male sexual subpopulation with such problems. In the US, in the age dysfunction for which pharmacotherapies are broadly avail group 45-64 years, the prevalence of FSAD is about 3.1 able. Sexual disorders other than ED, e.g., HSDD, are also million; of FOD, 2.4 million. Little overlap of these disorders common in men, although research on non-ED male sexual was found in the largest, most representative survey of wom disorders has lagged compared to that in women. However, en's sexual function (the PRESIDE study, Shifrenetal, ibid.), the cross-national US survey published in 1999 by Laumann so the overall number of US women affected with FSAD or et al. showed that male lack of interest in sex, at 15% of men FOD is over 5 million. aged 18-59, was about as frequent as erectile dysfunction 0006. In men, dysfunction in arousal (in erection) is well (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 to (ejaculation) also occurs with some frequency. If it causes men with HSDD vs. those with no sexual dysfunction. The significant sexual distress, the disorder is called Male Orgas men with HSDD had dramatic impairments on all rating US 2015/O 150946 A1 Jun. 4, 2015

scales relating to HSDD: on the Sexual Concerns Index without being masked by the side effects of either drug, and in Male, a measure of male sexual distress; the UCLA Psycho particular it will allow rapid relief of symptoms because the sexual Diary’s measure of sexual activity; and the Male effective dose can be given immediately due to the low Desire Scale, a measure of sexual desire; but did not have ED: expected side effects, instead of requiring weeks of up-titra International Index of Erectile Function (IIEF)-5 median tion to overcome side effects over time. This makes Lor score or depression Beck Depression scale or low testoster exyS(R), a fixed combination of bupropion and traZodone, of one: men with low or low-normal testosterone levels (<300 special value for male HSDD and sexual performance anxiety ng/dL) were excluded. Their data show that male HSDD is a as disorders that cause distress and disrupt quality of life on real problem of clinical magnitude. p-0.0001 for each vari the days when a man is to have sex with a partner. able; sample sizes were about 100 0016. The current invention relates to combinations of a 0011 No pharmacologic treatment is available in most 5-HT, receptor agonist and/or 5-HT, receptor antagonist countries including the US for either men or women with (e.g., traZodone, nefazodone, mirtazapine, flibanserin ket sexual disorders other than for men with ED, although a anserin, ritanserin, clozapine, olanzapine, quetiapine, risperi testosterone transdermal system was approved for women done, asenapine, MDL-100.907, cyproheptadine, aripipra with postmenopausal HSDD in Europe in 2005. Zole, and the general class of 2-alkyl-4-aryl-tetrahydro 0012 Yet another male sexual dysfunction is frequent, pyrimido-azepines), a norepinephrine-dopamine reuptake though not the subject of a DSM-IV-TR diagnosis: Male inhibitor (e.g., bupropion), and/or an oxytocin receptor sexual performance anxiety was a problem for 17% of US (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon R.) men age 18-59 in the cross-national survey published by and their use to augment sexual desire, arousal, and orgasm. Laumann in 1999 in JAMA, about the same incidence as for Their ability to help men feel desire will also aid male sexual erectile dysfunction (ED) and male lack of sexual interest. performance anxiety. These combinations will be particularly Male sexual performance anxiety was about twice as preva effective for each of these disorders in men and women lent as ED in US men under age 50. It is little studied but can because they will allow the corrective effects of the individual cause significant distress, especially in male patients in infer agents to become manifest without being masked by the side tility clinics. Peterson B D, Newton CR, and Feingold T. in effects of either drug, and in particular it will allow rapid "Anxiety and sexual stress in men and women undergoing relief of symptoms because the effective dose can be given infertility treatment,” in Fertility and Sterility 2007 October; immediately due to the low expected side effects, instead of 88(4):911-4, Epub 2007 Apr. 11, found in a prospective study requiring weeks of up-titration to overcome side effects over at a University-affiliated teaching hospital for in vitro fertili time. This makes LorexySR, a fixed combination of bupro zation and intrauterine insemination (306 women, 295 men) a pion and trazodone, of special value for male HSDD and strong linkage between anxiety and sexual stress in men and sexual performance anxiety as disorders that cause distress concluded that sexual stress among infertile men may be and disrupt quality of life on the days when a man is to have more closely tied to performance anxiety rather than to a more sex with a partner. general deterioration in sexual satisfaction associated with 0017. The current invention also relates to combinations infertility. of a 5-HT, receptoragonist and/or 5-HT2 receptor antago 0013 Male sexual performance anxiety, while not a dis nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin order recognized in DSM-IV-TR or ICD-10, is recognized as ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris a necessary focus in the recommended clinical evaluation of peridone, asenapine, MDL-100.907, cyproheptadine, arip men with sexual dysfunction according to the Third Interna iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro tional Consultation on Sexual Medicine (Paris, July 2009). pyrimido-azepines), and/or a 5-HT, receptor antagonist, Hatzichristou D. Rosen RC, Derogatis L. R. et al. Recom and/or a 5HT-2c receptor agonist, (e.g., lorcaserin, vabi mendations for the Clinical Evaluation of Men and Women caserin, PRX-00933, YM348, and metachlorophenylpipera with Sexual Dysfunction, J Sex Med2010; 7:337-348. These zine, mCPP), a norepinephrine-dopamine reuptake inhibitor experts recommend diagnostic workup for male sexual per (e.g., bupropion), and/or other non-abusable agents (agents formance anxiety because it may cause or result from the not scheduled by the DEA) that augment dopamine and/or recognized male sexual disorders such as ED (psychogenic norepinephrine in the brain, e.g., atomoxetine, reboxetine, impotence) and premature ejaculation. amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, 0014. The model of sexual functioning that is most lortalamine, mazindol, nisoxetine, talopram, talsupram, tan accepted is one in which sexual desire leads to arousal, and damine, Viloxazine, maprotiline, ciclazindol, manifaxine, eventually orgasm. Even E. D. currently the most treatable of radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo sexual dysfunctions, is unlikely to be aided by pharmaco biloba), and/or an oxytocin receptor (OXTR) agonist (e.g., therapy unless desire can be restored. Thus, loss of desire is of carbetocin, oxytocin, Syntocinon R) and their use to augment primary concern for treating all disorders of sexual function. sexual desire, arousal, and orgasm. Their ability to help men 0.015 The current invention relates to combinations of a feel desire will also aid male sexual performance anxiety. 5-HT, receptor agonist and/or 5-HT, receptor antagonist These combinations will be particularly effective for each of (e.g., traZodone, nefazodone, mirtazapine, flibanserin), a these disorders in men and women because they will allow the norepinephrine-dopamine reuptake inhibitor (e.g., bupro corrective effects of the individual agents to become manifest pion), and/or an oxytocin receptor (OXTR) agonist (e.g., without being masked by the side effects of either drug, and in carbetocin, oxytocin, Syntocinon R) and their use to augment particular it will allow rapid relief of symptoms because the sexual desire, arousal, and orgasm. Their ability to help men effective dose can be given immediately due to the low feel desire will also aid male sexual performance anxiety. expected side effects, instead of requiring weeks of up-titra These combinations will be particularly effective for each of tion to overcome side effects over time. This makes Lor these disorders in men and women because they will allow the exyS(R), a fixed combination of bupropion and traZodone, of corrective effects of the individual agents to become manifest special value for male HSDD and sexual performance anxiety US 2015/O 150946 A1 Jun. 4, 2015

as disorders that cause distress and disrupt quality of life on deteriorated in frequency and/or satisfaction because of the days when a man is to have sex with a partner. increasing loss of trust and/or anxiety about performance, 0018 Disorders of cognition are also frequent, and are of avoidance patterns etc., that occur as a consequence of any of particular concern because of their high prevalence in older the recognized sexual dysfunction disorders: in the male part patients (an enlarging segment of the population), the disabil ner, HSDD, ED, PE, MOD, and dyspareunia, and in (the ity they cause, and their intractability to current treatments. epidemiologically frequent but not DSM-IV-recognized con Improvement in cognition as augmentation of cognition for dition of) male sexual performance anxiety; in the female therapeutic purposes is also of interest, e.g., in the circum partner, HSDD, FSAD, FOD, and dyspareunia. It is a novel stances of Subjects whose cognitive skills are limiting for aspect of the invention that the same properties of oxytocin, tasks that require learning or vigilance. The invention pro aiding trust and reducing social anxiety, will aid most of the vides a method of treating a subject Suffering from or Suscep other subtypes of each of these disorders of sexual function, tible to a cognitive disorder or otherwise in need of improve i.e., the Subtypes "due to psychological factors and "due to ment in cognition with a composition comprising a 5-HT combined factors.’ “Situational is defined in DSM-IV-TR as agonist, a 5-HT, antagonist, a norepinephrine-dopamine applying "if the sexual dysfunction is limited to certain types reuptake inhibitor, an oxytocin receptor (OXTR) agonist, and of stimulation, situations, or partners, which is the opposite a pharmaceutically acceptable carrier. of the Generalized type. “Due to Psychological Factors' 0019 Depressive disorders are also frequent (lifetime risk applies “when psychological factors are judged to have the in women, 10-25%; in men, 5-12%) and are of particular major role in the onset, severity, exacerbation, or maintenance concern because of the disability they cause, the high likeli of the Sexual Dysfunction....” “Due to Combined Factors' hood of failure with initial treatment (only about 50% of is defined as applying “when psychological factors are judged patients with Major Depressive Disorder respond to any one to have a role in the onset, severity, exacerbation, or mainte antidepressant, the high frequency of incomplete response to nance of the Sexual Dysfunction . . . .” currently available treatments (only about 30% of patients 0022. It is a novel aspect of the invention that oxytocin is achieve full remission with a given antidepressant), their useful to treat the aforementioned Subtypes of every diagnos increasing frequency of treatment-resistance, and especially tic category of sexual dysfunction. Drawing on clinical expe because they often lead to suicide, in about 15% of patients rience in couples having a long-term partnered relationship, (DSM-IV-TR). The invention provides a method of treating a sexual dysfunction in one partner ordinarily worsens because subject suffering from or susceptible to a depressive disorder of the other partner's reaction over time to that sexual dys comprising administering to a subject in need thereofathera function, and can cause sexual dysfunction in the partner, too. peutically effective amount of a composition comprising a For example, generalized HSDD in a woman is likely to lead 5-HT agonist, a 5-HTantagonist, a norepinephrine her to non-receptivity, which may lead her to a psychosocially dopamine reuptake inhibitor, an oxytocin receptor (OXTR) destructive pattern of avoidance behavior regarding potential agonist, and a pharmaceutically acceptable carrier. sexual situations. The male partner learns to avoid sexual 0020. It is not readily apparent from published literature frustration, anger, arguments etc. by also practicing avoid reports that oxytocin (OT) can relieve human sexual dysfunc ance behavior. At first this may simply be sublimation, but the tion. Though a case report of pro-sexual effects of transnasal likely result over time is atrophy of all sexual aspects of the OT has been published for each of three very different union, including sexual dysfunction in the male partner— patients a postpartum woman without sexual dysfunction: performance anxiety likely occurring first, then HSDD, ED, Anderson-Hunt and Dennerstein, BritMed J. 1994; 309:929: and/or PE. That leads to further decline in the sexual relation an elderly man with orgasmic disorder: Ishak et al., J Sex ship. The woman's HSDD was originally, and logically Med. 2008; 5:1022-4, and a complex psychiatric patient with remains, generalized. But both partners’ sexual disorders out sexual dysfunction: MacDonald and Feifel, J Sex Med may then alternatively be subtyped as situational, due to 2012; 9:1407-1410, the only published placebo-controlled psychological factors, or due to combined factors. study showed no significant advantage for oxytocin: 24 Inter 0023. Similarly, it is another aspect of the invention that national Units (IU) of intranasal OTfailed to increase arousal oxytocin specifically aids all additionally proposed DSM-5 or orgasm in men on the primary outcome scale, the "Acute sexual dysfunction disorders (Male HSDD, Erectile Disorder, Sexual Experiences Scale (ASES). The authors concluded Delayed Ejaculation, Female Sexual Interest/Arousal Disor that “the effects of OT on sexual behavior were equivocal ... der, Genito-Pelvic Pain/Penetration Disorder, Substance? Burri et al., Psychoneuroendocrinology. 2008; 33:591 Medication-Induced Sexual Dysfunction, and Sexual Dys 600. Also, in the most recent review of the side effects of function Not Elsewhere Classified) with the proposed transnasal OT, in which almost a thousand Subjects were Specifiers of Situational, Partner factors (e.g., partner's treated with OT (Syntocinon R in almost all studies) in con sexual problems, partner's health status), and Relationship trolled studies to investigate non-sexual effects, no events of factors (e.g., poor communication, discrepancies in desire for any type of increase in sexual function were reported Mac sexual activity). www.dsm5.org, Aug. 2, 2012. Donald et al., Psychoneuroendocrinology. 2011 September; 0024. The current invention relates to combinations of a 36(8): 1114-26. 5-HT, receptor agonist, 5-HT2 receptor antagonist, 0021 However, OT mediates pro-social and anti-anxiety 5-HT, receptor antagonist, or combinations thereof (e.g., effects, doing so through effects on the amygdala in a pla traZodone). The current invention also relates to combina cebo-controlled study. Kirsch et al., J. Neuroscience 2005; tions of a 5-HT, receptor agonist, 5-HT2 receptor antago 25(49): 11489-11493. It is a novel aspect of the invention that nist, 5-HT, receptor antagonist, or combinations thereof these properties will specifically aid all DSM-IV-TR-recog (e.g., traZodone), and a norepinephrine-dopamine reuptake nized sexual dysfunction disorders listed as having the DSM inhibitor (e.g. bupropion), and/or an oxytocin receptor IV-TR subtype “due to situational factors, i.e., in men or (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon R) to women who are in a relationship in which sexual activity has augment cognition, improve failing mental processes in cog US 2015/O150946 A1 Jun. 4, 2015 nitive disorders, and improve mood and the depressive symp ratio of Lorexys, will neutralize the main side effects of each toms that accompany mood disorders. The current invention of the two drugs. This makes Lorexys(R), a fixed combination also relates to combinations of a 5-HT, receptor agonist, of bupropion and trazodone, of special value for treating acute 5-HT2 receptor antagonist (e.g., trazodone, nefazodone, Symptoms such as suicidality, disabling symptoms such as mirtazapine, flibanserin), a norepinephrine-dopamine inability to work or otherwise function, especially for older reuptake inhibitor (e.g. bupropion), and/oran oxytocin recep patients who generally are more prone to side effects and for tor (OXTR) agonist (e.g., carbetocin, oxytocin, Syntoci whom adverse effects cause more risk, and especially non-R) to augment cognition, improve failing mental pro because such a combination can be prescribed by a health cesses in cognitive disorders, and improve mood and the provider with less specialized expertise in pharmacologic depressive symptoms that accompany mood disorders. These treatment of neuro-psychiatric disorders. combinations are particularly effective for each of these dis 0026. The current invention also relates to combinations orders as they allow the corrective effects of the individual of a 5-HT1 receptoragonist and/or 5-HT, receptor antago agents to become manifest without being masked by the side nist (e.g., trazodone, nefazodone, mirtazapine, flibanserin effects of either drug, and in particular it allow rapid relief of ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris Symptoms because the effective dose can be given immedi peridone, asenapine, MDL-100.907, cyproheptadine, arip ately due to the low expected side effects, instead of requiring iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro weeks of up-titration to overcome side effects over time. pyrimido-azepines), and/or a 5-HT, receptor antagonist, Reduced toxicity is provided by a compound of the invention and/or a 5HT-2c receptor agonist, (e.g., lorcaserin, vabi when administered in Vivo, e.g., formulating bupropion, by caserin, PRX-00933, YM348, and metachlorophenylpipera itself a mild stimulant, with trazodone, by itself a moderate zine, mCPP), a norepinephrine-dopamine reuptake inhibitor sedative, in the proprietary ratio of Lorexys, will neutralize (e.g., bupropion), and/or other non-abusable agents (agents the main side effects of each of the two drugs. This makes not scheduled by the DEA) that augment dopamine and/or Lorexys(R), a fixed combination of bupropion and trazodone, norepinephrine in the brain, e.g., atomoxetine, reboxetine, of special value for treating acute symptoms such as suicid amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, ality, disabling symptoms such as inability to work or other lortalamine, mazindol, nisoxetine, talopram, talsupram, tan wise function, especially for older patients who generally are damine, Viloxazine, maprotiline, ciclazindol, manifaxine, more prone to side effects and for whom adverse effects cause radafaxine, tapentadol, teniloxazine, St. John's wort, ginkgo more risk, and especially because such a combination can be biloba), and/or an oxytocin receptor (OXTR) agonist (e.g., prescribed by a health provider with less specialized expertise carbetocin, oxytocin, Syntocinon(R) to augment cognition, in pharmacologic treatment of neuro-psychiatric disorders. improve failing mental processes in cognitive disorders, and improve mood and the depressive symptoms that accompany 0025. The current invention relates to combinations of a 5-HT, receptor agonist, 5-HT, receptor antagonist, mood disorders. The current invention also relates to combi 5-HT2 receptor antagonist, or combinations thereof (e.g., nations of a 5-HT, receptor agonist, 5-HT, receptor traZodone, nefazodone, mirtazapine, flibanserin ketanserin, antagonist (e.g., trazodone, nefazodone, mirtazapine, fli ritanserin, clozapine, olanzapine, quetiapine, risperidone, banserin), a norepinephrine-dopamine reuptake inhibitor asenapine, MDL-100.907, cyproheptadine, aripiprazole, and (e.g. bupropion), and/or an oxytocin receptor (OXTR) ago the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido nist (e.g., carbetocin, oxytocin, Syntocinon(R) to augment aZepines). The current invention also relates to combinations cognition, improve failing mental processes in cognitive dis of a 5-HT, receptor agonist, 5-HT, receptor antagonist, orders, and improve mood and the depressive symptoms that 5-HT2 receptor antagonist, or combinations thereof (e.g., accompany mood disorders. These combinations are particu traZodone), and a norepinephrine-dopamine reuptake inhibi larly effective for each of these disorders as they allow the tor (e.g. bupropion), and/or an oxytocin receptor (OXTR) corrective effects of the individual agents to become manifest agonist (e.g., carbetocin, oxytocin, Syntocinon R) to augment without being masked by the side effects of either drug, and in cognition, improve failing mental processes in cognitive dis particular it allow rapid relief of symptoms because the effec orders, and improve mood and the depressive symptoms that tive dose can be given immediately due to the low expected accompany mood disorders. The current invention also side effects, instead of requiring weeks of up-titration to relates to combinations of a 5-HT, receptor agonist, 5-HT overcome side effects overtime. Reduced toxicity is provided receptor antagonist (e.g., trazodone, nefazodone, mirtazap by a compound of the invention when administered in vivo. ine, flibanserin), a norepinephrine-dopamine reuptake inhibi e.g., formulating bupropion, by itself a mild stimulant, with tor (e.g. bupropion), and/or an oxytocin receptor (OXTR) traZodone, by itself a moderate sedative, in the proprietary agonist (e.g., carbetocin, oxytocin, Syntocinon R) to augment ratio of Lorexys, will neutralize the main side effects of each cognition, improve failing mental processes in cognitive dis of the two drugs. This makes Lorexys(R), a fixed combination orders, and improve mood and the depressive symptoms that of bupropion and trazodone, of special value for treating acute accompany mood disorders. These combinations are particu symptoms such as Suicidality, disabling symptoms such as larly effective for each of these disorders as they allow the inability to work or otherwise function, especially for older corrective effects of the individual agents to become manifest patients who generally are more prone to side effects and for without being masked by the side effects of either drug, and in whom adverse effects cause more risk, and especially particularit allow rapid relief of symptoms because the effec because such a combination can be prescribed by a health tive dose can be given immediately due to the low expected provider with less specialized expertise in pharmacologic side effects, instead of requiring weeks of up-titration to treatment of neuro-psychiatric disorders. overcome side effects overtime. Reduced toxicity is provided by a compound of the invention when administered in vivo, SUMMARY OF THE INVENTION e.g., formulating bupropion, by itself a mild stimulant, with 0027. In one aspect, the invention provides compositions trazodone, by itself a moderate sedative, in the proprietary and methods of treating a subject suffering from or suscep US 2015/O 150946 A1 Jun. 4, 2015

tible to a sexual disorder or symptom thereof (e.g., HSDD, asenapine, MDL-100.907, cyproheptadine, aripiprazole, and FSAD, FOD, erectile disorder, male sexual performance the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido anxiety, sexual interest-arousal disorder, female sexual dys azepines). The current invention also relates to combinations function (FSD), male sexual dysfunction (MSD), and the of a 5-HT, receptor agonist, 5-HT, receptor antagonist, like) comprising administering to a Subject in need thereof a 5-HT, receptor antagonist, a 5-HT2 receptor agonist (e.g., therapeutically effective amount of a composition delineated lorcaserin, vabicaserin, PRX-00933, YM348, and metachlo herein. rophenylpiperazine, mCPP), or combinations thereof (e.g., 0028. The current invention relates to combinations of a traZodone, nefazodone, mirtazapine, flibanserin ketanserin, 5-HT, receptor agonist, 5-HT, receptor antagonist, ritanserin, clozapine, olanzapine, quetiapine, risperidone, 5-HT, receptor antagonist, or combinations thereof (e.g., asenapine, MDL-100.907, cyproheptadine, aripiprazole, and traZodone). The current invention also relates to combina the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido tions of a 5-HT, receptor agonist, 5-HT2 receptor antago azepines), and/or a norepinephrine-dopamine reuptake nist, 5-HT, receptor antagonist, or combinations thereof inhibitor (e.g. bupropion), and/or other non-abusable agents (e.g., traZodone), and a norepinephrine-dopamine reuptake (agents not scheduled by the DEA) that augment dopamine inhibitor (e.g. bupropion), and/or an oxytocin receptor and/or norepinephrine in the brain, e.g., atomoxetine, rebox (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR). etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox 0029. The current invention relates to combinations of a etine, lortalamine, mazindol, nisoxetine, talopram, talsu 5-HT, receptor agonist, 5-HT2 receptor antagonist, pram, tandamine, Viloxazine, maprotiline, ciclaZindol, 5-HT, receptor antagonist, or combinations thereof (e.g., manifaxine, radafaxine, tapentadol, teniloxazine, St. John's traZodone, nefazodone, mirtazapine, flibanserin ketanserin, wort, ginkgo biloba), and/or an oxytocin receptor (OXTR) ritanserin, clozapine, olanzapine, quetiapine, risperidone, agonist (e.g., carbetocin, oxytocin, SyntocinonR). asenapine, MDL-100.907, cyproheptadine, aripiprazole, and 0032. In one aspect, the invention provides a composition the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido comprising a 5-HT, antagonist, a norepinephrine-dopamine azepines). The current invention also relates to combinations reuptake inhibitor, and a pharmaceutically acceptable carrier. of a 5-HT, receptor agonist, 5-HT2 receptor antagonist, In another aspect the composition is that wherein the norepi 5-HT, receptor antagonist, or combinations thereof (e.g., nephrine-dopamine reuptake inhibitor is also an alpha adren traZodone, nefazodone, mirtazapine, flibanserin ketanserin, ergic blocker (e.g., bupropion). In another aspect the compo ritanserin, clozapine, olanzapine, quetiapine, risperidone, sition is that wherein the 5-HT, antagonist is also a 5-HT asenapine, MDL-100.907, cyproheptadine, aripiprazole, and receptor agonist. In another aspect the composition is that the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido wherein the 5-HT2 receptor antagonist is also a 5-HT, azepines), and a norepinephrine-dopamine reuptake inhibitor receptor antagonist. In another aspect the composition is that (e.g. bupropion), and/or an oxytocin receptor (OXTR) ago wherein the 5-HT2 receptor antagonist is also a 5-HT, nist (e.g., carbetocin, oxytocin, SyntocinonR). receptor antagonist and a 5-HT, receptor agonist (e.g., tra 0030 The current invention relates to combinations of a Zodone). In another aspect the composition is that wherein the 5-HT, receptor agonist, 5-HT2 receptor antagonist, 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or 5-HT, receptor antagonist, or combinations thereof (e.g., 5-HT, receptor antagonist is also an alpha adrenergic traZodone, nefazodone, mirtazapine, flibanserin ketanserin, blocker (e.g., traZodone). In another aspect the composition is ritanserin, clozapine, olanzapine, quetiapine, risperidone, that comprising traZodone and bupropion. In another aspect asenapine, MDL-100.907, cyproheptadine, aripiprazole, and the composition is that comprising traZodone in a dosage the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido range of 1-450 mg and bupropion in a dosage range of 1-450 azepines). The current invention also relates to combinations ng. of a 5-HT, receptor agonist, 5-HT2 receptor antagonist, 0033. In one aspect, the invention provides a composition 5-HT, receptor antagonist, or combinations thereof (e.g., comprising a 5-HT, antagonist, a norepinephrine-dopamine traZodone, nefazodone, mirtazapine, flibanserin ketanserin, reuptake inhibitor, other non-abusable agents (agents not ritanserin, clozapine, olanzapine, quetiapine, risperidone, scheduled by the DEA) that augment dopamine and/or nore asenapine, MDL-100.907, cyproheptadine, aripiprazole, and pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta azepines), and/or a norepinephrine-dopamine reuptake lamine, mazindol, nisoxetine, talopram, talsupram, inhibitor (e.g. bupropion), and/or an oxytocin receptor tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo and/or other non-abusable agents (agents not scheduled by biloba), and a pharmaceutically acceptable carrier. In another the DEA) that augment dopamine and/or norepinephrine in aspect the composition is that wherein the norepinephrine the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, dopamine reuptake inhibitor is also an alpha adrenergic 332, daledalin, edivoxetine, esreboxetine, lortalamine, blocker (e.g., bupropion). In another aspect the composition mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox is that wherein the 5-HT, antagonist is also a 5-HT, recep azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap toragonist. In another aspect the composition is that wherein entadol, teniloxazine, St. John’s wort, ginkgo biloba). the 5-HT2 receptor antagonist is also a 5-HT, receptor 0031. The current invention relates to combinations of a antagonist. In another aspect the composition is that wherein 5-HT, receptor agonist, 5-HT2 receptor antagonist, the 5-HT2 receptor antagonist is also a 5-HT, receptor 5-HT, receptor antagonist, a 5-HT, receptor agonist (e.g., antagonist and a 5-HT, receptoragonist (e.g., trazodone). In lorcaserin, vabicaserin, PRX-00933, YM348, and metachlo another aspect the composition is that wherein the 5-HT rophenylpiperazine, mCPP) or combinations thereof (e.g., receptor antagonist, 5-HT, receptor agonist, and/or 5-HT, traZodone, nefazodone, mirtazapine, flibanserin ketanserin, receptor antagonist is also an alpha adrenergic blocker (e.g., ritanserin, clozapine, olanzapine, quetiapine, risperidone, traZodone). In another aspect the composition is that com US 2015/O 150946 A1 Jun. 4, 2015 prising traZodone, bupropion, and at least one of the group talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, consisting of atomoxetine, reboxetine, amedalin, CP-39,332, manifaxine, radafaxine, tapentadol, teniloxazine, St. John's daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, wort, and ginkgo biloba. In another aspect the composition is nisoxetine, talopram, talSupram, tandamine, Viloxazine, that comprising traZodone in a dosage range of 1-450 mg and maprotiline, ciclaZindol, manifaxine, radafaxine, tapentadol, bupropion in a dosage range of 1-450 mg. teniloxazine, St. John's wort, and ginkgo biloba. In another 0036. In one aspect, the invention provides a composition aspect the composition is that comprising traZodone in a comprising a 5-HT, antagonist, a norepinephrine-dopamine dosage range of 1-450mg and bupropion in a dosage range of reuptake inhibitor, and an oxytocin receptor (OXTR) agonist, 1-450 mg. and a pharmaceutically acceptable carrier. In another aspect 0034. In one aspect, the invention provides a composition the composition is that wherein the norepinephrine-dopam comprising a 5-HT, antagonist, a norepinephrine-dopamine ine reuptake inhibitor is also an alpha adrenergic blocker reuptake inhibitor, a 5-HT, agonist (e.g., lorcaserin, vabi (e.g., bupropion). In another aspect the composition is that caserin, PRX-00933, YM348, and metachlorophenylpipera wherein the 5-HT, antagonist is also a 5-HT, receptor zine, mCPP) and a pharmaceutically acceptable carrier. In agonist. In another aspect the composition is that wherein the another aspect the composition is that wherein the norepi 5-HT2 receptor antagonist is also a 5-HT, receptor antago nephrine-dopamine reuptake inhibitor is also an alpha adren nist. In another aspect the composition is that wherein the ergic blocker (e.g., bupropion). In another aspect the compo 5-HT2 receptor antagonist is also a 5-HT, receptor antago sition is that wherein the 5-HT, antagonist is also a 5-HT nist and a 5-HT, receptor agonist (e.g., traZodone). In receptor agonist. In another aspect the composition is that another aspect the composition is that wherein the 5-HT, wherein the 5-HT2 receptor antagonist is also a 5-HT, receptor antagonist, 5-HT, receptor agonist, and/or 5-HT, receptor antagonist. In another aspect the composition is that receptor antagonist is also an alpha adrenergic blocker (e.g., wherein the 5-HT2 receptor antagonist is also a 5-HT, traZodone). In another aspect the composition is that com receptor antagonist and a 5-HT, receptor agonist (e.g., tra prising traZodone, bupropion, and oxytocin (e.g., Syntoci Zodone). In another aspect the composition is that wherein the nonR). In another aspect the composition is that comprising 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or traZodone in a dosage range of 1-450 mg, bupropion in a 5-HT, receptor antagonist is also an alpha adrenergic dosage range of 1-450 mg, and oxytocin in a dosage range of blocker (e.g., traZodone). In another aspect the composition is 4-400 International Units. that comprising traZodone, bupropion, and one or more 0037. In one aspect, the invention provides a composition 5-HT2, agonists selected from the group consisting of lor comprising a 5-HT, antagonist, a norepinephrine-dopamine caserin, vabicaserin, PRX-00933, YM348, and metachlo reuptake inhibitor, other non-abusable agents (agents not rophenylpiperazine, and mCPP. In another aspect the compo scheduled by the DEA) that augment dopamine and/or nore sition is that comprising traZodone in a dosage range of 1-450 pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda mg and bupropion in a dosage range of 1-450 mg. lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta 0035. In one aspect, the invention provides a composition lamine, mazindol, nisoxetine, talopram, talsupram, comprising a 5-HT, antagonist, a norepinephrine-dopamine tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, reuptake inhibitor, a 5-HT2, agonist (e.g., lorcaserin, vabi radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo caserin, PRX-00933, YM348, and metachlorophenylpipera biloba), and an oxytocin receptor (OXTR) agonist, and a Zine, mCPP), other non-abusable agents (agents not sched pharmaceutically acceptable carrier. In another aspect the uled by the DEA) that augment dopamine and/or composition is that wherein the norepinephrine-dopamine norepinephrine in the brain, e.g., atomoxetine, reboxetine, reuptake inhibitor is also an alpha adrenergic blocker (e.g., amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, bupropion). In another aspect the composition is that wherein lortalamine, mazindol, nisoxetine, talopram, talsupram, tan the 5-HT, antagonist is also a 5-HT, receptor agonist. In damine, Viloxazine, maprotiline, ciclazindol, manifaxine, another aspect the composition is that wherein the 5-HT, radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo receptor antagonist is also a 5-HT, receptor antagonist. In biloba), and a pharmaceutically acceptable carrier. In another another aspect the composition is that wherein the 5-HT aspect the composition is that wherein the norepinephrine receptor antagonist is also a 5-HT, receptor antagonistanda dopamine reuptake inhibitor is also an alpha adrenergic 5-HT, receptor agonist (e.g., traZodone). In another aspect blocker (e.g., bupropion). In another aspect the composition the composition is that wherein the 5-HT, receptor antago is that wherein the 5-HT, antagonist is also a 5-HT, recep nist, 5-HT, receptor agonist, and/or 5-HT2 receptor toragonist. In another aspect the composition is that wherein antagonist is also an alpha adrenergic blocker (e.g., traZ the 5-HT, receptor antagonist is also a 5-HT, receptor odone). In another aspect the composition is that comprising antagonist. In another aspect the composition is that wherein traZodone; bupropion; at least one of the group consisting of the 5-HT, receptor antagonist is also a 5-HT, receptor atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, antagonistand a 5-HT, receptoragonist (e.g., traZodone). In ediVoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, another aspect the composition is that wherein the 5-HT talopram, talsupram, tandamine, Viloxazine, maprotiline, receptor antagonist, 5-HT, receptoragonist, and/or 5-HT, ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, receptor antagonist is also an alpha adrenergic blocker (e.g., St. John’s wort, and ginkgo biloba; and oxytocin (e.g., Syn traZodone). In another aspect the composition is that com tocinonR). In another aspect the composition is that compris prising traZodone; bupropion; one or more 5-HT2, agonists ing traZodone in a dosage range of 1-450 mg, bupropion in a selected from the group consisting of lorcaserin, vabicaserin, dosage range of 1-450 mg, and oxytocin in a dosage range of PRX-00933, YM348, metachlorophenylpiperazine, and 4-400 International Units. mCPP, and at least one of the group consisting of atomoxet 0038. In one aspect, the invention provides a composition ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, comprising a 5-HT, antagonist, a norepinephrine-dopamine eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, reuptake inhibitor, a 5-HT2, agonist (e.g., lorcaserin, vabi US 2015/O 150946 A1 Jun. 4, 2015 caserin, PRX-00933, YM348, and metachlorophenylpipera In another aspect the composition is that wherein the 5-HT zine, mCPP), an oxytocin receptor (OXTR) agonist, and a antagonist is also a 5-HT, receptoragonist. In another aspect pharmaceutically acceptable carrier. In another aspect the the composition is that wherein the 5-HT2 receptor antago composition is that wherein the norepinephrine-dopamine nist is also a 5-HT, receptor agonist. In another aspect the reuptake inhibitor is also an alpha adrenergic blocker (e.g., composition is that wherein the 5-HT2 receptor antagonist is bupropion). In another aspect the composition is that wherein also a 5-HT, receptor antagonist. In another aspect the com the 5-HT, antagonist is also a 5-HT, receptor agonist. In position is that wherein the 5-HT2 receptor antagonist is also another aspect the composition is that wherein the 5-HT a 5-HT, receptor antagonist and a 5-HT, receptor agonist receptor antagonist is also a 5-HT, receptor antagonist. In (e.g., traZodone). In another aspect the composition is that another aspect the composition is that wherein the 5-HT wherein the 5-HT2 receptor antagonist, 5-HT, receptor receptor antagonist is also a 5-HT, receptor antagonistanda agonist, and/or 5-HT, receptor antagonist is also an alpha 5-HT, receptor agonist (e.g., traZodone). In another aspect adrenergic blocker (e.g., traZodone). In another aspect the the composition is that wherein the 5-HT, receptor antago composition is that comprising traZodone and oxytocin. In nist, 5-HT, receptor agonist, and/or 5-HT2 receptor another aspect the composition is that comprising traZodone antagonist is also an alpha adrenergic blocker (e.g., traZ in a dosage range of 25-450 mg and oxytocin in a dosage odone). In another aspect the composition is that comprising range of 4-400 International Units. traZodone, bupropion, oxytocin (e.g., Syntocinon R.), and one 0041. In one aspect, the invention provides a composition or more 5-HT, agonists selected from the group consisting comprising a 5-HT, antagonist, an oxytocin receptor of lorcaserin, vabicaserin, PRX-00933, YM348, metachlo (OXTR) agonist, other non-abusable agents (agents not rophenylpiperazine, and mCPP. In another aspect the compo scheduled by the DEA) that augment dopamine and/or nore sition is that comprising traZodone in a dosage range of 1-450 pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda mg, bupropionina dosage range of 1-450 mg, and oxytocin in lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta a dosage range of 4-400 International Units. lamine, mazindol, nisoxetine, talopram, talsupram, 0039. In one aspect, the invention provides a composition tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, comprising a 5-HT, antagonist, a norepinephrine-dopamine radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo reuptake inhibitor, a 5-HT, agonist (e.g., lorcaserin, vabi biloba), and a pharmaceutically acceptable carrier. In another caserin, PRX-00933, YM348, and metachlorophenylpipera aspect the composition is that wherein the 5-HT, antagonist Zine, mCPP), other non-abusable agents (agents not sched is also a 5-HT, receptor agonist. In another aspect the com uled by the DEA) that augment dopamine and/or position is that wherein the 5-HT2 receptor antagonist is also norepinephrine in the brain, e.g., atomoxetine, reboxetine, a 5-HT, receptoragonist. In another aspect the composition amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, is that wherein the 5-HT, 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-HT, receptor antagonist is also a radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo 5-HT, receptor antagonist and a 5-HT, receptor agonist biloba), an oxytocin receptor (OXTR) agonist, and a pharma (e.g., traZodone). In another aspect the composition is that ceutically acceptable carrier. In another aspect the composi wherein the 5-HT2 receptor antagonist, 5-HT, receptor tion is that wherein the norepinephrine-dopamine reuptake agonist, and/or 5-HT, receptor antagonist is also an alpha inhibitoris also an alpha adrenergic blocker (e.g., bupropion). adrenergic blocker (e.g., traZodone). In another aspect the In another aspect the composition is that wherein the 5-HT composition is that comprising traZodone; oxytocin, and at antagonist is also a 5-HT, receptoragonist. In another aspect least one of the group consisting of atomoxetine, reboxetine, the composition is that wherein the 5-HT2 receptor antago amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, nist is also a 5-HT, receptorantagonist. In another aspect the lortalamine, mazindol, nisoxetine, talopram, talsupram, tan composition is that wherein the 5-HT, receptor antagonist is damine, Viloxazine, maprotiline, ciclazindol, manifaxine, also a 5-HT, receptor antagonist and a 5-HT, receptor radafaxine, tapentadol, teniloxazine, St. John's wort, and agonist (e.g., traZodone). In another aspect the composition is ginkgo biloba. In another aspect the composition is that com that wherein the 5-HT2 receptor antagonist, 5-HT, receptor prising traZodone in a dosage range of 25-450 mg and oxy agonist, and/or 5-HT, receptor antagonist is also an alpha tocin in a dosage range of 4-400 International Units. adrenergic blocker (e.g., traZodone). In another aspect the 0042. In one aspect, the invention provides a composition composition is that comprising traZodone; bupropion; oxyto comprising a 5-HT, antagonist, an oxytocin receptor cin (e.g., SyntocinonR); one or more 5-HT, agonists (OXTR) agonist, a 5-HT2, agonist (e.g., lorcaserin, vabi selected from the group consisting of lorcaserin, vabicaserin, caserin, PRX-00933, YM348, metachlorophenylpiperazine, PRX-00933, YM348, metachlorophenylpiperazine, and and mOPP) and a pharmaceutically acceptable carrier. In mCPP, and at least one of the group consisting of atomoxet another aspect the composition is that wherein the 5-HT, ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, antagonist is also a 5-HT, receptoragonist. In another aspect eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, the composition is that wherein the 5-HT2 receptor antago talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, nist is also a 5-HT, receptor agonist. In another aspect the manifaxine, radafaxine, tapentadol, teniloxazine, St. John's composition is that wherein the 5-HT2 receptor antagonist is wort, and ginkgo biloba. In another aspect the composition is also a 5-HT, receptor antagonist. In another aspect the com that comprising traZodone in a dosage range of 1-450 mg. position is that wherein the 5-HT2 receptor antagonist is also bupropion in a dosage range of 1-450 mg, and oxytocin in a a 5-HT, receptor antagonist and a 5-HT, receptor agonist dosage range of 4-400 International Units. (e.g., traZodone). In another aspect the composition is that 0040. In one aspect, the invention provides a composition wherein the 5-HT2 receptor antagonist, 5-HT, receptor comprising a 5-HT, antagonist, an oxytocin receptor agonist, and/or 5-HT, receptor antagonist is also an alpha (OXTR) agonist, and a pharmaceutically acceptable carrier. adrenergic blocker (e.g., traZodone). In another aspect the US 2015/O 150946 A1 Jun. 4, 2015 composition is that comprising traZodone; oxytocin, and one bupropion; oxytocin, and at least one of the group consisting or more 5-HT2, agonists selected from the group consisting of atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, of lorcaserin, vabicaserin, PRX-00933, YM348, metachlo ediVoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, rophenylpiperazine, and mCPP. In another aspect the compo talopram, talsupram, tandamine, Viloxazine, maprotiline, sition is that comprising traZodone in a dosage range of ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, 25-450 mg and oxytocin in a dosage range of 4-400 Interna St. John’s wort, and ginkgo biloba. In another aspect the tional Units. composition is that comprising bupropion in a dosage range 0043. In one aspect, the invention provides a composition of 200-450 mg and oxytocin in a dosage range of 4-400 comprising a 5-HT, antagonist, an oxytocin receptor International Units. In another aspect the composition is that (OXTR) agonist, a 5-HT, agonist (e.g., lorcaserin, vabi comprising bupropion in a dosage range of 25-450 mg and caserin, PRX-00933, YM348, metachlorophenylpiperazine, oxytocin in a dosage range of 4-400 International Units. and mCPP), other non-abusable agents (agents not scheduled 0046. In one aspect, the invention provides a composition by the DEA) that augment dopamine and/or norepinephrine comprising a norepinephrine-dopamine reuptake inhibitor, in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, an oxytocin receptor (OXTR) agonist, a 5-HT, agonist (e.g., 332, daledalin, edivoxetine, esreboxetine, lortalamine, lorcaserin, vabicaserin, PRX-00933, YM348, metachlo mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox rophenylpiperazine, and mCPP), and a pharmaceutically azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap acceptable carrier. In another aspect the composition is that entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a comprising bupropion; oxytocin, and one or more 5-HT, pharmaceutically acceptable carrier. In another aspect the agonists selected from the group consisting of lorcaserin, composition is that wherein the 5-HT, antagonist is also a vabicaserin, PRX-00933, YM348, metachlorophenylpipera 5-HT, receptoragonist. In another aspect the composition is zine, and mCPP. In another aspect the composition is that that wherein the 5-HT2 receptor antagonist is also a 5-HT comprising bupropion in a dosage range of 200-450 mg and receptor agonist. In another aspect the composition is that oxytocin in a dosage range of 4-400 International Units. In wherein the 5-HT2 receptor antagonist is also a 5-HT, another aspect the composition is that comprising bupropion receptor antagonist. In another aspect the composition is that in a dosage range of 25-450 mg and oxytocin in a dosage wherein the 5-HT, receptor antagonist is also a 5-HT, range of 4-400 International Units. receptor antagonist and a 5-HT, receptor agonist (e.g., tra 0047. In one aspect, the invention provides a composition Zodone). In another aspect the composition is that wherein the comprising a norepinephrine-dopamine reuptake inhibitor, 5-HT, receptor antagonist, 5-HT, receptor agonist, and/or an oxytocin receptor (OXTR) agonist, a 5-HT2, agonist (e.g., 5-HT, receptor antagonist is also an alpha adrenergic lorcaserin, vabicaserin, PRX-00933, YM348, metachlo blocker (e.g., traZodone). In another aspect the composition is rophenylpiperazine, and mCPP), other non-abusable agents that comprising traZodone; oxytocin, one or more 5-HT, (agents not scheduled by the DEA) that augment dopamine agonists selected from the group consisting of lorcaserin, and/or norepinephrine in the brain, e.g., atomoxetine, rebox vabicaserin, PRX-00933, YM348, metachlorophenylpipera etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox Zine, and mCPP, and at least one of the group consisting of etine, lortalamine, mazindol, nisoxetine, talopram, talsu atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, pram, tandamine, Viloxazine, maprotiline, ciclaZindol, ediVoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, manifaxine, radafaxine, tapentadol, teniloxazine, St. John's talopram, talsupram, tandamine, Viloxazine, maprotiline, wort, ginkgo biloba), and a pharmaceutically acceptable car ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, rier. In another aspect the composition is that comprising St. John’s wort, and ginkgo biloba. In another aspect the bupropion; oxytocin, one or more 5-HT, agonists selected composition is that comprising traZodone in a dosage range of from the group consisting of lorcaserin, vabicaserin, PRX 25-450 mg and oxytocin in a dosage range of 4-400 Interna 00933, YM348, metachlorophenylpiperazine, and mCPP; tional Units. and at least one of the group consisting of atomoxetine, 0044. In one aspect, the invention provides a composition reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, comprising a norepinephrine-dopamine reuptake inhibitor, eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, an oxytocin receptor (OXTR) agonist, and a pharmaceuti talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, cally acceptable carrier. In another aspect the composition is manifaxine, radafaxine, tapentadol, teniloxazine, St. John's that comprising bupropion and oxytocin. In another aspect wort, and ginkgo biloba. In another aspect the composition is the composition is that comprising bupropion in a dosage that comprising bupropion in a dosage range of 200-450 mg range of 200-450 mg and oxytocin in a dosage range of 4-400 and oxytocin in a dosage range of 4-400 International Units. International Units. In another aspect the composition is that In another aspect the composition is that comprising bupro comprising bupropion in a dosage range of 25-450 mg and pion in a dosage range of 25-450 mg and oxytocin in a dosage oxytocin in a dosage range of 4-400 International Units. range of 4-400 International Units. 0045. In one aspect, the invention provides a composition 0048. In one aspect, the invention provides a composition comprising a norepinephrine-dopamine reuptake inhibitor, comprising an oxytocin receptor (OXTR) agonist and a phar an oxytocin receptor (OXTR) agonist, other non-abusable maceutically acceptable carrier. In another aspect the compo agents (agents not scheduled by the DEA) that augment sition is that comprising oxytocin. In another aspect the com dopamine and/or norepinephrine in the brain, e.g., atomoxet position is that comprising oxytocin in a dosage range of ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, 4-400 International Units. eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, 0049. In one aspect, the invention provides a composition talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, comprising an oxytocin receptor (OXTR) agonist, other non manifaxine, radafaxine, tapentadol, teniloxazine, St. John's abusable agents (agents not scheduled by the DEA) that aug wort, ginkgo biloba), and a pharmaceutically acceptable car ment dopamine and/or norepinephrine in the brain, e.g., ato rier. In another aspect the composition is that comprising moxetine, reboxetine, amedalin, CP-39,332, daledalin, US 2015/O 150946 A1 Jun. 4, 2015

ediVoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, 0054. In one embodiment, the composition is that com talopram, talsupram, tandamine, Viloxazine, maprotiline, prising oxytocin, comprising oxytocin in a dosage range of ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, 4-400 International Units. St. John’s wort, ginkgo biloba), and a pharmaceutically 0055. In one aspect, the invention provides a method of acceptable carrier. In another aspect the composition is that treating a Subject Suffering from or Susceptible to a sexual comprising oxytocin and at least one of the group consisting disorder comprising administering to a Subject in need of atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, thereof a therapeutically effective amount of a composition ediVoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, comprising a 5-HT, antagonist, a norepinephrine-dopamine talopram, talsupram, tandamine, Viloxazine, maprotiline, reuptake inhibitor, and a pharmaceutically acceptable carrier. ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, In another aspect the composition is that wherein the norepi St. John’s wort, and ginkgo biloba. In another aspect the nephrine-dopamine reuptake inhibitor is also an alpha adren composition is that comprising oxytocin in a dosage range of ergic blocker (e.g., bupropion). In another aspect the compo 4-400 International Units. sition is that wherein the 5-HT, antagonist is also a 5-HT 0050. In one aspect, the invention provides a composition receptor agonist. In another aspect the composition is that comprising an oxytocin receptor (OXTR) agonist, a 5-HT, wherein the 5-HT2 receptor antagonist is also a 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, receptor antagonist. 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 another aspect the composition is receptor antagonist and a 5-HT, receptor agonist (e.g., tra that comprising oxytocin and one or more 5-HT2, agonists Zodone). In another aspect the composition is that wherein the selected from the group consisting of lorcaserin, vabicaserin, 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or PRX-00933, YM348, metachlorophenylpiperazine, and 5-HT, receptor antagonist is also an alpha adrenergic mCPP. In another aspect the composition is that comprising blocker (e.g., traZodone). oxytocin in a dosage range of 4-400 International Units. 0056. In one aspect, the invention provides a method of 0051. In one aspect, the invention provides a composition treating a Subject Suffering from or Susceptible to a sexual comprising an oxytocin receptor (OXTR) agonist, a 5-HT, disorder 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-dopamine able agents (agents not scheduled by the DEA) that augment reuptake inhibitor, other non-abusable agents (agents not dopamine and/or norepinephrine in the brain, e.g., atomoxet scheduled by the DEA) that augment dopamine and/or nore ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, lamine, mazindol, nisoxetine, talopram, talsupram, manifaxine, radafaxine, tapentadol, teniloxazine, St. John's tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, wort, ginkgo biloba), and a pharmaceutically acceptable car radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo rier. In another aspect the composition is that comprising biloba), and a pharmaceutically acceptable carrier. In another oxytocin, one or more 5-HT, agonists selected from the aspect the composition is that wherein the norepinephrine group consisting of lorcaserin, vabicaserin, PRX-00933, dopamine reuptake inhibitor is also an alpha adrenergic YM348, metachlorophenylpiperazine, and mCPP; and at blocker (e.g., bupropion). In another aspect the composition least one of the group consisting of atomoxetine, reboxetine, is that wherein the 5-HT, antagonist is also a 5-HT, recep amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, toragonist. 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, and the 5-HT, receptor antagonist is also a 5-HT, receptor ginkgo biloba. In another aspect the composition is that com antagonist and a 5-HT, receptoragonist (e.g., traZodone). In another aspect the composition is that wherein the 5-HT prising oxytocin in a dosage range of 4-400 International receptor antagonist, 5-HT, receptor agonist, and/or 5-HT, Units. receptor antagonist is also an alpha adrenergic blocker (e.g., 0052. In one embodiment, the composition is that com traZodone). prising bupropion, comprising bupropionina dosage range of 0057. In one aspect, the invention provides a method of 200-450 mg; comprising bupropion in a dosage range of treating a Subject Suffering from or Susceptible to a sexual 225-300 mg; or comprising bupropion in a dosage range of disorder comprising administering to a Subject in need 200-275 mg; comprising bupropion in a dosage range of thereof a therapeutically effective amount of a composition 100-450 mg; comprising bupropion in a dosage range of comprising a 5-HT, antagonist, a norepinephrine-dopamine 100-275 mg; comprising bupropion in a dosage range of reuptake inhibitor, a 5-HT2, agonist (e.g., lorcaserin, vabi 25-275 mg; comprising bupropion in a dosage range of XX caserin, PRX-00933, YM348, metachlorophenylpiperazine, YY mg, wherein XX is an integer between 5 and 400 and YY and mOPP), and a pharmaceutically acceptable carrier. In is an integer between 50 and 450. another aspect the composition is that wherein the norepi 0053. In one embodiment, the composition is that com nephrine-dopamine reuptake inhibitor is also an alpha adren prising traZodone, comprising traZodone in a dosage range of ergic blocker (e.g., bupropion). In another aspect the compo 25-450 mg; comprising traZodone in a dosage range of sition is that wherein the 5-HT, antagonist is also a 5-HT 75-150 mg; or comprising traZodone in a dosage range of receptor agonist. In another aspect the composition is that 50-100 mg; comprising traZodone in a dosage range of XX wherein the 5-HT2 receptor antagonist is also a 5-HT, YY mg, wherein XX is an integer between 25 and 400 andYY receptor antagonist. In another aspect the composition is that is an integer between 50 and 450. wherein the 5-HT2 receptor antagonist is also a 5-HT, US 2015/O 150946 A1 Jun. 4, 2015 receptor antagonist and a 5-HT, receptor agonist (e.g., tra the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido Zodone). In another aspect the composition is that wherein the azepines). In another aspect the composition is that wherein 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or the 5-HT, antagonist is also a 5-HT, receptorantagonist. In 5-HT, receptor antagonist is also an alpha adrenergic another aspect the composition is that wherein the 5-HT blocker (e.g., traZodone). receptor antagonist is also a 5-HT, receptor antagonist and a 0058. In one aspect, the invention provides a method of 5-HT, receptor agonist. (e.g., traZodone) In another aspect, treating a Subject Suffering from or Susceptible to a sexual the norepinephrine-dopamine reuptake inhibitor is also an disorder comprising administering to a Subject in need alpha adrenergic blocker (e.g., bupropion). In another aspect, thereof a therapeutically effective amount of a composition the alpha adrenergic blocker is also a 5-HT, antagonist, a comprising a 5-HT, antagonist, a norepinephrine-dopamine 5-HT, receptor agonist, and/or 5-HT, receptor antagonist reuptake inhibitor, a 5-HT2, agonist (e.g., lorcaserin, vabi (e.g., traZodone). caserin, PRX-00933, YM348, metachlorophenylpiperazine, and mCPP), other non-abusable agents (agents not scheduled 0061. In one aspect, the invention provides a method of by the DEA) that augment dopamine and/or norepinephrine treating a Subject Suffering from or Susceptible to a sexual in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, disorder comprising administering to a Subject in need 332, daledalin, edivoxetine, esreboxetine, lortalamine, thereof a therapeutically effective amount of a composition mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox comprising a 5-HT, antagonist, a norepinephrine-dopamine azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap reuptake inhibitor, an oxytocin receptor (OXTR) agonist entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a (e.g., carbetocin, oxytocin, Syntocinon R.), other non-abus pharmaceutically acceptable carrier. In another aspect the able agents (agents not scheduled by the DEA) that augment composition is that wherein the norepinephrine-dopamine dopamine and/or norepinephrine in the brain, e.g., atomoxet reuptake inhibitor is also an alpha adrenergic blocker (e.g., ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, bupropion). In another aspect the composition is that wherein the 5-HT, antagonist is also a 5-HT, receptor agonist. In eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, another aspect the composition is that wherein the 5-HT talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, receptor antagonist is also a 5-HT, receptor antagonist. In manifaxine, radafaxine, tapentadol, teniloxazine, St. John's another aspect the composition is that wherein the 5-HT wort, ginkgo biloba), and a pharmaceutically acceptable car receptor antagonist is also a 5-HT, receptor antagonistanda rier. In one aspect, one compound is both a 5-HT, antagonist 5-HT, receptor agonist (e.g., trazodone). In another aspect and a 5-HT, receptor agonist (e.g., trazodone, nefazodone, the composition is that wherein the 5-HT2 receptor antago mirtazapine, flibanserin, ketanserin, ritanserin, clozapine, nist, 5-HT, receptor agonist, and/or 5-HT2 receptor olanzapine, quetiapine, risperidone, asenapine, MDL-100, antagonist is also an alpha adrenergic blocker (e.g., traZ 907, cyproheptadine, aripiprazole, and the general class of odone). 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another 0059. In one aspect, the invention provides a method of aspect the composition is that wherein the 5-HT, antagonist treating a Subject Suffering from or Susceptible to a sexual is also a 5-HT, receptor antagonist. In another aspect the disorder comprising administering to a Subject in need composition is that wherein the 5-HT2 receptor antagonist is thereof a therapeutically effective amount of a composition also a 5-HT, receptor antagonist and a 5-HT, receptor comprising a 5-HT, antagonist, a norepinephrine-dopamine agonist. (e.g., traZodone) In another aspect, the norepineph reuptake inhibitor, an oxytocin receptor (OXTR) agonist rine-dopamine reuptake inhibitor is also an alpha adrenergic (e.g., carbetocin, oxytocin, Syntocinon R.), and a pharmaceu blocker (e.g., bupropion). In another aspect, the alpha adren tically acceptable carrier. In one aspect, one compound is ergic blocker is also a 5-HT, antagonist, a 5-HT, receptor both a 5-HT2, antagonistand a 5-HT, receptoragonist (e.g., agonist, and/or 5-HT, receptor antagonist (e.g., trazodone). traZodone, nefazodone, mirtazapine, flibanserin). In another 0062. In one aspect, the invention provides a method of aspect the composition is that wherein the 5-HT, antagonist treating a Subject Suffering from or Susceptible to a sexual is also a 5-HT, receptor antagonist. In another aspect the disorder comprising administering to a Subject in need composition is that wherein the 5-HT, receptor antagonist is thereof a therapeutically effective amount of a composition also a 5-HT, receptor antagonist and a 5-HT, receptor comprising a 5-HT, antagonist, a norepinephrine-dopamine agonist. (e.g., traZodone) In another aspect, the norepineph reuptake inhibitor, an oxytocin receptor (OXTR) agonist rine-dopamine reuptake inhibitor is also an alpha adrenergic (e.g., carbetocin, oxytocin, Syntocinon R.), a 5-HT2, agonist blocker (e.g., bupropion). In another aspect, the alpha adren (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, ergic blocker is also a 5-HT, antagonist, a 5-HT, receptor metachlorophenylpiperazine, and mCPP), and a pharmaceu agonist, and/or 5-HT, receptor antagonist (e.g., traZodone). tically acceptable carrier. In one aspect, one compound is 0060. In one aspect, the invention provides a method of both a 5-HT, antagonist and a 5-HT, receptoragonist (e.g., treating a Subject Suffering from or Susceptible to a sexual traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, disorder comprising administering to a Subject in need ritanserin, clozapine, olanzapine, quetiapine, risperidone, thereof a therapeutically effective amount of a composition asenapine, MDL-100.907, cyproheptadine, aripiprazole, and comprising a 5-HT, antagonist, a norepinephrine-dopamine the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido reuptake inhibitor, an oxytocin receptor (OXTR) agonist azepines). In another aspect the composition is that wherein (e.g., carbetocin, oxytocin, Syntocinon R.), and a pharmaceu the 5-HT, antagonist is also a 5-HT, receptorantagonist. In tically acceptable carrier. In one aspect, one compound is another aspect the composition is that wherein the 5-HT, both a 5-HT2, antagonistand a 5-HT, receptoragonist (e.g., receptor antagonist is also a 5-HT, receptor antagonistanda traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, 5-HT, receptor agonist. (e.g., traZodone) In another aspect, ritanserin, clozapine, olanzapine, quetiapine, risperidone, the norepinephrine-dopamine reuptake inhibitor is also an asenapine, MDL-100.907, cyproheptadine, aripiprazole, and alpha adrenergic blocker (e.g., bupropion). In another aspect, US 2015/O 150946 A1 Jun. 4, 2015 the alpha adrenergic blocker is also a 5-HT, antagonist, a composition is that wherein the 5-HT2 receptor antagonist is 5-HT, receptor agonist, and/or 5-HT, receptor antagonist also a 5-HT, receptoragonist. In another aspect the compo (e.g., traZodone). sition is that wherein the 5-HT, antagonist is also a 5-HT, 0063. In one aspect, the invention provides a method of receptor antagonist. In another aspect the composition is that treating a Subject Suffering from or Susceptible to a sexual wherein the 5-HT2 receptor antagonist is also a 5-HT, disorder comprising administering to a Subject in need receptor antagonist and a 5-HT, receptor agonist (e.g., tra thereof a therapeutically effective amount of a composition Zodone). In another aspect the composition is that wherein the comprising a 5-HT, antagonist, a norepinephrine-dopamine 5-HTantagonist, 5-HT, receptor agonist, and/or 5-HT, reuptake inhibitor, an oxytocin receptor (OXTR) agonist receptor antagonist is also an alpha adrenergic blocker (e.g., (e.g., carbetocin, oxytocin, Syntocinon R.), a 5-HT2, agonist traZodone). (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, 0066. In one aspect, the invention provides a method of metachlorophenylpiperazine, and mOPP), other non-abus treating a Subject Suffering from or Susceptible to a sexual able agents (agents not scheduled by the DEA) that augment disorder comprising administering to a Subject in need dopamine and/or norepinephrine in the brain, e.g., atomoxet thereof a therapeutically effective amount of a composition ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, comprising a 5-HT, receptor agonist, a 5-HT, antagonist, eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, other non-abusable agents (agents not scheduled by the DEA) talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, that augment dopamine and/or norepinephrine in the brain, manifaxine, radafaxine, tapentadol, teniloxazine, St. John's e.g., atomoxetine, reboxetine, amedalin, CP-39,332, daleda wort, ginkgo biloba), and a pharmaceutically acceptable car lin, edivoxetine, esreboxetine, lortalamine, mazindol, nisox rier. In one aspect, one compound is both a 5-HT, antagonist etine, talopram, talsupram, tandamine, Viloxazine, mapro and a 5-HT, receptor agonist (e.g., trazodone, nefazodone, tiline, ciclaZindol, manifaxine, radafaxine, tapentadol, mirtazapine, flibanserin, ketanserin, ritanserin, clozapine, teniloxazine, St. John’s wort, ginkgo biloba), and a pharma olanzapine, quetiapine, risperidone, asenapine, MDL-100, ceutically acceptable carrier. In one aspect, one compound is 907, cyproheptadine, aripiprazole, and the general class of the 5-HT, receptoragonist and the 5-HT, antagonist (e.g., 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, aspect the composition is that wherein the 5-HT, antagonist ritanserin, clozapine, olanzapine, quetiapine, risperidone, is also a 5-HT, receptor antagonist. In another aspect the asenapine, MDL-100.907, cyproheptadine, aripiprazole, and composition is that wherein the 5-HT, receptor antagonist is the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido also a 5-HT, receptor antagonist and a 5-HT, receptor azepines). In another aspect the composition is that wherein agonist. (e.g., traZodone) In another aspect, the norepineph the 5-HT2 receptor antagonist is also a 5-HT, receptor rine-dopamine reuptake inhibitor is also an alpha adrenergic agonist. In another aspect the composition is that wherein the blocker (e.g., bupropion). In another aspect, the alpha adren 5-HT, antagonist is also a 5-HT, receptor antagonist. In ergic blocker is also a 5-HT, antagonist, a 5-HT, receptor another aspect the composition is that wherein the 5-HT, agonist, and/or 5-HT, receptor antagonist (e.g., traZodone). receptor antagonist is also a 5-HT, receptor antagonistanda 0064. In one aspect, the invention provides a method of 5-HT, receptor agonist (e.g., trazodone). In another aspect treating a Subject Suffering from or Susceptible to a sexual the composition is that wherein the 5-HT, antagonist, disorder comprising administering to a Subject in need 5-HT, receptor agonist, and/or 5-HT, receptor antagonist thereof a therapeutically effective amount of a composition is also an alpha adrenergic blocker (e.g., traZodone). comprising a 5-HT, receptor agonist, a 5-HT, antagonist, 0067. In one aspect, the invention provides a method of and a pharmaceutically acceptable carrier. In one aspect, one treating a Subject Suffering from or Susceptible to a sexual compound is the 5-HT, receptor agonist and the 5-HT disorder comprising administering to a Subject in need antagonist (e.g., traZodone, nefazodone, mirtazapine, fli thereof a therapeutically effective amount of a composition banserin). In another aspect the composition is that wherein comprising a 5-HT, receptoragonist, a 5-HT, antagonist, a the 5-HT2 receptor antagonist is also a 5-HT, receptor 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, agonist. In another aspect the composition is that wherein the YM348, metachlorophenylpiperazine, and mOPP), and a 5-HT, antagonist is also a 5-HT, receptor antagonist. 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 receptor antagonist is also a 5-HT, receptor antagonistanda nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, 5-HT, receptor agonist (e.g., traZodone). In another aspect ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris the composition is that wherein the 5-HT, antagonist, peridone, asenapine, MDL-100.907, cyproheptadine, arip 5-HT, receptor agonist, and/or 5-HT, receptor antagonist iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro is also an alpha adrenergic blocker (e.g., traZodone). pyrimido-azepines). In another aspect the composition is that 0065. In one aspect, the invention provides a method of wherein the 5-HT2 receptor antagonist is also a 5-HT treating a Subject Suffering from or Susceptible to a sexual receptor agonist. In another aspect the composition is that disorder comprising administering to a Subject in need wherein the 5-HT, antagonist is also a 5-HT, receptor thereof a therapeutically effective amount of a composition antagonist. In another aspect the composition is that wherein comprising a 5-HT, receptor agonist, a 5-HT, antagonist, the 5-HT, receptor antagonist is also a 5-HT, receptor and a pharmaceutically acceptable carrier. In one aspect, one antagonist and a 5-HT, receptoragonist (e.g., traZodone). In compound is the 5-HT, receptor agonist and the 5-HT another aspect the composition is that wherein the 5-HT antagonist (e.g., traZodone, nefazodone, mirtazapine, fli antagonist, 5-HT, receptoragonist, and/or 5-HT, receptor banserin, ketanserin, ritanserin, clozapine, olanzapine, que antagonist is also an alpha adrenergic blocker (e.g., traZ tiapine, risperidone, asenapine, MDL-100.907, cyprohepta odone). dine, aripiprazole, and the general class of 2-alkyl-4-aryl 0068. In one aspect, the invention provides a method of tetrahydro-pyrimido-azepines). In another aspect the treating a Subject Suffering from or Susceptible to a sexual US 2015/O 150946 A1 Jun. 4, 2015 disorder comprising administering to a Subject in need a 5-HT, receptor antagonist. In another aspect the compo thereof a therapeutically effective amount of a composition sition is that wherein the 5-HT2 receptor antagonist is also a comprising a 5-HT, receptoragonist, a 5-HT, antagonist, a 5-HT, receptor antagonist and a 5-HT, receptor agonist 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, (e.g., traZodone). In another aspect the composition is that YM348, metachlorophenylpiperazine, and mCPP), other wherein the 5-HT2 receptor antagonist, 5-HT, receptor non-abusable agents (agents not scheduled by the DEA) that agonist, and/or 5-HT, receptor antagonist is also an alpha augment dopamine and/or norepinephrine in the brain, e.g., adrenergic blocker (e.g., traZodone). atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, 0071. In one aspect, the invention provides a method of ediVoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, treating a Subject Suffering from or Susceptible to a sexual talopram, talsupram, tandamine, Viloxazine, maprotiline, disorder comprising administering to a Subject in need ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, thereof a therapeutically effective amount of a composition St. John’s wort, ginkgo biloba), and a pharmaceutically comprising a 5-HT, receptor agonist, a 5-HT, antagonist, acceptable carrier. In one aspect, one compound is the 5-HT an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy receptor agonist and the 5-HT, antagonist (e.g., traZodone, tocin, Syntocinon R.), other non-abusable agents (agents not nefazodone, mirtazapine, flibanserin, ketanserin, ritanserin, scheduled by the DEA) that augment dopamine and/or nore clozapine, olanzapine, quetiapine, risperidone, asenapine, pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda MDL-100.907, cyproheptadine, aripiprazole, and the general lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In lamine, mazindol, nisoxetine, talopram, talsupram, another aspect the composition is that wherein the 5-HT tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, receptor antagonist is also a 5-HT, receptor agonist. In radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo another aspect the composition is that wherein the 5-HT biloba), and a pharmaceutically acceptable carrier. In one antagonist is also a 5-HT, receptor antagonist. In another aspect, one compound is the 5-HT, receptoragonist and the aspect the composition is that wherein the 5-HT, receptor 5-HTantagonist (e.g., traZodone, nefazodone, mirtazapine, antagonist is also a 5-HT2 receptor antagonist and a 5-HT flibanserin, ketanserin, ritanserin, clozapine, olanzapine, receptor agonist (e.g., traZodone). In another aspect the com quetiapine, risperidone, asenapine, MDL-100.907, cypro position is that wherein the 5-HT, antagonist, 5-HT, recep heptadine, aripiprazole, and the general class of 2-alkyl-4- toragonist, and/or 5-HT2 receptorantagonist 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 is 0069. In one aspect, the invention provides a method of also a 5-HT, receptoragonist. In another aspect the compo treating a Subject Suffering from or Susceptible to a sexual sition is that wherein the 5-HT, antagonist is also a 5-HT, disorder comprising administering to a Subject in need receptor antagonist. In another aspect the composition is that thereof a therapeutically effective amount of a composition wherein the 5-HT2 receptor antagonist is also a 5-HT, comprising a 5-HT, receptor agonist, a 5-HT, antagonist, receptor antagonist and a 5-HT, receptor agonist (e.g., tra an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy Zodone). In another aspect the composition is that wherein the tocin, Syntocinon R.), and a pharmaceutically acceptable car 5-HT, receptor antagonist, 5-HT, receptor agonist, and/or rier. In one aspect, one compound is the 5-HT, receptor 5-HT, receptor antagonist is also an alpha adrenergic agonist and the 5-HT, antagonist (e.g., traZodone, nefaz blocker (e.g., traZodone). odone, mirtazapine, flibanserin). In another aspect the com 0072. In one aspect, the invention provides a method of position is that wherein the 5-HT2 receptor antagonist is also treating a Subject Suffering from or Susceptible to a sexual a 5-HT, receptoragonist. In another aspect the composition disorder comprising administering to a Subject in need is that wherein the 5-HT, antagonist is also a 5-HT, recep thereof a therapeutically effective amount of a composition tor antagonist. In another aspect the composition is that comprising a 5-HT, receptor agonist, a 5-HT, antagonist, wherein the 5-HT, receptor antagonist is also a 5-HT, an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy receptor antagonist and a 5-HT, receptor agonist (e.g., tra tocin, Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, vabi Zodone). In another aspect the composition is that wherein the caserin, PRX-00933, YM348, metachlorophenylpiperazine, 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or and mOPP), and a pharmaceutically acceptable carrier. In one 5-HT, receptor antagonist is also an alpha adrenergic aspect, one compound is the 5-HT, receptoragonist and the blocker (e.g., traZodone). 5-HT, antagonist (e.g., trazodone, nefazodone, mirtazapine, 0070. In one aspect, the invention provides a method of flibanserin, ketanserin, ritanserin, clozapine, olanzapine, treating a Subject Suffering from or Susceptible to a sexual quetiapine, risperidone, asenapine, MDL-100.907, cypro disorder comprising administering to a Subject in need heptadine, aripiprazole, and the general class of 2-alkyl-4- thereof a therapeutically effective amount of a composition aryl-tetrahydro-pyrimido-azepines). In another aspect the comprising a 5-HT, receptor agonist, a 5-HT, antagonist, composition is that wherein the 5-HT2 receptor antagonist is an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy also a 5-HT, receptoragonist. In another aspect the compo tocin, Syntocinon R.), and a pharmaceutically acceptable car sition is that wherein the 5-HT, antagonist is also a 5-HT, rier. 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, nefaz wherein the 5-HT, receptor antagonist is also a 5-HT, odone, mirtazapine, flibanserin, ketanserin, ritanserin, cloza receptor antagonist and a 5-HT, receptor agonist (e.g., tra pine, olanzapine, quetiapine, risperidone, asenapine, MDL Zodone). In another aspect the composition is that wherein the 100,907, cyproheptadine, aripiprazole, and the general class 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another 5-HT, receptor antagonist is also an alpha adrenergic aspect the composition is that wherein the 5-HT2 receptor blocker (e.g., traZodone). antagonist is also a 5-HT, receptoragonist. In another aspect 0073. In one aspect, the invention provides a method of the composition is that wherein the 5-HT, antagonist is also treating a Subject Suffering from or Susceptible to a sexual US 2015/O 150946 A1 Jun. 4, 2015 disorder comprising administering to a Subject in need another aspect, the composition also includes an alpha adr thereof a therapeutically effective amount of a composition energic blocker (e.g., traZodone). comprising a 5-HT, receptor agonist, a 5-HT, antagonist, 0077. In one aspect, the invention provides a method of an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy treating a Subject Suffering from or Susceptible to a sexual tocin, Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, vabi disorder comprising administering to a Subject in need caserin, PRX-00933, YM348, metachlorophenylpiperazine, thereof a therapeutically effective amount of a composition and mCPP), other non-abusable agents (agents not scheduled comprising a norepinephrine-dopamine reuptake inhibitor, by the DEA) that augment dopamine and/or norepinephrine an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, tocin, SyntocinonR), a 5-HT, agonist (e.g., lorcaserin, vabi 332, daledalin, edivoxetine, esreboxetine, lortalamine, caserin, PRX-00933, YM348, metachlorophenylpiperazine, mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox and mCPP), other non-abusable agents (agents not scheduled azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap by the DEA) that augment dopamine and/or norepinephrine entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, pharmaceutically acceptable carrier. In one aspect, one com 332, daledalin, edivoxetine, esreboxetine, lortalamine, pound is the 5-HT, receptoragonist and the 5-HT, antago mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a peridone, asenapine, MDL-100.907, cyproheptadine, arip pharmaceutically acceptable carrier. In another aspect, the iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro composition also includes an alpha adrenergic blocker (e.g., pyrimido-azepines). In another aspect the composition is that traZodone). wherein the 5-HT2 receptor antagonist is also a 5-HT 0078. In one aspect, the invention provides a method of receptor agonist. In another aspect the composition is that treating a Subject Suffering from or Susceptible to a sexual wherein the 5-HT, antagonist is also a 5-HT, receptor disorder comprising administering to a Subject in need antagonist. In another aspect the composition is that wherein thereof a therapeutically effective amount of a composition the 5-HT, receptor antagonist is also a 5-HT, receptor comprising an oxytocin receptor (OXTR) agonist (e.g., car antagonistand a 5-HT, receptoragonist (e.g., traZodone). In betocin, oxytocin, Syntocinon R) and a pharmaceutically another aspect the composition is that wherein the 5-HT acceptable carrier. receptor antagonist, 5-HT, receptoragonist, and/or 5-HT, 0079. In one aspect, the invention provides a method of receptor antagonist is also an alpha adrenergic blocker (e.g., treating a subject suffering from or susceptible to a sexual traZodone). disorder comprising administering to a Subject in need 0074. In one aspect, the invention provides a method of thereof a therapeutically effective amount of a composition treating a Subject Suffering from or Susceptible to a sexual comprising an oxytocin receptor (OXTR) agonist (e.g., car disorder comprising administering to a Subject in need betocin, oxytocin, Syntocinon R.), other non-abusable agents thereof a therapeutically effective amount of a composition (agents not scheduled by the DEA) that augment dopamine comprising a norepinephrine-dopamine reuptake inhibitor, and/or norepinephrine in the brain, e.g., atomoxetine, rebox an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox tocin, Syntocinon R.), and a pharmaceutically acceptable car etine, lortalamine, mazindol, nisoxetine, talopram, talsu rier. In another aspect, the composition also includes an alpha pram, tandamine, Viloxazine, maprotiline, ciclaZindol, adrenergic blocker (e.g., traZodone). manifaxine, radafaxine, tapentadol, teniloxazine, St. John's 0075. In one aspect, the invention provides a method of wort, ginkgo biloba), and a pharmaceutically acceptable car treating a Subject Suffering from or Susceptible to a sexual 1. disorder comprising administering to a Subject in need 0080. In aspects, the method is that wherein the sexual thereof a therapeutically effective amount of a composition disorder is female sexual disorder (FSD). In aspects, the comprising a norepinephrine-dopamine reuptake inhibitor, method is that wherein the sexual disorder is female orgasmic an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy disorder (FOD); wherein the sexual disorder is female sexual tocin, Syntocinon R.), other non-abusable agents (agents not arousal disorder (FSAD); or wherein the sexual disorder is scheduled by the DEA) that augment dopamine and/or nore sexual pain disorder or dysfunction. In aspects, the method is pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda that wherein the FSD includes one or more simultaneous lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta dysfunctions of sexual desire, arousal, orgasm, and/or pain. In lamine, mazindol, nisoxetine, talopram, talsupram, aspects, the method is that wherein the sexual disorder is male tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, sexual disorder (MSD). In aspects, the method is that wherein radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo the sexual disorder is male Hypoactive Sexual Desire Disor biloba), and a pharmaceutically acceptable carrier. In another der (HSDD); wherein the sexual disorder is male sexual aspect, the composition also includes an alpha adrenergic arousal disorder (FSAD); wherein the sexual disorder is male blocker (e.g., traZodone). orgasmic disorder (MOD; delayed ejaculation); wherein the 0076. In one aspect, the invention provides a method of sexual disorder is premature ejaculation (PE); wherein the treating a Subject Suffering from or Susceptible to a sexual sexual dysfunction is sexual performance anxiety; or wherein disorder comprising administering to a Subject in need the sexual disorder is sexual pain disorder or dysfunction. In thereof a therapeutically effective amount of a composition aspects, the method is that wherein the MSD includes one or comprising a norepinephrine-dopamine reuptake inhibitor, more simultaneous dysfunctions of sexual desire, arousal, an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy orgasm, and/or pain. tocin, Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, vabi I0081. In one aspect, the invention provides a method of caserin, PRX-00933, YM348, metachlorophenylpiperazine, treating a subject Suffering from or Susceptible to a cognitive and mOPP), and a pharmaceutically acceptable carrier. In disorder comprising administering to a Subject in need US 2015/O 150946 A1 Jun. 4, 2015 thereof a therapeutically effective amount of a composition 907, cyproheptadine, aripiprazole, and the general class of comprising a 5-HT, antagonist, a norepinephrine-dopamine 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another reuptake inhibitor, an oxytocin receptor (OXTR) agonist aspect the composition is that wherein the norepinephrine (e.g., carbetocin, oxytocin, Syntocinon R.), and a pharmaceu dopamine reuptake inhibitor is also an alpha adrenergic tically acceptable carrier. In one aspect, one compound is blocker (e.g., bupropion). In another aspect the composition both a 5-HT, antagonist and a 5-HT, receptoragonist (e.g., is that wherein the 5-HT, receptor antagonist is also a traZodone, nefazodone, mirtazapine, flibanserin). In another 5-HT, receptoragonist. In another aspect the composition is aspect the composition is that wherein the norepinephrine that wherein the 5-HT2 receptor antagonist is also a 5-HT, dopamine reuptake inhibitor is also an alpha adrenergic receptor antagonist. In another aspect the composition is that blocker (e.g., bupropion). In another aspect the composition wherein the 5-HT2 receptor antagonist is also a 5-HT, is that wherein the 5-HT, receptor antagonist is also a receptor antagonist and a 5-HT, receptor agonist (e.g., tra 5-HT, receptoragonist. In another aspect the composition is Zodone). In another aspect the composition is that wherein the that wherein the 5-HT, receptor antagonist is also a 5-HT, 5-HT, receptor antagonist, 5-HT, receptor agonist, and/or receptor antagonist. In another aspect the composition is that 5-HT, receptor antagonist is also an alpha adrenergic wherein the 5-HT2 receptor antagonist is also a 5-HT, blocker (e.g., traZodone). receptor antagonist and a 5-HT, receptor agonist (e.g., tra I0084. In one aspect, the invention provides a method of Zodone). In another aspect the composition is that wherein the treating a subject Suffering from or Susceptible to a cognitive 5-HT, receptor antagonist, 5-HT, receptor agonist, and/or disorder comprising administering to a Subject in need 5-HT, receptor antagonist is also an alpha adrenergic thereof a therapeutically effective amount of a composition blocker (e.g., traZodone). comprising a 5-HT, antagonist, a norepinephrine-dopamine 0082 In one aspect, the invention provides a method of reuptake inhibitor, an oxytocin receptor (OXTR) agonist treating a subject Suffering from or Susceptible to a cognitive (e.g., carbetocin, oxytocin, Syntocinon R.), a 5-HT2, agonist disorder comprising administering to a Subject in need (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-dopamine able agents (agents not scheduled by the DEA) that augment reuptake inhibitor, an oxytocin receptor (OXTR) agonist dopamine and/or norepinephrine in the brain, e.g., atomoxet (e.g., carbetocin, oxytocin, Syntocinon R.), and a pharmaceu ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, tically acceptable carrier. In one aspect, one compound is eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, both a 5-HT2 antagonistanda 5-HT1 receptoragonist (e.g., talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, manifaxine, radafaxine, tapentadol, teniloxazine, St. John's ritanserin, clozapine, olanzapine, quetiapine, risperidone, wort, ginkgo biloba), and a pharmaceutically acceptable car asenapine, MDL-100.907, cyproheptadine, aripiprazole, and rier. In one aspect, one compound is both a 5-HT, antagonist the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido and a 5-HT, receptor agonist (e.g., trazodone, nefazodone, azepines). In another aspect the composition is that wherein mirtazapine, flibanserin, ketanserin, ritanserin, clozapine, the norepinephrine-dopamine reuptake inhibitor is also an olanzapine, quetiapine, risperidone, asenapine, MDL-100, alpha adrenergic blocker (e.g., bupropion). In another aspect 907, cyproheptadine, aripiprazole, and the general class of the composition is that wherein the 5-HT2 receptor antago 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another nist is also a 5-HT, receptor agonist. In another aspect the aspect the composition is that wherein the norepinephrine composition is that wherein the 5-HT, receptor antagonist is dopamine reuptake inhibitor is also an alpha adrenergic also a 5-HT, receptor antagonist. In another aspect the com blocker (e.g., bupropion). In another aspect the composition position is that wherein the 5-HT2 receptor antagonist is also is that wherein the 5-HT2 receptor antagonist is also a a 5-HT, receptor antagonist and a 5-HT, receptor agonist 5-HT, receptoragonist. In another aspect the composition is (e.g., traZodone). In another aspect the composition is that that wherein the 5-HT, receptor antagonist is also a 5-HT, wherein the 5-HT2 receptor antagonist, 5-HT, receptor receptor antagonist. In another aspect the composition is that agonist, and/or 5-HT, receptor antagonist is also an alpha wherein the 5-HT, receptor antagonist is also a 5-HT, adrenergic blocker (e.g., traZodone). receptor antagonist and a 5-HT, receptor agonist (e.g., tra 0083. In one aspect, the invention provides a method of Zodone). In another aspect the composition is that wherein the treating a subject Suffering from or Susceptible to a cognitive 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or disorder comprising administering to a Subject in need 5-HT, receptor antagonist is also an alpha adrenergic thereof a therapeutically effective amount of a composition blocker (e.g., traZodone). comprising a 5-HT, antagonist, a norepinephrine-dopamine I0085. In one aspect, the invention provides a method of reuptake inhibitor, an oxytocin receptor (OXTR) agonist treating a subject Suffering from or Susceptible to a cognitive (e.g., carbetocin, oxytocin, Syntocinon R.), other non-abus disorder comprising administering to a Subject in need able agents (agents not scheduled by the DEA) that augment thereof a therapeutically effective amount of a composition dopamine and/or norepinephrine in the brain, e.g., atomoxet comprising a 5-HT, antagonist, a norepinephrine-dopamine ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, reuptake inhibitor, an oxytocin receptor (OXTR) agonist eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, (e.g., carbetocin, oxytocin, Syntocinon R.), a 5-HT2, agonist talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, (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 car able agents (agents not scheduled by the DEA) that augment rier. In one aspect, one compound is both a 5-HT, antagonist dopamine and/or norepinephrine in the brain, e.g., atomoxet and a 5-HT, receptor agonist (e.g., traZodone, nefazodone, ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, mirtazapine, flibanserin, ketanserin, ritanserin, clozapine, eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, olanzapine, quetiapine, risperidone, asenapine, MDL-100, talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, US 2015/O 150946 A1 Jun. 4, 2015

