Reducing the addictive liability of opioid analgesics by co- administering 5HT2 receptor agonists

Abstract

The present disclosure provides methods and compositions for reducing the addictive liability of opioid analgesics in a subject, for example, by co-administering to the subject the opioid and a serotonin receptor type 2 (5HT2) agonist or a serotonin (5HT) releasing agent. The disclosed methods include methods for preventing opioid abuse, methods for reducing the rewarding effect of an opioid, methods for reducing the addictive liability of an opioid, methods for eliminating or substantially reducing the tendency for a subject to develop physical dependence, tolerance, and / or withdrawal symptoms with respect to an opioid, and methods for eliminating or substantially reducing the tendency for a subject to use opioids in ways not prescribed, take opioids more often or in larger amounts than prescribed, and / or use opioids recreationally. The methods can be performed on a subject, such as a patient (e.g., a human patient).

Description

PATENT Atorney Docket No. 079445-015220PC-1525714Client Reference No. S24-402 REDUCING THE ADDICTIVE LIABILITY OF OPIOID ANALGESICS BY CO- ADMINISTERING 5HT2 RECEPTOR AGONISTS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 721,295, filed November 15, 2024, and U.S. Provisional Application No. 63 / 908,577, filed October 30, 2025, the disclosures of which are herein incorporated by reference in their entirety for all purposes.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This invention was made with Government support under contract DA042012 awarded by the National Institutes of Health. The Government has certain rights in the invention.BACKGROUND

[0003] Opioids are a hugely important class of analgesics, but the addictive liability of opioids has fueled an epidemic. Modifying opioid drug reward may facilitate better treatment of patient pain. However, to our knowledge there are no existing technologies that are aimed at reducing the addictive liability of these drugs.

[0004] The serotonergic system interacts with the mesocorticolimbic circuitry of the brain regulating reward and reinforcing behaviors. There has been a great deal of pre-clinical and clinical work investigating whether 5HT2a and 5HT2c agonists, especially 5HT2c agonists such as lorcaserin (Belviq), can be used to treat substance use disorder (McCann et al. Drug and alcohol dependence. 2024; Brandt et al. Drug and Alcohol Dependence. 2020; Shanahan et al. Nicotine &Tobacco Research. 2017; Negus and Banks. Neuropsychopharmacololgy.2020). Several Phase I and II clinical trials, with hundreds of patients, showed extremely limited efficacy. These results largely put an end to clinical testing of selective 5HT2c agonist for substance use disorder.SUMMARY

[0005] In one aspect, the present disclosure provides methods for preventing opioid abuse in a subject in need of treatment of pain. In some embodiments, the methods comprise administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subj ect and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject. In some embodiments, the opioid therapeutic effect includes treatment of pain, anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof. In certain embodiments, the opioid therapeutic effect includes treatment of pain and, optionally, further includes anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof.

[0006] In some embodiments, the 5HT2 agonist reduces the addictive liability of the opioid in the subject. In some embodiments, the 5HT2 agonist reduces the rewarding effect of the opioid in the subject. In some embodiments, the 5HT2 agonist eliminates or substantially reduces the tendency for the subject to develop physical dependence, tolerance, and / or withdrawal symptoms with respect to the opioid. In some embodiments, the 5HT2 agonist eliminates or substantially reduces the tendency for the subject to use opioids in ways not prescribed, take opioids more often or in larger amounts than prescribed, and / or use opioids recreationally. In some embodiments, the 5HT2 agonist does not diminish the analgesic properties of the opioid in the subject.

[0007] In some embodiments, the pain comprises perioperative pain, post-operative pain, acute pain, chronic pain, nociceptive pain, neuropathic pain, or any combination thereof. In certain embodiments, the pain is secondary to blunt or penetrating trauma. In certain embodiments, the pain is severe acute headache pain, pain associated with gall-stones, pain associated with kidney stones, or pain associated with biliary spasms. In some embodiments, the subject is not currently on opioid therapy. In some embodiments, the subject is a human.

[0008] In some embodiments, the method comprises co-administering the 5HT2 agonist and the opioid to the subject. In some embodiments, the method comprises administering the 5HT2 agonist to the subject prior to the administration of the opioid. In some embodiments, the method comprises administering the 5HT2 agonist to the subject prior to the administration of the opioid and subsequently co-administering the 5HT2 agonist and the opioid to the subject.

[0009] In some embodiments, (i) the opioid and / or (ii) the 5HT2 agonist are administered orally, intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously,intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, by inhalation, or topical administration. In some embodiments, the opioid and / or the 5HT2 agonist are administered orally. In some embodiments, the opioid and the 5HT2 agonist are administered orally (e.g., in a combined formulation). In some embodiments, the opioid and / or the 5HT2 agonist are administered intravenously. In some embodiments, the opioid and the 5HT2 agonist are administered intravenously (e.g., in a combined formulation).

[0010] In some embodiments, the amount of the opioid is about 0.005 mg / kg to about 10 mg / kg body weight, optionally about 0.01 mg / kg to about 4 mg / kg or about 0.02 mg / kg to about 2 mg / kg. In some embodiments, the amount of the 5HT2 agonist is about 0.01 mg / kg to about 5 mg / kg body weight, optionally about 0.02 mg / kg to about 4 mg / kg body weight, about 0.03 mg / kg to about 2 mg / kg body weight, or about 0.04 mg / kg to about 1 mg / kg body weight. In some embodiments, the ratio of the amount of opioid to the amount of 5HT2 agonist administered to the subject is about 25: 1 to about 1 : 10 (e.g., about 10: 1 to about 1:5, about 5:1 to about 1:5, about 3 : 1 to about 1 :3, about 2: 1 to about 1 :2, or about 1 : 1).

[0011] In some embodiments, the 5HT2 agonist comprises a 5HT2a agonist, 5HT2c agonist, or 5HT2a / 2c agonist. In some embodiments, the 5HT2 agonist comprises (or is) a 5HT2c agonist. In some embodiments, the 5HT2 agonist comprises (or is) a selective 5HT2c agonist. In some embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 1-155 and 200-215 disclosed herein, or a mixture of two or more such compounds. In some embodiments, the 5HT2 agonist is part of a pharmaceutical composition that comprises, for example, a pharmaceutically acceptable carrier.