manifaxine, radafaxine, tapentadol, teniloxazine, St. John's blocker (e.g., bupropion). In another aspect the composition wort, ginkgo biloba), other non-abusable agents (agents not is that wherein the 5-HT2 receptor antagonist is also a scheduled by the DEA) that augment dopamine and/or nore 5-HT, receptoragonist. In another aspect the composition is pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda that wherein the 5-HT, receptor antagonist is also a 5-HT, lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta receptor antagonist. In another aspect the composition is that lamine, mazindol, nisoxetine, talopram, talsupram, wherein the 5-HT, receptor antagonist is also a 5-HT, tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, receptor antagonist and a 5-HT, receptor agonist (e.g., tra radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo Zodone). In another aspect the composition is that wherein the biloba), and a pharmaceutically acceptable carrier. In one 5-HT, receptor antagonist, 5-HT, receptor agonist, and/or aspect, one compound is both a 5-HT, antagonist and a 5-HT, receptor antagonist is also an alpha adrenergic 5-HT, receptor agonist (e.g., trazodone, nefazodone, mir blocker (e.g., traZodone). tazapine, flibanserin, ketanserin, ritanserin, clozapine, olan I0088. In one aspect, the invention provides a method of Zapine, quetiapine, risperidone, asenapine, MDL-100.907. treating a subject Suffering from or Susceptible to a cognitive cyproheptadine, aripiprazole, and the general class of disorder comprising administering to a Subject in need 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another thereof a therapeutically effective amount of a composition aspect the composition is that wherein the norepinephrine comprising a 5-HT, antagonist, a norepinephrine-dopamine dopamine reuptake inhibitor is also an alpha adrenergic reuptake inhibitor, other non-abusable agents (agents not blocker (e.g., bupropion). In another aspect the composition scheduled by the DEA) that augment dopamine and/or nore is that wherein the 5-HT2 receptor antagonist is also a pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda 5-HT, receptoragonist. In another aspect the composition is lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta that wherein the 5-HT2 receptor antagonist is also a 5-HT, lamine, mazindol, nisoxetine, talopram, talsupram, receptor antagonist. In another aspect the composition is that tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, wherein the 5-HT, receptor antagonist is also a 5-HT, radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo receptor antagonist and a 5-HT, receptor agonist (e.g., tra biloba), and a pharmaceutically acceptable carrier. In one Zodone). In another aspect the composition is that wherein the aspect, one compound is both a 5-HT, antagonist and a 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or 5-HT, receptor agonist (e.g., trazodone, nefazodone, mir 5-HT, receptor antagonist is also an alpha adrenergic tazapine, flibanserin, ketanserin, ritanserin, clozapine, olan blocker (e.g., traZodone). Zapine, quetiapine, risperidone, asenapine, MDL-100.907. I0086. In one aspect, the invention provides a method of cyproheptadine, aripiprazole, and the general class of treating a subject Suffering from or Susceptible to a cognitive 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another disorder comprising administering to a Subject in need aspect the composition is that wherein the norepinephrine thereof a therapeutically effective amount of a composition dopamine reuptake inhibitor is also an alpha adrenergic comprising a 5-HT, antagonist, a norepinephrine-dopamine blocker (e.g., bupropion). In another aspect the composition reuptake inhibitor, and a pharmaceutically acceptable carrier. is that wherein the 5-HT2 receptor antagonist is also a In one aspect, one compound is both a 5-HT, antagonistand 5-HT, receptoragonist. In another aspect the composition is a 5-HT, receptoragonist (e.g., traZodone, nefazodone, mir that wherein the 5-HT2 receptor antagonist is also a 5-HT, tazapine, flibanserin). In another aspect the composition is receptor antagonist. In another aspect the composition is that that wherein the norepinephrine-dopamine reuptake inhibitor wherein the 5-HT, receptor antagonist is also a 5-HT, is also an alpha adrenergic blocker (e.g., bupropion). In receptor antagonist and a 5-HT, receptor agonist (e.g., tra another aspect the composition is that wherein the 5-HT Zodone). In another aspect the composition is that wherein the receptor antagonist is also a 5-HT, receptor agonist. In 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or another aspect the composition is that wherein the 5-HT 5-HT, receptor antagonist is also an alpha adrenergic receptor antagonist is also a 5-HT, receptor antagonist. In blocker (e.g., traZodone). another aspect the composition is that wherein the 5-HT I0089. In one aspect, the invention provides a method of receptor antagonist is also a 5-HT, receptor antagonistanda treating a subject Suffering from or Susceptible to a cognitive 5-HT, receptor agonist (e.g., traZodone). In another aspect disorder comprising administering to a Subject in need the composition is that wherein the 5-HT2 receptor antago thereof a therapeutically effective amount of a composition nist, 5-HT, receptor agonist, and/or 5-HT2 receptor comprising a 5-HT, antagonist, a norepinephrine-dopamine antagonist is also an alpha adrenergic blocker (e.g., traZ reuptake inhibitor, a 5-HT2, agonist (e.g., lorcaserin, vabi odone). caserin, PRX-00933, YM348, metachlorophenylpiperazine, 0087. In one aspect, the invention provides a method of and mOPP), and a pharmaceutically acceptable carrier. In one treating a subject Suffering from or Susceptible to a cognitive aspect, one compound is both a 5-HT, antagonist and a disorder comprising administering to a Subject in need 5-HT, receptor agonist (e.g., trazodone, nefazodone, mir thereof a therapeutically effective amount of a composition tazapine, flibanserin, ketanserin, ritanserin, clozapine, olan comprising a 5-HT, antagonist, a norepinephrine-dopamine Zapine, quetiapine, risperidone, asenapine, MDL-100.907. reuptake inhibitor, and a pharmaceutically acceptable carrier. cyproheptadine, aripiprazole, and the general class of In one aspect, one compound is both a 5-HT, antagonistand 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another a 5-HT, receptor agonist (e.g., trazodone, nefazodone, mir aspect the composition is that wherein the norepinephrine tazapine, flibanserin, ketanserin, ritanserin, clozapine, olan dopamine reuptake inhibitor is also an alpha adrenergic Zapine, quetiapine, risperidone, asenapine, MDL-100.907. blocker (e.g., bupropion). In another aspect the composition cyproheptadine, aripiprazole, and the general class of is that wherein the 5-HT2 receptor antagonist is also a 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another 5-HT, receptoragonist. In another aspect the composition is aspect the composition is that wherein the norepinephrine that wherein the 5-HT2 receptor antagonist is also a 5-HT, dopamine reuptake inhibitor is also an alpha adrenergic receptor antagonist. In another aspect the composition is that US 2015/O 150946 A1 Jun. 4, 2015 wherein the 5-HT2 receptor antagonist is also a 5-HT, and a pharmaceutically acceptable carrier. In one aspect, one receptor antagonist and a 5-HT, receptor agonist (e.g., tra compound is the 5-HT, receptor agonist and the 5-HT Zodone). In another aspect the composition is that wherein the antagonist (e.g., traZodone, nefazodone, mirtazapine, fli 5-HT, receptor antagonist, 5-HT, receptor agonist, and/or banserin, ketanserin, ritanserin, clozapine, olanzapine, que 5-HT, receptor antagonist is also an alpha adrenergic tiapine, risperidone, asenapine, MDL-100.907, cyprohepta blocker (e.g., traZodone). dine, aripiprazole, and the general class of 2-alkyl-4-aryl 0090. In one aspect, the invention provides a method of tetrahydro-pyrimido-azepines). In another aspect the treating a subject Suffering from or Susceptible to a cognitive composition is that wherein the 5-HT2 receptor antagonist is disorder comprising administering to a Subject in need also a 5-HT, receptoragonist. In another aspect the compo thereof a therapeutically effective amount of a composition sition is that wherein the 5-HT2 receptor antagonist is also a comprising a 5-HT, antagonist, a norepinephrine-dopamine 5-HT, receptor antagonist. In another aspect the composi reuptake inhibitor, a 5-HT, agonist (e.g., lorcaserin, vabi tion is that wherein the 5-HT2 receptor antagonist is also a caserin, PRX-00933, YM348, metachlorophenylpiperazine, 5-HT, receptor antagonist and a 5-HT, receptor agonist and mCPP), other non-abusable agents (agents not scheduled (e.g., traZodone). In another aspect the composition is that by the DEA) that augment dopamine and/or norepinephrine wherein the 5-HT2 receptor antagonist, 5-HT, receptor in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, agonist, and/or 5-HT, receptor antagonist is also an alpha 332, daledalin, edivoxetine, esreboxetine, lortalamine, adrenergic blocker (e.g., traZodone). mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox 0093. In one aspect, the invention provides a method of azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap treating a subject Suffering from or Susceptible to a cognitive entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a disorder comprising administering to a Subject in need pharmaceutically acceptable carrier. In one aspect, one com thereof a therapeutically effective amount of a composition pound is both a 5-HT, antagonist and a 5-HT, receptor comprising a 5-HT, receptor agonist, a 5-HT, antagonist, agonist (e.g., traZodone, nefazodone, mirtazapine, fli other non-abusable agents (agents not scheduled by the DEA) banserin, ketanserin, ritanserin, clozapine, olanzapine, que that augment dopamine and/or norepinephrine in the brain, tiapine, risperidone, asenapine, MDL-100.907, cyprohepta e.g., atomoxetine, reboxetine, amedalin, CP-39,332, daleda dine, aripiprazole, and the general class of 2-alkyl-4-aryl lin, edivoxetine, esreboxetine, lortalamine, mazindol, nisox tetrahydro-pyrimido-azepines). In another aspect the etine, talopram, talsupram, tandamine, Viloxazine, mapro composition is that wherein the norepinephrine-dopamine tiline, ciclaZindol, manifaxine, radafaxine, tapentadol, reuptake inhibitor is also an alpha adrenergic blocker (e.g., teniloxazine, St. John’s wort, ginkgo biloba), and a pharma bupropion). In another aspect the composition is that wherein ceutically acceptable carrier. In one aspect, one compound is the 5-HT2 receptor antagonist is also a 5-HT, receptor the 5-HT, receptoragonist and the 5-HT, antagonist (e.g., agonist. In another aspect the composition is that wherein the traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, 5-HT, receptor antagonist is also a 5-HT, receptor antago ritanserin, clozapine, olanzapine, quetiapine, risperidone, nist. In another aspect the composition is that wherein the asenapine, MDL-100.907, cyproheptadine, aripiprazole, and 5-HT, receptor antagonist is also a 5-HT, receptor antago the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido nist and a 5-HT, receptor agonist (e.g., traZodone). In azepines). In another aspect the composition is that wherein another aspect the composition is that wherein the 5-HT the 5-HT2 receptor antagonist is also a 5-HT, receptor receptor antagonist, 5-HT, receptoragonist, and/or 5-HT, agonist. In another aspect the composition is that wherein the receptor antagonist is also an alpha adrenergic blocker (e.g., 5-HT2 receptor antagonist is also a 5-HT, receptor antago traZodone). nist. In another aspect the composition is that wherein the 0091. In one aspect, the invention provides a method of 5-HT2 receptor antagonist is also a 5-HT, receptor antago treating a subject Suffering from or Susceptible to a cognitive nist and a 5-HT, receptor agonist (e.g., traZodone). In disorder comprising administering to a Subject in need another aspect the composition is that wherein the 5-HT, thereof a therapeutically effective amount of a composition receptor antagonist, 5-HT, receptor agonist, and/or 5-HT, comprising a 5-HT, receptor agonist, a 5-HT, antagonist, receptor antagonist is also an alpha adrenergic blocker (e.g., and a pharmaceutically acceptable carrier. In one aspect, one traZodone). compound is the 5-HT, receptor agonist and the 5-HT 0094. In one aspect, the invention provides a method of antagonist (e.g., traZodone, nefazodone, mirtazapine, fli treating a subject Suffering from or Susceptible to a cognitive banserin). In another aspect the composition is that wherein disorder comprising administering to a Subject in need the 5-HT, receptor antagonist is also a 5-HT, receptor thereof a therapeutically effective amount of a composition agonist. In another aspect the composition is that wherein the comprising a 5-HT, receptoragonist, a 5-HT, antagonist, a 5-HT2 receptor antagonist is also a 5-HT, receptor antago 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, nist. In another aspect the composition is that wherein the YM348, metachlorophenylpiperazine, and mOPP), other 5-HT2 receptor antagonist is also a 5-HT, receptor antago non-abusable agents (agents not scheduled by the DEA) that nist and a 5-HT, receptor agonist (e.g., trazodone). In augment dopamine and/or norepinephrine in the brain, e.g., another aspect the composition is that wherein the 5-HT atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, receptor antagonist, 5-HT, receptoragonist, and/or 5-HT, ediVoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, receptor antagonist is also an alpha adrenergic blocker (e.g., talopram, talsupram, tandamine, Viloxazine, maprotiline, traZodone). ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, 0092. In one aspect, the invention provides a method of St. John’s wort, ginkgo biloba), and a pharmaceutically treating a subject Suffering from or Susceptible to a cognitive acceptable carrier. In one aspect, one compound is the 5-HT disorder comprising administering to a Subject in need receptor agonist and the 5-HT, antagonist (e.g., traZodone, thereof a therapeutically effective amount of a composition nefazodone, mirtazapine, flibanserin, ketanserin, ritanserin, comprising a 5-HT, receptor agonist, a 5-HT, antagonist, clozapine, olanzapine, quetiapine, risperidone, asenapine, US 2015/O 150946 A1 Jun. 4, 2015

MDL-100.907, cyproheptadine, aripiprazole, and the general tion is that wherein the 5-HT2 receptor antagonist is also a class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In 5-HT, receptor antagonist and a 5-HT, receptor agonist another aspect the composition is that wherein the 5-HT (e.g., traZodone). In another aspect the composition is that receptor antagonist is also a 5-HT, receptor agonist. In wherein the 5-HT, receptor antagonist, 5-HT, receptor another aspect the composition is that wherein the 5-HT agonist, and/or 5-HT, receptor antagonist is also an alpha receptor antagonist is also a 5-HT, receptor antagonist. In adrenergic blocker (e.g., traZodone). another aspect the composition is that wherein the 5-HT 0097. In one aspect, the invention provides a method of receptor antagonist is also a 5-HT, receptor antagonistanda treating a subject Suffering from or Susceptible to a cognitive 5-HT, receptor agonist (e.g., trazodone). In another aspect disorder comprising administering to a Subject in need the composition is that wherein the 5-HT2 receptor antago thereof a therapeutically effective amount of a composition nist, 5-HT, receptor agonist, and/or 5-HT, receptor comprising a 5-HT, receptor agonist, a 5-HT, antagonist, antagonist is also an alpha adrenergic blocker (e.g., traZ an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy odone). tocin, Syntocinon R.), and a pharmaceutically acceptable car 0095. In one aspect, the invention provides a method of rier. In one aspect, one compound is the 5-HT, receptor treating a subject Suffering from or Susceptible to a cognitive agonist and the 5-HT, antagonist (e.g., traZodone, nefaz disorder comprising administering to a Subject in need odone, mirtazapine, flibanserin, ketanserin, ritanserin, cloza thereof a therapeutically effective amount of a composition pine, olanzapine, quetiapine, risperidone, asenapine, MDL comprising a 5-HT, receptoragonist, a 5-HT, antagonist, a 100.907, cyproheptadine, aripiprazole, and the general class 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another YM348, metachlorophenylpiperazine, and mCPP), other aspect the composition is that wherein the 5-HT2 receptor non-abusable agents (agents not scheduled by the DEA) that antagonist is also a 5-HT, receptoragonist. In another aspect augment dopamine and/or norepinephrine in the brain, e.g., the composition is that wherein the 5-HT2 receptor antago atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, nist is also a 5-HT, receptor antagonist. In another aspect the ediVoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, composition is that wherein the 5-HT2 receptor antagonist is talopram, talsupram, tandamine, Viloxazine, maprotiline, also a 5-HT, receptor antagonist and a 5-HT, receptor ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, agonist (e.g., traZodone). In another aspect the composition is St. John's wort, ginkgo biloba), other non-abusable agents that wherein the 5-HT2 receptorantagonist, 5-HT, receptor (agents not scheduled by the DEA) that augment dopamine agonist, and/or 5-HT, receptor antagonist is also an alpha and/or norepinephrine in the brain, e.g., atomoxetine, rebox adrenergic blocker (e.g., trazodone). etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox 0098. In one aspect, the invention provides a method of etine, lortalamine, mazindol, nisoxetine, talopram, talsu treating a subject Suffering from or Susceptible to a cognitive pram, tandamine, Viloxazine, maprotiline, ciclaZindol, disorder comprising administering to a Subject in need manifaxine, radafaxine, tapentadol, teniloxazine, St. John's thereof a therapeutically effective amount of a composition wort, ginkgo biloba), and a pharmaceutically acceptable car comprising a 5-HT, receptor agonist, a 5-HT, antagonist, rier. In one aspect, one compound is the 5-HT, receptor an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy agonist and the 5-HT, antagonist (e.g., traZodone, nefaz tocin, Syntocinon R.), other non-abusable agents (agents not odone, mirtazapine, flibanserin, ketanserin, ritanserin, cloza scheduled by the DEA) that augment dopamine and/or nore pine, olanzapine, quetiapine, risperidone, asenapine, MDL pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda 100,907, cyproheptadine, aripiprazole, and the general class lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another lamine, mazindol, nisoxetine, talopram, talsupram, aspect the composition is that wherein the 5-HT2 receptor tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, antagonist is also a 5-HT, receptoragonist. In another aspect radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo the composition is that wherein the 5-HT, receptor antago biloba), and a pharmaceutically acceptable carrier. In one nist is also a 5-HT, receptorantagonist. In another aspect the aspect, one compound is the 5-HT, receptoragonist and the composition is that wherein the 5-HT, receptor antagonist is 5-HTantagonist (e.g., traZodone, nefazodone, mirtazapine, also a 5-HT, receptor antagonist and a 5-HT, receptor flibanserin, ketanserin, ritanserin, clozapine, olanzapine, agonist (e.g., traZodone). In another aspect the composition is quetiapine, risperidone, asenapine, MDL-100.907, cypro that wherein the 5-HT2 receptor antagonist, 5-HT, receptor heptadine, aripiprazole, and the general class of 2-alkyl-4- 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 is 0096. In one aspect, the invention provides a method of also a 5-HT, receptoragonist. In another aspect the compo treating a subject Suffering from or Susceptible to a cognitive sition is that wherein the 5-HT2 receptor antagonist is also a disorder comprising administering to a Subject in need 5-HT, receptor antagonist. In another aspect the composi thereof a therapeutically effective amount of a composition tion is that wherein the 5-HT2 receptor antagonist is also a comprising a 5-HT, receptor agonist, a 5-HT, antagonist, 5-HT, receptor antagonist and a 5-HT, receptor agonist an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy (e.g., traZodone). In another aspect the composition is that tocin, Syntocinon R.), and a pharmaceutically acceptable car wherein the 5-HT, receptor antagonist, 5-HT, receptor rier. In one aspect, one compound is the 5-HT, receptor agonist, and/or 5-HT, receptor antagonist is also an alpha agonist and the 5-HT, antagonist (e.g., traZodone, nefaz adrenergic blocker (e.g., traZodone). odone, mirtazapine, flibanserin). In another aspect the com 0099. In one aspect, the invention provides a method of position is that wherein the 5-HT2 receptor antagonist is also treating a subject Suffering from or Susceptible to a cognitive a 5-HT, receptoragonist. In another aspect the composition disorder comprising administering to a Subject in need is that wherein the 5-HT2 receptor antagonist is also a thereof a therapeutically effective amount of a composition 5-HT, receptor antagonist. In another aspect the composi comprising a 5-HT, receptor agonist, a 5-HT, antagonist, US 2015/O 150946 A1 Jun. 4, 2015 an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy disorder comprising administering to a Subject in need tocin, Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, vabi thereof a therapeutically effective amount of a composition caserin, PRX-00933, YM348, metachlorophenylpiperazine, comprising a norepinephrine-dopamine reuptake inhibitor, and mOPP), and a pharmaceutically acceptable carrier. In one an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy aspect, one compound is the 5-HT, receptoragonist and the tocin, Syntocinon R.), other non-abusable agents (agents not 5-HT, antagonist (e.g., trazodone, nefazodone, mirtazapine, scheduled by the DEA) that augment dopamine and/or nore flibanserin, ketanserin, ritanserin, clozapine, olanzapine, pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda quetiapine, risperidone, asenapine, MDL-100.907, cypro lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta heptadine, aripiprazole, and the general class of 2-alkyl-4- lamine, mazindol, nisoxetine, talopram, talsupram, aryl-tetrahydro-pyrimido-azepines). In another aspect the tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, composition is that wherein the 5-HT, receptor antagonist is radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo also a 5-HT, receptoragonist. In another aspect the compo biloba), and a pharmaceutically acceptable carrier. In another sition is that wherein the 5-HT, 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). 5-HT, receptor antagonist and a 5-HT, receptor agonist 0103) In one aspect, the invention provides a method of (e.g., traZodone). In another aspect the composition is that treating a subject Suffering from or Susceptible to a cognitive wherein the 5-HT, receptor antagonist, 5-HT, receptor disorder comprising administering to a Subject in need agonist, and/or 5-HT, receptor antagonist is also an alpha thereof a therapeutically effective amount of a composition adrenergic blocker (e.g., traZodone). comprising a norepinephrine-dopamine reuptake inhibitor, 0100. In one aspect, the invention provides a method of an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy treating a subject Suffering from or Susceptible to a cognitive tocin, Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, vabi disorder comprising administering to a Subject in need caserin, PRX-00933, YM348, metachlorophenylpiperazine, thereof a therapeutically effective amount of a composition and mOPP), and a pharmaceutically acceptable carrier. In comprising a 5-HT, receptor agonist, a 5-HT, antagonist, another aspect the composition is that wherein the norepi an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy nephrine-dopamine reuptake inhibitor is also an alpha adren tocin, Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, vabi ergic blocker (e.g., bupropion). caserin, PRX-00933, YM348, metachlorophenylpiperazine, 0104. In one aspect, the invention provides a method of and mCPP), other non-abusable agents (agents not scheduled treating a subject suffering from or susceptible to a cognitive by the DEA) that augment dopamine and/or norepinephrine disorder comprising administering to a Subject in need in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, thereof a therapeutically effective amount of a composition 332, daledalin, edivoxetine, esreboxetine, lortalamine, comprising a norepinephrine-dopamine reuptake inhibitor, mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap tocin, Syntocinon R.), a 5-HT2, agonist (e.g., lorcaserin, vabi entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a caserin, PRX-00933, YM348, metachlorophenylpiperazine, pharmaceutically acceptable carrier. In one aspect, one com and mCPP), other non-abusable agents (agents not scheduled pound is the 5-HT, receptoragonist and the 5-HT, antago by the DEA) that augment dopamine and/or norepinephrine nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris 332, daledalin, edivoxetine, esreboxetine, lortalamine, peridone, asenapine, MDL-100.907, cyproheptadine, arip mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap pyrimido-azepines). In another aspect the composition is that entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a wherein the 5-HT2 receptor antagonist is also a 5-HT pharmaceutically acceptable carrier. In another aspect the receptor agonist. In another aspect the composition is that composition is that wherein the norepinephrine-dopamine wherein the 5-HT, receptor antagonist is also a 5-HT, reuptake inhibitor is also an alpha adrenergic blocker (e.g., receptor antagonist. In another aspect the composition is that bupropion). wherein the 5-HT, receptor antagonist is also a 5-HT, 0105. In one aspect, the invention provides a method of receptor antagonist and a 5-HT, receptor agonist (e.g., tra treating a subject Suffering from or Susceptible to a cognitive Zodone). In another aspect the composition is that wherein the disorder comprising administering to a Subject in need 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or thereof a therapeutically effective amount of a composition 5-HT, receptor antagonist is also an alpha adrenergic comprising an oxytocin receptor (OXTR) agonist (e.g., car blocker (e.g., traZodone). betocin, oxytocin, Syntocinon R) and a pharmaceutically 0101. In one aspect, the invention provides a method of acceptable carrier. treating a subject Suffering from or Susceptible to a cognitive 0106. In one aspect, the invention provides a method of disorder comprising administering to a Subject in need treating a subject Suffering from or Susceptible to a cognitive thereof a therapeutically effective amount of a composition disorder comprising administering to a Subject in need comprising a norepinephrine-dopamine reuptake inhibitor, thereof a therapeutically effective amount of a composition an oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxy comprising an oxytocin receptor (OXTR) agonist (e.g., car tocin, Syntocinon R.), and a pharmaceutically acceptable car betocin, oxytocin, Syntocinon R.), other non-abusable agents rier. In another aspect the composition is that wherein the (agents not scheduled by the DEA) that augment dopamine norepinephrine-dopamine reuptake inhibitor is also an alpha and/or norepinephrine in the brain, e.g., atomoxetine, rebox adrenergic blocker (e.g., bupropion). etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox 0102. In one aspect, the invention provides a method of etine, lortalamine, mazindol, nisoxetine, talopram, talsu treating a subject Suffering from or Susceptible to a cognitive pram, tandamine, Viloxazine, maprotiline, ciclaZindol, US 2015/O 150946 A1 Jun. 4, 2015