[0012] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 1 to 50 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound comprising at least a first ring structure A and a second ring structure B, and wherein the first ring A is a 6-member aromatic ring, optionally a heterocycle, and optionally substituted; the second ring B is a 5- to 9-member ring, optionally a heterocycle, optionally aromatic, and optionally substituted; wherein the first ring A is fused to the second ring B and the compound has 5HT2c receptor agonist activity, and, optionally, wherein the compound comprises 5HT2c agonist activity (e.g., selective 5HT2c agonist activity Y

[0013] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 51 to 137 disclosed herein. In some embodiments, the 5HT2agonist comprises (or is) a compound comprising a first aromatic ring structure A and a second ring structure B according to the structure of Compound L:Compound Lwherein: R1is C; R2is NR2’, CH2, CHR2', CR2', or O; R3is, independently, CH2, CHR3’, CH, CR3’, or CH(CH3)C(O); R4is N, NH, NR4', CH2, C(CH3)2, CH, or CR4'; R5is, independently, CH2, CH, CH(CH3), or O; R6is C; R7is CH or N; R8is CH, CR8’, or N; R9is CH, CR9’, or NR9’; R10is CH, CR10’, or N; m is 0, 1 or 2; n is 0, 1 or 2; R2’ is a Ci-Ce alkyl, an alkylamine, or a benzyl group, or part of a third ring structure C; R3’ is a Ci-Ce alkyl or an alkylamine group, or part of a third ring structure C; R4’ is CH3or part of a third ring structure C; R8’ is an electron withdrawing (EW) group, or part of a third ring structure C; R9’ is a Ci-Ce alkyl or EW group, or part of a third ring structure C; R10’ is a Ci-Ce alkyl, amine, alkylamine, heterocycle, or EW group, or part of a third ring structure C; wherein ring C, if present, is fused to ring A, ring B, or both; is optionally a heterocycle; and optionally includes one or more substituents; and wherein the compound has 5HT2c receptor agonist activity and, optionally wherein the compound comprises 5HT2c agonist.(e.g., selective 5HT2c agonist activity).

[0014] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 138 to 140 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LI:Wherein R1is -H or -CH3; R2is -H, -CH3, -CH2CH3, or -OH; and R3is -F, -Cl, -CF3, a clorophenyl group (e.g., orthoclorophenyl), -Br, or -I.

[0015] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 141 to 142 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LIII:Compound LIIIwherein: R1is -H, -CH3, or a -C2-6 alkyl group; R2is -H, -F, -Cl, -CF3, or -CONHCH2CHF2; and R3is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

[0016] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 143 to 145 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LV:Compound LVwherein: R1is -CH3, -CH2CH3; and R2is -H or -CH3; or R1 and R2 together are -CH2CH2CH2-

[0017] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 146 to 150 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LVII:Compound LVIIwherein: R1 is -CH2CH2F, -CH2CHCH2, -CH2CH2CH2F, -CH2C(F)CH2; and R2 is -F or -Cl.

[0018] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 151 to 155 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LVIII:Compound LVIIIwherein: R1is -H or -CH3; R2is -H; R3is -H or -CF3; and R4is -H or -CF3.

[0019] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 200 to 215 disclosed herein. In some embodiments, the 5HT2 agonist is a compound comprising at least a first ring structure A and a second ring structure B, and wherein the first ring A is a 6-member aromatic ring, optionally a heterocycle, and optionally substituted; the second ring B is a 6-member ring, optionally a heterocycle, optionally aromatic, and optionally substituted; wherein the first ring A is directly bound to the second ring B and the compound has 5HT2c receptor agonist activity, and, optionally, wherein the compound comprises 5HT2c agonist activity (e.g., selective 5HT2c agonist activity).

[0020] In some embodiments, the opioid comprises (or is) a compound selected from the group consisting of Compounds I-XXVIII of Table 1, a derivative or analog thereof, or a combination of any of the foregoing. In some embodiments, the opioid comprises (or is) acompound selected from the group consisting of Compounds I-XXVIII of Table 1. In some embodiments, the opioid comprises (or is) a compound selected from Compound II (morphine), Compound I (codeine), Compound IV (hydrocodone), Compound V (hydromorphone), Compound VI (oxycodone), Compound XIII (fentanyl), and Compound XXVIII (tramadol). In some embodiments, the opioid comprises (or is) Compound IV (hydrocodone). In some embodiments, the opioid comprises (or is) Compound V (hydromorphone). In some embodiments, the opioid comprises (or is) Compound VI (oxycodone).

[0021] In another aspect, the present disclosure provides a method for preventing opioid abuse in a subject in need of treatment of pain. In some embodiments, the method comprises administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin (5HT) releasing agent effective to prevent opioid abuse in the subject. In some embodiments, the opioid therapeutic effect includes treatment of pain, anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof. In some embodiments, the opioid therapeutic effect includes treatment of pain and, optionally, further includes anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof.

[0022] In some embodiments, the 5HT releasing agent reduces the addictive liability of the opioid in the subject. In some embodiments, the 5HT releasing agent reduces the rewarding effect of the opioid in the subject. In some embodiments, the 5HT releasing agent eliminates or substantially reduces the tendency for the subject to develop physical dependence, tolerance, and / or withdrawal symptoms with respect to the opioid. In some embodiments, the 5HT releasing agent eliminates or substantially reduces the tendency for the subject to use opioids in ways not prescribed, take opioids more often or in larger amounts than prescribed, and / or use opioids recreationally. In some embodiments, the 5HT releasing agent does not diminish the analgesic properties of the opioid in the subject.

[0023] In some embodiments, the pain comprises perioperative pain, post-operative pain, acute pain, chronic pain, nociceptive pain, neuropathic pain, or any combination thereof. In certain embodiments, the pain is secondary to blunt or penetrating trauma. In certain embodiments, the pain is severe acute headache pain, pain associated with gall-stones, pain associated with kidney stones, or pain associated with biliary spasms. In some embodiments, the subject is not currently on opioid therapy. In some embodiments, the subject is a human.

[0024] In some embodiments, the method comprises co-administering the 5HT releasing agent and the opioid to the subject. In some embodiments, the method comprises administering the 5HT releasing agent to the subject prior to the administration of the opioid. In some embodiments, the method comprises administering the 5HT releasing agent to the subject prior to the administration of the opioid and subsequently co-administering the 5HT releasing agent and the opioid to the subject.

[0025] In some embodiments, (i) the opioid and / or (ii) the 5HT releasing agent are administered orally, intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, by inhalation, or topical administration. In some embodiments, the opioid and / or the 5HT releasing agent are administered orally. In some embodiments, the opioid and the 5HT releasing agent are administered orally (e.g., in a combined formulation). In some embodiments, the opioid and / or the 5HT releasing agent are administered intravenously. In some embodiments, the opioid and the 5HT releasing agent are administered intravenously (e.g., in a combined formulation).

[0026] In some embodiments, the amount of the opioid is about 0.005 mg / kg to about 10 mg / kg body weight, optionally about 0.01 mg / kg to about 4 mg / kg or about 0.02 mg / kg to about 2 mg / kg. In some embodiments, the amount of the 5HT releasing agent is about 0.01 mg / kg to about 5 mg / kg body weight, optionally about 0.02 mg / kg to about 4 mg / kg body weight, about 0.03 mg / kg to about 2 mg / kg body weight, or about 0.04 mg / kg to about 1 mg / kg body weight. In some embodiments, the ratio of the amount of opioid to the amount of 5HT releasing agent in the pharmaceutical composition is about 12:1 to about 1:24 (e.g., about 6:1 to about 1:10, about 5:1 to about 1:5, about 3:1 to about 1:5, or about 2:1 to about 1:2, or about 1:1).

[0027] In some embodiments, the 5HT releasing agent comprises (or is) a compound according to any one of Embodiments 300-332 disclosed herein, or a mixture of two or more such compounds. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compounds C-CXXV of Table 3, a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compounds C-CXXV. In some embodiments, the 5HT2agonist is part of a pharmaceutical composition that comprises, for example, a pharmaceutically acceptable carrier.

[0028] In some embodiments, the 5HT releasing agent comprises a derivative of phenethylamine, a derivative of amphetamine, a derivative of indane and / or a derivative of 2-aminoindane.

[0029] In some embodiments, the 5HT releasing agent comprises a derivative of aminoindane. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CXXIV (MMAI), Compound CXXV (TAI), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0030] In some embodiments, the 5HT releasing agent comprises a derivative of phenethylamine. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CII (fenfluramine), Compound CIII (dexfenfluramine), Compound CIV (chlorophentermine), Compound CV (cloforex), Compound CVI (etolorex), Compound CVII (flucetorex), Compound CVIII (tiflorex), Compound CXI (MDMA), Compound CXII (MDEA), Compound CXIII (MBDB), Compound CXIV (MDA), Compound CXV (2-methyl-MDA), Compound CXVI (MMA), Compound CXVII (EDMA), Compound CXVIII (PMA), Compound CXIX (PMEA), Compound CXX (PMMA), Compound CXXI (4-MTA), Compound CXXII (5-APDB), Compound CXXIII (5-APDI), Compound XCI (mescaline), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CII, Compound CIII, a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CII and Compound CIII.

[0031] In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CIX (indeloxazine), Compound CX (carbamazepine), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0032] In some embodiments, the 5HT releasing agent comprises (or is) a compound having a structure according to Compound C:Compound Cwherein: R2is -H or -CH3; R3is -H, -CH2CH2R4, or an electron withdrawing group; R4is -H, -CH3, -CH2-R3, or an electron withdrawing group; R5is -H; R6is -H or -CH2- (when R6=Ral); Ralis -H, an alkyl group, such as -CH3 or -CH2CH3, or -CH2- (when Ral= R6); Ra2is -H or -CH3; RNis -H, an alkyl group, such as -CH3 or -CH2CH3, an alcohol group, such as -CH2CH3OH, or a carbonyl-containing group, such as -CORN; and RNis an alkoxy group, such as -OCH2CH3, or an aromatic group, such as -CH2OC6H5, optionally substituted, wherein the compound comprises 5HT releasing activity.

[0033] In some embodiments, the 5HT releasing agent comprises (or is) a compound having a structure according to Compound CI:wherein: R1is -H or -CH3; R2is -H, -CH3, or a -C2-5 alkyl group; R3is -H or -CF3; and R4is -H or -CF3. In some embodiments, R1is -H; R2is -CH2CH3; R3is -CF3; and R4is -H.

[0034] In some embodiments, the opioid comprises (or is) a compound selected from the group consisting of Compounds I-XXVIII of Table 1, a derivative or analog thereof, or a combination of any of the foregoing. In some embodiments, the opioid comprises (or is) a compound selected from the group consisting of Compounds I-XXVIII of Table 1. In some embodiments, the opioid comprises (or is) a compound selected from Compound II (morphine), Compound I (codeine), Compound IV (hydrocodone), Compound V (hydromorphone),Compound VI (oxycodone), Compound XIII (fentanyl), and Compound XXVIII (tramadol). In some embodiments, the opioid comprises (or is) Compound IV (hydrocodone). In some embodiments, the opioid comprises (or is) Compound V (hydromorphone). In some embodiments, the opioid comprises (or is) Compound VI (oxycodone).

[0035] In another aspect, the present disclosure provides methods for reducing the rewarding effect and / or addictive liability of an opioid administered to a subject. In certain embodiments, the method comprises administering to the subject a serotonin receptor type 2 (5HT2) agonist in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject. In certain embodiments, the methods reduce the rewarding effect of an opioid administered to the subject. For example, in certain embodiments, the methods reduce euphoria, intoxication, or the like in the subject. In certain embodiments, the methods reduce the addictive liability of an opioid administered to the subject. For example, in certain embodiments, the methods reduce psychological addiction experienced by the subject.

[0036] In some embodiments, the opioid therapeutic effect includes treatment of pain, anesthetic effect, antitussive effect, anti -diarrheal effect, sedative effect, or any combination thereof. In certain embodiments, the opioid therapeutic effect includes treatment of pain and, optionally, further includes anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof.

[0037] In some embodiments, the pain comprises perioperative pain, post-operative pain, acute pain, chronic pain, nociceptive pain, neuropathic pain, or any combination thereof. In certain embodiments, the pain is secondary to blunt or penetrating trauma. In certain embodiments, the pain is severe acute headache pain, pain associated with gall-stones, pain associated with kidney stones, or pain associated with biliary spasms. In some embodiments, the subject is not currently on opioid therapy. In some embodiments, the subject is a human.

[0038] In some embodiments, the method comprises co-administering the 5HT2 agonist and the opioid to the subject. In some embodiments, the method comprises administering the 5HT2 agonist to the subject prior to the administration of the opioid. In some embodiments, the method comprises administering the 5HT2 agonist to the subject prior to the administration of the opioid and subsequently co-administering the 5HT2 agonist and the opioid to the subject.

[0039] In some embodiments, (i) the opioid and / or (ii) the 5HT2 agonist are administered orally, intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously,intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, by inhalation, or topical administration. In some embodiments, the opioid and / or the 5HT2 agonist are administered orally. In some embodiments, the opioid and the 5HT2 agonist are administered orally (e.g., in a combined formulation). In some embodiments, the opioid and / or the 5HT2 agonist are administered intravenously. In some embodiments, the opioid and the 5HT2 agonist are administered intravenously (e.g., in a combined formulation).

[0040] In some embodiments, the amount of the opioid is about 0.005 mg / kg to about 10 mg / kg body weight, optionally about 0.01 mg / kg to about 4 mg / kg or about 0.02 mg / kg to about 2 mg / kg. In some embodiments, the amount of the 5HT2 agonist is about 0.01 mg / kg to about 5 mg / kg body weight, optionally about 0.02 mg / kg to about 4 mg / kg body weight, about 0.03 mg / kg to about 2 mg / kg body weight, or about 0.04 mg / kg to about 1 mg / kg body weight. In some embodiments, the ratio of the amount of opioid to the amount of 5HT2 agonist administered to the subject is about 25: 1 to about 1 : 10 (e.g., about 10: 1 to about 1:5, about 5:1 to about 1:5, about 3 : 1 to about 1 :3, about 2: 1 to about 1 :2, or about 1 : 1).

[0041] In some embodiments, the 5HT2 agonist comprises a 5HT2a agonist, 5HT2c agonist, or 5HT2a / 2c agonist. In some embodiments, the 5HT2 agonist comprises (or is) a 5HT2c agonist. In some embodiments, the 5HT2 agonist comprises (or is) a selective 5HT2c agonist. In some embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 1-155 and 200-215 disclosed herein, or a mixture of two or more such compounds. In some embodiments, the 5HT2 agonist is part of a pharmaceutical composition that comprises, for example, a pharmaceutically acceptable carrier.