manifaxine, radafaxine, tapentadol, teniloxazine, St. John's composition is that wherein the 5-HT2 receptor antagonist is wort, ginkgo biloba), and a pharmaceutically acceptable car also a 5-HT, receptor antagonist. In another aspect the com rier. position is that wherein the 5-HT2 receptor antagonist is also 0107. In one aspect, the invention provides a method of a 5-HT, receptor antagonist and a 5-HT, receptor agonist treating a subject Suffering from or Susceptible to a cognitive (e.g., traZodone). In another aspect the composition is that disorder comprising administering to a Subject in need wherein the 5-HT, receptor antagonist, 5-HT, receptor thereof a therapeutically effective amount of a composition agonist, and/or 5-HT, receptor antagonist is also an alpha comprising an oxytocin receptor (OXTR) agonist (e.g., car adrenergic blocker (e.g., traZodone). betocin, oxytocin, SyntocinonR), a 5-HT, agonist (e.g., lor 0.115. In one aspect, the invention provides a method of caserin, vabicaserin, PRX-00933, YM348, metachlorophe enhancing cognition comprising administering to a subject in nylpiperazine, and mCPP), and a pharmaceutically need thereof a therapeutically effective amount of a compo acceptable carrier. sition comprising a 5-HT, antagonist, a norepinephrine 0108. In one aspect, the invention provides a method of dopamine reuptake inhibitor, an oxytocin receptor (OXTR) treating a subject Suffering from or Susceptible to a cognitive agonist (e.g., carbetocin, oxytocin, SyntocinonR), and a disorder comprising administering to a Subject in need pharmaceutically acceptable carrier. In one aspect, one com thereof a therapeutically effective amount of a composition pound is both a 5-HT, antagonist and a 5-HT, receptor comprising an oxytocin receptor (OXTR) agonist (e.g., car agonist (e.g., traZodone, nefazodone, mirtazapine, fli betocin, oxytocin, Syntocinon R.), a 5-HT, agonist (e.g., lor banserin, ketanserin, ritanserin, clozapine, olanzapine, que caserin, vabicaserin, PRX-00933, YM348, metachlorophe tiapine, risperidone, asenapine, MDL-100.907, cyprohepta nylpiperazine, and mCPP), other non-abusable agents (agents dine, aripiprazole, and the general class of 2-alkyl-4-aryl not scheduled by the DEA) that augment dopamine and/or tetrahydro-pyrimido-azepines). In another aspect the norepinephrine in the brain, e.g., atomoxetine, reboxetine, composition is that wherein the norepinephrine-dopamine amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, reuptake inhibitor is also an alpha adrenergic blocker (e.g., lortalamine, mazindol, nisoxetine, talopram, talsupram, tan bupropion). In another aspect the composition is that wherein damine, Viloxazine, maprotiline, ciclazindol, manifaxine, the 5-HT2 receptor antagonist is also a 5-HT, receptor radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo agonist. In another aspect the composition is that wherein the biloba), and a pharmaceutically acceptable carrier. 5-HT2 receptor antagonist is also a 5-HT, receptor antago 0109. In aspects, the method is that wherein the cognitive nist. In another aspect the composition is that wherein the disorder is dementia, where dementia can refer to Alzhe 5-HT2 receptor antagonist is also a 5-HT2 receptor antago imer's disease, frontotemporal lobar degeneration, dementia nist and a 5-HT, receptor agonist (e.g., traZodone). In with Lewy bodies, Parkinson's disease, Huntington's dis another aspect the composition is that wherein the 5-HT, ease, multi-infarct dementia, dementia resulting from infec receptor antagonist, 5-HT, receptor agonist, and/or 5-HT, tions affecting the central nervous system, dementia resulting receptor antagonist is also an alpha adrenergic blocker (e.g., from chronic drug use, dementia resulting from hydroceph traZodone). alus, dementia resulting from brain injury, or dementia result 0116. In one aspect, the invention provides a method of ing from a brain tumor. enhancing cognition comprising administering to a subject in 0110. In aspects, the method is that wherein the cognitive need thereof a therapeutically effective amount of a compo disorder is cognitive disability, where cognitive disability can sition comprising a 5-HT, antagonist, a norepinephrine refer to schizophrenia, schizoaffective disorder, bipolar dis dopamine reuptake inhibitor, an oxytocin receptor (OXTR) order, or major depression. agonist (e.g., carbetocin, oxytocin, Syntocinon R.), other non 0111. In aspects, the method is that wherein the cognitive abusable agents (agents not scheduled by the DEA) that aug disorder is cognitive disability, where cognitive disability can ment dopamine and/or norepinephrine in the brain, e.g., ato refer to schizophrenia, schizoaffective disorder, bipolar dis moxetine, reboxetine, amedalin, CP-39,332, daledalin, order, social anxiety disorder, or major depression. ediVoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, 0112. In aspects, the method is that wherein the cognitive talopram, talsupram, tandamine, Viloxazine, maprotiline, disorder is developmental cognitive impairment, where cog ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, nitive impairment can refer to Autism, Asperger's syndrome, St. John’s wort, ginkgo biloba), and a pharmaceutically or pervasive developmental disorder. acceptable carrier. In one aspect, one compound is both a 0113. In aspects, the method is that wherein the cognitive 5-HT, antagonist and a 5-HT, receptor agonist (e.g., traZ disorder is mild cognitive decline. odone, nefazodone, mirtazapine, flibanserin, ketanserin, 0114. In one aspect, the invention provides a method of ritanserin, clozapine, olanzapine, quetiapine, risperidone, enhancing cognition comprising administering to a subject in asenapine, MDL-100.907, cyproheptadine, aripiprazole, and need thereof a therapeutically effective amount of a compo the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido sition comprising a 5-HT, antagonist, a norepinephrine azepines). In another aspect the composition is that wherein dopamine reuptake inhibitor, an oxytocin receptor (OXTR) the norepinephrine-dopamine reuptake inhibitor is also an agonist (e.g., carbetocin, oxytocin, SyntocinonR), and a alpha adrenergic blocker (e.g., bupropion). In another aspect pharmaceutically acceptable carrier. In one aspect, one com the composition is that wherein the 5-HT2 receptor antago pound is both a 5-HT, antagonist and a 5-HT, receptor nist is also a 5-HT, receptor agonist. In another aspect the agonist (e.g., traZodone, nefazodone, mirtazapine, fli composition is that wherein the 5-HT2 receptor antagonist is banserin). In another aspect the composition is that wherein also a 5-HT, receptor antagonist. In another aspect the com the norepinephrine-dopamine reuptake inhibitor is also an position is that wherein the 5-HT2 receptor antagonist is also alpha adrenergic blocker (e.g., bupropion). In another aspect a 5-HT, receptor antagonist and a 5-HT, receptor agonist the composition is that wherein the 5-HT2 receptor antago (e.g., traZodone). In another aspect the composition is that nist is also a 5-HT, receptor agonist. In another aspect the wherein the 5-HT2 receptor antagonist, 5-HT, receptor US 2015/O 150946 A1 Jun. 4, 2015 20 agonist, and/or 5-HT, receptor antagonist is also an alpha 0119. In one aspect, the invention provides a method of adrenergic blocker (e.g., traZodone). enhancing cognition comprising administering to a subject in need thereof a therapeutically effective amount of a compo 0117. In one aspect, the invention provides a method of sition comprising a 5-HT, antagonist, a norepinephrine enhancing cognition comprising administering to a subject in dopamine reuptake inhibitor, and a pharmaceutically accept need thereof a therapeutically effective amount of a compo able carrier. In one aspect, one compound is both a 5-HT, sition comprising a 5-HT, antagonist, a norepinephrine antagonist and a 5-HT, receptor agonist (e.g., traZodone, dopamine reuptake inhibitor, an oxytocin receptor (OXTR) nefazodone, mirtazapine, flibanserin). In another aspect the agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, composition is that wherein the norepinephrine-dopamine agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, reuptake inhibitor is also an alpha adrenergic blocker (e.g., metachlorophenylpiperazine, and mCPP), and a pharmaceu bupropion). In another aspect the composition is that wherein tically acceptable carrier. In one aspect, one compound is the 5-HT2 receptor antagonist is also a 5-HT, receptor both a 5-HT2, antagonistand a 5-HT, receptoragonist (e.g., agonist. In another aspect the composition is that wherein the traZodone, nefazodone, mirtazapine, flibanserin, ketanserin, 5-HT2 receptor antagonist is also a 5-HT, receptor antago ritanserin, clozapine, olanzapine, quetiapine, risperidone, nist. In another aspect the composition is that wherein the asenapine, MDL-100.907, cyproheptadine, aripiprazole, and 5-HT, receptor antagonist is also a 5-HT, receptor antago the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido nist and a 5-HT, receptor agonist (e.g., traZodone). In azepines). In another aspect the composition is that wherein another aspect the composition is that wherein the 5-HT, the norepinephrine-dopamine reuptake inhibitor is also an receptor antagonist, 5-HT, receptor agonist, and/or 5-HT, alpha adrenergic blocker (e.g., bupropion). In another aspect receptor antagonist is also an alpha adrenergic blocker (e.g., the composition is that wherein the 5-HT, receptor antago traZodone). nist is also a 5-HT, receptor agonist. In another aspect the I0120 In one aspect, the invention provides a method of composition is that wherein the 5-HT, receptor antagonist is enhancing cognition comprising administering to a subject in also a 5-HT2 receptor antagonist. In another aspect the com need thereof a therapeutically effective amount of a compo position is that wherein the 5-HT2 receptor antagonist is also sition comprising a 5-HT, antagonist, a norepinephrine a 5-HT, receptor antagonist and a 5-HT, receptor agonist dopamine reuptake inhibitor, and a pharmaceutically accept (e.g., traZodone). In another aspect the composition is that able carrier. In one aspect, one compound is both a 5-HT wherein the 5-HT, receptor antagonist, 5-HT, receptor antagonist and a 5-HT, receptor agonist (e.g., traZodone, agonist, and/or 5-HT, receptor antagonist is also an alpha nefazodone, mirtazapine, flibanserin, ketanserin, ritanserin, adrenergic blocker (e.g., traZodone). clozapine, olanzapine, quetiapine, risperidone, asenapine, 0118. In one aspect, the invention provides a method of MDL-100.907, cyproheptadine, aripiprazole, and the general enhancing cognition comprising administering to a subject in class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In need thereof a therapeutically effective amount of a compo another aspect the composition is that wherein the norepi sition comprising a 5-HT, antagonist, a norepinephrine nephrine-dopamine reuptake inhibitor is also an alpha adren dopamine reuptake inhibitor, an oxytocin receptor (OXTR) ergic blocker (e.g., bupropion). In another aspect the compo agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, sition is that wherein the 5-HT2 receptor antagonist is also a agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, 5-HT, receptoragonist. In another aspect the composition is metachlorophenylpiperazine, and mOPP), other non-abus that wherein the 5-HT, receptor antagonist is also a 5-HT, able agents (agents not scheduled by the DEA) that augment receptor antagonist. In another aspect the composition is that dopamine and/or norepinephrine in the brain, e.g., atomoxet wherein the 5-HT, receptor antagonist is also a 5-HT, ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, receptor antagonist and a 5-HT, receptor agonist (e.g., tra eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, Zodone). In another aspect the composition is that wherein the talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, 5-HT, receptor antagonist, 5-HT, receptor agonist, and/or manifaxine, radafaxine, tapentadol, teniloxazine, St. John's 5-HT, receptor antagonist is also an alpha adrenergic wort, ginkgo biloba), and a pharmaceutically acceptable car blocker (e.g., traZodone). rier. In one aspect, one compound is both a 5-HT, antagonist I0121. In one aspect, the invention provides a method of and a 5-HT, receptor agonist (e.g., traZodone, nefazodone, enhancing cognition comprising administering to a subject in mirtazapine, flibanserin, ketanserin, ritanserin, clozapine, need thereof a therapeutically effective amount of a compo olanzapine, quetiapine, risperidone, asenapine, MDL-100, sition comprising a 5-HT, antagonist, a norepinephrine 907, cyproheptadine, aripiprazole, and the general class of dopamine reuptake inhibitor, other non-abusable agents 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another (agents not scheduled by the DEA) that augment dopamine aspect the composition is that wherein the norepinephrine and/or norepinephrine in the brain, e.g., atomoxetine, rebox dopamine reuptake inhibitor is also an alpha adrenergic etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox blocker (e.g., bupropion). In another aspect the composition etine, lortalamine, mazindol, nisoxetine, talopram, talsu is that wherein the 5-HT2 receptor antagonist is also a pram, tandamine, Viloxazine, maprotiline, ciclaZindol, 5-HT, receptoragonist. In another aspect the composition is manifaxine, radafaxine, tapentadol, teniloxazine, St. John's that wherein the 5-HT2 receptor antagonist is also a 5-HT, wort, ginkgo biloba), and a pharmaceutically acceptable car receptor antagonist. In another aspect the composition is that rier. In one aspect, one compound is both a 5-HT, antagonist wherein the 5-HT2 receptor antagonist is also a 5-HT, and a 5-HT, receptor agonist (e.g., traZodone, nefazodone, receptor antagonist and a 5-HT, receptor agonist (e.g., tra mirtazapine, flibanserin, ketanserin, ritanserin, clozapine, Zodone). In another aspect the composition is that wherein the olanzapine, quetiapine, risperidone, asenapine, MDL-100, 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or 907, cyproheptadine, aripiprazole, and the general class of 5-HT, receptor antagonist is also an alpha adrenergic 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another blocker (e.g., traZodone). aspect the composition is that wherein the norepinephrine US 2015/O 150946 A1 Jun. 4, 2015 dopamine reuptake inhibitor is also an alpha adrenergic 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another blocker (e.g., bupropion). In another aspect the composition aspect the composition is that wherein the norepinephrine is that wherein the 5-HT2 receptor antagonist is also a dopamine reuptake inhibitor is also an alpha adrenergic 5-HT, receptoragonist. In another aspect the composition is blocker (e.g., bupropion). In another aspect the composition that wherein the 5-HT2 receptor antagonist is also a 5-HT, is that wherein the 5-HT2 receptor antagonist is also a receptor antagonist. In another aspect the composition is that 5-HT, receptoragonist. In another aspect the composition is wherein the 5-HT2 receptor antagonist is also a 5-HT, that wherein the 5-HT2 receptor antagonist is also a 5-HT, receptor antagonist and a 5-HT, receptor agonist (e.g., tra receptor antagonist. In another aspect the composition is that Zodone). In another aspect the composition is that wherein the wherein the 5-HT, receptor antagonist is also a 5-HT, 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or receptor antagonist and a 5-HT, receptor agonist (e.g., tra 5-HT, receptor antagonist is also an alpha adrenergic Zodone). In another aspect the composition is that wherein the blocker (e.g., traZodone). 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or 0122. In one aspect, the invention provides a method of 5-HT, receptor antagonist is also an alpha adrenergic enhancing cognition comprising administering to a subject in blocker (e.g., traZodone). need thereof a therapeutically effective amount of a compo 0.124. In one aspect, the invention provides a method of sition comprising a 5-HT, antagonist, a norepinephrine enhancing cognition comprising administering to a subject in dopamine reuptake inhibitor, a 5-HT, agonist (e.g., lor need thereof a therapeutically effective amount of a compo caserin, vabicaserin, PRX-00933, YM348, sition comprising a 5-HT, receptor agonist, a 5-HT metachlorophenylpiperazine, and mOPP), other non-abus antagonist, and a pharmaceutically acceptable carrier. In one able agents (agents not scheduled by the DEA) that augment aspect, one compound is the 5-HT, receptoragonist and the dopamine and/or norepinephrine in the brain, e.g., atomoxet 5-HT, antagonist (e.g., trazodone, nefazodone, mirtazapine, ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, flibanserin). In another aspect the composition is that wherein eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, the 5-HT2 receptor antagonist is also a 5-HT, receptor talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, agonist. In another aspect the composition is that wherein the manifaxine, radafaxine, tapentadol, teniloxazine, St. John's 5-HT2 receptor antagonist is also a 5-HT, receptor antago wort, ginkgo biloba), and a pharmaceutically acceptable car nist. In another aspect the composition is that wherein the rier. In one aspect, one compound is both a 5-HT, antagonist 5-HT2 receptor antagonist is also a 5-HT, receptor antago and a 5-HT, receptor agonist (e.g., traZodone, nefazodone, nist and a 5-HT, receptor agonist (e.g., trazodone). In mirtazapine, flibanserin, ketanserin, ritanserin, clozapine, another aspect the composition is that wherein the 5-HT, olanzapine, quetiapine, risperidone, asenapine, MDL-100, receptor antagonist, 5-HT, receptor agonist, and/or 5-HT, 907, cyproheptadine, aripiprazole, and the general class of receptor antagonist is also an alpha adrenergic blocker (e.g., 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another traZodone). aspect the composition is that wherein the norepinephrine 0.125. In one aspect, the invention provides a method of dopamine reuptake inhibitor is also an alpha adrenergic enhancing cognition comprising administering to a subject in blocker (e.g., bupropion). In another aspect the composition need thereof a therapeutically effective amount of a compo is that wherein the 5-HT2 receptor antagonist is also a sition comprising a 5-HT, receptor agonist, a 5-HT 5-HT, receptoragonist. In another aspect the composition is antagonist, and a pharmaceutically acceptable carrier. In one that wherein the 5-HT, receptor antagonist is also a 5-HT, aspect, one compound is the 5-HT, receptoragonist and the receptor antagonist. In another aspect the composition is that 5-HTantagonist (e.g., traZodone, nefazodone, mirtazapine, wherein the 5-HT, receptor antagonist is also a 5-HT, flibanserin, ketanserin, ritanserin, clozapine, olanzapine, receptor antagonist and a 5-HT, receptor agonist (e.g., tra quetiapine, risperidone, asenapine, MDL-100.907, cypro Zodone). In another aspect the composition is that wherein the heptadine, aripiprazole, and the general class of 2-alkyl-4- 5-HT, receptor antagonist, 5-HT, receptor agonist, and/or aryl-tetrahydro-pyrimido-azepines). In another aspect the 5-HT, receptor antagonist is also an alpha adrenergic composition is that wherein the 5-HT2 receptor antagonist is blocker (e.g., traZodone). also a 5-HT, receptoragonist. In another aspect the compo 0123. In one aspect, the invention provides a method of sition is that wherein the 5-HT2 receptor antagonist is also a enhancing cognition comprising administering to a subject in 5-HT, receptor antagonist. In another aspect the composi need thereof a therapeutically effective amount of a compo tion is that wherein the 5-HT, receptor antagonist is also a sition comprising a 5-HT, antagonist, a norepinephrine 5-HT, receptor antagonist and a 5-HT, receptor agonist dopamine reuptake inhibitor, a 5-HT2, agonist (e.g., lor (e.g., traZodone). In another aspect the composition is that caserin, vabicaserin, PRX-00933, YM348, wherein the 5-HT2 receptor antagonist, 5-HT, receptor metachlorophenylpiperazine, and mOPP), other non-abus agonist, and/or 5-HT, receptor antagonist is also an alpha able agents (agents not scheduled by the DEA) that augment adrenergic blocker (e.g., traZodone). dopamine and/or norepinephrine in the brain, e.g., atomoxet I0126. In one aspect, the invention provides a method of ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, enhancing cognition comprising administering to a subject in eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, need thereof a therapeutically effective amount of a compo talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, sition comprising a 5-HT, receptor agonist, a 5-HT manifaxine, radafaxine, tapentadol, teniloxazine, St. John's antagonist, other non-abusable agents (agents not scheduled wort, ginkgo biloba), and a pharmaceutically acceptable car by the DEA) that augment dopamine and/or norepinephrine rier. In one aspect, one compound is both a 5-HT, antagonist in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, and a 5-HT, receptor agonist (e.g., traZodone, nefazodone, 332, daledalin, edivoxetine, esreboxetine, lortalamine, mirtazapine, flibanserin, ketanserin, ritanserin, clozapine, mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox olanzapine, quetiapine, risperidone, asenapine, MDL-100, azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap 907, cyproheptadine, aripiprazole, and the general class of entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a US 2015/O 150946 A1 Jun. 4, 2015 22 pharmaceutically acceptable carrier. In one aspect, one com wherein the 5-HT2 receptor antagonist is also a 5-HT, pound is the 5-HT, receptoragonist and the 5-HT, antago receptor antagonist and a 5-HT, receptor agonist (e.g., tra nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, Zodone). In another aspect the composition is that wherein the ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris 5-HT, receptor antagonist, 5-HT, receptor agonist, and/or peridone, asenapine, MDL-100.907, cyproheptadine, arip 5-HT, receptor antagonist is also an alpha adrenergic iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro blocker (e.g., traZodone). pyrimido-azepines). In another aspect the composition is that I0129. In one aspect, the invention provides a method of wherein the 5-HT2 receptor antagonist is also a 5-HT enhancing cognition comprising administering to a subject in receptor agonist. In another aspect the composition is that need thereof a therapeutically effective amount of a compo wherein the 5-HT2 receptor antagonist is also a 5-HT, sition comprising a 5-HT, receptor agonist, a 5-HT receptor antagonist. In another aspect the composition is that antagonist, an oxytocin receptor (OXTR) agonist (e.g., car wherein the 5-HT2 receptor antagonist is also a 5-HT, betocin, oxytocin, Syntocinon R.), and a pharmaceutically receptor antagonist and a 5-HT, receptor agonist (e.g., tra acceptable carrier. In one aspect, one compound is the 5-HT Zodone). In another aspect the composition is that wherein the receptor agonist and the 5-HT, antagonist (e.g., trazodone, 5-HT2 receptor antagonist, 5-HT, receptor agonist, and/or nefazodone, mirtazapine, flibanserin). In another aspect the 5-HT, receptor antagonist is also an alpha adrenergic composition is that wherein the 5-HT2 receptor antagonist is blocker (e.g., traZodone). also a 5-HT, receptoragonist. In another aspect the compo 0127. In one aspect, the invention provides a method of sition is that wherein the 5-HT2 receptor antagonist is also a enhancing cognition comprising administering to a subject in 5-HT, receptor antagonist. In another aspect the composi need thereof a therapeutically effective amount of a compo tion is that wherein the 5-HT2 receptor antagonist is also a sition comprising a 5-HT, receptor agonist, a 5-HT 5-HT, receptor antagonist and a 5-HT, receptor agonist antagonist, a 5-HT2, agonist (e.g., lorcaserin, Vabicaserin, (e.g., traZodone). In another aspect the composition is that PRX-00933, YM348, metachlorophenylpiperazine, and wherein the 5-HT2 receptor antagonist, 5-HT, receptor mCPP), and a pharmaceutically acceptable carrier. In one agonist, and/or 5-HT, receptor antagonist is also an alpha aspect, one compound is the 5-HT, receptoragonist and the adrenergic blocker (e.g., traZodone). 5-HT, antagonist (e.g., trazodone, nefazodone, mirtazapine, 0.130. In one aspect, the invention provides a method of flibanserin, ketanserin, ritanserin, clozapine, olanzapine, enhancing cognition comprising administering to a subject in quetiapine, risperidone, asenapine, MDL-100.907, cypro need thereof a therapeutically effective amount of a compo heptadine, aripiprazole, and the general class of 2-alkyl-4- sition comprising a 5-HT, receptor agonist, a 5-HT aryl-tetrahydro-pyrimido-azepines). In another aspect the antagonist, an oxytocin receptor (OXTR) agonist (e.g., car composition is that wherein the 5-HT, receptor antagonist is betocin, oxytocin, Syntocinon R.), and a pharmaceutically also a 5-HT, receptoragonist. In another aspect the compo acceptable carrier. In one aspect, one compound is the 5-HT sition is that wherein the 5-HT, receptor antagonist is also a receptor agonist and the 5-HT, antagonist (e.g., traZodone, 5-HT, receptor antagonist. In another aspect the composi nefazodone, mirtazapine, flibanserin, ketanserin, ritanserin, tion is that wherein the 5-HT2 receptor antagonist is also a clozapine, olanzapine, quetiapine, risperidone, asenapine, 5-HT, receptor antagonist and a 5-HT, receptor agonist MDL-100.907, cyproheptadine, aripiprazole, and the general (e.g., traZodone). In another aspect the composition is that class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In wherein the 5-HT, receptor antagonist, 5-HT, receptor another aspect the composition is that wherein the 5-HT, agonist, and/or 5-HT, receptor antagonist is also an alpha receptor antagonist is also a 5-HT, receptor agonist. In adrenergic blocker (e.g., traZodone). another aspect the composition is that wherein the 5-HT 0128. In one aspect, the invention provides a method of receptor antagonist is also a 5-HT, receptor antagonist. In enhancing cognition comprising administering to a subject in another aspect the composition is that wherein the 5-HT need thereof a therapeutically effective amount of a compo receptor antagonist is also a 5-HT, receptor antagonist and a sition comprising a 5-HT, receptor agonist, a 5-HT 5-HT, receptor agonist (e.g., traZodone). In another aspect antagonist, a 5-HT2, agonist (e.g., lorcaserin, Vabicaserin, the composition is that wherein the 5-HT2 receptor antago PRX-00933, YM348, metachlorophenylpiperazine, and nist, 5-HT, receptor agonist, and/or 5-HT2 receptor mCPP), other non-abusable agents (agents not scheduled by antagonist is also an alpha adrenergic blocker (e.g., traZ the DEA) that augment dopamine and/or norepinephrine in odone). the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, I0131. In one aspect, the invention provides a method of 332, daledalin, edivoxetine, esreboxetine, lortalamine, enhancing cognition comprising administering to a subject in mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox need thereof a therapeutically effective amount of a compo azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap sition comprising a 5-HT, receptor agonist, a 5-HT entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a antagonist, an oxytocin receptor (OXTR) agonist (e.g., car pharmaceutically acceptable carrier. In one aspect, one com betocin, oxytocin, Syntocinon R.), other non-abusable agents pound is the 5-HT, receptoragonist and the 5-HT, antago (agents not scheduled by the DEA) that augment dopamine nist (e.g., traZodone, nefazodone, mirtazapine, flibanserin, and/or norepinephrine in the brain, e.g., atomoxetine, rebox ketanserin, ritanserin, clozapine, olanzapine, quetiapine, ris etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox peridone, asenapine, MDL-100.907, cyproheptadine, arip etine, lortalamine, mazindol, nisoxetine, talopram, talsu iprazole, and the general class of 2-alkyl-4-aryl-tetrahydro pram, tandamine, Viloxazine, maprotiline, ciclaZindol, pyrimido-azepines). In another aspect the composition is that manifaxine, radafaxine, tapentadol, teniloxazine, St. John's wherein the 5-HT2 receptor antagonist is also a 5-HT wort, ginkgo biloba), and a pharmaceutically acceptable car receptor agonist. In another aspect the composition is that rier. In one aspect, one compound is the 5-HT, receptor wherein the 5-HT2 receptor antagonist is also a 5-HT, agonist and the 5-HT, antagonist (e.g., traZodone, nefaz receptor antagonist. In another aspect the composition is that odone, mirtazapine, flibanserin, ketanserin, ritanserin, cloza US 2015/O 150946 A1 Jun. 4, 2015 pine, olanzapine, quetiapine, risperidone, asenapine, MDL 5-HT, receptor antagonist and a 5-HT, receptor agonist 100,907, cyproheptadine, aripiprazole, and the general class (e.g., traZodone). In another aspect the composition is that of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In another wherein the 5-HT2 receptor antagonist, 5-HT, receptor aspect the composition is that wherein the 5-HT, receptor agonist, and/or 5-HT, receptor antagonist is also an alpha antagonist is also a 5-HT, receptoragonist. In another aspect adrenergic blocker (e.g., traZodone). the composition is that wherein the 5-HT, receptor antago I0134. In one aspect, the invention provides a method of nist is also a 5-HT, receptorantagonist. In another aspect the enhancing cognition comprising administering to a subject in composition is that wherein the 5-HT, receptor antagonist is need thereof a therapeutically effective amount of a compo also a 5-HT, receptor antagonist and a 5-HT, receptor sition comprising a norepinephrine-dopamine reuptake agonist (e.g., traZodone). In another aspect the composition is inhibitor, an oxytocin receptor (OXTR) agonist (e.g., carbe that wherein the 5-HT, receptor antagonist, 5-HT, receptor tocin, oxytocin, Syntocinon R.), and a pharmaceutically agonist, and/or 5-HT, receptor antagonist is also an alpha acceptable carrier. In another aspect, the norepinephrine adrenergic blocker (e.g., traZodone). dopamine reuptake inhibitor is also a alpha adrenergic 0.132. In one aspect, the invention provides a method of blocker (e.g., bupropion). enhancing cognition comprising administering to a subject in I0135) In one aspect, the invention provides a method of need thereof a therapeutically effective amount of a compo enhancing cognition comprising administering to a subject in sition comprising a 5-HT, receptor agonist, a 5-HT need thereof a therapeutically effective amount of a compo antagonist, an oxytocin receptor (OXTR) agonist (e.g., car sition comprising a norepinephrine-dopamine reuptake betocin, oxytocin, SyntocinonR), a 5-HT, agonist (e.g., lor inhibitor, an oxytocin receptor (OXTR) agonist (e.g., carbe caserin, vabicaserin, PRX-00933, YM348, metachlorophe tocin, oxytocin, Syntocinon R.), other non-abusable agents nylpiperazine, and mCPP), and a pharmaceutically (agents not scheduled by the DEA) that augment dopamine acceptable carrier. In one aspect, one compound is the 5-HT and/or norepinephrine in the brain, e.g., atomoxetine, rebox receptor agonist and the 5-HT, antagonist (e.g., traZodone, etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox nefazodone, mirtazapine, flibanserin, ketanserin, ritanserin, etine, lortalamine, mazindol, nisoxetine, talopram, talsu clozapine, olanzapine, quetiapine, risperidone, asenapine, pram, tandamine, Viloxazine, maprotiline, ciclaZindol, MDL-100.907, cyproheptadine, aripiprazole, and the general manifaxine, radafaxine, tapentadol, teniloxazine, St. John's class of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines). In wort, ginkgo biloba), and a pharmaceutically acceptable car another aspect the composition is that wherein the 5-HT rier. In another aspect, the norepinephrine-dopamine receptor antagonist is also a 5-HT1 receptor agonist. In reuptake inhibitor is also a alpha adrenergic blocker (e.g., another aspect the composition is that wherein the 5-HT bupropion). receptor antagonist is also a 5-HT, receptor antagonist. In 0.136. In one aspect, the invention provides a method of another aspect the composition is that wherein the 5-HT enhancing cognition comprising administering to a subject in receptor antagonist is also a 5-HT, receptor antagonistanda need thereof a therapeutically effective amount of a compo 5-HT, receptor agonist (e.g., traZodone). In another aspect sition comprising a norepinephrine-dopamine reuptake the composition is that wherein the 5-HT2 receptor antago inhibitor, an oxytocin receptor (OXTR) agonist (e.g., carbe nist, 5-HT, receptor agonist, and/or 5-HT2 receptor tocin, oxytocin, Syntocinon R.), a 5-HT2, agonist (e.g., lor antagonist is also an alpha adrenergic blocker (e.g., traZ caserin, vabicaserin, PRX-00933, YM348, metachlorophe odone). nylpiperazine, and mCPP), and a pharmaceutically 0133. In one aspect, the invention provides a method of acceptable carrier. In another aspect, the norepinephrine enhancing cognition comprising administering to a subject in dopamine reuptake inhibitor is also a alpha adrenergic need thereof a therapeutically effective amount of a compo blocker (e.g., bupropion). sition comprising a 5-HT, receptor agonist, a 5-HT 0.137 In one aspect, the invention provides a method of antagonist, an oxytocin receptor (OXTR) agonist (e.g., car enhancing cognition comprising administering to a subject in betocin, oxytocin, SyntocinonR), a 5-HT, agonist (e.g., lor need thereof a therapeutically effective amount of a compo caserin, vabicaserin, PRX-00933, YM348, metachlorophe sition comprising a norepinephrine-dopamine reuptake nylpiperazine, and mCPP), other non-abusable agents (agents inhibitor, an oxytocin receptor (OXTR) agonist (e.g., carbe not scheduled by the DEA) that augment dopamine and/or tocin, oxytocin, Syntocinon R.), other non-abusable agents norepinephrine in the brain, e.g., atomoxetine, reboxetine, (agents not scheduled by the DEA) that augment dopamine amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, and/or norepinephrine in the brain, e.g., atomoxetine, rebox lortalamine, mazindol, nisoxetine, talopram, talsupram, tan etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox damine, Viloxazine, maprotiline, ciclazindol, manifaxine, etine, lortalamine, mazindol, nisoxetine, talopram, talsu radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo pram, tandamine, Viloxazine, maprotiline, ciclaZindol, biloba), and a pharmaceutically acceptable carrier. In one manifaxine, radafaxine, tapentadol, teniloxazine, St. John's aspect, one compound is the 5-HT, receptoragonist and the wort, ginkgo biloba), a 5-HT2, agonist (e.g., lorcaserin, vabi 5-HT, antagonist (e.g., traZodone, nefazodone, mirtazapine, caserin, PRX-00933, YM348, metachlorophenylpiperazine, flibanserin, ketanserin, ritanserin, clozapine, olanzapine, and mOPP), and a pharmaceutically acceptable carrier. In quetiapine, risperidone, asenapine, MDL-100.907, cypro another aspect, the norepinephrine-dopamine reuptake heptadine, aripiprazole, and the general class of 2-alkyl-4- inhibitor is also a alpha adrenergic blocker (e.g., bupropion). aryl-tetrahydro-pyrimido-azepines). In another aspect the 0.138. In one aspect, the invention provides a method of composition is that wherein the 5-HT, receptor antagonist is enhancing cognition comprising administering to a subject in also a 5-HT, receptoragonist. In another aspect the compo need thereof a therapeutically effective amount of a compo sition is that wherein the 5-HT2 receptor antagonist is also a sition comprising an oxytocin receptor (OXTR) agonist (e.g., 5-HT, receptor antagonist. In another aspect the composi carbetocin, oxytocin, Syntocinon R) and a pharmaceutically tion is that wherein the 5-HT2 receptor antagonist is also a acceptable carrier. US 2015/O 150946 A1 Jun. 4, 2015 24

0.139. In one aspect, the invention provides a method of for at least two weeks), Mood Disorder due to a General enhancing cognition comprising administering to a subject in Medical Condition, Substance-Induced Mood Disorder, and need thereof a therapeutically effective amount of a compo Depressive Disorder Not Otherwise Specified. Each of these sition comprising an oxytocin receptor (OXTR) agonist (e.g., disorders includes specifiers of With or Without Psychotic carbetocin, oxytocin, Syntocinon R.), other non-abusable Features. With Catatonic Features (or without). With Melan agents (agents not scheduled by the DEA) that augment cholic Features (or without). With Atypical Features (or with dopamine and/or norepinephrine in the brain, e.g., atomoxet out), and With Postpartum Onset. Lesser depressive disor ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, ders, but still associated with significant disability, include eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, Dysthymic Disorder (lesser symptoms Such as low energy but talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, not loss of pleasure in all activities; feelings of hopeless but manifaxine, radafaxine, tapentadol, teniloxazine, St. John's not Suicidality, on a majority of days for at least two years) wort, ginkgo biloba), and a pharmaceutically acceptable car and Depressive Disorder Not Otherwise Specified (too few rier. symptoms or too little constancy to meet criteria for MDD/ 0140. In one aspect, the invention provides a method of MDE but still causing disability, including premenstrual dys enhancing cognition comprising administering to a subject in phoric disorder, minor depressive disorder (less than 5 need thereof a therapeutically effective amount of a compo depressive symptoms), recurrent brief depressive disorder sition comprising an oxytocin receptor (OXTR) agonist (e.g., (episodes lasting less than 2 weeks), post-psychotic depres carbetocin, oxytocin, Syntocinon R, a 5-HT, agonist (e.g., sive disorder of Schizophrenia. lorcaserin, vabicaserin, PRX-00933, YM348, metachlo 0.148. Another aspect is an extended release composition rophenylpiperazine, and mCPP), and a pharmaceutically comprising a 5-HT, antagonist, a norepinephrine-dopamine acceptable carrier. reuptake inhibitor (e.g., bupropion), and a pharmaceutically 0141. In one aspect, the invention provides a method of acceptable carrier. enhancing cognition comprising administering to a subject in 0149 Another aspect is an extended release composition need thereof a therapeutically effective amount of a compo comprising a 5-HT, antagonist, a norepinephrine-dopamine sition comprising an oxytocin receptor (OXTR) agonist (e.g., reuptake inhibitor (e.g., bupropion), other non-abusable carbetocin, oxytocin, Syntocinon R.), other non-abusable agents (agents not scheduled by the DEA) that augment agents (agents not scheduled by the DEA) that augment dopamine and/or norepinephrine in the brain, e.g., atomoxet dopamine and/or norepinephrine in the brain, e.g., atomoxet ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, talopram, eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, radafaxine, tapentadol, teniloxazine, St. John's manifaxine, radafaxine, tapentadol, teniloxazine, St. John's wort, ginkgo biloba), and a pharmaceutically acceptable car wort, ginkgo biloba), a 5-HT2, agonist (e.g., lorcaserin, vabi 1er caserin, PRX-00933, YM348, metachlorophenylpiperazine, 0150. Another aspect is an extended release composition and mOPP), and a pharmaceutically acceptable carrier. comprising a 5-HT, antagonist, a norepinephrine-dopamine 0142. In aspects, the method is that wherein the cognition reuptake inhibitor (e.g., bupropion), a 5-HT, agonist (e.g., enhancement is improving mental activities such as attention, lorcaserin, vabicaserin, PRX-00933, YM348, metachlo perception, learning, memory, language, planning, decision rophenylpiperazine, and mCPP), and a pharmaceutically making, organization, conceptualization, reorganization, acceptable carrier. synthesis of facts, synthesis of data, recall, calculation, Spa 0151. Another aspect is an extended release composition tiotemporal visualization, mental flexibility, creativity, or the comprising a 5-HT, antagonist, a norepinephrine-dopamine ability to accept challenging intellectual or cultural pursuits. reuptake inhibitor (e.g., bupropion), a 5-HT, agonist (e.g., 0143 Another aspect is a method of treating a disease, lorcaserin, vabicaserin, PRX-00933, YM348, metachlo disorder or symptom thereof described in the Diagnostic and rophenylpiperazine, and mCPP), other non-abusable agents Statistical Manual of Mental Disorders (DSM-IV-TR) in a (agents not scheduled by the DEA) that augment dopamine Subject comprising administering to the Subject a compound and/or norepinephrine in the brain, e.g., atomoxetine, rebox or composition herein. etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox 0144. Another aspect is a method of treating erectile dys etine, lortalamine, mazindol, nisoxetine, talopram, talsu function (ED) in a subject comprising administering to the pram, tandamine, Viloxazine, maprotiline, ciclaZindol, Subject a compound or composition herein. manifaxine, radafaxine, tapentadol, teniloxazine, St. John's 0145 Another aspect is a method of treating male HSDD wort, ginkgo biloba), and a pharmaceutically acceptable car in a Subject comprising administering to the Subject a com 1. pound or composition herein. 0152 Another aspect is an extended release composition 014.6 Another aspect is a method of treating male sexual comprising a 5-HT, antagonist, a norepinephrine-dopamine disorders in a subject comprising administering to the Subject reuptake inhibitor (e.g., bupropion), an oxytocin receptor a compound or composition herein. (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), 0147 Another aspect is a method of treating depressive and a pharmaceutically acceptable carrier. disorders in a subject comprising administering to the Subject 0153. Another aspect is an extended release composition a compound or composition herein. Depressive disorders and comprising a 5-HT, antagonist, a norepinephrine-dopamine “depression” as used in this document includes each of the reuptake inhibitor (e.g., bupropion), an oxytocin receptor depressive disorder recognized and defined by the DSM-IV (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), TR: Major Depressive Disorder and Major Depressive Epi other non-abusable agents (agents not scheduled by the DEA) sode (MDD/MDE: at least five major symptoms such as that augment dopamine and/or norepinephrine in the brain, impairment of ability to work and suicidality nearly every day e.g., atomoxetine, reboxetine, amedalin, CP-39,332, daleda US 2015/O 150946 A1 Jun. 4, 2015

lin, edivoxetine, esreboxetine, lortalamine, mazindol, nisox (e.g., bupropion), an oxytocin receptor (OXTR) agonist (e.g., etine, talopram, talsupram, tandamine, Viloxazine, mapro carbetocin, oxytocin, Syntocinon R.), and a pharmaceutically tiline, ciclaZindol, manifaxine, radafaxine, tapentadol, acceptable carrier. teniloxazine, St. John’s wort, ginkgo biloba), and a pharma 0.161 Another aspect is an extended release composition ceutically acceptable carrier. comprising a norepinephrine-dopamine reuptake inhibitor 0154 Another aspect is an extended release composition (e.g., bupropion), an oxytocin receptor (OXTR) agonist (e.g., comprising a 5-HT, antagonist, a norepinephrine-dopamine carbetocin, oxytocin, Syntocinon R.), other non-abusable reuptake inhibitor (e.g., bupropion), an oxytocin receptor agents (agents not scheduled by the DEA) that augment (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon R.), a dopamine and/or norepinephrine in the brain, e.g., atomoxet 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, YM348, metachlorophenylpiperazine, and mOPP), and a eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, pharmaceutically acceptable carrier. talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, radafaxine, tapentadol, teniloxazine, St. John's 0155 Another aspect is an extended release composition wort, ginkgo biloba), and a pharmaceutically acceptable car comprising a 5-HT, antagonist, a norepinephrine-dopamine 1. reuptake inhibitor (e.g., bupropion), an oxytocin receptor 0162 Another aspect is an extended release composition (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon R.), a comprising a norepinephrine-dopamine reuptake inhibitor 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, (e.g., bupropion), an oxytocin receptor (OXTR) agonist (e.g., YM348, metachlorophenylpiperazine, and mCPP), other carbetocin, oxytocin, Syntocinon R.), a 5-HT, agonist (e.g., non-abusable agents (agents not scheduled by the DEA) that lorcaserin, vabicaserin, PRX-00933, YM348, metachlo augment dopamine and/or norepinephrine in the brain, e.g., rophenylpiperazine, and mCPP), and a pharmaceutically atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, acceptable carrier. ediVoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, 0163 Another aspect is an extended release composition talopram, talsupram, tandamine, Viloxazine, maprotiline, comprising a norepinephrine-dopamine reuptake inhibitor ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, (e.g., bupropion), an oxytocin receptor (OXTR) agonist (e.g., St. John’s wort, ginkgo biloba), and a pharmaceutically carbetocin, oxytocin, SyntocinonR), a 5-HT, agonist (e.g., acceptable carrier. lorcaserin, vabicaserin, PRX-00933, YM348, metachlo 0156 Another aspect is an extended release composition rophenylpiperazine, and mCPP), other non-abusable agents comprising a 5-HT2, antagonist, an oxytocin receptor (agents not scheduled by the DEA) that augment dopamine (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), and/or norepinephrine in the brain, e.g., atomoxetine, rebox and a pharmaceutically acceptable carrier. etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox 0157 Another aspect is an extended release composition etine, lortalamine, mazindol, nisoxetine, talopram, talsu comprising a 5-HT, antagonist, an oxytocin receptor pram, tandamine, Viloxazine, maprotiline, ciclaZindol, (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), manifaxine, radafaxine, tapentadol, teniloxazine, St. John's other non-abusable agents (agents not scheduled by the DEA) wort, ginkgo biloba), and a pharmaceutically acceptable car that augment dopamine and/or norepinephrine in the brain, 1er e.g., atomoxetine, reboxetine, amedalin, CP-39,332, daleda 0164. Another aspect is an extended release composition lin, edivoxetine, esreboxetine, lortalamine, mazindol, nisox comprising an oxytocin receptor (OXTR) agonist (e.g., car etine, talopram, talsupram, tandamine, Viloxazine, mapro betocin, oxytocin, Syntocinon R) and a pharmaceutically tiline, ciclaZindol, manifaxine, radafaxine, tapentadol, acceptable carrier. teniloxazine, St. John’s wort, ginkgo biloba), and a pharma 0.165 Another aspect is an extended release composition ceutically acceptable carrier. comprising an oxytocin receptor (OXTR) agonist (e.g., car 0158 Another aspect is an extended release composition betocin, oxytocin, Syntocinon R.), other non-abusable agents comprising a 5-HT, antagonist, an oxytocin receptor (agents not scheduled by the DEA) that augment dopamine (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon R.), a and/or norepinephrine in the brain, e.g., atomoxetine, rebox 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox YM348, metachlorophenylpiperazine, and mOPP), and a etine, lortalamine, mazindol, nisoxetine, talopram, talsu pharmaceutically acceptable carrier. pram, tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, radafaxine, tapentadol, teniloxazine, St. John's 0159. Another aspect is an extended release composition wort, ginkgo biloba), and a pharmaceutically acceptable car comprising a 5-HT, antagonist, an oxytocin receptor 1er (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon R.), a 0166 Another aspect is an extended release composition 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, comprising an oxytocin receptor (OXTR) agonist (e.g., car YM348, metachlorophenylpiperazine, and mCPP), other betocin, oxytocin, Syntocinon R.), a 5-HT, agonist (e.g., lor non-abusable agents (agents not scheduled by the DEA) that caserin, vabicaserin, PRX-00933, YM348, metachlorophe augment dopamine and/or norepinephrine in the brain, e.g., nylpiperazine, and mCPP), and a pharmaceutically atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, acceptable carrier. ediVoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, 0.167 Another aspect is an extended release composition talopram, talsupram, tandamine, Viloxazine, maprotiline, comprising an oxytocin receptor (OXTR) agonist (e.g., car ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, betocin, oxytocin, SyntocinonR), a 5-HT, agonist (e.g., lor St. John’s wort, ginkgo biloba), and a pharmaceutically caserin, vabicaserin, PRX-00933, YM348, metachlorophe acceptable carrier. nylpiperazine, and mCPP), other non-abusable agents (agents 0160 Another aspect is an extended release composition not scheduled by the DEA) that augment dopamine and/or comprising a norepinephrine-dopamine reuptake inhibitor norepinephrine in the brain, e.g., atomoxetine, reboxetine, US 2015/O 150946 A1 Jun. 4, 2015 26 amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a lortalamine, mazindol, nisoxetine, talopram, talsupram, tan pharmaceutically acceptable carrier. damine, Viloxazine, maprotiline, ciclazindol, manifaxine, 0176). In one aspect, the invention provides a composition radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo comprising the 5-HT, receptor agonist and 5-HT2, antago biloba), and a pharmaceutically acceptable carrier. nist flibanserin and a pharmaceutically acceptable carrier. 0.168. In one aspect, the invention provides a composition 0177. In one aspect, the invention provides a composition comprising the 5-HT, receptor agonist and 5-HT, antago comprising the 5-HT, receptoragonist, and 5-HT, antago nist nefazodone and a pharmaceutically acceptable carrier. nist flibanserin, other non-abusable agents (agents not sched 0169. In one aspect, the invention provides a composition uled by the DEA) that augment dopamine and/or norepineph comprising the 5-HT, receptoragonist, and 5-HT, antago rine in the brain, e.g., atomoxetine, reboxetine, amedalin, nist nefazodone, other non-abusable agents (agents not CP-39,332, daledalin, edivoxetine, esreboxetine, lorta scheduled by the DEA) that augment dopamine and/or nore lamine, mazindol, nisoxetine, talopram, talsupram, tan pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda damine, Viloxazine, maprotiline, ciclazindol, manifaxine, lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo lamine, mazindol, nisoxetine, talopram, talsupram, biloba), and a pharmaceutically acceptable carrier. tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, 0178. In one aspect, the invention provides a composition radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo comprising the 5-HT, receptor agonist and 5-HT2, antago biloba), and a pharmaceutically acceptable carrier. nist flibanserin, a 5-HT, agonist (e.g., lorcaserin, vabi 0170 In one aspect, the invention provides a composition caserin, PRX-00933, YM348, metachlorophenylpiperazine, comprising the 5-HT, receptor agonist and 5-HT, antago and mOPP), and a pharmaceutically acceptable carrier. nist nefazodone, a 5-HT2, agonist (e.g., lorcaserin, vabi 0179. In one aspect, the invention provides a composition caserin, PRX-00933, YM348, metachlorophenylpiperazine, comprising the 5-HT, receptor agonist and 5-HT2, antago and mOPP), and a pharmaceutically acceptable carrier. nist flibanserin, a 5-HT, agonist (e.g., lorcaserin, vabi 0171 In one aspect, the invention provides a composition caserin, PRX-00933, YM348, metachlorophenylpiperazine, comprising the 5-HT, receptor agonist and 5-HT2, antago and mCPP), ther non-abusable agents (agents not scheduled nist nefazodone, a 5-HT, agonist (e.g., lorcaserin, vabi by the DEA) that augment dopamine and/or norepinephrine caserin, PRX-00933, YM348, metachlorophenylpiperazine, in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, and mCPP), ther non-abusable agents (agents not scheduled 332, daledalin, edivoxetine, esreboxetine, lortalamine, by the DEA) that augment dopamine and/or norepinephrine mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap 332, daledalin, edivoxetine, esreboxetine, lortalamine, entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox pharmaceutically acceptable carrier. azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap 0180. In one aspect, the invention provides a composition entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a comprising the 5-HT, receptor agonist, 5-HT, receptor pharmaceutically acceptable carrier. antagonist, and/or 5-HT, receptor antagonist traZodone and 0172. In one aspect, the invention provides a composition a pharmaceutically acceptable carrier. comprising the 5-HT, receptor agonist and 5-HT2, antago 0181. In one aspect, the invention provides a composition nist mirtazapine and a pharmaceutically acceptable carrier. comprising the 5-HT, receptoragonist, and 5-HT, antago 0173. In one aspect, the invention provides a composition nist traZodone, other non-abusable agents (agents not sched comprising the 5-HT, receptoragonist, and 5-HT, antago uled by the DEA) that augment dopamine and/or norepineph nist mirtazapine, other non-abusable agents (agents not rine in the brain, e.g., atomoxetine, reboxetine, amedalin, scheduled by the DEA) that augment dopamine and/or nore CP-39,332, daledalin, edivoxetine, esreboxetine, lorta pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda lamine, mazindol, nisoxetine, talopram, talsupram, tan lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta damine, Viloxazine, maprotiline, ciclazindol, manifaxine, lamine, mazindol, nisoxetine, talopram, talsupram, radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, biloba), and a pharmaceutically acceptable carrier. radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo 0182. In one aspect, the invention provides a composition biloba), and a pharmaceutically acceptable carrier. comprising the 5-HT, receptor agonist and 5-HT2, antago 0.174. In one aspect, the invention provides a composition nist trazodone, a 5-HT, agonist (e.g., lorcaserin, vabi comprising the 5-HT, receptor agonist and 5-HT2, antago caserin, PRX-00933, YM348, metachlorophenylpiperazine, nist mirtazapine, a 5-HT2, agonist (e.g., lorcaserin, vabi and mOPP), and a pharmaceutically acceptable carrier. caserin, PRX-00933, YM348, metachlorophenylpiperazine, 0183 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 0.175. In one aspect, the invention provides a composition nist traZodone, a 5-HT2, agonist (e.g., lorcaserin, vabi comprising the 5-HT, receptor agonist and 5-HT2, antago caserin, PRX-00933, YM348, metachlorophenylpiperazine, nist mirtazapine, a 5-HT2, agonist (e.g., lorcaserin, vabi and mCPP), ther non-abusable agents (agents not scheduled caserin, PRX-00933, YM348, metachlorophenylpiperazine, by the DEA) that augment dopamine and/or norepinephrine and mCPP), ther non-abusable agents (agents not scheduled in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, by the DEA) that augment dopamine and/or norepinephrine 332, daledalin, edivoxetine, esreboxetine, lortalamine, in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox 332, daledalin, edivoxetine, esreboxetine, lortalamine, azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap pharmaceutically acceptable carrier. US 2015/O150946 A1 Jun. 4, 2015 27

0184 Other aspects include those, wherein the composi solutions (alcoholic drinks) sufficient in color to show that the tion is administered orally; wherein the composition is drink has been tampered with. administered topically; wherein the subject is diagnosed and (0194 In another aspect of the invention, a formulation of being treated for depression; wherein the subject is not under bupropion and trazodone to treat sexual disorders has an outer going treatment for depression; wherein the subject is con layer that releases a nontoxic gelling agent in water or water currently prescribed an additional therapeutic agent; or alcohol solutions sufficient to thicken or solidify the drink to wherein the subject is concurrently not prescribed an addi show it has been tampered with. tional therapeutic agent; wherein the subject is concurrently (0195 In one aspect, the invention provides a composition administered an additional therapeutic agent; or wherein the comprising the 5-HT, receptor agonist and 5-HT, antago subject is concurrently not administered an additional thera nist nefazodone and a pharmaceutically acceptable carrier. peutic agent. (0196. In one aspect, the invention provides a composition 0185. In one aspect, the invention provides a composition comprising the 5-HT, receptor agonist, and 5-HT2, antago comprising a 5-HT, receptor agonist, a 5-HT24 antagonist, nist nefazodone, other non-abusable agents (agents not and a pharmaceutically acceptable carrier. scheduled by the DEA) that augment dopamine and/or nore 0186. In one aspect, the invention provides a composition pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda comprising the 5-HT, receptoragonist, and 5-HT, antago lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta nist, other non-abusable agents (agents not scheduled by the lamine, mazindol, nisoxetine, talopram, talsupram, DEA) that augment dopamine and/or norepinephrine in the tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, brain, e.g., atomoxetine, reboxetine, amedalin, CP-39,332, radafaxine, tapentadol, teniloxazine, St. John's Wort, ginkgo daledalin, edivoxetine, esreboxetine, lortalamine, maZindol, biloba), and a pharmaceutically acceptable carrier. nisoxetine, talopram, talsupram, tandamine, Viloxazine, (0197) In one aspect, the invention provides a composition maprotiline, ciclazindol, manifaxine, radafaxine, tapentadol. comprising the 5-HT, receptor agonist and 5-HT2, antago teniloxazine, St. John's wort, ginkgo biloba), and a pharma nist nefazodone, a 5-HT2, agonist (e.g., lorcaserin, vabi ceutically acceptable carrier. caserin, PRX-00933, YM348, metachlorophenylpiperazine, 0187. In one aspect, the invention provides a composition and mOPP), and a pharmaceutically acceptable carrier. comprising the 5-HT, receptor agonist and 5-HT, antago (0198 In one aspect, the invention provides a composition nist, a 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX comprising the 5-HT, receptor agonist and 5-HT2, antago 00933, YM348, metachlorophenylpiperazine, and mCPP), nist nefazodone, a 5-HT2, agonist (e.g., lorcaserin, Vabi and a pharmaceutically acceptable carrier. caserin, PRX-00933, YM348, metachlorophenylpiperazine, 0188 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, a 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, 00933, YM348, metachlorophenylpiperazine, and mCPP), 332, daledalin, edivoxetine, esreboxetine, lortalamine, other non-abusable agents (agents not scheduled by the DEA) mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox that augment dopamine and/or norepinephrine in the brain, azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap e.g., atomoxetine, reboxetine, amedalin, CP-39,332, daleda entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a lin, edivoxetine, esreboxetine, lortalamine, mazindol, nisoX pharmaceutically acceptable carrier. etine, talopram, talsupram, tandamine, Viloxazine, mapro (0199. In one aspect, the invention provides a composition tiline, ciclazindol, manifaxine, radafaxine, tapentadol, comprising the 5-HT, receptor agonist and 5-HT2, antago teniloxazine, St. John's wort, ginkgo biloba), and a pharma nist mirtazapine and a pharmaceutically acceptable carrier. ceutically acceptable carrier. (0200. In one aspect, the invention provides a composition (0189 In another aspect of the invention, a formulation of comprising the 5-HT, receptor agonist, and 5-HT2, antago bupropion and trazodone to treat sexual disorders meets the nist mirtazapine, other non-abusable agents (agents not specific concerns of men including onset of action within an scheduled by the DEA) that augment dopamine and/or nore hour and continuation of efficacy overnight after a dose. pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda (0190. In another aspect of the invention, a formulation of lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta bupropion and trazodone to treat sexual disorders has a dose lamine, mazindol, nisoxetine, talopram, talsupram, up to 50% larger of the two components compared to a for tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, mulation for women. radafaxine, tapentadol, teniloxazine, St. John's wort, ginkgo (0191). In another aspect of the invention, a formulation of biloba), and a pharmaceutically acceptable carrier. bupropion and trazodone to treat sexual disorders has an outer 0201 In one aspect, the invention provides a composition layer with rapid release of an effective but well tolerated comprising the 5-HT, receptor agonist and 5-HT2, antago amount of trazodone and bupropion, and an inner core with a nist mirtazapine, a 5-HT, agonist (e.g., lorcaserin, vabi sustained release of an effective and well tolerated amount of caserin, PRX-00933, YM348, metachlorophenylpiperazine, trazodone and bupropion. and mCPP), and a pharmaceutically acceptable carrier. (0192. In another aspect of the invention, a formulation of 0202) In one aspect, the invention provides a composition bupropion and trazodone to treat sexual disorders has a highly comprising the 5-HT, receptor agonist and 5-HT2, antago soluble outer layer and a matrix inner layer that remains nist mirtazapine, a 5-HT, agonist (e.g., lorcaserin, Vabi insoluble in water or water-alcohol solutions (alcoholic caserin, PRX-00933, YM348, metachlorophenylpiperazine, drinks) and is large enough to be easily visible and show that and mCPP), ther non-abusable agents (agents not scheduled the drink has been tampered with. by the DEA) that augment dopamine and/or norepinephrine (0193 In another aspect of the invention, a formulation of in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, bupropion and trazodone to treat sexual disorders has an outer 332, daledalin, edivoxetine, esreboxetine, lortalamine. layer that releases a nontoxic dye in water or water-alcohol mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox US 2015/O 150946 A1 Jun. 4, 2015 28 azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap 0211. In another aspect of the invention, a formulation of entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a bupropion, traZodone, and oxytocin to treat sexual disorders pharmaceutically acceptable carrier. has an outer layer with rapid release of an effective but well 0203. In one aspect, the invention provides a composition tolerated amount of bupropion, traZodone, and oxytocin, and comprising the 5-HT, receptor agonist and 5-HT2, antago an inner core with a sustained release of an effective and well nist flibanserin and a pharmaceutically acceptable carrier. tolerated amount of bupropion, traZodone, and oxytocin. 0204. In one aspect, the invention provides a composition 0212. In another aspect of the invention, a formulation of comprising the 5-HT, receptoragonist, and 5-HT, antago bupropion, traZodone, and oxytocin to treat sexual disorders nist flibanserin, other non-abusable agents (agents not sched has a highly soluble outer layer and a matrix inner layer that uled by the DEA) that augment dopamine and/or norepineph remains insoluble in water or water-alcohol solutions (alco rine in the brain, e.g., atomoxetine, reboxetine, amedalin, holic drinks) and is large enough to be easily visible and show CP-39,332, daledalin, edivoxetine, esreboxetine, lorta that the drink has been tampered with. lamine, mazindol, nisoxetine, talopram, talsupram, tan 0213. In another aspect of the invention, a formulation of damine, Viloxazine, maprotiline, ciclazindol, manifaxine, bupropion, traZodone, and oxytocin to treat sexual disorders radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo has an outer layer that releases a nontoxic dye in water or biloba), and a pharmaceutically acceptable carrier. water-alcohol solutions (alcoholic drinks) sufficient in color 0205. In one aspect, the invention provides a composition to show that the drink has been tampered with. comprising the 5-HT, receptor agonist and 5-HT2, antago 0214. In another aspect of the invention, a formulation of nist flibanserin, a 5-HT2, agonist (e.g., lorcaserin, vabi bupropion, traZodone, and oxytocin to treat sexual disorders caserin, PRX-00933, YM348, metachlorophenylpiperazine, has an outer layer that releases a nontoxic gelling agent in and mOPP), and a pharmaceutically acceptable carrier. water or water-alcohol solutions sufficient to thicken or 0206. In one aspect, the invention provides a composition solidify the drink to show it has been tampered with. comprising the 5-HT, receptor agonist and 5-HT2, antago 0215. In another aspect of the invention, a formulation of nist flibanserin, a 5-HT2, agonist (e.g., lorcaserin, vabi bupropion and oxytocinto treat sexual disorders has an outer caserin, PRX-00933, YM348, metachlorophenylpiperazine, layer with rapid release of an effective but well tolerated and mCPP), ther non-abusable agents (agents not scheduled amount of bupropion and oxytocin, and an inner core with a by the DEA) that augment dopamine and/or norepinephrine sustained release of an effective and well tolerated amount of in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, bupropion and oxytocin. 332, daledalin, edivoxetine, esreboxetine, lortalamine, 0216. In another aspect of the invention, a formulation of mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox bupropion and oxytocinto treat sexual disorders has a highly azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap soluble outer layer and a matrix inner layer that remains entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a insoluble in water or water-alcohol solutions (alcoholic pharmaceutically acceptable carrier. drinks) and is large enough to be easily visible and show that 0207. In one aspect, the invention provides a composition the drink has been tampered with. comprising the 5-HT, receptor agonist, 5-HT, receptor 0217. In another aspect of the invention, a formulation of antagonist, and/or 5-HT, receptor antagonist traZodone and bupropion and oxytocinto treat sexual disorders has an outer a pharmaceutically acceptable carrier. layer that releases a nontoxic dye in water or water-alcohol 0208. In one aspect, the invention provides a composition solutions (alcoholic drinks) sufficient in color to show that the comprising the 5-HT, receptoragonist, and 5-HT, antago drink has been tampered with. nist traZodone, other non-abusable agents (agents not sched 0218. In another aspect of the invention, a formulation of uled by the DEA) that augment dopamine and/or norepineph bupropion and oxytocinto treat sexual disorders has an outer rine in the brain, e.g., atomoxetine, reboxetine, amedalin, layer that releases a nontoxic gelling agent in water or water CP-39,332, daledalin, edivoxetine, esreboxetine, lorta alcohol solutions sufficient to thicken or solidify the drink to lamine, mazindol, nisoxetine, talopram, talsupram, tan show it has been tampered with. damine, Viloxazine, maprotiline, ciclazindol, manifaxine, 0219. In another aspect of the invention, a formulation of radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo traZodone and oxytocinto treat sexual disorders has an outer biloba), and a pharmaceutically acceptable carrier. layer with rapid release of an effective but well tolerated 0209. In one aspect, the invention provides a composition amount of traZodone and oxytocin, and an inner core with a comprising the 5-HT, receptor agonist and 5-HT2, antago sustained release of an effective and well tolerated amount of nist traZodone, a 5-HT2, agonist (e.g., lorcaserin, vabi traZodone and oxytocin. caserin, PRX-00933, YM348, metachlorophenylpiperazine, 0220. In another aspect of the invention, a formulation of and mOPP), and a pharmaceutically acceptable carrier. traZodone and oxytocinto treat sexual disorders has a highly 0210. In one aspect, the invention provides a composition soluble outer layer and a matrix inner layer that remains comprising the 5-HT, receptor agonist and 5-HT2, antago insoluble in water or water-alcohol solutions (alcoholic nist traZodone, a 5-HT2, agonist (e.g., lorcaserin, vabi drinks) and is large enough to be easily visible and show that caserin, PRX-00933, YM348, metachlorophenylpiperazine, the drink has been tampered with. and mCPP), ther non-abusable agents (agents not scheduled 0221. In another aspect of the invention, a formulation of by the DEA) that augment dopamine and/or norepinephrine traZodone and oxytocinto treat sexual disorders has an outer in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, layer that releases a nontoxic dye in water or water-alcohol 332, daledalin, edivoxetine, esreboxetine, lortalamine, solutions (alcoholic drinks) sufficient in color to show that the mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox drink has been tampered with. azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap 0222. In another aspect of the invention, a formulation of entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a traZodone and oxytocinto treat sexual disorders has an outer pharmaceutically acceptable carrier. layer that releases a nontoxic gelling agent in water or water US 2015/O 150946 A1 Jun. 4, 2015 29 alcohol solutions sufficient to thicken or solidify the drink to 0234. In one aspect, the invention provides a composition show it has been tampered with. comprising the 5-HT, receptor agonist and 5-HT2, antago 0223) In another aspect of the invention, a formulation of nist nefazodone, a 5-HT2, agonist (e.g., lorcaserin, vabi oxytocinto treat sexual disorders has an outer layer with rapid caserin, PRX-00933, YM348, metachlorophenylpiperazine, release of an effective but well tolerated amount of oxytocin, and mCPP), ther non-abusable agents (agents not scheduled and an inner core with a Sustained release of an effective and by the DEA) that augment dopamine and/or norepinephrine well tolerated amount of oxytocin. in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, 0224. In another aspect of the invention, a formulation of 332, daledalin, edivoxetine, esreboxetine, lortalamine, oxytocin to treat sexual disorders has a highly soluble outer mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox layer and a matrix inner layer that remains insoluble in water azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap or water-alcohol Solutions (alcoholic drinks) and is large entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a enough to be easily visible and show that the drink has been pharmaceutically acceptable carrier. tampered with. 0235. In one aspect, the invention provides a composition 0225. In another aspect of the invention, a formulation of comprising the 5-HT, receptor agonist and 5-HT2, antago oxytocin to treat sexual disorders has an outer layer that nist mirtazapine and a pharmaceutically acceptable carrier. releases a nontoxic dye in water or water-alcohol Solutions 0236. In one aspect, the invention provides a composition (alcoholic drinks) sufficient in color to show that the drink has comprising the 5-HT, receptoragonist, and 5-HT, antago been tampered with. nist mirtazapine, other non-abusable agents (agents not scheduled by the DEA) that augment dopamine and/or nore 0226. In another aspect of the invention, a formulation of pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda oxytocin to treat sexual disorders has an outer layer that lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta releases a nontoxic gelling agent in water or water-alcohol lamine, mazindol, nisoxetine, talopram, talsupram, solutions sufficient to thicken or solidify the drink to show it tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, has been tampered with. radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo 0227. In another aspect of the invention, a formulation of biloba), and a pharmaceutically acceptable carrier. bupropion and traZodone to treat cognitive disorders has an 0237. In one aspect, the invention provides a composition outer layer with rapid release of an effective but well tolerated comprising the 5-HT, receptor agonist and 5-HT2, antago amount of traZodone and bupropion, and an inner core with a nist mirtazapine, a 5-HT, agonist (e.g., lorcaserin, vabi sustained release of an effective and well tolerated amount of caserin, PRX-00933, YM348, metachlorophenylpiperazine, trazodone and bupropion. and mOPP), and a pharmaceutically acceptable carrier. 0228. In another aspect of the invention, a formulation of 0238. In one aspect, the invention provides a composition bupropion and traZodone to treat cognitive disorders has a comprising the 5-HT, receptor agonist and 5-HT2, antago highly soluble outer layer and a matrix inner layer that nist mirtazapine, a 5-HT, agonist (e.g., lorcaserin, vabi remains insoluble in water or water-alcohol Solutions (alco caserin, PRX-00933, YM348, metachlorophenylpiperazine, holic drinks) and is large enough to be easily visible and show and mCPP), ther non-abusable agents (agents not scheduled that the drink has been tampered with. by the DEA) that augment dopamine and/or norepinephrine 0229. In another aspect of the invention, a formulation of in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, bupropion and traZodone to treat cognitive disorders has an 332, daledalin, edivoxetine, esreboxetine, lortalamine, outer layer that releases a nontoxic dye in water or water mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox alcohol solutions (alcoholic drinks) sufficient in color to show azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap that the drink has been tampered with. entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a 0230. In another aspect of the invention, a formulation of pharmaceutically acceptable carrier. bupropion and traZodone to treat cognitive disorders has an 0239. In one aspect, the invention provides a composition outer layer that releases a nontoxic gelling agent in water or comprising the 5-HT, receptor agonist and 5-HT2, antago water-alcohol solutions sufficient to thicken or solidify the nist flibanserin and a pharmaceutically acceptable carrier. drink to show it has been tampered with. 0240. In one aspect, the invention provides a composition 0231. 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-HT2, antago nist flibanserin, other non-abusable agents (agents not sched nist nefazodone and a pharmaceutically acceptable carrier. uled by the DEA) that augment dopamine and/or norepineph 0232. In one aspect, the invention provides a composition rine in the brain, e.g., atomoxetine, reboxetine, amedalin, comprising the 5-HT, receptoragonist, and 5-HT, antago CP-39,332, daledalin, edivoxetine, esreboxetine, lorta nist nefazodone, other non-abusable agents (agents not lamine, mazindol, nisoxetine, talopram, talsupram, tan scheduled by the DEA) that augment dopamine and/or nore damine, Viloxazine, maprotiline, ciclazindol, manifaxine, pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta biloba), and a pharmaceutically acceptable carrier. lamine, mazindol, nisoxetine, talopram, talsupram, 0241. In one aspect, the invention provides a composition tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, comprising the 5-HT, receptor agonist and 5-HT2, antago radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo nist flibanserin, a 5-HT2, agonist (e.g., lorcaserin, vabi biloba), and a pharmaceutically acceptable carrier. caserin, PRX-00933, YM348, metachlorophenylpiperazine, 0233. 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 0242. In one aspect, the invention provides a composition nist nefazodone, a 5-HT2, agonist (e.g., lorcaserin, vabi comprising the 5-HT, receptor agonist and 5-HT2, antago caserin, PRX-00933, YM348, metachlorophenylpiperazine, nist flibanserin, a 5-HT2, agonist (e.g., lorcaserin, vabi and mOPP), and a pharmaceutically acceptable carrier. caserin, PRX-00933, YM348, metachlorophenylpiperazine, US 2015/O 150946 A1 Jun. 4, 2015 30 and mCPP), ther non-abusable agents (agents not scheduled amount of bupropion and oxytocin, and an inner core with a by the DEA) that augment dopamine and/or norepinephrine sustained release of an effective and well tolerated amount of in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, bupropion and oxytocin. 332, daledalin, edivoxetine, esreboxetine, lortalamine, 0252. In another aspect of the invention, a formulation of mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox bupropion and oxytocin to treat cognitive disorders has a azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap highly soluble outer layer and a matrix inner layer that entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a remains insoluble in water or water-alcohol solutions (alco pharmaceutically acceptable carrier. holic drinks) and is large enough to be easily visible and show 0243 In one aspect, the invention provides a composition that the drink has been tampered with. comprising a 5-HT, receptor agonist, 5-HT2 receptor 0253) In another aspect of the invention, a formulation of antagonist, and/or 5-HT, receptor antagonist trazodone and bupropion and oxytocin to treat cognitive disorders has an a pharmaceutically acceptable carrier. outer layer that releases a nontoxic dye in water or water 0244. In one aspect, the invention provides a composition alcohol solutions (alcoholic drinks) sufficient in color to show comprising the 5-HT, receptoragonist, and 5-HT, antago that the drink has been tampered with. nist traZodone, other non-abusable agents (agents not sched 0254. In another aspect of the invention, a formulation of uled by the DEA) that augment dopamine and/or norepineph bupropion and oxytocin to treat cognitive disorders has an rine in the brain, e.g., atomoxetine, reboxetine, amedalin, outer layer that releases a nontoxic gelling agent in water or CP-39,332, daledalin, edivoxetine, esreboxetine, lorta water-alcohol solutions sufficient to thicken or solidify the lamine, mazindol, nisoxetine, talopram, talsupram, tan drink to show it has been tampered with. damine, Viloxazine, maprotiline, ciclazindol, manifaxine, 0255. 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. outer layer with rapid release of an effective but well tolerated 0245. In one aspect, the invention provides a composition amount of traZodone and oxytocin, and an inner core with a comprising the 5-HT, receptor agonist and 5-HT2, antago sustained release of an effective and well tolerated amount of nist traZodone, a 5-HT2, agonist (e.g., lorcaserin, vabi traZodone and oxytocin. caserin, PRX-00933, YM348, metachlorophenylpiperazine, 0256 In another aspect of the invention, a formulation of and mOPP), and a pharmaceutically acceptable carrier. traZodone and oxytocin to treat cognitive disorders has a 0246. In one aspect, the invention provides a composition highly soluble outer layer and a matrix inner layer that comprising the 5-HT, receptor agonist and 5-HT, antago remains insoluble in water or water-alcohol solutions (alco nist traZodone, a 5-HT2, agonist (e.g., lorcaserin, vabi holic drinks) and is large enough to be easily visible and show caserin, PRX-00933, YM348, metachlorophenylpiperazine, that the drink has been tampered with. and mCPP), ther non-abusable agents (agents not scheduled 0257. In another aspect of the invention, a formulation of by the DEA) that augment dopamine and/or norepinephrine traZodone and oxytocin to treat cognitive disorders has an in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, outer layer that releases a nontoxic dye in water or water 332, daledalin, edivoxetine, esreboxetine, lortalamine, alcohol solutions (alcoholic drinks) sufficient in color to show mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox that the drink has been tampered with. azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap 0258. In another aspect of the invention, a formulation of entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a traZodone and oxytocin to treat cognitive disorders has an pharmaceutically acceptable carrier. outer layer that releases a nontoxic gelling agent in water or 0247. In another aspect of the invention, a formulation of water-alcohol solutions sufficient to thicken or solidify the bupropion, traZodone, and oxytocin to treat cognitive disor drink to show it has been tampered with. ders has an outer layer with rapid release of an effective but 0259. In another aspect of the invention, a formulation of well tolerated amount of bupropion, traZodone, and oxytocin, oxytocin to treat cognitive disorders has an outer layer with and an inner core with a Sustained release of an effective and rapid release of an effective but well tolerated amount of well tolerated amount of bupropion, traZodone, and oxytocin. oxytocin, and an inner core with a Sustained release of an 0248. In another aspect of the invention, a formulation of effective and well tolerated amount of oxytocin. bupropion, traZodone, and oxytocin to treat cognitive disor 0260. In another aspect of the invention, a formulation of ders has a highly soluble outer layer and a matrix inner layer oxytocin to treat cognitive disorders has a highly soluble that remains insoluble in water or water-alcohol solutions outer layer and a matrix inner layer that remains insoluble in (alcoholic drinks) and is large enough to be easily visible and water or water-alcohol Solutions (alcoholic drinks) and is show that the drink has been tampered with. large enough to be easily visible and show that the drink has 0249. In another aspect of the invention, a formulation of been tampered with. bupropion, traZodone, and oxytocin to treat cognitive disor 0261. In another aspect of the invention, a formulation of ders has an outer layer that releases a nontoxic dye in water or oxytocin to treat cognitive disorders has an outer layer that water-alcohol solutions (alcoholic drinks) sufficient in color releases a nontoxic dye in water or water-alcohol Solutions to show that the drink has been tampered with. (alcoholic drinks) sufficient in color to show that the drink has 0250 In another aspect of the invention, a formulation of been tampered with. bupropion, traZodone, and oxytocin to treat cognitive disor 0262. In another aspect of the invention, a formulation of ders has an outer layer that releases a nontoxic gelling agent oxytocin to treat cognitive disorders has an outer layer that in water or water-alcohol solutions sufficient to thicken or releases a nontoxic gelling agent in water or water-alcohol solidify the drink to show it has been tampered with. solutions sufficient to thicken or solidify the drink to show it 0251. In another aspect of the invention, a formulation of has been tampered with. bupropion and oxytocin to treat cognitive disorders has an 0263. In another aspect of the invention, a formulation of outer layer with rapid release of an effective but well tolerated bupropion and traZodone to enhance cognition has an outer US 2015/O 150946 A1 Jun. 4, 2015

layer with rapid release of an effective but well tolerated 0273. In one aspect, the invention provides a composition amount of traZodone and bupropion, and an inner core with a comprising the 5-HT, receptor agonist and 5-HT2, antago sustained release of an effective and well tolerated amount of nist mirtazapine, a 5-HT2, agonist (e.g., lorcaserin, vabi traZodone and bupropion. caserin, PRX-00933, YM348, metachlorophenylpiperazine, 0264. In another aspect of the invention, a formulation of and mOPP), and a pharmaceutically acceptable carrier. bupropion and traZodone to enhance cognition has a highly 0274. In one aspect, the invention provides a composition soluble outer layer and a matrix inner layer that remains comprising the 5-HT, receptor agonist and 5-HT2, antago insoluble in water or water-alcohol solutions (alcoholic nist mirtazapine, a 5-HT2, agonist (e.g., lorcaserin, vabi drinks) and is large enough to be easily visible and show that caserin, PRX-00933, YM348, metachlorophenylpiperazine, the drink has been tampered with. and mCPP), ther non-abusable agents (agents not scheduled 0265. In another aspect of the invention, a formulation of by the DEA) that augment dopamine and/or norepinephrine bupropion and traZodone to enhance cognition has an outer in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, layer that releases a nontoxic dye in water or water-alcohol 332, daledalin, edivoxetine, esreboxetine, lortalamine, solutions (alcoholic drinks) sufficient in color to show that the mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox drink has been tampered with. azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap 0266. In another aspect of the invention, a formulation of entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a bupropion and traZodone to enhance cognition has an outer pharmaceutically acceptable carrier. layer that releases a nontoxic gelling agent in water or water 0275. In one aspect, the invention provides a composition alcohol solutions sufficient to thicken or solidify the drink to comprising the 5-HT, receptor agonist and 5-HT2, antago show it has been tampered with. nist flibanserin and a pharmaceutically acceptable carrier. 0276. In one aspect, the invention provides a composition 0267 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-HT2, antago nist flibanserin, other non-abusable agents (agents not sched nist nefazodone and a pharmaceutically acceptable carrier. uled by the DEA) that augment dopamine and/or norepineph 0268. In one aspect, the invention provides a composition rine in the brain, e.g., atomoxetine, reboxetine, amedalin, comprising the 5-HT, receptoragonist, and 5-HT, antago CP-39,332, daledalin, edivoxetine, esreboxetine, lorta nist nefazodone, other non-abusable agents (agents not lamine, mazindol, nisoxetine, talopram, talsupram, tan scheduled by the DEA) that augment dopamine and/or nore damine, Viloxazine, maprotiline, ciclazindol, manifaxine, pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta biloba), and a pharmaceutically acceptable carrier. lamine, mazindol, nisoxetine, talopram, talsupram, 0277. In one aspect, the invention provides a composition tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, comprising the 5-HT, receptor agonist and 5-HT2, antago radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo nist flibanserin, a 5-HT, agonist (e.g., lorcaserin, vabi biloba), and a pharmaceutically acceptable carrier. caserin, PRX-00933, YM348, metachlorophenylpiperazine, 0269. 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 0278. In one aspect, the invention provides a composition nist nefazodone, a 5-HT, agonist (e.g., lorcaserin, vabi comprising the 5-HT, receptor agonist and 5-HT2, antago caserin, PRX-00933, YM348, metachlorophenylpiperazine, nist flibanserin, a 5-HT, agonist (e.g., lorcaserin, vabi and mOPP), and a pharmaceutically acceptable carrier. caserin, PRX-00933, YM348, metachlorophenylpiperazine, 0270. 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 nefazodone, a 5-HT, agonist (e.g., lorcaserin, vabi in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, caserin, PRX-00933, YM348, metachlorophenylpiperazine, 332, daledalin, edivoxetine, esreboxetine, lortalamine, and mCPP), ther non-abusable agents (agents not scheduled mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox by the DEA) that augment dopamine and/or norepinephrine azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a 332, daledalin, edivoxetine, esreboxetine, lortalamine, pharmaceutically acceptable carrier. mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox 0279. In one aspect, the invention provides a composition azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap comprising a 5-HT, receptor agonist, 5-HT2 receptor entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a antagonist, and/or 5-HT, receptor antagonist trazodone and pharmaceutically acceptable carrier. a pharmaceutically acceptable carrier. 0271 In one aspect, the invention provides a composition 0280. In one aspect, the invention provides a composition comprising the 5-HT, receptor agonist and 5-HT2, antago comprising the 5-HT, receptoragonist, and 5-HT, antago nist mirtazapine and a pharmaceutically acceptable carrier. nist traZodone, other non-abusable agents (agents not sched 0272. In one aspect, the invention provides a composition uled by the DEA) that augment dopamine and/or norepineph comprising the 5-HT, receptoragonist, and 5-HT, antago rine in the brain, e.g., atomoxetine, reboxetine, amedalin, nist mirtazapine, other non-abusable agents (agents not CP-39,332, daledalin, edivoxetine, esreboxetine, lorta scheduled by the DEA) that augment dopamine and/or nore lamine, mazindol, nisoxetine, talopram, talsupram, tan pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda damine, Viloxazine, maprotiline, ciclazindol, manifaxine, lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo lamine, mazindol, nisoxetine, talopram, talsupram, biloba), and a pharmaceutically acceptable carrier. tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, 0281. In one aspect, the invention provides a composition radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo comprising the 5-HT, receptor agonist and 5-HT2, antago biloba), and a pharmaceutically acceptable carrier. nist traZodone, a 5-HT2, agonist (e.g., lorcaserin, vabi US 2015/O 150946 A1 Jun. 4, 2015 32 caserin, PRX-00933, YM348, metachlorophenylpiperazine, 0292. In another aspect of the invention, a formulation of and mOPP), and a pharmaceutically acceptable carrier. traZodone and oxytocin to enhance cognition has a highly 0282. In one aspect, the invention provides a composition soluble outer layer and a matrix inner layer that remains comprising the 5-HT, receptor agonist and 5-HT, antago insoluble in water or water-alcohol solutions (alcoholic nist traZodone, a 5-HT2, agonist (e.g., lorcaserin, vabi drinks) and is large enough to be easily visible and show that caserin, PRX-00933, YM348, metachlorophenylpiperazine, the drink has been tampered with. and mCPP), ther non-abusable agents (agents not scheduled 0293. In another aspect of the invention, a formulation of by the DEA) that augment dopamine and/or norepinephrine traZodone and oxytocin to enhance cognition has an outer in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, layer that releases a nontoxic dye in water or water-alcohol 332, daledalin, edivoxetine, esreboxetine, lortalamine, solutions (alcoholic drinks) sufficient in color to show that the mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox drink has been tampered with. azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap 0294. In another aspect of the invention, a formulation of entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a traZodone and oxytocin to enhance cognition has an outer pharmaceutically acceptable carrier. layer that releases a nontoxic gelling agent in water or water 0283. In another aspect of the invention, a formulation of alcohol solutions sufficient to thicken or solidify the drink to bupropion, traZodone, and oxytocinto enhance cognition has show it has been tampered with. an outer layer with rapid release of an effective but well 0295. In another aspect of the invention, a formulation of tolerated amount of bupropion, traZodone, and oxytocin, and oxytocin to enhance cognition has an outer layer with rapid an inner core with a sustained release of an effective and well release of an effective but well tolerated amount of oxytocin, tolerated amount of bupropion, traZodone, and oxytocin. and an inner core with a Sustained release of an effective and 0284. In another aspect of the invention, a formulation of well tolerated amount of oxytocin. bupropion, traZodone, and oxytocinto enhance cognition has 0296. In another aspect of the invention, a formulation of a highly soluble outer layer and a matrix inner layer that oxytocinto enhance cognition has a highly soluble outer layer remains insoluble in water or water-alcohol Solutions (alco and a matrix inner layer that remains insoluble in water or holic drinks) and is large enough to be easily visible and show water-alcohol Solutions (alcoholic drinks) and is large enough that the drink has been tampered with. to be easily visible and show that the drink has been tampered 0285. In another aspect of the invention, a formulation of with. bupropion, traZodone, and oxytocinto enhance cognition has 0297. In another aspect of the invention, a formulation of an outer layer that releases a nontoxic dye in water or water oxytocinto enhance cognition has an outer layer that releases alcohol solutions (alcoholic drinks) sufficient in color to show a nontoxic dye in water or water-alcohol Solutions (alcoholic that the drink has been tampered with. drinks) sufficient in color to show that the drink has been 0286. In another aspect of the invention, a formulation of tampered with. bupropion, traZodone, and oxytocinto enhance cognition has 0298. In another aspect of the invention, a formulation of an outer layer that releases a nontoxic gelling agent in water oxytocinto enhance cognition has an outer layer that releases or water-alcohol solutions sufficient to thicken or solidify the a nontoxic gelling agent in water or water-alcohol Solutions drink to show it has been tampered with. sufficient to thicken or solidify the drink to show it has been 0287. In another aspect of the invention, a formulation of tampered with. bupropion and oxytocin to enhance cognition has an outer 0299. In one embodiment, the composition is that com layer with rapid release of an effective but well tolerated prising bupropion, comprising bupropion in a dosage range of amount of bupropion and oxytocin, and an inner core with a 100-450 mg qd; comprising bupropion in a dosage range of sustained release of an effective and well tolerated amount of 200-450 mg qd; comprising bupropion in a dosage range of bupropion and oxytocin. 100-300 mg qd; comprising bupropion in a dosage range of 0288. In another aspect of the invention, a formulation of 225-300 mg qd; comprising bupropion in a dosage range of bupropion and oxytocin to enhance cognition has a highly 100-275 mg qd; or comprising bupropion in a dosage range of soluble outer layer and a matrix inner layer that remains 200-275 mg qd; comprising bupropion in a dosage range of insoluble in water or water-alcohol solutions (alcoholic XX-YY mg qd, wherein XX is an integer between 5 and 400 drinks) and is large enough to be easily visible and show that and YY is an integer between 50 and 450. the drink has been tampered with. 0300. In one embodiment, the composition is that com 0289. In another aspect of the invention, a formulation of prising traZodone, comprising traZodone in a dosage range of bupropion and oxytocin to enhance cognition has an outer 25-450 mg qd; comprising traZodone in a dosage range of layer that releases a nontoxic dye in water or water-alcohol 75-150 mg qd; or comprising traZodone in a dosage range of solutions (alcoholic drinks) sufficient in color to show that the 50-100 mg qd; comprising traZodone in a dosage range of drink has been tampered with. XX-YY mg qd, wherein XX is an integer between 25 and 400 0290. In another aspect of the invention, a formulation of and YY is an integer between 50 and 450. bupropion and oxytocin to enhance cognition has an outer 0301 In one embodiment, the composition is that com layer that releases a nontoxic gelling agent in water or water prising oxytocin, comprising oxytocin in a dosage range of alcohol solutions sufficient to thicken or solidify the drink to 4-400 International Units. show it has been tampered with. 0302) In one embodiment, the composition is that com 0291. In another aspect of the invention, a formulation of prising bupropion and traZodone, comprising bupropion in a traZodone and oxytocin to enhance cognition has an outer dosage range of 50-450 mg and traZodone in a dosage range layer with rapid release of an effective but well tolerated of 25-450 mg; comprising bupropion in a dosage range of amount of traZodone and oxytocin, and an inner core with a 200-450 mg and traZodone in a dosage range of 25-450 mg: sustained release of an effective and well tolerated amount of comprising bupropion in a dosage range of 100-300 mg qd traZodone and oxytocin. and comprising traZodone in a dosage range of 75-150 mg qd; US 2015/O 150946 A1 Jun. 4, 2015

comprising bupropion in a dosage range of 225-300 mg qd 0307. In one aspect, the invention provides a method of and comprising trazodone in a dosage range of 75-150 mg qd; making a composition comprising combining a 5-HT ago comprising bupropion in a dosage range of 100-275 mg qd nist/5-HT, antagonist, a norepinephrine-dopamine reuptake and comprising trazodone in a dosage range of 50-100 mg qd; inhibitor, other non-abusable agents (agents not scheduled by or comprising bupropion in a dosage range of 200-275 mg qd the DEA) that augment dopamine and/or norepinephrine in and comprising trazodone in a dosage range of 50-100 mg qd. the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, 0303. In one embodiment, the composition is that com 332, daledalin, edivoxetine, esreboxetine, lortalamine, prising bupropion, traZodone, and oxytocin, comprising mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox bupropion in a dosage range of 50-450 mg. traZodone in a azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap dosage range of 25-450 mg, and oxytocin in a dose range of entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a 4-400 International Units; comprising bupropion in a dosage pharmaceutically acceptable carrier. In one aspect, the inven range of 200-450 mg. trazodone in a dosage range of 25-450 tion provides a method of making a composition comprising mg, and oxytocinina dose range of 4-400 International Units: combining a 5-HT, receptor agonist, a 5-HT, antagonist, comprising bupropion in a dosage range of 100-300 mg qd, and a pharmaceutically acceptable carrier. In one aspect, the comprising traZodone in a dosage range of 75-150 mg qd, and invention provides a method of making a composition com oxytocin in a dose range of 4-400 International Units qd; prising combining a 5-HT, receptor agonist, and a pharma comprising bupropion in a dosage range of 225-300 mg qd, ceutically acceptable carrier. In one aspect, the invention comprising traZodone in a dosage range of 75-150 mg qd, and provides a method of making a composition comprising com oxytocin in a dose range of 4-400 International Units qd; bining a 5-HT, receptor agonist, 5-HT, receptor antago comprising bupropion in a dosage range of 100-275 mg qd, nist, and/or 5-HT, receptor antagonist, and a pharmaceuti comprising traZodone in a dosage range of 50-100 mg qd, and cally acceptable carrier. comprising oxytocin in a dose range of 4-400 International 0308. In one aspect, the invention provides a method of Units qd; or comprising bupropion in a dosage range of 200 making a composition comprising combining a 5-HT ago 275 mg qd, comprising traZodone in a dosage range of 50-100 nist/5-HT, antagonist, a norepinephrine-dopamine reuptake mg qd, and comprising oxytocin in a dose range of 4-400 inhibitor, a 5-HT agonist (e.g., lorcaserin, vabicaserin, International Units. PRX-00933, YM348, metachlorophenylpiperazine, and mCPP), and a pharmaceutically acceptable carrier. In one 0304. In one embodiment, the composition is that com aspect, the invention provides a method of making a compo prising bupropion and oxytocin, comprising bupropion in a sition comprising combining a 5-HT, receptor agonist, a dosage range of 50-450 mg and oxytocin in a dosage range of 5-HT, antagonist, and a pharmaceutically acceptable car 4-400 International Units; comprising bupropion in a dosage rier. In one aspect, the invention provides a method of making range of 200-450 mg and oxytocin in a dosage range of 4-400 a composition comprising combining a 5-HT, receptorago International Units; comprising bupropion in a dosage range nist, and a pharmaceutically acceptable carrier. In one aspect, of 100-300 mg qd and comprising oxytocin in a dosage range the invention provides a method of making a composition of 4-400 International Units qd; comprising bupropion in a comprising combining a 5-HT, receptor agonist, 5-HT, dosage range of 225-300 mg qd and comprising oxytocin in a receptor antagonist, and/or 5-HT2 receptor antagonist, and a dosage range of 4-400 International Units qd; comprising pharmaceutically acceptable carrier. bupropion in a dosage range of 100-275 mg qd and compris ing oxytocin in a dosage range of 4-400 International Units 0309. In one aspect, the invention provides a method of qd; or comprising bupropion in a dosage range of 200-275 mg making a composition comprising combining a 5-HT ago qd and comprising oxytocin in a dosage range of 4-400 Inter nist/5-HT, antagonist, a norepinephrine-dopamine reuptake inhibitor, a 5-HT, agonist (e.g., lorcaserin, vabicaserin, national Units qd. PRX-00933, YM348, metachlorophenylpiperazine, and 0305. In one embodiment, the composition is that com mCPP), other non-abusable agents (agents not scheduled by prising oxytocin and traZodone, comprising oxytocin in a the DEA) that augment dopamine and/or norepinephrine in dosage range of 4-400 International Units and traZodone in a the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, dosage range of 25-450 mg; comprising oxytocin in a dosage 332, daledalin, edivoxetine, esreboxetine, lortalamine, range of 4-400 International Units qd and comprising traZ mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox odone in a dosage range of 75-150 mg qd; or comprising azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap oxytocin in a dosage range of 4-400 International Units qd entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a and comprising trazodone in a dosage range of 50-100 mg qd. pharmaceutically acceptable carrier. In one aspect, the inven 0306 In one aspect, the invention provides a method of tion provides a method of making a composition comprising making a composition comprising combining a 5-HTago combining a 5-HT, receptor agonist, a 5-HT, antagonist, nist/5-HT, antagonist, a norepinephrine-dopamine reuptake and a pharmaceutically acceptable carrier. In one aspect, the inhibitor, and a pharmaceutically acceptable carrier. In one invention provides a method of making a composition com aspect, the invention provides a method of making a compo prising combining a 5-HT, receptor agonist, and a pharma sition comprising combining a 5-HT, receptor agonist, a ceutically acceptable carrier. In one aspect, the invention 5-HT, antagonist, and a pharmaceutically acceptable car provides a method of making a composition comprising com rier. In one aspect, the invention provides a method of making bining a 5-HT, receptor agonist, 5-HT, receptor antago a composition comprising combining a 5-HT, receptorago nist, and/or 5-HT, receptor antagonist, and a pharmaceuti nist, and a pharmaceutically acceptable carrier. In one aspect, cally acceptable carrier. the invention provides a method of making a composition 0310. In one aspect, the method of making a composition comprising combining a 5-HT, receptor agonist, 5-HT comprises combining a 5-HT, receptor agonist, a norepi receptor antagonist, and/or 5-HT, receptor antagonist, and a nephrine-dopamine reuptake inhibitor and a pharmaceuti pharmaceutically acceptable carrier. cally acceptable carrier Such that the composition comprises US 2015/O 150946 A1 Jun. 4, 2015 34 a range of 25-450 mg of a 5-HT, receptoragonist. In another 0315. In one embodiment, the method comprises combin aspect, the invention provides a method of making a compo ing bupropion, traZodone, other non-abusable agents (agents sition comprising combining a 5-HT, receptor agonist, not scheduled by the DEA) that augment dopamine and/or 5-HT, receptor antagonist, and/or 5-HT, receptor antago norepinephrine in the brain, e.g., atomoxetine, reboxetine, nist and a pharmaceutically acceptable carrier Such that the amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, composition comprises a range of 25-450 mg of a 5-HT, lortalamine, mazindol, nisoxetine, talopram, talsupram, tan antagonist and a norepinephrine-dopamine reuptake inhibi damine, Viloxazine, maprotiline, ciclazindol, manifaxine, tOr. radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo 0311. In one aspect, the method of making a composition biloba), and a pharmaceutically acceptable carrier. comprises combining a 5-HT, receptor agonist, a norepi 0316. In one embodiment, the method comprises combin nephrine-dopamine reuptake inhibitor, other non-abusable ing bupropion, trazodone, a 5-HT, agonist (e.g., lorcaserin, agents (agents not scheduled by the DEA) that augment vabicaserin, PRX-00933, YM348, metachlorophenylpipera dopamine and/or norepinephrine in the brain, e.g., atomoxet Zine, and mCPP), and a pharmaceutically acceptable carrier. ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, 0317. In one embodiment, the method comprises combin eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, ing bupropion, traZodone, a 5-HT, agonist (e.g., lorcaserin, talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, vabicaserin, PRX-00933, YM348, metachlorophenylpipera manifaxine, radafaxine, tapentadol, teniloxazine, St. John's Zine, other non-abusable agents (agents not scheduled by the wort, ginkgo biloba), and a pharmaceutically acceptable car DEA) that augment dopamine and/or norepinephrine in the rier Such that the composition comprises a range of 25-450 brain, e.g., atomoxetine, reboxetine, amedalin, CP-39,332, mg of a 5-HT, receptoragonist. In another aspect, the inven daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, tion provides a method of making a composition comprising nisoxetine, talopram, talSupram, tandamine, Viloxazine, combining a 5-HT, receptor agonist, 5-HT, receptor maprotiline, ciclazindol, manifaxine, radafaxine, tapentadol, antagonist, and/or 5-HT, receptor antagonist and a pharma teniloxazine, St. John's wort, ginkgo biloba), and mOPP), and ceutically acceptable carrier Such that the composition com a pharmaceutically acceptable carrier. prises a range of 25-450 mg of a 5-HT, antagonist and a 0318. In one aspect, the method of making a composition norepinephrine-dopamine reuptake inhibitor. comprises combining a 5-HT, receptor agonist, a norepi 0312. In one aspect, the method of making a composition nephrine-dopamine reuptake inhibitor (e.g., bupropion), an comprises combining a 5-HT, receptor agonist, a norepi oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto nephrine-dopamine reuptake inhibitor, a 5-HT agonist cin, SyntocinonR), and a pharmaceutically acceptable carrier (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, Such that the composition comprises a range of 25-450 mg of metachlorophenylpiperazine, and mCPP), and a pharmaceu a 5-HT, receptor agonist. In another aspect, the method of tically acceptable carrier Such that the composition comprises making comprises combining a 5-HT agonist/5-HT a range of 25-450 mg of a 5-HT, receptoragonist. In another antagonist (e.g., traZodone, nefazodone, mirtazapine, fli aspect, the invention provides a method of making a compo banserin) and a pharmaceutically acceptable carrier Such that sition comprising combining a 5-HT, receptor agonist, the composition comprises a range of 25-450 mg of a 5-HT 5-HT2 receptor antagonist, and/or 5-HT, receptor antago antagonist, a norepinephrine-dopamine reuptake inhibitor nist and a pharmaceutically acceptable carrier Such that the (e.g., bupropion), and an oxytocin receptor (OXTR) agonist composition comprises a range of 25-450 mg of a 5-HT (e.g., carbetocin, oxytocin, SyntocinonR). antagonist and a norepinephrine-dopamine reuptake inhibi 0319. In one aspect, the method of making a composition comprises combining a 5-HT, receptor agonist, a norepi tOr. nephrine-dopamine reuptake inhibitor (e.g., bupropion), an 0313. In one aspect, the method of making a composition oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto comprises combining a 5-HT, receptor agonist, a norepi cin, Syntocinon R.), and a pharmaceutically acceptable carrier nephrine-dopamine reuptake inhibitor, a 5-HT2, agonist Such that the composition comprises a range of 25-450 mg of (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, a 5-HT, receptor agonist. In another aspect, the method of metachlorophenylpiperazine, and mOPP), other non-abus making comprises combining a 5-HT agonist/5-HT able agents (agents not scheduled by the DEA) that augment antagonist (e.g., traZodone, nefazodone, mirtazapine, fli dopamine and/or norepinephrine in the brain, e.g., atomoxet banserin, ketanserin, ritanserin, clozapine, olanzapine, que ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, tiapine, risperidone, asenapine, MDL-100.907, cyprohepta eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, dine, aripiprazole, and the general class of 2-alkyl-4-aryl talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, tetrahydro-pyrimido-azepines) and a pharmaceutically manifaxine, radafaxine, tapentadol, teniloxazine, St. John's acceptable carrier Such that the composition comprises a wort, ginkgo biloba), and a pharmaceutically acceptable car range of 25-450mg of a 5-HT, antagonist, a norepinephrine rier Such that the composition comprises a range of 25-450 dopamine reuptake inhibitor (e.g., bupropion), and an oxyto mg of a 5-HT, receptoragonist. In another aspect, the inven cin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syn tion provides a method of making a composition comprising tocinonR). combining a 5-HT, receptor agonist, 5-HT, receptor 0320 In one aspect, the method of making a composition antagonist, and/or 5-HT, receptor antagonist and a pharma comprises combining a 5-HT, receptor agonist, a norepi ceutically acceptable carrier Such that the composition com nephrine-dopamine reuptake inhibitor (e.g., bupropion), an prises a range of 25-450 mg of a 5-HT, antagonist and a oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto norepinephrine-dopamine reuptake inhibitor. cin, Syntocinon R.), other non-abusable agents (agents not 0314. In one embodiment, the method comprises combin scheduled by the DEA) that augment dopamine and/or nore ing bupropion, traZodone, and a pharmaceutically acceptable pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda carrier. lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta US 2015/O 150946 A1 Jun. 4, 2015 lamine, mazindol, nisoxetine, talopram, talsupram, 0324. In one aspect, the method of making a composition tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, comprises combining a 5-HT, receptor antagonist (e.g., tra radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo Zodone, nefazodone, mirtazapine, flibanserin), a norepineph biloba), and a pharmaceutically acceptable carrier Such that rine-dopamine reuptake inhibitor (e.g., bupropion), an oxy the composition comprises a range of 25-450mg of a 5-HT tocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, receptor agonist. In another aspect, the method of making Syntocinon R.), and a pharmaceutically acceptable carrier comprises combining a 5-HT agonist/5-HT, antagonist Such that the composition comprises a range of 50-450 mg of (e.g., traZodone, nefazodone, mirtazapine, flibanserin, ket a norepinephrine-dopamine reuptake inhibitor, a 5-HT anserin, ritanserin, clozapine, olanzapine, quetiapine, risperi antagonist, and an oxytocin receptor (OXTR) agonist. done, asenapine, MDL-100.907, cyproheptadine, aripipra 0325 In one aspect, the method of making a composition Zole, and the general class of 2-alkyl-4-aryl-tetrahydro comprises combining a 5-HT, receptor antagonist (e.g., tra pyrimido-azepines) and a pharmaceutically acceptable Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, carrier Such that the composition comprises a range of 25-450 ritanserin, clozapine, olanzapine, quetiapine, risperidone, mg of a 5-HT, antagonist, a norepinephrine-dopamine asenapine, MDL-100.907, cyproheptadine, aripiprazole, and reuptake inhibitor (e.g., bupropion), and an oxytocin receptor the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR). azepines), a norepinephrine-dopamine reuptake inhibitor 0321. In one aspect, the method of making a composition (e.g., bupropion), an oxytocin receptor (OXTR) agonist (e.g., comprises combining a 5-HT, receptor agonist, a norepi carbetocin, oxytocin, Syntocinon R.), and a pharmaceutically nephrine-dopamine reuptake inhibitor (e.g., bupropion), an acceptable carrier Such that the composition comprises a oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto range of 50-450 mg of a norepinephrine-dopamine reuptake cin, SyntocinonR), a 5-HT, agonist (e.g., lorcaserin, vabi inhibitor, a 5-HT, antagonist, and an oxytocin receptor caserin, PRX-00933, YM348, metachlorophenylpiperazine), (OXTR) agonist. and a pharmaceutically acceptable carrier Such that the com 0326 In one aspect, the method of making a composition position comprises a range of 25-450 mg of a 5-HT, receptor comprises combining a 5-HT, receptor antagonist (e.g., tra agonist. In another aspect, the method of making comprises Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, combining a 5-HT agonist/5-HT, antagonist (e.g., traz ritanserin, clozapine, olanzapine, quetiapine, risperidone, odone, 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 (e.g., azepines) and a pharmaceutically acceptable carrier Such that carbetocin, oxytocin, Syntocinon R.), other non-abusable the composition comprises a range of 25-450mg of a 5-HT agents (agents not scheduled by the DEA) that augment antagonist, a norepinephrine-dopamine reuptake inhibitor dopamine and/or norepinephrine in the brain, e.g., atomoxet (e.g., bupropion), and an oxytocin receptor (OXTR) agonist ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, (e.g., carbetocin, oxytocin, SyntocinonR). eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, 0322. In one aspect, the method of making a composition talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, comprises combining a 5-HT, receptor agonist, a norepi manifaxine, radafaxine, tapentadol, teniloxazine, St. John's nephrine-dopamine reuptake inhibitor (e.g., bupropion), an wort, ginkgo biloba), and a pharmaceutically acceptable car oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto rier such that the composition comprises a range of 50-450 cin, Syntocinon R.), a 5-HT, agonist (e.g., lorcaserin, vabi mg of a norepinephrine-dopamine reuptake inhibitor, a caserin, PRX-00933, YM348, metachlorophenylpiperazine), 5-HT, antagonist, and an oxytocin receptor (OXTR) ago other non-abusable agents (agents not scheduled by the DEA) nist. that augment dopamine and/or norepinephrine in the brain, 0327. In one aspect, the method of making a composition e.g., atomoxetine, reboxetine, amedalin, CP-39,332, daleda comprises combining a 5-HT, receptor antagonist (e.g., tra lin, edivoxetine, esreboxetine, lortalamine, mazindol, nisox Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, etine, talopram, talsupram, tandamine, Viloxazine, mapro ritanserin, clozapine, olanzapine, quetiapine, risperidone, tiline, ciclaZindol, manifaxine, radafaxine, tapentadol, asenapine, MDL-100.907, cyproheptadine, aripiprazole, and teniloxazine, St. John’s wort, ginkgo biloba), and a pharma the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido ceutically acceptable carrier Such that the composition com azepines), a norepinephrine-dopamine reuptake inhibitor prises a range of 25-450 mg of a 5-HT, receptor agonist. In (e.g., bupropion), an oxytocin receptor (OXTR) agonist (e.g., another aspect, the method of making comprises combining a carbetocin, oxytocin, Syntocinon R.), a 5-HT, agonist (e.g., 5-HT agonist/5-HT, antagonist (e.g., traZodone, nefaZ lorcaserin, vabicaserin, PRX-00933, YM348, metachlo odone, mirtazapine, flibanserin, ketanserin, ritanserin, cloza rophenylpiperazine), and a pharmaceutically acceptable car pine, olanzapine, quetiapine, risperidone, asenapine, MDL rier such that the composition comprises a range of 50-450 100,907, cyproheptadine, aripiprazole, and the general class mg of a norepinephrine-dopamine reuptake inhibitor, a of 2-alkyl-4-aryl-tetrahydro-pyrimido-azepines) and a phar 5-HT, antagonist, and an oxytocin receptor (OXTR) ago maceutically acceptable carrier Such that the composition nist. comprises a range of 25-450 mg of a 5-HT, antagonist, a 0328. In one aspect, the method of making a composition norepinephrine-dopamine reuptake inhibitor (e.g., bupro comprises combining a 5-HT, receptor antagonist (e.g., tra pion), and an oxytocin receptor (OXTR) agonist (e.g., carbe Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, tocin, oxytocin, SyntocinonR). ritanserin, clozapine, olanzapine, quetiapine, risperidone, 0323. In one embodiment, the method comprises combin asenapine, MDL-100.907, cyproheptadine, aripiprazole, and ing bupropion, traZodone, oxytocin (SyntocinonR), and a the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido pharmaceutically acceptable carrier. azepines), a norepinephrine-dopamine reuptake inhibitor US 2015/O 150946 A1 Jun. 4, 2015 36