[0042] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 1 to 50 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound comprising at least a first ring structure A and a second ring structure B, and wherein the first ring A is a 6-member aromatic ring, optionally a heterocycle, and optionally substituted; the second ring B is a 5- to 9-member ring, optionally a heterocycle, optionally aromatic, and optionally substituted; wherein the first ring A is fused to the second ring B and the compound has 5HT2c receptor agonist activity, and, optionally, wherein the compound comprises 5HT2c agonist activity (e.g., selective 5HT2c agonist activity Y

[0043] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 51 to 137 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound comprising a first aromatic ring structure A and a secondring structure B according to the structure of Compound L (see Table 2 and above), wherein: R1is C; R2is NR2’, CH2, CHR2', CR2', or O; R3is, independently, CH2, CHR3’, CH, CR3’, or CH(CH3)C(O); R4is N, NH, NR4', CH2, C(CH3)2, CH, or CR4'; R5is, independently, CH2, CH, CH(CH3), or O; R6is C; R7is CH or N; R8is CH, CR8’, or N; R9is CH, CR9’, or NR9’; R10is CH, CR10’, or N; m is 0, 1 or 2; n is 0, 1 or 2; R2’ is a Ci-Ce alkyl, an alkylamine, or a benzyl group, or part of a third ring structure C; R3’ is a Ci-Ce alkyl or an alkylamine group, or part of a third ring structure C; R4’ is CH3or part of a third ring structure C; R8’ is an electron withdrawing (EW) group, or part of a third ring structure C; R9’ is a Ci-Ce alkyl or EW group, or part of a third ring structure C; R10’ is a Ci-Ce alkyl, amine, alkylamine, heterocycle, or EW group, or part of a third ring structure C; wherein ring C, if present, is fused to ring A, ring B, or both; is optionally a heterocycle; and optionally includes one or more substituents; and wherein the compound has 5HT2c receptor agonist activity and, optionally wherein the compound comprises 5HT2c agonist.(e.g., selective 5HT2c agonist activity).

[0044] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 138 to 140 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LI (see Table 2 and above), wherein R1is -H or -CH3; R2is -H, -CH3, -CH2CH3, or -OH; and R3is -F, -Cl, -CF3, a clorophenyl group (e.g., orthoclorophenyl), -Br, or -I.

[0045] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 141 to 142 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LIII (see Table 2 and abvove), wherein: R1is -H, -CH3, or a -C2-6 alkyl group; R2is -H, -F, -Cl, -CF3, or -CONHCH2CHF2; and R3is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

[0046] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 143 to 145 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LV (see Table 2 and above), wherein: R1is -CH3, -CH2CH3; and R2is -H or -CH3; or R1 and R2 together are -CH2CH2CH2-.

[0047] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 146 to 150 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LVII (seeTable 2 and above), wherein: R1 is -CH2CH2F, -CH2CHCH2, -CH2CH2CH2F, -CH2C(F)CH2; and R2 is -F or -Cl.

[0048] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 151 to 155 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LVIII (see Table 2 and above), wherein: R1is -H or -CH3; R2is -H; R3is -H or -CF3; and R4is -H or -CF3.

[0049] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 200 to 215 disclosed herein. In some embodiments, the 5HT2 agonist is a compound comprising at least a first ring structure A and a second ring structure B, and wherein the first ring A is a 6-member aromatic ring, optionally a heterocycle, and optionally substituted; the second ring B is a 6-member ring, optionally a heterocycle, optionally aromatic, and optionally substituted; wherein the first ring A is directly bound to the second ring B and the compound has 5HT2c receptor agonist activity, and, optionally, wherein the compound comprises 5HT2c agonist activity (e.g., selective 5HT2c agonist activity).

[0050] In some embodiments, the 5HT2 agonist comprises (or is) a compound selected from the group consisting of Compounds L-XCIX of Table 2, a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing. In some embodiments, the 5HT2 agonist comprises (or is) a compound selected from the group consisting of Compounds L-XCIX of Table 2.

[0051] In some embodiments, the 5HT2 agonist comprises (or is) a 5HT2c agonist selected from the group consisting of Compound LII (lorcaserin), Compound LIV (vabicaserin), Compound LVI (bexicaserin), Compound LIX (norfenfluramine), Compound LX (dexnorfenfluramin), and Compound XCVII (CMY-16). In some embodiments, the 5HT2 agonist comprises (or is) Compound LII. In some embodiments, the 5HT2 agonist comprises (or is) Compound LIV. In some embodiments, the 5HT2 agonist comprises (or is) Compound LVI. In some embodiments, the 5HT2 agonist comprises (or is) Compound LIX. In some embodiments, the 5HT2 agonist comprises (or is) Compound LX. In some embodiments, the 5HT2 agonist comprises (or is) Compound XCVII.

[0052] In some embodiments, the opioid comprises a compound selected from the group consisting of Compounds I-XXVIII of Table 1, a derivative or analog thereof, or a combination of any of the foregoing. In some embodiments, the opioid comprises a compound selected from the group consisting of Compounds I-XXVIII of Table 1. In some embodiments, theopioid comprises (or is) a compound selected from Compound II (morphine), Compound I (codeine), Compound IV (hydrocodone), Compound V (hydromorphone), Compound VI (oxycodone), Compound XIII (fentanyl), and Compound XXVIII (tramadol). In some embodiments, the opioid comprises (or is) Compound IV (hydrocodone). In some embodiments, the opioid comprises (or is) Compound V (hydromorphone). In some embodiments, the opioid comprises (or is) Compound VI (oxycodone).

[0053] In another aspect, the present disclosure provides methods for reducing the rewarding effect and / or addictive liability of an opioid administered to a subject. In certain embodiments, the method comprises administering to the subject a serotonin (5HT2) releasing agent in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject. In certain embodiments, the methods reduce the rewarding effect of an opioid administered to the subject. For example, in certain embodiments, the methods reduce euphoria, intoxication, or the like in the subject. In certain embodiments, the methods reduce the addictive liability of an opioid administered to the subject. For example, in certain embodiments, the methods reduce psychological addiction experienced by the subject.

[0054] In some embodiments, the opioid therapeutic effect includes treatment of pain, anesthetic effect, antitussive effect, anti -diarrheal effect, sedative effect, or any combination thereof. In some embodiments, the opioid therapeutic effect includes treatment of pain and, optionally, further includes anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof.

[0055] In some embodiments, the pain comprises perioperative pain, post-operative pain, acute pain, chronic pain, nociceptive pain, neuropathic pain, or any combination thereof. In certain embodiments, the pain is secondary to blunt or penetrating trauma. In certain embodiments, the pain is severe acute headache pain, pain associated with gall-stones, pain associated with kidney stones, or pain associated with biliary spasms. In some embodiments, the subject is not currently on opioid therapy. In some embodiments, the subject is a human.

[0056] In some embodiments, the method comprises co-administering the 5HT releasing agent and the opioid to the subject. In some embodiments, the method comprises administering the 5HT releasing agent to the subject prior to the administration of the opioid. In some embodiments, the method comprises administering the 5HT releasing agent to the subject priorto the administration of the opioid and subsequently co-administering the 5HT releasing agent and the opioid to the subject.

[0057] In some embodiments, (i) the opioid and / or (ii) the 5HT releasing agent are administered orally, intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, by inhalation, or topical administration. In some embodiments, the opioid and / or the 5HT releasing agent are administered orally. In some embodiments, the opioid and the 5HT releasing agent are administered orally (e.g., in a combined formulation). In some embodiments, the opioid and / or the 5HT releasing agent are administered intravenously. In some embodiments, the opioid and the 5HT releasing agent are administered intravenously (e.g., in a combined formulation).

[0058] In some embodiments, the amount of the opioid is about 0.005 mg / kg to about 10 mg / kg body weight, optionally about 0.01 mg / kg to about 4 mg / kg or about 0.02 mg / kg to about 2 mg / kg. In some embodiments, the amount of the 5HT releasing agent is about 0.01 mg / kg to about 5 mg / kg body weight, optionally about 0.02 mg / kg to about 4 mg / kg body weight, about 0.03 mg / kg to about 2 mg / kg body weight, or about 0.04 mg / kg to about 1 mg / kg body weight. In some embodiments, the ratio of the amount of opioid to the amount of 5HT releasing agent in the pharmaceutical composition is about 12:1 to about 1:24 (e.g., about 6:1 to about 1:10, about 5:1 to about 1:5, about 3:1 to about 1:5, or about 2:1 to about 1:2, or about 1:1).

[0059] In some embodiments, the 5HT releasing agent comprises (or is) a compound according to any one of Embodiments 300-332 disclosed herein, or a mixture of two or more such compounds. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compounds C-CXXV of Table 3, a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compounds C-CXXV of Table 3. In some embodiments, the 5HT2 agonist is part of a pharmaceutical composition that comprises, for example, a pharmaceutically acceptable carrier.

[0060] In some embodiments, the 5HT releasing agent comprises a derivative of phenethylamine, a derivative of amphetamine, a derivative of indane and / or a derivative of 2-aminoindane.

[0061] In some embodiments, the 5HT releasing agent comprises a derivative of aminoindane. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CXXIV (MMAI), Compound CXXV (TAI), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0062] In some embodiments, the 5HT releasing agent comprises a derivative of phenethylamine. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CII (fenfluramine), Compound CIII (dexfenfluramine), Compound CIV (chlorophentermine), Compound CV (cloforex), Compound CVI (etolorex), Compound CVII (flucetorex), Compound CVIII (tiflorex), Compound CXI (MDMA), Compound CXII (MDEA), Compound CXIII (MBDB), Compound CXIV (MDA), Compound CXV (2-methyl-MDA), Compound CXVI (MMA), Compound CXVII (EDMA), Compound CXVIII (PMA), Compound CXIX (PMEA), Compound CXX (PMMA), Compound CXXI (4-MTA), Compound CXXII (5-APDB), Compound CXXIII (5-APDI), Compound XCI (mescaline), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CII, Compound CIII, a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CII and Compound CIII.

[0063] In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CIX (indeloxazine), Compound CX (carbamazepine), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0064] In some embodiments, the 5HT releasing agent comprises (or is) a compound having a structure according to Compound C (see Table 3 and above), wherein: R2is -H or -CEE; R3is -H, -CH2CH2R4, or an electron withdrawing group; R4is -H, -CH3, -CH2-R3, or an electron withdrawing group; R5is -H; R6is -H or -CH2- (when R6=Ral); Ralis -H, an alkyl group, such as -CH3 or -CH2CH3, or -CH2- (when Ral= R6); Ra2is -H or -CH3; RNis -H, an alkyl group, such as -CH3 or -CH2CH3, an alcohol group, such as -CH2CH3OH, or a carbonyl-containing group, such as -CORN; and RNis an alkoxy group, such as -OCH2CH3, or an aromatic group,such as -CH2OC6H5, optionally substituted, wherein the compound comprises 5HT releasing activity.

[0065] In some embodiments, the 5HT releasing agent comprises (or is) a compound having a structure according to Compound CI (see Table 3 and above), wherein: R1is -H or -CH3; R2is -H, -CH3, or a -C2-5 alkyl group; R3is -H or -CF3; and R4is -H or -CF3. In some embodiments, R1is -H; R2is -CH2CH3; R3is -CF3; and R4is -H.

[0066] In some embodiments, the opioid comprises a compound selected from the group consisting of Compounds I-XXVIII of Table 1, a derivative or analog thereof, or a combination of any of the foregoing. In some embodiments, the opioid comprises a compound selected from the group consisting of Compounds I-XXVIII of Table 1. In some embodiments, the opioid comprises (or is) a compound selected from Compound II (morphine), Compound I (codeine), Compound IV (hydrocodone), Compound V (hydromorphone), Compound VI (oxycodone), Compound XIII (fentanyl), and Compound XXVIII (tramadol). In some embodiments, the opioid comprises (or is) Compound IV (hydrocodone). In some embodiments, the opioid comprises (or is) Compound V (hydromorphone). In some embodiments, the opioid comprises (or is) Compound VI (oxycodone).

[0067] In another aspect, the present disclosure provides a pharmaceutical composition comprising (i) an opioid and (ii) a serotonin receptor type 2 (5HT2) agonist. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0068] In some embodiments, the composition comprises an amount of the opioid effective for the treatment of pain in a subject in need thereof. In some embodiments, the pain comprises perioperative pain, post-operative pain, acute pain, chronic pain, nociceptive pain, neuropathic pain, or any combination thereof. In certain embodiments, the pain is secondary to blunt or penetrating trauma. In certain embodiments, the pain is severe acute headache pain, pain associated with gall-stones, pain associated with kidney stones, or pain associated with biliary spasms.

[0069] In some embodiments, the composition comprises an amount of the opioid effective for an opioid therapeutic effect in a subject. In some embodiments, the opioid therapeutic effect includes treatment of pain, anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof. In certain embodiments, the opioid therapeutic effect includes treatment of pain and, optionally, further includes anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof.

[0070] In some embodiments, the composition comprises an amount of the 5HT2 agonist effective to prevent opioid abuse in a subject. In certain embodiments, the composition comprises an amount of the 5HT2 agonist effective to reduce the rewarding effect of an opioid administered to a subject. For example, in certain embodiments, the composition comprises an amount of the 5HT2 agonist effective to reduce euphoria, intoxication, or the like in a subject. In certain embodiments, the composition comprises an amount of the 5HT2 agonist effective to reduce the addictive liability of an opioid administered to a subject. For example, in certain embodiments, the composition comprises an amount of the 5HT2 agonist effective to reduce psychological addiction experienced by the subject.

[0071] In some embodiments, the composition is formulated for oral, intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalational, or topical delivery. In some embodiments, the composition is formulated for oral delivery. In some embodiments, the composition is in the form of a tablet or capsule. In some embodiments, the composition is formulated for intravenous or intramuscular delivery. In some embodiments, the composition is in the form of a solution or suspension.