(e.g., bupropion), an oxytocin receptor (OXTR) agonist (e.g., asenapine, MDL-100.907, cyproheptadine, aripiprazole, and carbetocin, oxytocin, Syntocinon R.), a 5-HT, agonist (e.g., the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido lorcaserin, vabicaserin, PRX-00933, YM348, metachlo azepines), a norepinephrine-dopamine reuptake inhibitor rophenylpiperazine), other non-abusable agents (agents not (e.g., bupropion), an oxytocin receptor (OXTR) agonist (e.g., scheduled by the DEA) that augment dopamine and/or nore carbetocin, oxytocin, Syntocinon R.), a 5-HT, agonist (e.g., pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda lorcaserin, vabicaserin, PRX-00933, YM348, metachlo lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta rophenylpiperazine), and a pharmaceutically acceptable car lamine, mazindol, nisoxetine, talopram, talsupram, rier Such that the composition comprises a range of 4-400 tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, International Units of an oxytocin receptor (OXTR) agonist, radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo a norepinephrine-dopamine reuptake inhibitor, and a 5-HT biloba), and a pharmaceutically acceptable carrier Such that antagonist. the composition comprises a range of 50-450 mg of a nore 0334. In one aspect, the method of making a composition pinephrine-dopamine reuptake inhibitor, a 5-HT, antago comprises combining a 5-HT, receptor antagonist (e.g., tra nist, and an oxytocin receptor (OXTR) agonist. Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, 0329. In one embodiment, the method comprises combin ritanserin, clozapine, olanzapine, quetiapine, risperidone, ing bupropion, traZodone, oxytocin, and a pharmaceutically asenapine, MDL-100.907, cyproheptadine, aripiprazole, and acceptable carrier. the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido 0330. In one aspect, the method of making a composition azepines), a norepinephrine-dopamine reuptake inhibitor comprises combining a 5-HT, receptor antagonist (e.g., tra (e.g., bupropion), an oxytocin receptor (OXTR) agonist (e.g., Zodone, nefazodone, mirtazapine, flibanserin), a norepineph carbetocin, oxytocin, Syntocinon R.), a 5-HT, agonist (e.g., rine-dopamine reuptake inhibitor (e.g., bupropion), an oxy lorcaserin, vabicaserin, PRX-00933, YM348, metachlo tocin receptor (OXTR) agonist (e.g., carbetocin, oxytocin, rophenylpiperazine), other non-abusable agents (agents not Syntocinon R.), and a pharmaceutically acceptable carrier scheduled by the DEA) that augment dopamine and/or nore Such that the composition comprises a range of 4-400 Inter pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda national Units of an oxytocin receptor (OXTR) agonist, a lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta norepinephrine-dopamine reuptake inhibitor, and a 5-HT lamine, mazindol, nisoxetine, talopram, talsupram, antagonist. tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, 0331. In one aspect, the method of making a composition radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo comprises combining a 5-HT2 receptor antagonist (e.g., tra biloba), and a pharmaceutically acceptable carrier such that Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, the composition comprises a range of 4-400 International ritanserin, clozapine, olanzapine, quetiapine, risperidone, Units of an oxytocin receptor (OXTR) agonist, a norepineph asenapine, MDL-100.907, cyproheptadine, aripiprazole, and rine-dopamine reuptake inhibitor, and a 5-HT, antagonist. the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido 0335. In one embodiment, the method comprises combin azepines), a norepinephrine-dopamine reuptake inhibitor ing bupropion, traZodone, oxytocin, and a pharmaceutically (e.g., bupropion), an oxytocin receptor (OXTR) agonist (e.g., acceptable carrier. carbetocin, oxytocin, Syntocinon R.), and a pharmaceutically 0336. In one aspect, the method of making a composition acceptable carrier Such that the composition comprises a comprises combining a 5-HT, receptor agonist (e.g., traZ range of 4-400 International Units of an oxytocin receptor odone, nefazodone, mirtazapine, flibanserin), an oxytocin (OXTR) agonist, a norepinephrine-dopamine reuptake receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Synto inhibitor, and a 5-HT, antagonist. cinonR), and a pharmaceutically acceptable carrier Such that 0332. In one aspect, the method of making a composition the composition comprises a range of 25-450 mg of a 5-HT comprises combining a 5-HT, receptor antagonist (e.g., tra receptor agonist. In another aspect, the method of making Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, comprises combining a 5-HT agonist/5-HT, antagonist ritanserin, clozapine, olanzapine, quetiapine, risperidone, and a pharmaceutically acceptable carrier Such that the com asenapine, MDL-100.907, cyproheptadine, aripiprazole, and position comprises a range of 25-450 mg of a 5-HT, antago the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido nist and an oxytocin receptor (OXTR) agonist. azepines), a norepinephrine-dopamine reuptake inhibitor 0337. In one aspect, the method of making a composition (e.g., bupropion), an oxytocin receptor (OXTR) agonist (e.g., comprises combining a 5-HT, receptor agonist (e.g., traz carbetocin, oxytocin, Syntocinon R.), other non-abusable odone, nefazodone, mirtazapine, flibanserin, ketanserin, agents (agents not scheduled by the DEA) that augment ritanserin, clozapine, olanzapine, quetiapine, risperidone, dopamine and/or norepinephrine in the brain, e.g., atomoxet asenapine, MDL-100.907, cyproheptadine, aripiprazole, and ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, azepines), an oxytocin receptor (OXTR) agonist (e.g., carbe talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, tocin, oxytocin, Syntocinon R.), and a pharmaceutically manifaxine, radafaxine, tapentadol, teniloxazine, St. John's acceptable carrier Such that the composition comprises a wort, ginkgo biloba), and a pharmaceutically acceptable car range of 25-450 mg of a 5-HT, receptoragonist. In another rier Such that the composition comprises a range of 4-400 aspect, the method of making comprises combining a 5-HT International Units of an oxytocin receptor (OXTR) agonist, agonist/5-HT, antagonist and a pharmaceutically accept a norepinephrine-dopamine reuptake inhibitor, and a 5-HT able carrier Such that the composition comprises a range of antagonist. 25-450 mg of a 5-HT, antagonist and an oxytocin receptor 0333. In one aspect, the method of making a composition (OXTR) agonist. comprises combining a 5-HT, receptor antagonist (e.g., tra 0338. In one aspect, the method of making a composition Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, comprises combining a 5-HT, receptor agonist (e.g., traZ ritanserin, clozapine, olanzapine, quetiapine, risperidone, odone, nefazodone, mirtazapine, flibanserin, ketanserin, US 2015/O 150946 A1 Jun. 4, 2015 37 ritanserin, clozapine, olanzapine, quetiapine, risperidone, 0342. 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., tra the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido Zodone, nefazodone, mirtazapine, flibanserin), an oxytocin azepines), an oxytocin receptor (OXTR) agonist (e.g., carbe receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Synto tocin, oxytocin, Syntocinon R.), other non-abusable agents cinonR), and a pharmaceutically acceptable carrier Such that (agents not scheduled by the DEA) that augment dopamine the composition comprises a range of 4-400 International and/or norepinephrine in the brain, e.g., atomoxetine, rebox Units of an oxytocin receptor (OXTR) agonist and a 5-HT, etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox antagonist. etine, lortalamine, mazindol, nisoxetine, talopram, talsu 0343. In one aspect, the method of making a composition pram, tandamine, Viloxazine, maprotiline, ciclaZindol, comprises combining a 5-HT, receptor antagonist (e.g., tra manifaxine, radafaxine, tapentadol, teniloxazine, St. John's Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, wort, ginkgo biloba), and a pharmaceutically acceptable car ritanserin, clozapine, olanzapine, quetiapine, risperidone, rier Such that the composition comprises a range of 25-450 asenapine, MDL-100.907, cyproheptadine, aripiprazole, and mg of a 5-HT, receptor agonist. In another aspect, the the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido method of making comprises combining a 5-HT agonist/5- azepines), an oxytocin receptor (OXTR) agonist (e.g., carbe HT, antagonist and a pharmaceutically acceptable carrier tocin, oxytocin, Syntocinon R.), and a pharmaceutically Such that the composition comprises a range of 25-450 mg of acceptable carrier Such that the composition comprises a a 5-HT, antagonist and an oxytocin receptor (OXTR) ago range of 4-400 International Units of an oxytocin receptor nist. (OXTR) agonist and a 5-HT, antagonist. 0339. In one aspect, the method of making a composition 0344. In one aspect, the method of making a composition comprises combining a 5-HT, receptor agonist (e.g., traZ comprises combining a 5-HT, receptor antagonist (e.g., tra odone, nefazodone, mirtazapine, flibanserin, ketanserin, Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, ritanserin, clozapine, olanzapine, quetiapine, risperidone, ritanserin, clozapine, olanzapine, quetiapine, risperidone, asenapine, MDL-100.907, cyproheptadine, aripiprazole, and asenapine, MDL-100.907, cyproheptadine, aripiprazole, and the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido azepines), an oxytocin receptor (OXTR) agonist (e.g., carbe azepines), an oxytocin receptor (OXTR) agonist (e.g., carbe tocin, oxytocin, SyntocinonR), a 5-HT, agonist (e.g., lor tocin, oxytocin, Syntocinon R.), other non-abusable agents caserin, 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 25-450 mg of a 5-HT, receptoragonist. In another etine, lortalamine, mazindol, nisoxetine, talopram, talsu aspect, the method of making comprises combining a 5-HT pram, tandamine, Viloxazine, maprotiline, ciclaZindol, agonist/5-HT, antagonist and a pharmaceutically accept manifaxine, radafaxine, tapentadol, teniloxazine, St. John's able carrier Such that the composition comprises a range of wort, ginkgo biloba), and a pharmaceutically acceptable car 25-450 mg of a 5-HT, antagonist and an oxytocin receptor rier Such that the composition comprises a range of 4-400 (OXTR) agonist. International Units of an oxytocin receptor (OXTR) agonist and a 5-HT, antagonist. 0340. In one aspect, the method of making a composition 0345. In one aspect, the method of making a composition comprises combining a 5-HT, receptor agonist (e.g., traZ comprises combining a 5-HT, receptor antagonist (e.g., tra odone, nefazodone, mirtazapine, flibanserin, ketanserin, Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, ritanserin, clozapine, olanzapine, quetiapine, risperidone, ritanserin, clozapine, olanzapine, quetiapine, risperidone, asenapine, MDL-100.907, cyproheptadine, aripiprazole, and asenapine, MDL-100.907, cyproheptadine, aripiprazole, and the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido azepines), an oxytocin receptor (OXTR) agonist (e.g., carbe azepines), an oxytocin receptor (OXTR) agonist (e.g., carbe tocin, oxytocin, SyntocinonR), a 5-HT2, agonist (e.g., lor tocin, oxytocin, Syntocinon R.), a 5-HT2, agonist (e.g., lor caserin, vabicaserin, PRX-00933, YM348, caserin, vabicaserin, PRX-00933, YM348, metachlorophenylpiperazine), other non-abusable agents metachlorophenylpiperazine), and a pharmaceutically (agents not scheduled by the DEA) that augment dopamine acceptable carrier Such that the composition comprises a and/or norepinephrine in the brain, e.g., atomoxetine, rebox range of 4-400 International Units of an oxytocin receptor etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox (OXTR) agonist and a 5-HT, antagonist. etine, lortalamine, mazindol, nisoxetine, talopram, talsu 0346. In one aspect, the method of making a composition pram, tandamine, Viloxazine, maprotiline, ciclaZindol, comprises combining a 5-HT, receptor antagonist (e.g., tra manifaxine, radafaxine, tapentadol, teniloxazine, St. John's Zodone, nefazodone, mirtazapine, flibanserin, ketanserin, wort, ginkgo biloba), and a pharmaceutically acceptable car ritanserin, clozapine, olanzapine, quetiapine, risperidone, rier Such that the composition comprises a range of 25-450 asenapine, MDL-100.907, cyproheptadine, aripiprazole, and mg of a 5-HT, receptor agonist. In another aspect, the the general class of 2-alkyl-4-aryl-tetrahydro-pyrimido method of making comprises combining a 5-HT agonist/5- azepines), an oxytocin receptor (OXTR) agonist (e.g., carbe HT antagonist and a pharmaceutically acceptable carrier tocin, oxytocin, SyntocinonR), a 5-HT, agonist (e.g., lor Such that the composition comprises a range of 25-450 mg of caserin, vabicaserin, PRX-00933, YM348, a 5-HT, antagonist and an oxytocin receptor (OXTR) ago metachlorophenylpiperazine), other non-abusable agents nist. (agents not scheduled by the DEA) that augment dopamine 0341. In one embodiment, the method comprises combin and/or norepinephrine in the brain, e.g., atomoxetine, rebox ing traZodone, oxytocin, and a pharmaceutically acceptable etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox carrier. etine, lortalamine, mazindol, nisoxetine, talopram, talsu US 2015/O 150946 A1 Jun. 4, 2015

pram, tandamine, Viloxazine, maprotiline, ciclaZindol, tion comprises a range of 4-400 International Units of an manifaxine, radafaxine, tapentadol, teniloxazine, St. John's oxytocin receptor (OXTR) agonist and a norepinephrine wort, ginkgo biloba), and a pharmaceutically acceptable car dopamine reuptake inhibitor. rier Such that the composition comprises a range of 4-400 0354. In one aspect, the method of making a composition International Units of an oxytocin receptor (OXTR) agonist comprises combining a norepinephrine-dopamine reuptake and a 5-HT, antagonist. inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) 0347 In one embodiment, the method comprises combin agonist (e.g., carbetocin, oxytocin, Syntocinon R.), other non ing traZodone, oxytocin, and a pharmaceutically acceptable abusable agents (agents not scheduled by the DEA) that aug carrier. ment dopamine and/or norepinephrine in the brain, e.g., ato 0348. In one aspect, the method of making a composition moxetine, reboxetine, amedalin, CP-39,332, daledalin, comprises combining a norepinephrine-dopamine reuptake ediVoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) talopram, talsupram, tandamine, Viloxazine, maprotiline, agonist (e.g., carbetocin, oxytocin, SyntocinonR), and a ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, pharmaceutically acceptable carrier Such that the composi St. John’s wort, ginkgo biloba), and a pharmaceutically tion comprises a range of 50-450 mg of a norepinephrine acceptable carrier Such that the composition comprises a dopamine reuptake inhibitor and an oxytocin receptor range of 4-400 International Units of an oxytocin receptor (OXTR) agonist. (OXTR) agonist and a norepinephrine-dopamine reuptake 0349. In one aspect, the method of making a composition inhibitor. comprises combining a norepinephrine-dopamine reuptake 0355. In one aspect, the method of making a composition inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) comprises combining a norepinephrine-dopamine reuptake agonist (e.g., carbetocin, oxytocin, Syntocinon R.), other non inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) abusable agents (agents not scheduled by the DEA) that aug agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, ment dopamine and/or norepinephrine in the brain, e.g., ato agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, moxetine, reboxetine, amedalin, CP-39,332, daledalin, metachlorophenylpiperazine), and a pharmaceutically ediVoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, acceptable carrier Such that the composition comprises a talopram, talsupram, tandamine, Viloxazine, maprotiline, range of 4-400 International Units of an oxytocin receptor ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, (OXTR) agonist and a norepinephrine-dopamine reuptake St. John’s wort, ginkgo biloba), and a pharmaceutically inhibitor. acceptable carrier such that the composition comprises a 0356. In one aspect, the method of making a composition range of 50-450 mg of a norepinephrine-dopamine reuptake comprises combining a norepinephrine-dopamine reuptake inhibitor and an oxytocin receptor (OXTR) agonist. inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) 0350. In one aspect, the method of making a composition agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, comprises combining a norepinephrine-dopamine reuptake agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) metachlorophenylpiperazine), other non-abusable agents agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, (agents not scheduled by the DEA) that augment dopamine agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, and/or norepinephrine in the brain, e.g., atomoxetine, rebox metachlorophenylpiperazine), and a pharmaceutically etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox acceptable carrier Such that the composition comprises a etine, lortalamine, mazindol, nisoxetine, talopram, talsu range of 50-450 mg of a norepinephrine-dopamine reuptake pram, tandamine, Viloxazine, maprotiline, ciclaZindol, inhibitor and an oxytocin receptor (OXTR) agonist. manifaxine, radafaxine, tapentadol, teniloxazine, St. John's 0351. In one aspect, the method of making a composition wort, ginkgo biloba), and a pharmaceutically acceptable car comprises combining a norepinephrine-dopamine reuptake rier Such that the composition comprises a range of 4-400 inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) International Units of an oxytocin receptor (OXTR) agonist agonist (e.g., carbetocin, oxytocin, SyntocinonR), a 5-HT, and a norepinephrine-dopamine reuptake inhibitor. agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, 0357. In one embodiment, the method comprises combin metachlorophenylpiperazine), other non-abusable agents ing bupropion, oxytocin, and a pharmaceutically acceptable (agents not scheduled by the DEA) that augment dopamine carrier. and/or norepinephrine in the brain, e.g., atomoxetine, rebox 0358. In one aspect, the invention provides a kit compris etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox ing a composition delineated herein and a label providing etine, lortalamine, mazindol, nisoxetine, talopram, talsu instructions for administration of the composition to a subject pram, tandamine, Viloxazine, maprotiline, ciclaZindol, for treating or ameliorating sexual disorders or symptoms manifaxine, radafaxine, tapentadol, teniloxazine, St. John's thereof in the subject. wort, ginkgo biloba), and a pharmaceutically acceptable car 0359. In one aspect, the invention provides a kit compris rier such that the composition comprises a range of 50-450 ing a composition delineated herein and a label providing mg of a norepinephrine-dopamine reuptake inhibitor and an instructions for administration of the composition to a subject oxytocin receptor (OXTR) agonist. for treating or ameliorating cognitive disorders or symptoms 0352. In one embodiment, the method comprises combin thereof in the subject. ing bupropion, oxytocin, and a pharmaceutically acceptable 0360. In one aspect, the invention provides a kit compris carrier. ing a composition delineated herein and a label providing 0353. In one aspect, the method of making a composition instructions for administration of the composition to a subject comprises combining a norepinephrine-dopamine reuptake for enhancing cognition in the Subject. inhibitor (e.g., bupropion), an oxytocin receptor (OXTR) 0361. In another aspect, the invention provides a method agonist (e.g., carbetocin, oxytocin, SyntocinonR), and a of treating sexual disorders in a Subject comprising adminis pharmaceutically acceptable carrier Such that the composi tering to the Subject a 5-HT, receptoragonist, and a 5-HT US 2015/O 150946 A1 Jun. 4, 2015 39 antagonist. The methods herein can further comprise those 0365. In another embodiment, the invention provides a wherein the subject is identified as in need of such treatment, method of treating a subject suffering from or Susceptible to a and those wherein the Subject is treated upon administration sexual disorder comprising administering to a Subject in need of the compounds and/or compositions herein. The methods thereof a therapeutically effective amount of a composition can include those wherein the subject has not previously been comprising any one of a 5-HT, antagonist, a norepineph administered the compounds and/or compositions herein, or rine-dopamine reuptake inhibitor (e.g., bupropion), a 5-HT wherein the subject has not previously been administered the receptor agonist, an oxytocin receptor (OXTR) agonist (e.g., compounds and/or compositions herein at the Stated dosage carbetocin, oxytocin, SyntocinonR), an endocrine active levels or administration regimens. agent, or any combination thereof and a pharmaceutically acceptable carrier. 0362. In another aspect, the invention provides a method of treating sexual disorders in a Subject comprising adminis 0366. In another embodiment, the invention provides a tering to the Subject a 5-HT, receptor agonist, a 5-HT method of treating a subject suffering from or Susceptible to a antagonist, and ther non-abusable agents (agents not sched sexual disorder comprising administering to a Subject in need uled by the DEA) that augment dopamine and/or norepineph thereof a therapeutically effective amount of a composition rine in the brain, e.g., atomoxetine, reboxetine, amedalin, comprising any one of a 5-HT, antagonist, a norepineph CP-39,332, daledalin, edivoxetine, esreboxetine, lorta rine-dopamine reuptake inhibitor (e.g., bupropion), a 5-HT lamine, mazindol, nisoxetine, talopram, talsupram, tan receptor agonist, an oxytocin receptor (OXTR) agonist (e.g., damine, Viloxazine, maprotiline, ciclazindol, manifaxine, carbetocin, oxytocin, Syntocinon R.), a 5-HT, agonist (e.g., radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo lorcaserin, vabicaserin, PRX-00933, YM348, metachlo biloba). The methods herein can further comprise those rophenylpiperazine), other non-abusable agents (agents not wherein the subject is identified as in need of such treatment, scheduled by the DEA) that augment dopamine and/or nore and those wherein the Subject is treated upon administration pinephrine in the brain, e.g., atomoxetine, reboxetine, ameda of the compounds and/or compositions herein. The methods lin, CP-39,332, daledalin, edivoxetine, esreboxetine, lorta can include those wherein the subject has not previously been lamine, mazindol, nisoxetine, talopram, talsupram, administered the compounds and/or compositions herein, or tandamine, Viloxazine, maprotiline, ciclaZindol, manifaxine, wherein the subject has not previously been administered the radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo compounds and/or compositions herein at the Stated dosage biloba), an endocrine active agent, or any combination levels or administration regimens. thereof and a pharmaceutically acceptable carrier. 0367. In another aspect, the invention provides a method 0363. In another aspect, the invention provides a method of treating sexual disorders in a Subject comprising adminis of treating sexual disorders in a Subject comprising adminis tering to the Subject a therapeutically effective amount of any tering to the Subject a 5-HT, receptor agonist, a 5-HT one of a 5-HT, antagonist, a norepinephrine-dopamine antagonist, and a 5-HT2, agonist (e.g., lorcaserin, vabi reuptake inhibitor (e.g., bupropion), a 5-HT, receptor ago caserin, PRX-00933, YM348, metachlorophenylpiperazine). nist, an oxytocin receptor (OXTR) agonist (e.g., carbetocin, The methods herein can further comprise those wherein the oxytocin, Syntocinon R.), an endocrine active agent, or any Subject is identified as in need of Such treatment, and those combination thereof. wherein the subject is treated upon administration of the 0368. In another aspect, the invention provides a method compounds and/or compositions herein. The methods can of treating sexual disorders in a Subject comprising adminis include those wherein the subject has not previously been tering to the Subject a therapeutically effective amount of any administered the compounds and/or compositions herein, or one of a 5-HT, antagonist, a norepinephrine-dopamine wherein the subject has not previously been administered the reuptake inhibitor (e.g., bupropion), a 5-HT, receptor ago compounds and/or compositions herein at the Stated dosage nist, an oxytocin receptor (OXTR) agonist (e.g., carbetocin, levels or administration regimens. oxytocin, Syntocinon R.), other non-abusable agents (agents 0364. In another aspect, the invention provides a method not scheduled by the DEA) that augment dopamine and/or of treating sexual disorders in a Subject comprising adminis norepinephrine in the brain, e.g., atomoxetine, reboxetine, tering to the subject a 5-HT, receptor agonist, a 5-HT amedalin, CP-39,332, daledalin, edivoxetine, esreboxetine, antagonist, other non-abusable agents (agents not scheduled lortalamine, mazindol, nisoxetine, talopram, talsupram, tan by the DEA) that augment dopamine and/or norepinephrine damine, Viloxazine, maprotiline, ciclazindol, manifaxine, in the brain, e.g., atomoxetine, reboxetine, amedalin, CP-39, radafaxine, tapentadol, teniloxazine, St. John’s wort, ginkgo 332, daledalin, edivoxetine, esreboxetine, lortalamine, biloba), a 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX mazindol, nisoxetine, talopram, talsupram, tandamine, Vilox 00933, YM348, metachlorophenylpiperazine), an endocrine azine, maprotiline, ciclazindol, manifaxine, radafaxine, tap active agent, or any combination thereof. entadol, teniloxazine, St. John’s wort, ginkgo biloba), and a 0369. In another aspect, the invention provides a method 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, of treating cognitive disorders in a Subject comprising admin YM348, metachlorophenylpiperazine). The methods herein istering to the Subject a 5-HT, receptor agonist, and a can further comprise those wherein the subject is identified as 5-HT, antagonist. The methods herein can further comprise in need of such treatment, and those wherein the subject is those wherein the subject is identified as in need of such treated upon administration of the compounds and/or com treatment, and those wherein the Subject is treated upon positions herein. The methods can include those wherein the administration of the compounds and/or compositions herein. Subject has not previously been administered the compounds The methods can include those wherein the subject has not and/or compositions herein, or wherein the Subject has not previously been administered the compounds and/or compo previously been administered the compounds and/or compo sitions herein, or wherein the subject has not previously been sitions herein at the Stated dosage levels or administration administered the compounds and/or compositions herein at regimens. the stated dosage levels or administration regimens. US 2015/O 150946 A1 Jun. 4, 2015 40

0370. In another aspect, the invention provides a method 0374. In another embodiment, the invention provides a of treating cognitive disorders in a subject comprising admin method of treating a subject suffering from or Susceptible to a istering to the Subject a 5-HT, receptor agonist, other non cognitive disorder comprising administering to a subject in abusable agents (agents not scheduled by the DEA) that aug need thereof a therapeutically effective amount of a compo ment dopamine and/or norepinephrine in the brain, e.g., sition comprising any one of a 5-HT, antagonist, a norepi atomoxetine, reboxetine, amedalin, CP-39,332, daledalin, nephrine-dopamine reuptake inhibitor (e.g., bupropion), a ediVoxetine, esreboxetine, lortalamine, mazindol, nisoxetine, 5-HT, receptor agonist, an oxytocin receptor (OXTR) ago talopram, talsupram, tandamine, Viloxazine, maprotiline, nist (e.g., carbetocin, oxytocin, Syntocinon R.), a 5-HTago ciclazindol, manifaxine, radafaxine, tapentadol, teniloxazine, nist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, St. John’s wort, ginkgo biloba), and a 5-HT, antagonist. The metachlorophenylpiperazine), other non-abusable agents methods herein can further comprise those wherein the sub (agents not scheduled by the DEA) that augment dopamine ject is identified as in need of Such treatment, and those and/or norepinephrine in the brain, e.g., atomoxetine, rebox wherein the subject is treated upon administration of the etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox compounds and/or compositions herein. The methods can etine, lortalamine, mazindol, nisoxetine, talopram, talsu include those wherein the subject has not previously been pram, tandamine, Viloxazine, maprotiline, ciclaZindol, administered the compounds and/or compositions herein, or manifaxine, radafaxine, tapentadol, teniloxazine, St. John's wherein the subject has not previously been administered the wort, ginkgo biloba), an endocrine active agent, or any com compounds and/or compositions herein at the Stated dosage bination thereof and a pharmaceutically acceptable carrier. levels or administration regimens. 0375. In another aspect, the invention provides a method 0371. In another aspect, the invention provides a method of treating cognitive disorders in a Subject comprising admin of treating cognitive disorders in a subject comprising admin istering to the subject a therapeutically effective amount of istering to the Subject a 5-HT, receptor agonist, a 5-HT, any one of a 5-HT, antagonist, a norepinephrine-dopamine agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, reuptake inhibitor (e.g., bupropion), a 5-HT, receptor ago metachlorophenylpiperazine), and a 5-HT, antagonist. The nist, an oxytocin receptor (OXTR) agonist (e.g., carbetocin, methods herein can further comprise those wherein the sub oxytocin, Syntocinon R.), an endocrine active agent, or any ject is identified as in need of Such treatment, and those combination thereof. wherein the subject is treated upon administration of the 0376. In another aspect, the invention provides a method compounds and/or compositions herein. The methods can of treating cognitive disorders in a Subject comprising admin include those wherein the subject has not previously been istering to the subject a therapeutically effective amount of administered the compounds and/or compositions herein, or any one of a 5-HT, antagonist, a norepinephrine-dopamine wherein the subject has not previously been administered the reuptake inhibitor (e.g., bupropion), a 5-HT, receptor ago compounds and/or compositions herein at the Stated dosage nist, an oxytocin receptor (OXTR) agonist (e.g., carbetocin, levels or administration regimens. oxytocin, SyntocinonR), a 5-HT, agonist (e.g., lorcaserin, 0372. In another aspect, the invention provides a method vabicaserin, PRX-00933, YM348, metachlorophenylpipera of treating cognitive disorders in a subject comprising admin Zine), other non-abusable agents (agents not scheduled by the istering to the subject a 5-HT, receptor agonist, a 5-HT, DEA) that augment dopamine and/or norepinephrine in the agonist (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, brain, e.g., atomoxetine, reboxetine, amedalin, CP-39,332, metachlorophenylpiperazine), other non-abusable agents daledalin, edivoxetine, esreboxetine, lortalamine, mazindol, (agents not scheduled by the DEA) that augment dopamine nisoxetine, talopram, talSupram, tandamine, Viloxazine, and/or norepinephrine in the brain, e.g., atomoxetine, rebox maprotiline, ciclazindol, manifaxine, radafaxine, tapentadol, etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox teniloxazine, St. John’s wort, ginkgo biloba), an endocrine etine, lortalamine, mazindol, nisoxetine, talopram, talsu active agent, or any combination thereof. pram, tandamine, Viloxazine, maprotiline, ciclaZindol, 0377. In another aspect, the invention provides a method manifaxine, radafaxine, tapentadol, teniloxazine, St. John's of enhancing cognition in a Subject comprising administering wort, ginkgo biloba), and a 5-HT, antagonist. The methods to the Subject a 5-HT, receptor agonist, and a 5-HT herein can further comprise those wherein the subject is iden antagonist. The methods herein can further comprise those tified as in need of such treatment, and those wherein the wherein the subject is identified as in need of such treatment, Subject is treated upon administration of the compounds and/ and those wherein the Subject is treated upon administration or compositions herein. The methods can include those of the compounds and/or compositions herein. The methods wherein the subject has not previously been administered the can include those wherein the subject has not previously been compounds and/or compositions herein, or wherein the Sub administered the compounds and/or compositions herein, or ject has not previously been administered the compounds wherein the subject has not previously been administered the and/or compositions herein at the stated dosage levels or compounds and/or compositions herein at the Stated dosage administration regimens. levels or administration regimens. 0373) In another embodiment, the invention provides a 0378. In another aspect, the invention provides a method method of treating a Subject suffering from or Susceptible to a of enhancing cognition in a Subject comprising administering cognitive disorder comprising administering to a subject in to the Subject a 5-HT, receptor agonist, other non-abusable need thereof a therapeutically effective amount of a compo agents (agents not scheduled by the DEA) that augment sition comprising any one of a 5-HT, antagonist, a norepi dopamine and/or norepinephrine in the brain, e.g., atomoxet nephrine-dopamine reuptake inhibitor (e.g., bupropion), a ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, 5-HT, receptor agonist, an oxytocin receptor (OXTR) ago eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, nist (e.g., carbetocin, oxytocin, Syntocinon R.), an endocrine talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, active agent, or any combination thereof and a pharmaceuti manifaxine, radafaxine, tapentadol, teniloxazine, St. John's cally acceptable carrier. wort, ginkgo biloba), and a 5-HT, antagonist. The methods US 2015/O 150946 A1 Jun. 4, 2015

herein can further comprise those wherein the subject is iden ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, tified as in need of such treatment, and those wherein the eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, Subject is treated upon administration of the compounds and/ talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, or compositions herein. The methods can include those manifaxine, radafaxine, tapentadol, teniloxazine, St. John's wherein the subject has not previously been administered the wort, ginkgo biloba), an endocrine active agent, or any com compounds and/or compositions herein, or wherein the Sub bination thereof and a pharmaceutically acceptable carrier. ject has not previously been administered the compounds 0383. In another aspect, the invention provides a method and/or compositions herein at the stated dosage levels or of enhancing cognition in a Subject comprising administering administration regimens. to the subject a therapeutically effective amount of any one of 0379. In another aspect, the invention provides a method a 5-HT, antagonist, a norepinephrine-dopamine reuptake of enhancing cognition in a subject comprising administering inhibitor (e.g., bupropion), a 5-HT, receptor agonist, an to the Subject a 5-HT, receptor agonist, a 5-HT2, agonist oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, cin, Syntocinon R.), an endocrine active agent, or any combi metachlorophenylpiperazine), and a 5-HT, antagonist. The nation thereof. methods herein can further comprise those wherein the sub 0384. In another aspect, the invention provides a method ject is identified as in need of Such treatment, and those of enhancing cognition in a Subject comprising administering wherein the subject is treated upon administration of the to the subject a therapeutically effective amount of any one of compounds and/or compositions herein. The methods can a 5-HT, antagonist, a norepinephrine-dopamine reuptake include those wherein the subject has not previously been inhibitor (e.g., bupropion), a 5-HT, receptor agonist, an administered the compounds and/or compositions herein, or oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto wherein the subject has not previously been administered the cin, SyntocinonR), a 5-HT, agonist (e.g., lorcaserin, vabi compounds and/or compositions herein at the Stated dosage caserin, PRX-00933, YM348, metachlorophenylpiperazine), levels or administration regimens. other non-abusable agents (agents not scheduled by the DEA) 0380. In another aspect, the invention provides a method that augment dopamine and/or norepinephrine in the brain, of enhancing cognition in a subject comprising administering e.g., atomoxetine, reboxetine, amedalin, CP-39,332, daleda to the subject a 5-HT, receptor agonist, a 5-HT, agonist lin, edivoxetine, esreboxetine, lortalamine, mazindol, nisox (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, etine, talopram, talsupram, tandamine, Viloxazine, mapro metachlorophenylpiperazine), other non-abusable agents tiline, ciclaZindol, manifaxine, radafaxine, tapentadol, (agents not scheduled by the DEA) that augment dopamine teniloxazine, St. John’s wort, ginkgo biloba), an endocrine and/or norepinephrine in the brain, e.g., atomoxetine, rebox active agent, or any combination thereof. etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox 0385. In another aspect, the invention provides a method etine, lortalamine, mazindol, nisoxetine, talopram, talsu of relieving depression in a subject comprising administering pram, tandamine, Viloxazine, maprotiline, ciclaZindol, to the subject a 5-HT, receptor agonist, and a 5-HT, manifaxine, radafaxine, tapentadol, teniloxazine, St. John's antagonist. The methods herein can further comprise those wort, ginkgo biloba), and a 5-HT, antagonist. The methods wherein the subject is identified as in need of such treatment, herein can further comprise those wherein the subject is iden and those wherein the Subject is treated upon administration tified as in need of such treatment, and those wherein the of the compounds and/or compositions herein. The methods Subject is treated upon administration of the compounds and/ can include those wherein the subject has not previously been or compositions herein. The methods can include those administered the compounds and/or compositions herein, or wherein the subject has not previously been administered the wherein the subject has not previously been administered the compounds and/or compositions herein, or wherein the Sub compounds and/or compositions herein at the Stated dosage ject has not previously been administered the compounds levels or administration regimens. and/or compositions herein at the stated dosage levels or 0386. In another aspect, the invention provides a method administration regimens. of relieving depression in a subject comprising administering 0381. In another embodiment, the invention provides a to the Subject a 5-HT, receptor agonist, other non-abusable method of enhancing cognition comprising administering to a agents (agents not scheduled by the DEA) that augment subject in need thereofatherapeutically effective amount of a dopamine and/or norepinephrine in the brain, e.g., atomoxet composition comprising any one of a 5-HT, antagonist, a ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, norepinephrine-dopamine reuptake inhibitor (e.g., bupro eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, pion), a 5-HT, receptor agonist, an oxytocin receptor talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), manifaxine, radafaxine, tapentadol, teniloxazine, St. John's an endocrine active agent, or any combination thereof and a wort, ginkgo biloba), and a 5-HT, antagonist. The methods pharmaceutically acceptable carrier. herein can further comprise those wherein the subject is iden 0382. In another embodiment, the invention provides a tified as in need of such treatment, and those wherein the method of enhancing cognition comprising administering to a Subject is treated upon administration of the compounds and/ subject in need thereofatherapeutically effective amount of a or compositions herein. The methods can include those composition comprising any one of a 5-HT, antagonist, a wherein the subject has not previously been administered the norepinephrine-dopamine reuptake inhibitor (e.g., bupro compounds and/or compositions herein, or wherein the Sub pion), a 5-HT, receptor agonist, an oxytocin receptor ject has not previously been administered the compounds (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon R.), a and/or compositions herein at the stated dosage levels or 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, administration regimens. YM348, metachlorophenylpiperazine), other non-abusable 0387. In another aspect, the invention provides a method agents (agents not scheduled by the DEA) that augment of relieving depression in a subject comprising administering dopamine and/or norepinephrine in the brain, e.g., atomoxet to the Subject a 5-HT, receptor agonist, a 5-HT2, agonist US 2015/O 150946 A1 Jun. 4, 2015 42