[0072] In some embodiments, the 5HT2 agonist comprises a 5HT2a agonist, 5HT2c agonist, or 5HT2a / 2c agonist. In some embodiments, the 5HT2 agonist comprises (or is) a 5HT2c agonist. In some embodiments, the 5HT2 agonist comprises (or is) a selective 5HT2c agonist. In some embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 1-155 and 200-215 disclosed herein, or a mixture of two or more such compounds. In some embodiments, the 5HT2 agonist is part of a pharmaceutical composition that comprises, for example, a pharmaceutically acceptable carrier.

[0073] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 1 to 50 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound comprising at least a first ring structure A and a second ring structure B, and wherein the first ring A is a 6-member aromatic ring, optionally a heterocycle, and optionally substituted; the second ring B is a 5- to 9-member ring, optionally a heterocycle, optionally aromatic, and optionally substituted; wherein the first ring A is fused to the second ring B and the compound has 5HT2c receptor agonist activity, and, optionally, wherein the compound comprises 5HT2c agonist activity (e.g., selective 5HT2c agonist activity Y

[0074] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 51 to 137 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound comprising a first aromatic ring structure A and a second ring structure B according to the structure of Compound L (see Table 2 and above), wherein: R1is C; R2is NR2’, CH2, CHR2', CR2', or O; R3is, independently, CH2, CHR3’, CH, CR3’, or CH(CH3)C(O); R4is N, NH, NR4', CH2, C(CH3)2, CH, or CR4'; R5is, independently, CH2, CH, CH(CH3), or O; R6is C; R7is CH or N; R8is CH, CR8’, or N; R9is CH, CR9’, or NR9’; R10is CH, CR10’, or N; m is 0, 1 or 2; n is 0, 1 or 2; R2’ is a Ci-Ce alkyl, an alkylamine, or a benzyl group, or part of a third ring structure C; R3’ is a Ci-Ce alkyl or an alkylamine group, or part of a third ring structure C; R4’ is CH3or part of a third ring structure C; R8’ is an electron withdrawing (EW) group, or part of a third ring structure C; R9’ is a Ci-Ce alkyl or EW group, or part of a third ring structure C; R10’ is a Ci-Ce alkyl, amine, alkylamine, heterocycle, or EW group, or part of a third ring structure C; wherein ring C, if present, is fused to ring A, ring B, or both; is optionally a heterocycle; and optionally includes one or more substituents; and wherein the compound has 5HT2c receptor agonist activity and, optionally wherein the compound comprises 5HT2c agonist.(e.g., selective 5HT2c agonist activity).

[0075] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 138 to 140 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LI (see Table 2 and above), Wherein R1is -H or -CH3; R2is -H, -CH3, -CH2CH3, or -OH; and R3is -F, -Cl, -CF3, a clorophenyl group (e.g., orthoclorophenyl), -Br, or -I.

[0076] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 141 to 142 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LIII (see Table 2 and above), wherein: R1is -H, -CH3, or a -C2-6 alkyl group; R2is -H, -F, -Cl, -CF3, or -CONHCH2CHF2; and R3is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

[0077] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 143 to 145 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LV (see Table 2 and above), wherein: R1is -CH3, -CH2CH3; and R2is -H or -CH3; or R1 and R2 together are -CH2CH2CH2-.

[0078] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 146 to 150 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LVII (see Table 2 and above), wherein: R1 is -CH2CH2F, -CH2CHCH2, -CH2CH2CH2F, -CH2C(F)CH2; and R2 is -F or -Cl.

[0079] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 151 to 155 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LVIII (see Table 2 and above), wherein: R1is -H or -CH3; R2is -H; R3is -H or -CF3; and R4is -H or -CF3.

[0080] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 200 to 215 disclosed herein. In some embodiments, the 5HT2 agonist is a compound comprising at least a first ring structure A and a second ring structure B, and wherein the first ring A is a 6-member aromatic ring, optionally a heterocycle, and optionally substituted; the second ring B is a 6-member ring, optionally a heterocycle, optionally aromatic, and optionally substituted; wherein the first ring A is directly bound to the second ring B and the compound has 5HT2c receptor agonist activity, and, optionally, wherein the compound comprises 5HT2c agonist activity (e.g., selective 5HT2c agonist activity).

[0081] In some embodiments, the 5HT2 agonist comprises (or is) a compound selected from the group consisting of Compounds L-XCIX of Table 2, a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing. In some embodiments, the 5HT2 agonist comprises (or is) a compound selected from the group consisting of Compounds L-XCIX of Table 2.

[0082] In some embodiments, the 5HT2 agonist comprises (or is) a 5HT2c agonist selected from the group consisting of Compound LII (lorcaserin), Compound LIV (vabicaserin), Compound LVI (bexicaserin), Compound LIX (norfenfluramine), Compound LX (dexnorfenfluramin), and Compound XCVII (CMY-16). In some embodiments, the 5HT2 agonist comprises (or is) Compound LII. In some embodiments, the 5HT2 agonist comprises (or is) Compound LIV. In some embodiments, the 5HT2 agonist comprises (or is) Compound LVI. In some embodiments, the 5HT2 agonist comprises (or is) Compound LIX. In some embodiments, the 5HT2 agonist comprises (or is) Compound LX. In some embodiments, the 5HT2 agonist comprises (or is) Compound XCVII.

[0083] In some embodiments, the opioid comprises (or is) a compound selected from the group consisting of Compounds I-XXVIII of Table 1, a derivative or analog thereof, or a combination of any of the foregoing. In some embodiments, the opioid comprises (or is) a compound selected from the group consisting of Compounds I-XXVIII of Table 1. In some embodiments, the opioid comprises (or is) a compound selected from Compound II (morphine), Compound I (codeine), Compound IV (hydrocodone), Compound V (hydromorphone), Compound VI (oxycodone), Compound XIII (fentanyl), and Compound XXVIII (tramadol). In some embodiments, the opioid comprises (or is) Compound IV (hydrocodone). In some embodiments, the opioid comprises (or is) Compound V (hydromorphone). In some embodiments, the opioid comprises (or is) Compound VI (oxycodone).

[0084] In certain embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 2 mg to about 50 mg, or about 3 mg to about 25 mg) of the 5HT2 agonist. In certain embodiments, the pharmaceutical composition comprises about 1 mg to about 500 mg of opioid (e.g., about 2 mg to about 300 mg of opioid, or about 5 mg to about 200 mg of opioid). In certain embodiments, the pharmaceutical composition comprises a ratio of opioid to 5HT2 agonist of about 5:1 to about 1:5 (e.g., about 3:1 to about 1:3, about 2:1 to about 1:2, or about 1:1).