(e.g., lorcaserin, vabicaserin, PRX-00933, YM348, (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), metachlorophenylpiperazine), and a 5-HTantagonist. The an endocrine active agent, or any combination thereof. methods herein can further comprise those wherein the sub 0392. In another aspect, the invention provides a method ject is identified as in need of Such treatment, and those of relieving depression in a subject comprising administering wherein the subject is treated upon administration of the to the subject a therapeutically effective amount of any one of compounds and/or compositions herein. The methods can a 5-HT, antagonist, a norepinephrine-dopamine reuptake include those wherein the subject has not previously been inhibitor, a 5-HT, receptor agonist, an oxytocin receptor administered the compounds and/or compositions herein, or (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon R.), a wherein the subject has not previously been administered the 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, compounds and/or compositions herein at the Stated dosage YM348, metachlorophenylpiperazine), other non-abusable levels or administration regimens. agents (agents not scheduled by the DEA) that augment 0388. In another aspect, the invention provides a method dopamine and/or norepinephrine in the brain, e.g., atomoxet of relieving depression in a subject comprising administering ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, to the Subject a 5-HT, receptor agonist, a 5-HT2, agonist eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, (e.g., lorcaserin, vabicaserin, PRX-00933, YM348, talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, metachlorophenylpiperazine), other non-abusable agents manifaxine, radafaxine, tapentadol, teniloxazine, St. John's (agents not scheduled by the DEA) that augment dopamine wort, ginkgo biloba), an endocrine active agent, or any com and/or norepinephrine in the brain, e.g., atomoxetine, rebox bination thereof. etine, amedalin, CP-39,332, daledalin, edivoxetine, esrebox 0393. In aspects the endocrine agent is testosterone, which etine, lortalamine, mazindol, nisoxetine, talopram, talsu can be in an amount of a dosage range of 25 to 1000 mg per pram, tandamine, Viloxazine, maprotiline, ciclaZindol, day in men or 150 to 300 micrograms per day in women. manifaxine, radafaxine, tapentadol, teniloxazine, St. John's 0394. In aspects, the subject is that wherein the subject is wort, ginkgo biloba), and a 5-HT, antagonist. The methods not being treated with a selective serotonin reuptake inhibitor herein can further comprise those wherein the subject is iden (SSRI) agent. tified as in need of such treatment, and those wherein the 0395. In aspects, the subject is that wherein the subject is Subject is treated upon administration of the compounds and/ being treated with a selective serotonin reuptake inhibitor or compositions herein. The methods can include those (SSRI) agent. wherein the subject has not previously been administered the 0396. In aspects, the subject is that wherein the subject is compounds and/or compositions herein, or wherein the Sub identified as having selective serotonin reuptake inhibitor ject has not previously been administered the compounds (SSRI) agent induced sexual disorders. and/or compositions herein at the stated dosage levels or 0397. In aspects, the subject is that wherein the subject is administration regimens. being treated with a PDE-5 inhibitor compound (i.e., sildena 0389. In another embodiment, the invention provides a fil, tadalafil, and the like). method of relieving depression comprising administering to a 0398. In aspects, the subject is that wherein the subject is subject in need thereofatherapeutically effective amount of a not concurrently being treated with a PDE-5 inhibitor com composition comprising any one of a 5-HT, antagonist, a pound (i.e., sildenafil, tadalafil, and the like). norepinephrine-dopamine reuptake inhibitor (e.g., bupro 0399. In aspects, the subject is that wherein the subject is pion), a 5-HT, receptor agonist, an oxytocin receptor being treated with an endocrine agent (e.g., testosterone). (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), 0400. In aspects, the subject is that wherein the subject is an endocrine active agent, or any combination thereof and a not concurrently being treated with an endocrine agent (e.g., pharmaceutically acceptable carrier. testosterone). 0390. In another embodiment, the invention provides a 04.01. In another aspect, the methods herein comprise tak method of relieving depression comprising administering to a ing a sample (i.e., fluid, blood, urine, Saliva, tissue, etc.) and subject in need thereofatherapeutically effective amount of a assessing a biological marker (i.e., liver enzymes, CYP3A4, composition comprising any one of a 5-HT, antagonist, a and/or a genetic marker of the transport, receptor type, recep norepinephrine-dopamine reuptake inhibitor (e.g., bupro tor density, receptor affinity, metabolism, or activity of sero pion), a 5-HT, receptor agonist, an oxytocin receptor tonin, serotonin 1A or 2A Subtype, dopamine, or a receptor (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon R.), a Subtype of dopamine) to measure health status of the Subject 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, either prior to, during or after administration of the composi YM348, metachlorophenylpiperazine), other non-abusable tions herein. agents (agents not scheduled by the DEA) that augment dopamine and/or norepinephrine in the brain, e.g., atomoxet DETAILED DESCRIPTION OF THE INVENTION ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, 0402. The present inventors have now discovered a thera eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, peutic strategy that addresses sexual disorders, cognitive dis talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, orders, or offers cognition enhancement in a subject. manifaxine, radafaxine, tapentadol, teniloxazine, St. John's 0403. The present invention relates, at least in part, to the wort, ginkgo biloba), an endocrine active agent, or any com discovery that a combination of a 5-HT, antagonist (which is bination thereof and a pharmaceutically acceptable carrier. optionally a 5-HT, receptor agonist) (e.g., traZodone, nefa 0391. In another aspect, the invention provides a method Zodone, mirtazapine, flibanserin), a norepinephrine-dopam of relieving depression in a subject comprising administering ine reuptake inhibitor (e.g., bupropion), and oxytocin recep to the subject a therapeutically effective amount of any one of tor (OXTR) agonist (e.g., carbetocin, oxytocin, a 5-HT, antagonist, a norepinephrine-dopamine reuptake SyntocinonR), (and optionally an endocrine active agent) inhibitor, a 5-HT, receptor agonist, an oxytocin receptor provides unexpected Superior and synergistic results in US 2015/O 150946 A1 Jun. 4, 2015 addressing sexual disorders, cognitive disorders, or offers sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sul cognition enhancement in a subject. fonato, Sulfamoyl, Sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl alkylaryl, or an aromatic or het 1. DEFINITIONS eroaromatic moiety. It will be understood by those skilled in 0404 Before further description of the present invention, the art that the moieties substituted on the hydrocarbon chain and in order that the invention may be more readily under can themselves be substituted, if appropriate. Cycloalkyls can stood, certain terms are first defined and collected here for be further substituted, e.g., with the substituents described convenience. above. An “alkylaryl moiety is an alkyl substituted with an 04.05 The term “administration” or “administering aryl (e.g., phenylmethyl (benzyl)). The term “alkyl also includes routes of introducing the compound of the invention includes unsaturated aliphatic groups analogous in length and (s) to a subject to perform their intended function. Examples possible substitution to the alkyls described above, but that of routes of administration that may be used include injection contain at least one double or triple bond respectively. (Subcutaneous, intravenous, parenterally, intraperitoneally, 0408. Unless the number of carbons is otherwise speci intrathecal), oral, buccal, Sublingual, inhalation, rectal and fied, “lower alkyl as used herein means an alkyl group, as transdermal. The pharmaceutical preparations may be given defined above, but having from one to ten carbons, more by forms suitable for each administration route. For example, preferably from one to six, and still more preferably from one these preparations are administered intablets or capsule form, to four carbonatoms in its backbone structure, which may be by injection, inhalation, eye lotion, ointment, Suppository, straight or branched-chain. Examples of lower alkyl groups etc. administration by injection, infusion or inhalation; topi include methyl, ethyl, n-propyl, i-propyl, tert-butyl, hexyl, cal by lotion or ointment; and rectal by Suppositories. Oral heptyl, octyl and so forth. In preferred embodiment, the term administration is preferred. The injection can be bolus or can “lower alkyl includes a straight chain alkyl having 4 or fewer be continuous infusion. Depending on the route of adminis carbon atoms in its backbone, e.g., C1-C4 alkyl. tration, the compound of the invention can be coated with or disposed in a selected material to protect it from natural 04.09. The terms “alkoxyalkyl.” “polyaminoalkyl and conditions which may detrimentally effect its ability to per “thioalkoxyalkyl refer to alkyl groups, as described above, form its intended function. The compound of the invention which further include oxygen, nitrogen or Sulfur atoms can be administered alone, or in conjunction with either replacing one or more carbons of the hydrocarbon backbone, another agent as described above or with a pharmaceutically e.g., Oxygen, nitrogen or Sulfur atoms. acceptable carrier, or both. The compound of the invention 0410. The terms “alkenyl” and “alkynyl” refer to unsatur can be administered prior to the administration of the other ated aliphatic groups analogous in length and possible Sub agent, simultaneously with the agent, or after the administra stitution to the alkyls described above, but that contain at least tion of the agent. Furthermore, the compound of the invention one double or triple bond, respectively. For example, the can also be administered in a pro-drug form which is con invention contemplates cyano and propargyl groups. verted into its active metabolite, or more active metabolite in vivo. 0411. The term “aryl as used herein, refers to the radical 0406. The term “alkyl refers to the radical of saturated of aryl groups, including 5- and 6-membered single-ring aro aliphatic groups, including straight-chain alkyl groups, matic groups that may include from Zero to four heteroatoms, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, for example, benzene, pyrrole, furan, thiophene, imidazole, alkyl Substituted cycloalkyl groups, and cycloalkyl Substi benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, tuted alkyl groups. The term alkyl further includes alkyl pyridine, pyrazine, pyridazine and pyrimidine, and the like. groups, which can further include oxygen, nitrogen, Sulfur or Aryl groups also include polycyclic fused aromatic groups phosphorous atoms replacing one or more carbons of the Such as naphthyl, quinolyl, indolyl, and the like. Those aryl hydrocarbon backbone, e.g., oxygen, nitrogen, Sulfur or groups having heteroatoms in the ring structure may also be phosphorous atoms. In preferred embodiments, a straight referred to as “aryl heterocycles.” “heteroaryls' or “het chain or branched chain alkyl has 30 or fewer carbonatoms in eroaromatics. The aromatic ring can be substituted at one or its backbone (e.g., C1-C30 for straight chain, C-C for more ring positions with Such substituents as described branched chain), preferably 26 or fewer, and more preferably above, as for example, halogen, hydroxyl, alkoxy, alkylcar 20 or fewer, and still more preferably 4 or fewer. Likewise, bonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycar preferred cycloalkyls have from 3-10 carbon atoms in their bonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, ami ring structure, and more preferably have 3, 4, 5, 6 or 7 carbons nocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, in the ring structure. phosphinato, cyano, amino (including alkyl amino, dialky 04.07 Moreover, the term alkyl as used throughout the lamino, arylamino, diarylamino, and alkylarylamino), acy specification and sentences is intended to include both lamino (including alkylcarbonylamino, arylcarbonylamino, “unsubstituted alkyls' and “substituted alkyls, the latter of carbamoylandureido), amidino, imino, Sulfhydryl, alkylthio. which refers to alkyl moieties having Substituents replacing a arylthio, thiocarboxylate, Sulfates, Sulfonato, Sulfamoyl, Sul hydrogen on one or more carbons of the hydrocarbon back fonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, bone. Such Substituents can include, for example, halogen, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbo groups can also be fused or bridged with alicyclic or hetero nyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, cyclic rings which are not aromatic So as to form a polycycle alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, (e.g., tetralin). phosphate, phosphonato, phosphinato, cyano, amino (includ 0412. The term “associating with refers to a condition of ing alkyl amino, dialkylamino, arylamino, diarylamino, and proximity between a chemical entity or compound, or por alkylarylamino), acylamino (including alkylcarbonylamino, tions thereof, and a binding pocket or binding site on a pro arylcarbonylamino, carbamoyl and ureido), amidino, imino, tein. The association may be non-covalent (wherein the jux US 2015/O 150946 A1 Jun. 4, 2015 44 taposition is energetically favored by hydrogen bonding or compound of the invention can include a single treatment or, van der Waals or electrostatic interactions) or it may be cova preferably, can include a series of treatments. In one example, lent. a subject is treated with a compound of the invention in the 0413. The language “biological activities of a compound range of between about 0.1 to 20 mg/kg body weight, one of the invention includes all activities elicited by compound time per week for between about 1 to 10 weeks, preferably of the inventions in a responsive cell. It includes genomic and between 2 to 8 weeks, more preferably between about 3 to 7 non-genomic activities elicited by these compounds. weeks, and even more preferably for about 4, 5, or 6 weeks. It 0414 “Biological composition” or “biological sample' will also be appreciated that the effective dosage of a com refers to a composition containing or derived from cells or pound of the invention used for treatment may increase or biopolymers. Cell-containing compositions include, for decrease over the course of a particular treatment. Adminis example, mammalian blood, red cell concentrates, platelet tration regimens herein where designated are in accordance concentrates, leukocyte concentrates, blood cell proteins, with the following abbreviations: SID or QD-Once a day; blood plasma, platelet-rich plasma, a plasma concentrate, a BID=Twice a day, TID=Three times a day; QID=Four times precipitate from any fractionation of the plasma, a Superna a day; qh.Severy night. tant from any fractionation of the plasma, blood plasma pro 0419. The term “enantiomers’ refers to two stereoisomers tein fractions, purified or partially purified blood proteins or of a compound which are non-Superimposable minor images other components, serum, semen, mammalian colostrum, of one another. An equimolar mixture of two enantiomers is milk, saliva, placental extracts, a cryoprecipitate, a cryosu called a “racemic mixture' or a “racemate.” The compounds pernatant, a cell lysate, mammalian cell culture or culture of this invention may contain one or more asymmetric centers medium, products of fermentation, ascites fluid, proteins and thus occur as racemates and racemic mixtures, single induced in blood cells, and products produced in cell culture enantiomers, individual diastereomers and diastereomeric by normal or transformed cells (e.g., via recombinant DNA or mixtures. All Such isomeric forms of these compounds are monoclonal antibody technology). Biological compositions expressly included in the present invention. The compounds can be cell-free. In a preferred embodiment, a suitable bio of this invention may also be represented in multiple tauto logical composition or biological sample is a red blood cell meric forms, in Such instances, the invention expressly Suspension. In some embodiments, the blood cell Suspension includes all tautomeric forms of the compounds described includes mammalian blood cells. Preferably, the blood cells herein. All Such isomeric forms of Such compounds are are obtained from a human, a non-human primate, a dog, a expressly included in the present invention. All crystal forms cat, a horse, a cow, a goat, a sheep or a pig. In preferred of the compounds described herein are expressly included in embodiments, the blood cell suspension includes red blood the present invention. cells and/or platelets and/or leukocytes and/or bone marrow 0420. The term “haloalkyl is intended to include alkyl cells. groups as defined above that are mono-, di- or poly Substituted 0415. The term “chiral refers to molecules which have by halogen, e.g., fluoromethyl and trifluoromethyl. the property of non-Superimposability of the mirror image 0421. The term “halogen designates —F. —Cl, Br or partner, while the term “achiral” refers to molecules which —I. are Superimposable on their minor image partner. 0422. The term “hydroxyl” means –OH. 0416) The term "diastereomers’ refers to stereoisomers 0423. The term "heteroatom’ as used herein means an with two or more centers of dissymmetry and whose mol atom of any element other than carbon or hydrogen. Preferred ecules are not minor images of one another. heteroatoms are nitrogen, oxygen, Sulfur and phosphorus. 0417. The term “effective amount” includes an amount 0424 The term “homeostasis” is art-recognized to mean effective, at dosages and for periods of time necessary, to maintenance of static, or constant, conditions in an internal achieve the desired result, e.g., Sufficient to treat a sexual environment. disorder or hypoactive sexual desire disorder in a Subject. An 0425 The language “improved biological properties’ effective amount of compound of the invention may vary refers to any activity inherent in a compound of the invention according to factors such as the disease state, age, and weight that enhances its effectiveness in vivo. In a preferred embodi of the subject, and the ability of the compound of the inven ment, this term refers to any qualitative or quantitative tion to elicit a desired response in the Subject. Dosage regi improved therapeutic property of a compound of the inven mens may be adjusted to provide the optimum therapeutic tion, Such as reduced toxicity. response. An effective amount is also one in which any toxic 0426. The term “optionally substituted' is intended to or detrimental effects (e.g., side effects) of the compound of encompass groups that are unsubstituted or are Substituted by the invention are outweighed by the therapeutically beneficial other than hydrogen at one or more available positions, typi effects. cally 1, 2, 3, 4 or 5 positions, by one or more suitable groups 0418 Atherapeutically effective amount of compound of (which may be the same or different). Such optional substitu the invention (i.e., an effective dosage) may range from about ents include, for example, hydroxy, halogen, cyano, nitro, 0.001 to 30 mg/kg body weight, preferably about 0.01 to 25 C-Calkyl, C-Cs alkenyl, C-Calkynyl, C-Csalkoxy, mg/kg body weight, more preferably about 0.1 to 20 mg/kg C-Calkyl ether, C-Csalkanone, C-Csalkylthio, amino, body weight, and even more preferably about 1 to 10 mg/kg, mono- or di-(C1-Csalkyl)amino, haloC-Csalkyl, haloC 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body Calkoxy, C-Calkanoyl. C-Csalkanoyloxy, weight. The skilled artisan will appreciate that certain factors C-Calkoxycarbonyl, -COOH, -CONH, mono- or di may influence the dosage required to effectively treat a Sub (C-Calkyl)aminocarbonyl, -SONH2, and/or mono or ject, including but not limited to the severity of the disease or di (C-Csalkyl)sulfonamido, as well as carbocyclic and het disorder, previous treatments, the general health and/orage of erocyclic groups. Optional Substitution is also indicated by the Subject, and other diseases present. Moreover, treatment the phrase “substituted with from 0 to X substituents, where of a subject with a therapeutically effective amount of a X is the maximum number of possible substituents. Certain US 2015/O 150946 A1 Jun. 4, 2015

optionally substituted groups are substituted with from 0 to 2, stituents) aryland aryl-lower alkyl esters, amides, lower-alkyl 3 or 4 independently selected Substituents (i.e., are unsubsti amides, di-lower alkyl amides, and hydroxy amides. Pre tuted or substituted with up to the recited maximum number ferred prodrug moieties are propionoic acid esters and acyl of substituents). esters. Prodrugs which are converted to active forms through 0427. The term “isomers' or “stereoisomers' refers to other mechanisms in vivo are also included. compounds which have identical chemical constitution, but 0433. The language “a prophylactically effective amount differ with regard to the arrangement of the atoms or groups of a compound refers to an amount of a compound of the in space. invention any formula herein or otherwise described herein 0428 The term “modulate” refers to an increase or which is effective, upon single or multiple dose administra decrease, e.g., the alteration in sexual disorder or hypoactive tion to the patient, in preventing or treating a sexual disorder. sexual desire disorder and/or symptoms thereof in a subject 0434. The language “reduced toxicity' is intended to Such that a desired end result is achieved, e.g., a therapeutic include a reduction in any undesired side effect elicited by a result. compound of the invention when administered in Vivo e.g., 0429. The term “obtaining as in “obtaining a compound formulating bupropion, by itself a mild stimulant, with traZ useful in treating sexual disorder or hypoactive sexual desire odone, by itself a moderate sedative, in the proprietary ratio of disorder is intended to include purchasing, synthesizing or Lorexys will neutralize the main side effects of each of the otherwise acquiring the compound. two drugs. 0430. The phrases “parenteral administration' and 0435 The term “subject includes organisms which are “administered parenterally as used herein means modes of capable of suffering from a sexual disorder or who could administration other than enteral and topical administration, otherwise benefit from the administration of a compound or usually by injection, and includes, without limitation, intra composition of the invention, such as human (male or female) venous, intramuscular, intraarterial, intrathecal, intracapsu and non-human animals (male or female). Preferred humans lar, intraorbital, intracardiac, intradermal, intraperitoneal, include human patients suffering from or prone to Suffering transtracheal. Subcutaneous, Subcuticular, intraarticulare, from sexual disorder or hypoactive sexual desire disorder or Subcapsular, Subarachnoid, intraspinal and intrasternal injec associated State, as described herein. The term “non-human tion and infusion. animals' of the invention includes all vertebrates, e.g., mam 0431. The terms “polycyclyl” or “polycyclic radical” refer mals, e.g., rodents, e.g., mice, and non-mammals, such as to the radical of two or more cyclic rings (e.g., cycloalkyls, non-human primates, e.g., sheep, dog, cow, chickens, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in amphibians, reptiles, etc. which two or more carbons are common to two adjoining 0436 The term "susceptible to a sexual disorder or hypo rings, e.g., the rings are “fused rings'. Rings that are joined active sexual desire disorder is meant to include subjects at through non-adjacentatoms are termed “bridged rings. Each risk of developing sexual disorder or hypoactive sexual desire of the rings of the polycycle can be substituted with such disorder, e.g., Subjects previously diagnosed as having or Substituents as described above, as for example, halogen, having a family or medical history of sexual disorder or hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbo hypoactive sexual desire disorder, and the like. nyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, 0437. The phrases “systemic administration, “adminis alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, tered systemically”, “peripheral administration' and “admin phosphate, phosphonato, phosphinato, cyano, amino (includ istered peripherally as used herein mean the administration ing alkyl amino, dialkylamino, arylamino, diarylamino, and of a compound of the invention(s), drug or other material, alkylarylamino), acylamino (including alkylcarbonylamino, Such that it enters the patients system and, thus, is Subject to metabolism and other like processes, for example, Subcuta arylcarbonylamino, carbamoyl and ureido), amidino, imino, neous administration. sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sul 0438. The language “therapeutically effective amount of fonato, Sulfamoyl, Sulfonamido, nitro, trifluoromethyl, a compound of the invention of the invention refers to an cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or amount of an agent which is effective, upon single or multiple heteroaromatic moiety. dose administration to the patient, in modulating sexual dis 0432. The term “prodrug” or “pro-drug includes com order or hypoactive sexual desire disorder and/or symptoms pounds with moieties that can be metabolized in vivo. Gen of sexual disorder or hypoactive sexual desire disorder, or in erally, the prodrugs are metabolized in vivo by esterases or by improving the patient (either objectively or subjectively other mechanisms to active drugs. Examples of prodrugs and according to the patient or health care provider) beyond that their uses are well known in the art (See, e.g., Berge et al. (1977) “‘Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19). The expected in the absence of Such treatment. prodrugs can be prepared in situ during the final isolation and 0439 With respect to the nomenclature of a chiral center, purification of the compounds, or by separately reacting the terms “d” and “1” configuration are as defined by the IUPAC purified compound in its free acid form or hydroxyl with a Recommendations. As to the use of the terms, diastereomer, Suitable esterifying agent. Hydroxyl groups can be converted racemate, epimer and enantiomer will be used in their normal into esters via treatment with a carboxylic acid. Examples of context to describe the Stereochemistry of preparations. prodrug moieties include Substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., pro 2. COMPOUNDS OF THE INVENTION pionoic acid esters), lower alkenyl esters, di-lower alkyl 0440. In one aspect, the invention provides compounds amino lower-alkyl esters (e.g., dimethylaminoethyl ester), capable of modulating sexual disorder or hypoactive sexual acylamino lower alkyl esters (e.g., acetyloxymethyl ester), desire disorder in a subject. Such compounds include a acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), 5-HTantagonist (e.g., traZodone, nefazodone, mirtazapine, aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl flibanserin), a 5-HT, receptoragonist (e.g., traZodone, nefa ester), Substituted (e.g., with methyl, halo, or methoxy Sub Zodone, mirtazapine, flibanserin), a norepinephrine-dopam US 2015/O 150946 A1 Jun. 4, 2015 46 ine reuptake inhibitor (e.g., bupropion), an oxytocin receptor 0445. In another embodiment, the invention provides a (OXTR) agonist (e.g., carbetocin, oxytocin, SyntocinonR), compound (e.g., a compound herein) capable of modulating and an endocrine active agent. Compositions of the invention cognition disorder; and pharmaceutically acceptable esters, further include a pharmaceutically acceptable carrier. salts, isomers and prodrugs thereof. 0441. In one aspect, the invention provides compounds 0446. In another embodiment, the invention provides a capable of modulating sexual disorder or hypoactive sexual compound (e.g., a compound herein) capable of enhancing desire disorder in a subject. Such compounds include a cognition; and pharmaceutically acceptable esters, salts, iso 5-HT, antagonist (e.g., trazodone, nefazodone, mirtazapine, mers and prodrugs thereof. flibanserin), a 5-HT, receptoragonist (e.g., traZodone, nefa 0447 Naturally occurring or synthetic isomers can be Zodone, mirtazapine, flibanserin), a norepinephrine-dopam separated in several ways known in the art. Methods for ine reuptake inhibitor (e.g., bupropion), an oxytocin receptor separating a racemic mixture of two enantiomers include (OXTR) agonist (e.g., carbetocin, oxytocin, Syntocinon R.), a chromatography using a chiral stationary phase (see, e.g., 5-HT, agonist (e.g., lorcaserin, vabicaserin, PRX-00933, “Chiral Liquid Chromatography.” W.J. Lough, Ed. Chapman YM348, metachlorophenylpiperazine), other non-abusable and Hall, New York (1989)). Enantiomers can also be sepa agents (agents not scheduled by the DEA) that augment rated by classical resolution techniques. For example, forma dopamine and/or norepinephrine in the brain, e.g., atomoxet tion of diastereomeric salts and fractional crystallization can be used to separate enantiomers. For the separation of enan ine, reboxetine, amedalin, CP-39,332, daledalin, edivoxetine, tiomers of carboxylic acids, the diastereomeric salts can be eSreboxetine, lortalamine, mazindol, nisoxetine, talopram, formed by addition ofenantiomerically pure chiral bases such talsupram, tandamine, Viloxazine, maprotiline, ciclaZindol, asbrucine, quinine, ephedrine, Strychnine, and the like. Alter manifaxine, radafaxine, tapentadol, teniloxazine, St. John's natively, diastereomeric esters can be formed with enantio wort, ginkgo biloba), and an endocrine active agent. Compo merically pure chiral alcohols such as menthol, followed by sitions of the invention further include a pharmaceutically separation of the diastereomeric esters and hydrolysis to yield acceptable carrier. the free, enantiomerically enriched carboxylic acid. For sepa 0442. The compounds delineated herein include a 5-HT ration of the optical isomers of amino compounds, addition of antagonist (e.g., traZodone, nefazodone, mirtazapine, fli chiral carboxylic or Sulfonic acids, such as camphorsulfonic banserin), that is a compound that demonstrates antagonistic acid, tartaric acid, mandelic acid, or lactic acid can result in activity against the 5-HT2 receptor; a norepinephrine formation of the diastereomeric salts. dopamine reuptake inhibitor (e.g., bupropion); that is a com pound that exhibits inhibition activity in norepinephrine 3. USES OF THE COMPOUNDS OF THE dopamine reuptake; a 5-HT, receptor agonist (e.g., INVENTION traZodone, nefazodone, mirtazapine, flibanserin), that is a compound that demonstrates agonist activity against the 0448. In one embodiment, the invention provides methods 5-HT, receptor; an oxytocin receptor (OXTR) agonist (e.g., of treating a disease or disorder in a Subject comprising carbetocin, oxytocin, Syntocinon R.), that is a compound that administering to the Subject a composition delineated herein. demonstrates agonistic activity against the oxytocin receptor, In one embodiment, the invention provides methods of treat and an endocrine active agent, that is an agent that is active in ing sexual disorder in a Subject comprising administering to modulating the endocrine system. the Subject a composition delineated herein. In certain embodiments, the Subject is a mammal, e.g., a primate, e.g., a 0443) The compounds delineated herein include a 5-HT human. In aspect, the disease, disorder or symptom thereof in antagonist (e.g., traZodone, nefazodone, mirtazapine, fli which the compounds, compositions, and methods of treat banserin, ketanserin, ritanserin, clozapine, olanzapine, que ment relate to is one described in the Diagnostic and Statis tiapine, risperidone, asenapine, MDL-100.907, cyprohepta tical Manual of Mental Disorders 4" edition Text Revision, dine, aripiprazole, and the general class of 2-alkyl-4-aryl (DSM-I-TRV), American Psychiatric Association. tetrahydro-pyrimido-azepines), that is a compound that 0449 In certain embodiments, the methods of the inven demonstrates antagonistic activity against the 5-HT, recep tion include administering to a subject atherapeutically effec tor, a norepinephrine-dopamine reuptake inhibitor (e.g., tive amount of a compound of the invention in combination bupropion); that is a compound that exhibits inhibition activ with another pharmaceutically active compound. Examples ity in norepinephrine-dopamine reuptake; a 5-HT, receptor of pharmaceutically active compounds include compounds agonist (e.g., traZodone, nefazodone, mirtazapine, fli known to treat sexual disorder in a subject. Other pharmaceu banserin, ketanserin, ritanserin, clozapine, olanzapine, que tically active compounds that may be used can be found in tiapine, risperidone, asenapine, MDL-100.907, cyprohepta Harrison's Principles of Internal Medicine, Thirteenth Edi dine, aripiprazole, and the general class of 2-alkyl-4-aryl tion, Eds.T. R. Harrisonetal. McGraw-Hill N.Y., NY; and the tetrahydro-pyrimido-azepines), that is a compound that Physicians Desk Reference 50th Edition 1997, Oradell New demonstrates agonist activity against the 5-HT, receptor; an Jersey, Medical Economics Co., the complete contents of oxytocin receptor (OXTR) agonist (e.g., carbetocin, oxyto which are expressly incorporated herein by reference. The cin, Syntocinon R.), that is a compound that demonstrates compound of the invention and the pharmaceutically active agonistic activity against the oxytocin receptor, and an endo compound may be administered to the Subject in the same crine active agent, that is an agent that is active in modulating pharmaceutical composition or in different pharmaceutical the endocrine system. compositions (at the same time or at different times). 0444. In one embodiment, the invention provides a com 0450 Determination of a therapeutically effective sexual pound (e.g., a compound herein) capable of modulating disorder effective amount, a prophylactically effective sexual sexual disorder or hypoactive sexual desire disorder, and disorder or hypoactive sexual desire disorder amount of the pharmaceutically acceptable esters, salts, isomers and pro compound of the invention, can be readily made by the phy drugs thereof. sician or veterinarian (the “attending clinician'), as one US 2015/O 150946 A1 Jun. 4, 2015 47 skilled in the art, by the use of known techniques and by disorder, and packaged with instructions to treat a subject observing results obtained under analogous circumstances. Suffering from or Susceptible to a sexual disorder or hypoac The dosages may be varied depending upon the requirements tive sexual desire disorder. of the patient in the judgment of the attending clinician; the 0455 The subject may be at risk of a sexual disorder or severity of the condition being treated and the particular com hypoactive sexual desire disorder, may be exhibiting Symp pound being employed. In determining the therapeutically toms of a sexual disorder or hypoactive sexual desire disorder, effective sexual disorder or hypoactive sexual desire disorder may be susceptible to a sexual disorder or hypoactive sexual amount or dose, and the prophylactically effective sexual desire disorder and/or may have been diagnosed with a sexual disorder or hypoactive sexual desire disorder amount or dose, desire disorder. a number of factors are considered by the attending clinician, 0456. If the modulation of the status indicates that the including, but not limited to: the specific sexual disorder or Subject may have a favorable clinical response to the treat hypoactive sexual desire disorder involved; pharmacody ment, the subject may be treated with the compound. For namic characteristics of the particular agent and its mode and example, the Subject can be administered therapeutically route of administration; the desired time course of treatment; effective dose or doses of the compound. the species of mammal; its size, age, and general health; the 0457 Kits of the invention include kits for treating a specific disease involved; the degree of or involvement or the sexual disorder or hypoactive sexual desire disorder in a severity of the disease; the response of the individual patient; Subject. The kit may include a compound of the invention, for the particular compound administered; the mode of adminis example, a compound described herein, pharmaceutically tration; the bioavailability characteristics of the preparation acceptable esters, salts, and prodrugs thereof, and instruc administered; the dose regimen selected; the kind of concur tions for use. The instructions for use may include informa rent treatment (i.e., the interaction of the compound of the tion on dosage, method of delivery, storage of the kit, etc. In invention with other co-administered therapeutics); and other aspects, the kits (and methods of using them) comprise relevant circumstances. instructions indicating that the compositions and/or treatment 0451. The dosage administration can be in a single dosage methods are contraindicated for (or not to be administered to) form or multiple dosage forms. The dosages can be adminis subjects that: (i) require and/or are taking CYP3A4, CYP tered concurrently, simultaneously, or sequentially. The dos 2B6-, or CYP2D6-metabolized drugs; (ii) take any sex hor ages can be a single dosage immediately prior to sexual mone other than an approved hormonal contraceptive; (iii) activity, or can be one or more doses daily without regard to drink more than one alcoholic drink per day (e.g., 12-OZ beer, timing prior to sexual activity. Treatment can be initiated with 4-OZ, wine, etc). Smaller dosages, which are less than the optimum dose of the 0458 Alternatively, the effects of compound of the inven compound. Thereafter, the dosage may be increased by Small tion can be characterized in vivo using animals models. increments until the optimum effect under the circumstances 0459. In another embodiment, the invention provides is reached. For convenience, the total daily dosage may be methods of treating cognitive disorderina Subject comprising divided and administered in portions during the day if administering to the Subject a composition delineated herein. desired. A therapeutically effective amount and a prophylac In certain embodiments, the Subject is a mammal, e.g., a tically effective amount of a compound of the invention of the primate, e.g., a human. In aspect, the disease, disorder or invention is expected to vary from about 0.1 milligram per symptom thereof in which the compounds, compositions, and kilogram of body weight per day (mg/kg/day) to about 100 methods of treatment relate to is one described in the Diag mg/kg/day. nostic and Statistical Manual of Mental Disorders 4" edi 0452. The identification of those patients who are in need tion Text Revision, (DSM-I-TRV), American Psychiatric of prophylactic treatment for sexual disorder or hypoactive Association. sexual desire disorder is well within the ability and knowl 0460. In certain embodiments, the methods of the inven edge of one skilled in the art. Certain of the methods for tion include administering to a subject atherapeutically effec identification of patients which are at risk of developing tive amount of a compound of the invention in combination sexual disorder or hypoactive sexual desire disorder which with another pharmaceutically active compound. Examples can be treated by the subject method are appreciated in the of pharmaceutically active compounds include compounds medical arts, such as family history, and the presence of risk known to treat cognitive disorder in a subject. Other pharma factors associated with the development of that disease state ceutically active compounds that may be used can be found in in the Subject patient (e.g., use of antidepressant drugs, hor Harrison's Principles of Internal Medicine. Thirteenth Edi monal contraceptives, antihormonal and/or cytotoxic chemo tion, Eds.T. R. Harrisonetal. McGraw-Hill N.Y., NY; and the therapies, sedatives, antipsychotic drugs, antiepileptic drugs, Physicians Desk Reference 50th Edition 1997, Oradell New mood stabilizer drugs, opioid drugs, alcohol, or narcotic Jersey, Medical Economics Co., the complete contents of drugs). A clinician skilled in the art can readily identify Such which are expressly incorporated herein by reference. The candidate patients, by the use of, for example, clinical tests, compound of the invention and the pharmaceutically active physical examination and medical/family history. compound may be administered to the Subject in the same pharmaceutical composition or in different pharmaceutical 0453 As used herein, "obtaining a biological sample from compositions (at the same time or at different times). a Subject, includes obtaining a sample for use in the methods 0461) Determination of a therapeutically effective cogni described herein. A biological sample is described above. tive disorder effective amount, a prophylactically effective 0454. In another aspect, a compound of the invention is cognitive disorder amount of the compound of the invention, packaged in a therapeutically effective amount with a phar can be readily made by the physician or veterinarian (the maceutically acceptable carrier or diluent. The composition “attending clinician'), as one skilled in the art, by the use of may be formulated for treating a Subject Suffering from or known techniques and by observing results obtained under Susceptible to a sexual disorder or hypoactive sexual desire analogous circumstances. The dosages may be varied US 2015/O 150946 A1 Jun. 4, 2015 48 depending upon the requirements of the patient in the judg 0468. Kits of the invention include kits for treating a cog ment of the attending clinician; the severity of the condition nitive disorder in a Subject. The kit may include a compound being treated and the particular compound being employed. of the invention, for example, a compound described herein, In determining the therapeutically effective cognitive disor pharmaceutically acceptable esters, salts, and prodrugs der amount or dose, and the prophylactically effective cogni thereof, and instructions for use. The instructions for use may tive disorder amount or dose, a number of factors are consid include information on dosage, method of delivery, storage of ered by the attending clinician, including, but not limited to: the kit, etc. In aspects, the kits (and methods of using them) the specific cognitive disorder involved; pharmacodynamic comprise instructions indicating that the compositions and/or characteristics of the particular agent and its mode and route treatment methods are contraindicated for (or not to be of administration; the desired time course of treatment; the administered to) Subjects that: (i) require and/or are taking species of mammal; its size, age, and general health; the CYP3A4, CYP2B6-, or CYP2D6-metabolized drugs; (ii) specific disease involved; the degree of or involvement or the drink more than one alcoholic drink per day (e.g., 12-OZ beer, severity of the disease; the response of the individual patient; 4-oZ wine, etc). the particular compound administered; the mode of adminis 0469 Alternatively, the effects of compound of the inven tration; the bioavailability characteristics of the preparation tion can be characterized in vivo using animals models. administered; the dose regimen selected; the kind of concur 0470. In another embodiment, the invention provides rent treatment (i.e., the interaction of the compound of the methods of enhancing cognition in a Subject comprising invention with other co-administered therapeutics); and other administering to the Subject a composition delineated herein. relevant circumstances. In certain embodiments, the Subject is a mammal, e.g., a 0462. The dosage administration can be in a single dosage primate, e.g., a human. In aspect, the disease, disorder or form or multiple dosage forms. The dosages can be adminis symptom thereof in which the compounds, compositions, and tered concurrently, simultaneously, or sequentially. The dos methods of treatment relate to is one described in the Diag ages can be a single dosage, or can be one or more doses daily. nostic and Statistical Manual of Mental Disorders 4" edi Treatment can be initiated with Smaller dosages, which are tion Text Revision, (DSM-I-TRV), American Psychiatric less than the optimum dose of the compound. Thereafter, the Association. dosage may be increased by Small increments until the opti 0471. In certain embodiments, the methods of the inven mum effect under the circumstances is reached. For conve tion include administering to a subject atherapeutically effec nience, the total daily dosage may be divided and adminis tive amount of a compound of the invention in combination tered in portions during the day if desired. A therapeutically with another pharmaceutically active compound. Examples effective amount and a prophylactically effective amount of a of pharmaceutically active compounds include compounds compound of the invention of the invention is expected to known to enhance cognition in a Subject. Other pharmaceu vary from about 0.1 milligram per kilogram of body weight tically active compounds that may be used can be found in per day (mg/kg/day) to about 100 mg/kg/day. Harrison's Principles of Internal Medicine. Thirteenth Edi 0463. The identification of those patients who are in need tion, Eds.T. R. Harrisonetal. McGraw-Hill N.Y., NY; and the of prophylactic treatment for cognitive disorder is well within Physicians Desk Reference 50th Edition 1997, Oradell New the ability and knowledge of one skilled in the art. Certain of Jersey, Medical Economics Co., the complete contents of the methods for identification of patients which are at risk of which are expressly incorporated herein by reference. The developing cognitive disorder which can be treated by the compound of the invention and the pharmaceutically active Subject method are appreciated in the medical arts, such as compound may be administered to the Subject in the same family history, and the presence of risk factors associated pharmaceutical composition or in different pharmaceutical with the development of that disease state in the subject compositions (at the same time or at different times). patient. A clinician skilled in the art can readily identify Such 0472. Determination of a therapeutically effective cogni candidate patients, by the use of, for example, clinical tests, tion enhancing effective amount, a prophylactically effective physical examination and medical/family history. cognition enhancement amount of the compound of the 0464 As used herein, "obtaining a biological sample from invention, can be readily made by the physician or veterinar a Subject, includes obtaining a sample for use in the methods ian (the “attending clinician'), as one skilled in the art, by the described herein. A biological sample is described above. use of known techniques and by observing results obtained 0465. In another aspect, a compound of the invention is under analogous circumstances. The dosages may be varied packaged in a therapeutically effective amount with a phar depending upon the requirements of the patient in the judg maceutically acceptable carrier or diluent. The composition ment of the attending clinician; the severity of the condition may be formulated for treating a Subject Suffering from or being treated and the particular compound being employed. Susceptible to a cognition disorder, and packaged with In determining the therapeutically effective cognition instructions to treat a Subject Suffering from or Susceptible to enhancement amount or dose, and the prophylactically effec a cognitiondisorder. tive cognition enhancing amount or dose, a number of factors are considered by the attending clinician, including, but not 0466. The subject may be at risk of a cognition disorder, limited to: the specific cognition enhancement needed; phar may be exhibiting symptoms of a cognition disorder, may be macodynamic characteristics of the particular agent and its Susceptible to a cognitive disorder and/or may have been mode and route of administration; the desired time course of diagnosed with a cognition disorder. treatment; the species of mammal; its size, age, and general 0467. If the modulation of the status indicates that the health; the specific disease involved; the degree of or involve Subject may have a favorable clinical response to the treat ment or the severity of the disease; the response of the indi ment, the subject may be treated with the compound. For vidual patient; the particular compound administered; the example, the Subject can be administered therapeutically mode of administration; the bioavailability characteristics of effective dose or doses of the compound. the preparation administered; the dose regimen selected; the US 2015/O 150946 A1 Jun. 4, 2015 49 kind of concurrent treatment (i.e., the interaction of the com 4. PHARMACEUTICAL COMPOSITIONS pound of the invention with other co-administered therapeu 0481. The invention also provides a pharmaceutical com tics); and other relevant circumstances. position, comprising an effective amount of a compound 0473. The dosage administration can be in a single dosage described herein and a pharmaceutically acceptable carrier. form or multiple dosage forms. The dosages can be adminis In a further embodiment, the effective amount is effective to tered concurrently, simultaneously, or sequentially. The dos treat a sexual disorder or hypoactive sexual desire disorder, as ages can be a single dosage, or can be one or more doses daily. described previously. Treatment can be initiated with Smaller dosages, which are less than the optimum dose of the compound. Thereafter, the 0482 In an embodiment, the compound of the invention is dosage may be increased by Small increments until the opti administered to the Subject using a pharmaceutically-accept mum effect under the circumstances is reached. For conve able formulation, e.g., a pharmaceutically-acceptable formu nience, the total daily dosage may be divided and adminis lation that provides sustained delivery of the compound of the tered in portions during the day if desired. A therapeutically invention to a subject for at least 12 hours, 24 hours, 36 hours, effective amount and a prophylactically effective amount of a 48 hours, one week, two weeks, three weeks, or four weeks compound of the invention of the invention is expected to after the pharmaceutically-acceptable formulation is admin vary from about 0.1 milligram per kilogram of body weight istered to the subject. per day (mg/kg/day) to about 100 mg/kg/day. 0483. In certain embodiments, these pharmaceutical com positions are suitable for topical or oral, buccal or Sublingual 0474 The identification of those patients who are in need administration to a subject. In other embodiments, as of prophylactic treatment for cognition enhancement is well described in detail below, the pharmaceutical compositions of within the ability and knowledge of one skilled in the art. the present invention may be specially formulated for admin Certain of the methods for identification of patients which are istration in Solid or liquid form, including those adapted for at risk of needing cognition enhancement which can be the following: (1) oral administration, for example, drenches treated by the subject method are appreciated in the medical (aqueous or non-aqueous Solutions or Suspensions), tablets, arts, such as family history, and the presence of risk factors boluses, powders, granules, pastes; (2) parenteral administra associated with the development of that disease state in the tion, for example, by Subcutaneous, intramuscular or intrave Subject patient. A clinician skilled in the art can readily iden nous injection as, for example, a sterile solution or Suspen tify Such candidate patients, by the use of for example, clini sion; (3) topical application, for example, as a cream, cal tests, physical examination and medical/family history. ointment or spray applied to the skin; (4) intravaginally or 0475. As used herein, "obtaining a biological sample from intrarectally, for example, as a pessary, cream or foam; or (5) a Subject, includes obtaining a sample for use in the methods aerosol, for example, as an aqueous aerosol, liposomal prepa described herein. A biological sample is described above. ration or Solid particles containing the compound or compo 0476. In another aspect, a compound of the invention is sition herein. packaged in a therapeutically effective amount with a phar 0484 The phrase “pharmaceutically acceptable' refers to maceutically acceptable carrier or diluent. The composition those compound of the inventions of the present invention, may be formulated for treating a subject requiring or Suscep compositions containing Such compounds, and/or dosage tible to requiring cognition enhancement, and packaged with forms which are, within the scope of Sound medical judg instructions to treat a Subject requiring or Susceptible to ment, Suitable for use in contact with the tissues of human requiring cognition enhancement. beings and animals without excessive toxicity, irritation, 0477 The subject may be at risk requiring cognition allergic response, or other problem or complication, com enhancement, may be exhibiting symptoms of requiring cog mensurate with a reasonable benefit/risk ratio. nition enhancement, may be susceptible to requiring cogni 0485 The phrase “pharmaceutically-acceptable carrier' tion enhancement and/or may have been diagnosed with includes pharmaceutically-acceptable material, composition requiring cognition enhancement. or vehicle. Such as a liquid or Solid filler, diluent, excipient, 0478 If the modulation of the status indicates that the Solvent or encapsulating material, involved in carrying or Subject may have a favorable clinical response to the treat transporting the Subject chemical from one organ, or portion ment, the subject may be treated with the compound. For of the body, to another organ, or portion of the body. Each example, the Subject can be administered therapeutically carrier is “acceptable' in the sense of being compatible with effective dose or doses of the compound. the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as 0479. Kits of the invention include kits for enhancing cog pharmaceutically-acceptable carriers include: (1) Sugars, nition in a Subject. The kit may include a compound of the Such as lactose, glucose and Sucrose; (2) starches, such as invention, for example, a compound described herein, phar corn starch and potato starch; (3) cellulose, and its deriva maceutically acceptable esters, salts, and prodrugs thereof, tives, such as Sodium carboxymethyl cellulose, ethyl cellu and instructions for use. The instructions for use may include lose and cellulose acetate; (4) powdered tragacanth; (5) malt, information on dosage, method of delivery, storage of the kit, (6) gelatin; (7) talc.; (8) excipients, such as cocoa butter and etc. In aspects, the kits (and methods of using them) comprise Suppository waxes; (9) oils, such as peanut oil, cottonseed oil, instructions indicating that the compositions and/or treatment safflower oil, sesame oil, olive oil, corn oil and Soybean oil; methods are contraindicated for (or not to be administered to) (10) glycols, such as propylene glycol, (11) polyols, such as subjects that: (i) require and/or are taking CYP3A4, CYP glycerin, Sorbitol, mannitol and polyethylene glycol; (12) 2B6-, or CYP2D6-metabolized drugs; (ii) drink more than esters, such as ethyl oleate and ethyl laurate; (13) agar, (14) one alcoholic drink per day (e.g., 12-OZ beer, 4-OZ wine, etc). buffering agents, such as magnesium hydroxide and alumi 0480. Alternatively, the effects of compound of the inven num hydroxide: (15) alginic acid, (16) pyrogen-free water; tion can be characterized in Vivo using animals models. (17) isotonic saline: (18) Ringer's solution; (19) ethyl alco US 2015/O 150946 A1 Jun. 4, 2015 50 hol; (20) phosphate buffer solutions; and (21) other non-toxic alginic acid, certain silicates, and sodium carbonate; (5) solu compatible Substances employed in pharmaceutical formula tion retarding agents. Such as paraffin; (6) absorption accel tions. erators, such as quaternary ammonium compounds; (7) wet 0486 Wetting agents, emulsifiers and lubricants, such as ting agents, such as, for example, acetyl alcohol and glycerol Sodium lauryl Sulfate and magnesium Stearate, as well as monostearate; (8) absorbents, such as kaolin and bentonite coloring agents, release agents, coating agents, Sweetening, clay; (9) lubricants, such a talc, calcium Stearate, magnesium flavoring and perfuming agents, preservatives and antioxi Stearate, Solid polyethylene glycols, Sodium lauryl Sulfate, dants can also be present in the compositions. and mixtures thereof, and (10) coloring agents. In the case of 0487. Examples of pharmaceutically-acceptable antioxi capsules, tablets and pills, the pharmaceutical compositions dants include: (1) water Soluble antioxidants, such as ascorbic may also comprise buffering agents. Solid compositions of a acid, cysteine hydrochloride, Sodium bisulfate, Sodium met similar type may also be employed as fillers in soft and abisulfite, sodium sulfite and the like; (2) oil-soluble antioxi hard-filled gelatin capsules using Such excipients as lactose or dants, such as ascorbyl palmitate, butylated hydroxyanisole milk Sugars, as well as high molecular weight polyethylene (BHA), butylated hydroxytoluene (BHT), lecithin, propyl glycols and the like. gallate, alpha-tocopherol, and the like; and (3) metal chelat 0492. A tablet may be made by compression or molding, ing agents, such as citric acid, ethylenediamine tetraacetic optionally with one or more accessory ingredients. Com acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the pressed tablets may be prepared using binder (for example, like. gelatin or hydroxypropylmethyl cellulose), lubricant, inert 0488 Compositions containing a compound of the inven diluent, preservative, disintegrant (for example, sodium tion(s) include those Suitable for oral, nasal, topical (includ starch glycolate or cross-linked sodium carboxymethyl cel ing buccal and Sublingual), rectal, vaginal, aerosol and/or lulose), Surface-active or dispersing agent. Molded tablets parenteral administration. The compositions may conve may be made by molding in a Suitable machine a mixture of niently be presented in unit dosage form and may be prepared the powdered active ingredient moistened with an inert liquid by any methods well known in the art of pharmacy. The diluent. amount of active ingredient which can be combined with a 0493. The tablets, and other solid dosage forms of the carrier material to produce a single dosage form will vary pharmaceutical compositions of the present invention, Such depending upon the host being treated, the particular mode of as dragees, capsules, pills and granules, may optionally be administration. The amount of active ingredient which can be scored or prepared with coatings and shells, such as enteric combined with a carrier material to produce a single dosage coatings and other coatings well known in the pharmaceuti form will generally be that amount of the compound which cal-formulating art. They may also be formulated so as to produces a therapeutic effect. Generally, out of one hundred provide slow or controlled release of the active ingredient percent, this amount will range from about 1 percent to about therein using, for example, hydroxypropylmethyl cellulose in ninety-nine percent of active ingredient, preferably from varying proportions to provide the desired release profile, about 5 percent to about 70 percent, more preferably from other polymer matrices, liposomes and/or microspheres. about 10 percent to about 30 percent. They may be sterilized by, for example, filtration through a 0489 Methods of preparing these compositions include bacteria-retaining filter, or by incorporating sterilizing agents the step of bringing into association a compound of the inven in the form of sterile solid compositions which can be dis tion(s) with the carrier and, optionally, one or more accessory solved in sterile water, or some other sterile injectable ingredients. In general, the formulations are prepared by uni medium immediately before use. These compositions may formly and intimately bringing into association a compound also optionally contain opacifying agents and may be of a of the invention with liquid carriers, or finely divided solid composition that they release the active ingredient(s) only, or carriers, or both, and then, if necessary, shaping the product. preferentially, in a certain portion of the gastrointestinal tract, 0490 Compositions of the invention suitable for oral optionally, in a delayed manner. Examples of embedding administration may be in the form of capsules, cachets, pills, compositions which can be used include polymeric Sub tablets, lozenges (using a flavored basis, usually Sucrose and stances and waxes. The active ingredient can also be in micro acacia or tragacanth), powders, granules, or as a solution or a encapsulated form, if appropriate, with one or more of the Suspension in an aqueous or non-aqueous liquid, or as an above-described excipients. oil-in-water or water-in-oil liquid emulsion, or as an elixir or 0494 Liquid dosage forms for oral administration of the syrup, or as pastilles (using an inert base, Such as gelatin and compound of the invention(s) include pharmaceutically-ac glycerin, or Sucrose and acacia) and/or as mouth washes and ceptable emulsions, microemulsions, Solutions, Suspensions, the like, each containing a predetermined amount of a com syrups and elixirs. In addition to the active ingredient, the pound of the invention(s) as an active ingredient. A compound liquid dosage forms may contain inert diluents commonly may also be administered as a bolus, electuary or paste. used in the art, Such as, for example, water or other solvents, 0491. In solid dosage forms of the invention for oral solubilizing agents and emulsifiers, such as ethyl alcohol, administration (capsules, tablets, pills, dragees, powders, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alco granules and the like), the active ingredient is mixed with one hol, benzyl benzoate, propylene glycol. 1,3-butylene glycol, or more pharmaceutically-acceptable carriers, such as oils (in particular, cottonseed, groundnut, corn, germ, olive, Sodium citrate or dicalcium phosphate, and/or any of the castor and sesame oils), glycerol, tetrahydrofuryl alcohol, following: (1) fillers or extenders, such as starches, lactose, polyethylene glycols and fatty acid esters of Sorbitan, and Sucrose, glucose, mannitol, and/or silicic acid; (2) binders, mixtures thereof. Such as, for example, carboxymethylcellulose, alginates, 0495. In addition to inert diluents, the oral compositions gelatin, polyvinyl pyrrolidone, Sucrose and/or acacia; (3) can include adjuvants such as wetting agents, emulsifying humectants, such as glycerol; (4) disintegrating agents, such and Suspending agents, Sweetening, flavoring, coloring, per as agar-agar, calcium carbonate, potato or tapioca starch, fuming and preservative agents. US 2015/O 150946 A1 Jun. 4, 2015

0496 Suspensions, in addition to the active compound of trolled by either providing a rate controlling membrane or the invention(s) may contain Suspending agents as, for dispersing the active ingredient in a polymer matrix or gel. example, ethoxylated isostearyl alcohols, polyoxyethylene 0505 Ophthalmic formulations, eye ointments, powders, Sorbitol and Sorbitan esters, microcrystalline cellulose, alu Solutions and the like, are also contemplated as being within minum metahydroxide, bentonite, agar-agar and tragacanth, the scope of the invention. and mixtures thereof. 0506 Pharmaceutical compositions of the invention suit 0497 Pharmaceutical compositions of the invention for able for parenteral administration comprise one or more com rectal or vaginal administration may be presented as a Sup pound of the invention(s) in combination with one or more pository, which may be prepared by mixing one or more pharmaceutically-acceptable sterile isotonic aqueous or non compound of the invention(s) with one or more Suitable non aqueous solutions, dispersions, Suspensions or emulsions, or irritating excipients or carriers comprising, for example, sterile powders which may be reconstituted into sterile inject cocoa butter, polyethylene glycol, a Suppository wax or a able Solutions or dispersions just prior to use, which may salicylate, and which is solid at room temperature, but liquid contain antioxidants, buffers, bacteriostats, Solutes which at body temperature and, therefore, will melt in the rectum or render the formulation isotonic with the blood of the intended vaginal cavity and release the active agent. recipient or Suspending or thickening agents. 0498 Compositions of the present invention which are 0507 Examples of suitable aqueous and nonaqueous car Suitable for vaginal administration also include pessaries, riers, which may be employed in the pharmaceutical compo tampons, creams, gels, pastes, foams or spray formulations sitions of the invention include water, ethanol, polyols (Such containing Such carriers as are known in the art to be appro as glycerol, propylene glycol, polyethylene glycol, and the priate. like), and Suitable mixtures thereof, vegetable oils, such as 0499 Dosage forms for the topical or transdermal admin olive oil, and injectable organic esters, such as ethyl oleate. istration of a compound of the invention(s) include powders, Proper fluidity can be maintained, for example, by the use of sprays, ointments, pastes, creams, lotions, gels, Solutions, coating materials, such as lecithin, by the maintenance of the patches and inhalants. The active compound of the invention required particle size in the case of dispersions, and by the use (s) may be mixed under Sterile conditions with a pharmaceu of Surfactants. tically-acceptable carrier, and with any preservatives, buffers, 0508. These compositions may also contain adjuvants or propellants which may be required. Such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorgan 0500 The ointments, pastes, creams and gels may contain, isms may be ensured by the inclusion of various antibacterial in addition to compound of the invention(s) of the present and antifungal agents, for example, paraben, chlorobutanol, invention, excipients, such as animal and vegetable fats, oils, phenol sorbic acid, and the like. It may also be desirable to waxes, paraffins, starch, tragacanth, cellulose derivatives, include isotonic agents. Such as Sugars, sodium chloride, and polyethylene glycols, silicones, bentonites, silicic acid, talc the like into the compositions. In addition, prolonged absorp and Zinc oxide, or mixtures thereof. tion of the injectable pharmaceutical form may be brought 0501 Powders and sprays can contain, in addition to a about by the inclusion of agents which delay absorption Such compound of the invention(s), excipients such as lactose, talc, as aluminum monostearate and gelatin. silicic acid, aluminum hydroxide, calcium silicates and 0509. In some cases, in order to prolong the effect of a polyamide powder, or mixtures of these Substances. Sprays drug, it is desirable to slow the absorption of the drug from can additionally contain customary propellants. Such as chlo Subcutaneous or intramuscular injection. This may be accom rofluorohydrocarbons and volatile unsubstituted hydrocar plished by the use of a liquid Suspension of crystalline or bons, such as butane and propane. amorphous material having poor water solubility. The rate of 0502. The compound of the invention(s) can be alterna absorption of the drug then depends upon its rate of dissolu tively administered by aerosol. This is accomplished by pre tion which, in turn, may depend upon crystal size and crys paring an aqueous aerosol, liposomal preparation or Solid talline form. Alternatively, delayed absorption of a parenter particles containing the compound. A nonaqueous (e.g., fluo ally-administered drug form is accomplished by dissolving or rocarbon propellant) Suspension could be used. Sonic nebu Suspending the drug in an oil vehicle. lizers are preferred because they minimize exposing the agent 0510 Injectable depot forms are made by forming to shear, which can result in degradation of the compound. microencapsule matrices of compound of the invention(s) in 0503 Ordinarily, an aqueous aerosol is made by formulat biodegradable polymers such as polylactide-polyglycolide. ing an aqueous solution or Suspension of the agent together Depending on the ratio of drug to polymer, and the nature of with conventional pharmaceutically-acceptable carriers and the particular polymer employed, the rate of drug release can stabilizers. The carriers and stabilizers vary with the require be controlled. Examples of other biodegradable polymers ments of the particular compound, but typically include non include poly(orthoesters) and poly(anhydrides). Depot ionic Surfactants (Tweens, Pluronics, or polyethylene glycol), injectable formulations are also prepared by entrapping the innocuous proteins like serum albumin, Sorbitan esters, oleic drug in liposomes or microemulsions which are compatible acid, lecithin, amino acids such as glycine, buffers, salts, with body tissue. Sugars or Sugar alcohols. Aerosols generally are prepared 0511 When the compound of the invention(s) are admin from isotonic Solutions. istered as pharmaceuticals, to humans and animals, they can 0504 Transdermal patches have the added advantage of be given perse or as a pharmaceutical composition contain providing controlled delivery of a compound of the invention ing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) (s) to the body. Such dosage forms can be made by dissolving of active ingredient in combination with a pharmaceutically or dispersing the agent in the proper medium. Absorption acceptable carrier. enhancers can also be used to increase the flux of the active 0512 Regardless of the route of administration selected, ingredient across the skin. The rate of Such flux can be con the compound of the invention(s), which may be used in a US 2015/O 150946 A1 Jun. 4, 2015 52

Suitable hydrated form, and/or the pharmaceutical composi Example 2 tions of the present invention, are formulated into pharma 0520 Method. ceutically-acceptable dosage forms by conventional methods 0521. A 36 year-old healthy male volunteer in a stable known to those of skill in the art. marital relationship for two years with no current sexual 0513 Actual dosage levels and time course of administra disorders, exposed himself sequentially to four treatments, tion of the active ingredients in the pharmaceutical composi each for 4 weeks: (1) Treatment B: Instant-release (IR) tions of the invention may be varied so as to obtain an amount Bupropion (Bup) 150 mg in the morning and 100 mg in the of the active ingredient which is effective to achieve the evening; (2) Treatment T: IR trazodone (Trz) 50 mg. t.i.d.; (3) desired therapeutic response for a particular patient, compo Treatment L. IRTrz 25 mgb.i.d. plus IRBup 150 mg in the sition, and mode of administration, without being toxic to the morning and 100 mg in the evening; and (4) Treatment L. patient. An exemplary dose range is from 0.1 to 10 mg per IR Trz 50 mg. t.i.d. plus IRBup 75 mg. t.i.d. A washout of 1-4 day. weeks occurred between each treatment. Level and frequency 0514. A preferred dose of the compound of the invention of sexual desire was scored daily, as not improved (0), some for the present invention is the maximum that a patient can what improved (1), or markedly improved (2). Sexual events tolerate and not develop serious side effects. Preferably, the were counted, and three domains (sexual arousal, orgasm, compound of the invention of the present invention is admin and overall satisfaction with the event) were scored. Each of istered at a concentration of about 0.001 mg to about 100 mg the sexual event variables was converted to a simple patients per kilogram of body weight, about 0.001-about 10 mg/kg or global impression of improvement (PGI; improved or not about 0.001 mg-about 100 mg/kg of body weight. Ranges improved today compared to pre-treatment baseline). The 3 intermediate to the above-recited values are also intended to domains of sexual event improvements were Summed for be part of the invention. analysis. Bup is already recommended as a treatment for HSDD; Trz is not. Thus, Fisher's exact test was applied post EXAMPLES hoc to the PGIS for Treatment BVS. Treatment L (Lo)and VS. Treatment Li, (L). 0515. The invention is further illustrated by the following 0522 Results. examples which are intended to illustrate but not limit the (0523 For sexual desire, the mean score with Land Li, Scope of the invention. was about twice that with Treatment B (two-tailed paired t-test, p<0.0001), and Treatment B was superior to Treatment Materials T. For arousal, orgasm, and overall satisfaction with a sexual event, Li was associated with somewhat more improve 0516 Small-Molecule Compounds— ments than with Treatment B in the third and fourth weeks of 0517 bupropion, trazodone, oxytocin, and testosterone use. Li, was associated with significantly more improve (and their salt, Solvates, hydrates, isomers, enantiomers, dias ments than with Treatment B in the third and fourth weeks of teriomers, racemates; all of which are included herein) are use and in the total for all four weeks. Fisher's exact test, available from commercial Sources and/or readily synthe two-tailed, showed the combination of bupropion plus traz sized using methods and reagents know in the art. Bupropion odone superior, p<0.05, for the 3-domain sum of sexual event is also known as, i.e., B-Keto-3-chloro-N-tert-butylamphet improvement. This study conducted with the combination of amine, i.e., (E)-2-(tert-Butylamino)-1-(3-chlorophenyl)pro bupropion plus traZodone showed increased benefits in sexual pan-1-one; trazodone is also known as, i.e., 2-3-4-(3-chlo arousal, orgasm, and event satisfaction, after exposure for 4 rophenyl)piperazin-1-yl)propyl-1,2,4-triazolo 4.3-a weeks, compared to either bupropion alone or traZodone pyridin-3 (2H)-one; oxytocin is also known as, i.e., 1-((4R, alone. The effects occurred at or below the target dosage of 7S,10S,13S, 16S, 19R)-19-amino-7-(2-amino-2-oxoethyl)- bupropion or traZodone in their current (antidepressant) 10-(3-amino-3-oxopropyl)-16-(4-hydroxybenzoyl)-13 labeling. (1S)-1-methylpropyl-6,9,12,15,18-pentaoxo-1,2-dithia-5, 0524. An independent researcher then scored the desire 8,11,14, 17-pentaazacycloicosan-4-yl)carbonyl)-L-prolyl-L- results as unimproved=0, somewhat improved 1, and mark leucylglycinamide. edly improved=2. Upon the advice of the independent researcher the subject dichotomized his sexual event results Example 1 in a simple daily patient’s global impression of improvement: improved or not improved today (compared to pre-treatment 0518 Clinical Protocol baseline). The independent researcher, when told that the 0519 subjects in a single blind, sequential study are results were positive for the subject but before seeing any of administered bupropion and traZodone in increasing dosages the data, decided to apply categorical tests to the most obvious (a 3-4 weeks each, that is, from a 3 (or 4)-week placebo comparisons between treatments: for the first two weeks, the baseline, to an intermediate dose ((a) another 3-4 weeks), to a second two weeks, and for all four weeks of treatment, low maximum dose ((a) a final 3-4 weeks). The subjects’ feed dose combination of bupropion plus traZodone VS. corre back/reports on Subjective (e.g., feelings, sensations, general sponding dose of bupropion; and high-dose the combination response) and objective (e.g., response time, performance of bupropion plus traZodone vs. same dose of traZodone. The measures, partner response) is collated and analyzed against test used for the desire score was a two-tailed paired t test, dosage. Each study also includes one or more patient(s) serv using all scores within a given treatment as repeated mea ing as a control (in demonstrating the synergistic effect Sures. The test used for the two-category variables was an between the two actives) would receive only bupropion, while online two-tailed Fisher's exact test using all scores within a the second and third will each be given a different fixed dose given treatment as repeated measures. Both were from the combination products having a defined ratio of active ingre website graphpad.com.* dients (e.g., bupropion and traZodone). *http://graphpad.com quickcalcsi chiscuared1.cfm US 2015/O 150946 A1 Jun. 4, 2015

TABLE 0525 For sexual desire, the response to T (Treatment T) was low, to B (Treatment B) was intermediate, and to Land Scores of desire, and counts of sexual Li, was sometimes strong in the first two weeks and uni event domain improved per treatment formly strong (improvement rated as marked every day) in the 0-2 Daily Desire Score, PGI Improved for Sexual second two weeks of treatment. The differences between each total, 96 of max. (max. = 28), Events, Sum of 3 domains dose of L vs. B were highly statistically significant, p<0.0001. 0526 B was markedly superior to T, p<0.05 for all com meant SD, p-value n/N, 9% p-value parisons. Treatment vs. Bup' improved vs. Bup? 0527. For the sum of improvements in arousal, orgasm, Bup 9, 32% 0.65 + 0.74 4/15, 27% and overall satisfaction with a sexual event, L showed wks 1-2 Bup 14, 50% 2/15, 13% significantly more improvements than with B in the third and wks 3-4 fourth weeks of use, 52% vs. 20%, p<0.05. L., was associ ated with significantly more improvements than with B in the Bup total O.82 OSS 6/30, 20% third and fourth weeks of use (72% vs. 13%) and in the total wks 1-2 2, 7% 0.14 + 0.53 3/12, 25% l.S. p = 0.051 for all four weeks (61% vs. 20%). Fisher's exact test, two Trz O, 0% 3/18, 17% tailed, showed the combination of bupropion plus traZodone wks 3-4 superior, p<0.05, for each of these 3-domain sums of sexual event improvement. Trz total 2, 4% 0.07 + 0.38 6/30, 20% l.S. p<0.0001 0528 For improvements in orgasm or overall satisfaction Lllow 14, 50% 0.64 + 0.74, n.s. 3/15, 20% l.S. for a sexual event, the numbers appeared too small and the wks 1-2 numerical trends were generally too weak to show statisti Lloy 28, 100% 11/21, 52% cally significant differences. For arousal, however, L, was wks 3-4 associated with significantly more improvements than with B Lic, total 150 O.88 14/36, 39% l.S. in the third and fourth weeks of use (100% vs. 0%) and in the P<0.0001 total for all four weeks (91% vs. 20%). Fisher's exact test, I-high 20, 71% 1.43 + 0.94 6/15, 40% l.S. two-tailed, showed the combination of bupropion plus traz wks 1-2 p = 0.021 high 28, 100% 13/18, 72% odone superior, p<0.05, for each of these 3-domain sums of wks 3-4 sexual event improvement. A numerical trend also favored La, in weeks 1-2 by 4/5 vs. 2/5 (80% vs. 40%). List, total 1.71 + 0.71, 20/33, 61% O.OO19 0529. The applicability of these male results to female p<0.0001 subjects with HSDD is possible given the similarities of 'P-values vs. corresponding treatment Bup, paired ttest, two-tailed desire dysfunction in men and women Laumann 1999, and *P-values vs. corresponding treatment Bup, two-tailed Fisher's exact test is to be tested next. Sum of n improved in arousal, orgasm, and overall satisfaction Note: Example 3 P-values larger than 0.1 are omitted from the table. 0530 Additional Study Design. B or Bup is bupropion alone, Tor Trz is trazodone alone, Li is the lower dose of Bup Trz combination, Li, is the higher dose of Bup/Trz combination. 0531. Further study is conducted as delineated in the Sche matic below.

Schematic of Study Design

Week

1 2 3 4 5

Day 8-15 15-21 22-29 29-35 36 Period Screening First Washout Second Washout Final Dosing Dosing Evaluations Group Low dose drug B+ X High dose X X One Low dose drug T drug B+ High dose drug T Group High dose drug B X High dose X X Two drug T

B or BUP = SR bupropion Tor TRZ = SR trazodone US 2015/O 150946 A1 Jun. 4, 2015 54

Flow Chart of Study Data Collection Period First and 8th day Final Screening of each Treatment Evaluation Note: each subject undergoes 2 Final treatments, for 1 week each followed Evaluation by a 1-week washout informed consent X FSFI-1 wk recall; FSDS-R-1 wk recall X X X Both are self-rated (s) Psychiatric history X clinician-rated (c) Relational/marital history (c) X PHQ-9 self-rated (s) X Beck Anxiety Inventory (s) X Sexual Interest and Desire X nventory - F (c) Checklist for DSM-IV & DSM-5 X emale sexual disorders: FSD diagnoses (c) Marital Adjustment Test (MAT) (s) X X Physical examination X Prin. Only Laboratory analytes X X ECG, 12-lead X X Sexual Activity Log (s) X X X Sexual Desire Relationship Distress X X X Scale (SDRDS) (s) if available from authors Vital signs (Supine and standing b.p., X Pre-dose & 1, 2, X pulse)2 4, 8 & 24 hr post-dose AE inquiry and checklist2 Drug blood levels Pre-dose and 1, 2, 4, 6, 8, 12, 24 hr post-dose Cognitive test battery Pre-dose and 1, 2, and 4 hours post-dose Verbal Numeric Rating Scales of 6 X feeling states (s) Partner's tests (may do at home if use IIEF IIEF HTS) MAT (p) MAT (p) SDRDS (p) SDRDS (p)

0532. Week 0: Informed consent, screening evaluations 0536 Or Medical, psychiatric, social/relationship, and sexual history; 0537 Group 2 diagnostics, measures of sexual dysfunction, and safety 0538 150 mg SR BUP in the morning and 100 mg SR evaluations physical examination, ECG, standard laboratory BUP in the evening safety analytes 0539 Week 2: washout #1 0540 Week 3: Treatment #2: 0533 Week 1: Treatment #1 (0541 Group 1 0534 Group 1 0542 High Dose combination of bupropion plus traz odone (250 mg BUP+150 mg TRZ/day, given as 150 mg SR 0535 Low Dose combination of bupropion plus traz- BUP in the morning and 100 mg SR BUP in the evening and odone: 250 mg BUP+75 mg TRZ/day, given as 150 mg SR 150 mg SR trazodone q.d.) and test battery BUP in the morning and 100 mg SR BUP in the evening and (0543 or 75 mg SR trazodone q.d.; and test battery. The test battery (0544 Group 2 includes single-dose PK, steady-state PK and pharmacody (0545 150 mg SR trazodone q.d. namics. Pharmacodynamics includes a cognitive test battery 0546 Week 4: Washout #2 and numeric rating scales (NRS) offeeling states, which will be done in the morning of the first and last day of dosing, at Example 4 pre-dose and at 1, 2, 4 and 8 hours post-dose. The cognitive 0547 Compositions of the invention can be made by com testing battery includes choice reaction time, word recall, bining the active agents (i.e., bupropion and traZodone) with picture recognition, numeric and spatial working memory. one or more of the following excipients: The self-rated NRS offeeling states for sedation/activation 0548 CARNAUBA WAX, CYSTEINE HYDROCHLO includes drowsy, dizzy, nervous, agitated, and hyper. Cogni RIDE, HYPROMELLOSES, MAGNESIUM STEARATE, tive testing will be done within-20 minutes before the hour; CELLULOSE, MICROCRYSTALLINE, POLYETHYL blood sampling will be done exactly on the hour; and VAS ENE, GLYCOL, POLYSORBATE 80, TITANIUM DIOX will be done within +15 minutes after the hour. IDE, FD&C BLUE NO. 1; US 2015/O 150946 A1 Jun. 4, 2015 55

0549. Hydroxypropyl distarch phosphate (Contramid(R), The recitation of an embodiment herein includes that embodi Hypromellose, Sodium stearyl fumarate, Colloidal silicon ment as any single embodiment or in combination with any dioxide, Iron Oxide Yellow, Iron Oxide Red, Talc, Polyethyl other embodiments or portions thereof. ene Glycol 3350, Titanium Dioxide, Polyvinyl Alcohol, 0552. Although the invention has been disclosed with ref Black ink (food grade). erence to specific embodiments, it is apparent that other 0550 The disclosures of each and every patent, patent embodiments and variations of the invention may be devised application and publication cited herein are hereby incorpo by others skilled in the art without departing from the true rated herein by reference in their entirety. spirit and scope of the invention. The claims are intended to be 0551. The recitation of a listing of chemical groups in any construed to include all such embodiments and equivalent definition of a variable herein includes definitions of that variations. variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein Example 5 includes that embodiment as any single embodiment or in combination with any other embodiments orportions thereof. 0553

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 treatment #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 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 Mod/High Control Low-dose 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-R7 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) 15 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., X XX X XX X XX X X pulse' US 2015/O 150946 A1 Jun. 4, 2015 56

-continued

Flow Chart

Mod/High Control Low-dose dose Final Screening (placebo) OXYTOCIN OXYTOCIN Visit

AE inquiry & checklist'' (s, c) X XX X XX X XX X CBC, ALT, AST (others prn') 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 eachtreatment, supine and standing BP and pulse pre-dose and 3:30hours 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 0554

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 1062 Period Screening Control Washout Low-Dose Washout Moderate- Final treatinent #1 OXYTOCIN #2 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 IUb.i.d.* day 4 to 150 Uq.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, US 2015/O 150946 A1 Jun. 4, 2015 57

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-R7 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., X XX X XX X XX X X pulse' AE inquiry & checklist'' (s, c) X XX X XX X XX X CBC, ALT, AST (others prn') 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 eachtreatment, supine and standing BP and pulse pre-dose and 3:30hours post-dose, and p.r.n, palpitations, faintness, prother 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 gmpletes 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 0555

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 1062 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 “ModerateDose OT +TRZ.” doses will be increased, and a “High Dose OT + TRZ” of 40 IUOT and 150 mg TRZ b.i.d. will be implemented for subsequent patients, US 2015/O 150946 A1 Jun. 4, 2015 58

Flow Chart

Control Lower-dose Higher-dose Final Screening (BUP) OT + TRZ OT + TRZ 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-R7 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', Prin Prin Pap test (c) Dosing None Start End Start End Start End Supine & Standing b.p., X XX X XX X XX X X pulse' 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 eachtreatment, supine and standing BP and pulse pre-dose and 3:30hours 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 0556)

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 IUOT- Ot-TRZ 75 day 4 to 150 TRZ 75 mg b.i.d.* mg b.i.d. mg q.d.* US 2015/O 150946 A1 Jun. 4, 2015 59

-continued

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

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

'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 *Ifefficacy and the maximumwell tolerated dose are not found after 5-15 patients have been treated with the “ModerateDose OT +B+T.” doses will be increased, and a “High Dose OT +B+ T will be implemented for subsequent patients.

Flow Chart Mod/High Control Low-dose 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-R7 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', Prin Prin Pap test (c) Dosing None Start End Start End Start End Supine & Standing b.p., X XX X XX X XX X X pulse' 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 eachtreatment, supine and standing BP and pulse pre-dose and 3:30hours post-dose, and p.r.n, palpitations, faintness, grother 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, US 2015/O 150946 A1 Jun. 4, 2015 60

1. A composition comprising a 5-HT, antagonist, a nore 12. The method of claim 10, wherein the sexual disorder is pinephrine-dopamine reuptake inhibitor, an oxytocin recep female orgasm disorder (FOD). tor (OXTR) agonist, and a pharmaceutically acceptable car 13. The method of claim 10, wherein the sexual disorder is 1. female sexual arousal disorder (FSAD). 2. The composition of claim 1, wherein the 5-HT, antago 14. The method of claim 10, wherein the sexual disorder is nist is also a 5-HT, receptor agonist. sexual pain dysfunction. 3. The composition of claim 1, comprising traZodone, 15. The method of claim 10, wherein the sexual disorder is bupropion, and oxytocin. male HSDD. 4. The composition of claim 1, comprising bupropion in a 16.-19. (canceled) dosage range of 200-450 mg. 20. 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. according to claim 1. 6. The composition of claim 1, comprising oxytocin in a 21. The method in claim 20, wherein the cognitive disorder dosage range of 4-400 International Units. is dementia. 7. The composition of claim 1, comprising traZodone in a 22. The method in claim 21, wherein the dementia is Alzhe dosage range of 1-450 mg, bupropion in a dosage range of imer's disease, frontotemporal lobar degeneration, dementia 1-450 mg, and oxytocin in a dosage range of 4-400 Interna with Lewy bodies, Parkinson's disease, Huntington's dis tional Units. ease, multi-infarct dementia, dementia resulting from infec 8. A method of making a composition comprising combin tions affecting the central nervous system, dementia resulting ing a 5-HT agonist, a 5-HT, antagonist, a norepinephrine from chronic drug use, dementia resulting from hydroceph dopamine reuptake inhibitor, an oxytocin receptor (OXTR) alus, dementia resulting from brain injury, or dementia result agonist, and a pharmaceutically acceptable carrier. ing from a brain tumor. 9. The method of claim 8, comprising combining bupro 23. The method in claim 20, wherein the cognitive disorder pion, traZodone, oxytocin, and a pharmaceutically acceptable is cognitive disability. carrier. 10. A method of treating a sexual disorder in a subject 24. The method in claim 23, wherein the cognitive disabil comprising administering to the Subject a composition ity is schizophrenia, schizoaffective disorder, bipolar disor according to claim 1. der, or major depression. 11. The method of claim 10, wherein the sexual disorder is 25.-222. (canceled) hypoactive sexual desire disorder (HSDD). k k k k k