[0085] In some embodiments, the pharmaceutical composition is for use for in preventing opioid abuse in a subject. In some embodiments, the pharmaceutical composition is for use in reducing the rewarding effect (e.g., euphoria, intoxication, or the like) of an opioid administered to a subject. In some embodiments, the pharmaceutical composition is for use in reducing the addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject. In some embodiments, the pharmaceutical composition is for use in eliminating or substantially reducing the tendency for a subject to develop physical dependence, tolerance, and / or withdrawal symptoms with respect to the opioid. In some embodiments, the pharmaceutical composition is for use in eliminating or substantially reducing the tendency for a subject to use opioids in ways not prescribed, take opioids more often or in larger amounts than prescribed, and / or use opioids recreationally. In certain embodiments, the subject is a human (e.g., a human patient). In certain embodiments, the subject is not currently on opioid therapy.1

[0086] In yet another aspect, the present disclosure provides a pharmaceutical composition comprising (i) an opioid and (ii) a serotonin (5HT) releasing agent. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0087] In some embodiments, the composition comprises an amount of the opioid effective for the treatment of pain in a subject in need thereof. In some embodiments, the pain comprises perioperative pain, post-operative pain, acute pain, chronic pain, nociceptive pain, neuropathic pain, or any combination thereof. In certain embodiments, the pain is secondary to blunt or penetrating trauma. In certain embodiments, the pain is severe acute headache pain, pain associated with gall-stones, pain associated with kidney stones, or pain associated with biliary spasms.

[0088] In some embodiments, the composition comprises an amount of the opioid effective for an opioid therapeutic effect in a subject. In some embodiments, the opioid therapeutic effect includes treatment of pain, anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof. In certain embodiments, the opioid therapeutic effect includes treatment of pain and, optionally, further includes anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof.

[0089] In some embodiments, the composition comprises an amount of the 5HT releasing agent effective to prevent opioid abuse in a subject. In certain embodiments, the composition comprises an amount of the 5HT releasing agent effective to reduce the rewarding effect of an opioid administered to a subject. For example, in certain embodiments, the composition comprises an amount of the 5HT releasing agent effective to reduce euphoria, intoxication, or the like in a subject. In certain embodiments, the composition comprises an amount of the 5HT releasing agent effective to reduce the addictive liability of an opioid administered to a subject. For example, in certain embodiments, the composition comprises an amount of the 5HT releasing agent effective to reduce psychological addiction experienced by the subject.

[0090] In some embodiments, the composition is formulated for oral, intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalational, or topical delivery. In some embodiments, the composition is formulated for oral delivery. In some embodiments, the composition is in the form of a tablet or capsule. In some embodiments, the composition is formulated for intravenous or intramuscular delivery. In some embodiments, the composition is in the form of a solution or suspension.

[0091] In some embodiments, the 5HT releasing agent comprises (or is) a compound according to any one of Embodiments 300-332 disclosed herein, or a mixture of two or more such compounds. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compounds C-CXXV of Table 3, a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compounds C-CXXV of Table 3. In some embodiments, the 5HT2 agonist is part of a pharmaceutical composition that comprises, for example, a pharmaceutically acceptable carrier.

[0092] In some embodiments, the 5HT releasing agent comprises a derivative of phenethylamine, a derivative of amphetamine, a derivative of indane and / or a derivative of 2-aminoindane.

[0093] In some embodiments, the 5HT releasing agent comprises a derivative of aminoindane. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CXXIV (MMAI), Compound CXXV (TAI), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0094] In some embodiments, the 5HT releasing agent comprises a derivative of phenethylamine. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CII (fenfluramine), Compound CIII (dexfenfluramine), Compound CIV (chlorophentermine), Compound CV (cloforex), Compound CVI (etolorex), Compound CVII (flucetorex), Compound CVIII (tiflorex), Compound CXI (MDMA), Compound CXII (MDEA), Compound CXIII (MBDB), Compound CXIV (MDA), Compound CXV (2-methyl-MDA), Compound CXVI (MMA), Compound CXVII (EDMA), Compound CXVIII (PMA), Compound CXIX (PMEA), Compound CXX (PMMA), Compound CXXI (4-MTA), Compound CXXII (5-APDB), Compound CXXIII (5-APDI), Compound XCI (mescaline), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CII, Compound CIII, a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing. Insome embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CII and Compound CIII.

[0095] In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CIX (indeloxazine), Compound CX (carbamazepine), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0096] In some embodiments, the 5HT releasing agent comprises (or is) a compound having a structure according to Compound C (see Table 3 and above), wherein: R2is -H or -CH3; R3is -H, -CH2CH2R4, or an electron withdrawing group; R4is -H, -CH3, -CH2-R3, or an electron withdrawing group; R5is -H; R6is -H or -CH2- (when R6=Ral); Ralis -H, an alkyl group, such as -CH3 or -CH2CH3, or -CH2- (when Ral= R6); Ra2is -H or -CH3; RNis -H, an alkyl group, such as -CH3 or -CH2CH3, an alcohol group, such as -CH2CH3OH, or a carbonyl-containing group, such as -CORN; and RNis an alkoxy group, such as -OCH2CH3, or an aromatic group, such as -CH2OC6H5, optionally substituted, wherein the compound comprises 5HT releasing activity.

[0097] In some embodiments, the 5HT releasing agent comprises (or is) a compound having a structure according to Compound CI (see Table 3 and above), wherein: R1is -H or -CH3; R2is -H, -CH3, or a -C2-5 alkyl group; R3is -H or -CF3; and R4is -H or -CF3. In some embodiments, R1is -H; R2is -CH2CH3; R3is -CF3; and R4is -H.

[0098] In some embodiments, the opioid comprises (or is) a compound selected from the group consisting of Compounds I-XXVIII of Table 1, a derivative or analog thereof, or a combination of any of the foregoing. In some embodiments, the opioid comprises (or is) a compound selected from the group consisting of Compounds I-XXVIII of Table 1. In some embodiments, the opioid comprises (or is) a compound selected from Compound II (morphine), Compound I (codeine), Compound IV (hydrocodone), Compound V (hydromorphone), Compound VI (oxycodone), Compound XIII (fentanyl), and Compound XXVIII (tramadol). In some embodiments, the opioid comprises (or is) Compound IV (hydrocodone). In some embodiments, the opioid comprises (or is) Compound V (hydromorphone). In some embodiments, the opioid comprises (or is) Compound VI (oxycodone).

[0099] In certain embodiments, the pharmaceutical composition comprises about 1 mg to about 100 mg (e.g., about 5 mg to about 60 mg, or about 10 mg to about 40 mg) of the 5HT releasing agent. In certain embodiments, the pharmaceutical composition comprises about 1 mg to about500 mg of opioid (e.g., about 2 mg to about 300 mg of opioid, or about 5 mg to about 200 mg of opioid). In certain embodiments, the pharmaceutical composition comprises a ratio of opioid to 5HT releasing agent of about 5 : 1 to about 1 :5 (e.g., about 3 : 1 to about 1:3, about 2: 1 to about 1:2, or about 1:1).

[0100] In some embodiments, the pharmaceutical composition is for use for in preventing opioid abuse in a subject. In some embodiments, the pharmaceutical composition is for use in reducing the rewarding effect (e.g., euphoria, intoxication, or the like) of an opioid administered to a subject. In some embodiments, the pharmaceutical composition is for use in reducing the addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject. In some embodiments, the pharmaceutical composition is for use in eliminating or substantially reducing the tendency for a subject to develop physical dependence, tolerance, and / or withdrawal symptoms with respect to the opioid. In some embodiments, the pharmaceutical composition is for use in eliminating or substantially reducing the tendency for a subject to use opioids in ways not prescribed, take opioids more often or in larger amounts than prescribed, and / or use opioids recreationally. In certain embodiments, the subject is a human (e.g., a human patient). In certain embodiments, the subject is not currently on opioid therapy.

[0101] These and other advantages of the present disclosure are more fully set forth in the detailed description, including the description of the drawings and the drawings themselves, that follows.BRIEF DESCRIPTION OF THE DRAWINGS

[0102] FIGS. 1A and IB illustrate 5HT2c agonist WAY163909 can block morphine conditioned place preference (CPP). Male mice (16 each group) were administered either morphine (10 mg / kg) alone, or co-administered morphine (10 mg / kg) with WAY163909 (10 mg / kg).

[0103] FIGS. 2A and 2B illustrate 5HT2a / c agonist psilocin can block morphine conditioned place preference. Male mice (8 each group) were administered either morphine (10 mg / kg) alone, or co-administered morphine (10 mg / kg) with psilocin (2 mg / kg).

[0104] FIG. 3 illustrates a serotonin releasing agent, fenfluramine (fen), can block morphine conditioned place preference. Male mice (8 each group) were administered either morphine (10 mg / kg) alone, or co-administered morphine (10 mg / kg) with fenfluramine (10 mg / kg).

[0105] FIG. 4 illustrates a serotonin releasing agent, fenfluramine (fen), can block fentanyl conditioned place preference. Male mice (12 fentanyl alone group, 10 fentanyl with fenfluramine group) were administered either fentanyl (0.15 mg / kg) alone, or co-administered fentanyl (0.15 mg / kg) with fenfluramine (10 mg / kg).

[0106] FIG. 5 illustrates a selective 5HT2c agonist, lorcaserin, can block morphine induced place preference. Male mice (12 morphine along group, 12 morphine with lorcaserin group, 11 morphine with fenfluramine group) were administered either morphine (10 mg / kg) alone, coadministered morphine (10 mg / kg) with lorcaserin (7 mg / kg), or co-administered morphine (10 mg / kg) with fenfluramine (5 mg / kg).

[0107] FIG. 6 illustrates a serotonin releasing agent, fenfluramine (fen), can block conditioned place preference induced by oxycodone, a semi-synthetic opioid. Male mice (12 each group) were administered either oxycodone (3 mg / kg) alone, or co-administered oxycodone (3 mg / kg) with fenfluramine (10 mg / kg) or fenfluramine (5 mg / kg).

[0108] FIG. 7 illustrates 5HT2a / c agonist psilocybin alone does not cause CPP or CPA. Male mice (8) and female mice (8) were administered with psilocin (2 mg / kg) alone.

[0109] FIG. 8 illustrates 5HT2c agonist WAY163909 and 5HT2a / c agonist psilocin do not negatively affect morphine analgesia in a Von Frey Test. Male mice (10 each group) were administered either saline (as a negative control) or morphine (10 mg / kg) alone, or coadministered morphine (10 mg / kg) with WAY163909 (10 mg / kg) or psilocin (2 mg / kg).DETAILED DESCRIPTIONI. INTRODUCTION

[0110] Despite the ongoing opioid epidemic in the United States, opioids still represent the best-in-class analgesics for moderate to severe pain associated with trauma, surgery, and disease. A disproportionate percentage of illicit opioid users are introduced to these drugs during medical treatment for legitimate pain. Furthermore, the possibility of continued abuse following treatment has caused many patients to refuse pain treatment out of fear and physicians to take extremely cautious approaches to treating patients in need. Reducing the addictive liability of opioids, while maintaining their analgesic properties, would enable clinicians to more effectively treat patient pain while reducing the potential for negative outcomes post treatment. It would also provide fearful patients with better assurances that theirtreatment would not result in physical and / or mental dependence, opening the door to more patients who might otherwise not seek treatment. In summary, reducing the abuse liability of opioids by co-administering serotonin type 2 receptor agonists or serotonin releasing agents would facilitate more appropriate pain treatment by physicians, provide peace of mind to understandably wary patients who may not seek treatment, and represent a critical new tool in the ongoing fight against the opioid addiction in the United States and around the world.[OHl] The present disclosure is based in part on the surprising discovery that coadministering 5HT2 receptor agonists with opioids can reduce the addictive liability of opioid analgesics. The present disclosure is also based in part on the surprising discovery that coadministering 5HT releasing agents with opioids can reduce the addictive liability of opioid analgesics. Our data show that it is possible to reduce the addictive liability of opioid analgesics by co-administering an opioid, such as morphine, with a compound that agonizes the serotonin type 2 receptors (5HT2) in a nonselective fashion, or with a selective serotonin type 2c receptor (5HT2c) agonist, or a serotonin (5HT) releasing agent. A key innovation of this disclosure is the combination therapy of opioids for analgesic effects, and serotonin type 2 receptor agonists or 5HT releasing agents to mitigate abuse potential. Serotonin type 2 receptor agonists as monotherapy have previously been tested in humans, and found ineffective, for treatment of established substance use disorder.

[0112] The present disclosure demonstrates that, while 5HT2 agonists and / or serotonin-releasing agents are known to be ineffective in treating established substance use disorder, these agents are surprisingly and significantly effective at blocking the formation of addictive and drug seeking behavior when co-administered with opioids.

[0113] As used herein, “opioid abuse”, refers to the use of opioids by a subject that exceeds the amount or levels prescribed to the subject. The subject can be a person (e.g., a patient) or an animal other than person. Opioid abuse can, for example, include using opioids more often than prescribed, using opioids in larger amounts than prescribed, mixing opioids, and / or using opioids recreationally. Opioid abuse, can, for example, lead to physical dependence, tolerance, or withdrawal symptoms. As used herein, “opioid use disorder” or “OUD”, refers to a problematic pattern of opioid use characterized by compulsive use, despite negative consequences.

[0114] As used herein, “prevent opioid abuse” or “opioid abuse prevention” refers to reducing or eliminating the tendency for opioid abuse in a patient. For, example, preventingopioid abuse can include reducing or eliminating the tendency for a patient to (i) develop physical dependence, tolerance, or withdrawal symptoms with respect to opioids, and / or (ii) use opioids in ways not prescribed, take opioids more often or in larger amounts than prescribed, or use opioids recreationally.

[0115] As used herein, “co-administration” of (i) an opiate and (ii) a 5HT2 agonist and / or 5HT releasing agent encompasses both the simultaneous administration (e.g., when a single composite composition is administered) and separate administration of the opiate and 5HT2 agonist and / or 5HT releasing agent to a subject; provided that when the opiate and the 5HT2 agonist and / or 5HT releasing agent are administered to the subject separately, they are administered at times sufficiently proximal that the 5HT2 agonist and / or 5HT releasing agent is capable of preventing opioid abuse in the subject. In certain embodiments, the coadministration comprises administering the opioid and the 5HT2 agonist and / or 5HT releasing agent within 24 hours (e.g., within 20 hours, 16 hours, 12 hours, 8 hours, 4 hours, 2 hours, 1 hour, or less) of one another. In certain embodiments, the opioid and the 5HT2 agonist and / or 5HT releasing agent are administered within sixty (60) minutes of one another (e.g., within 55, 50, 45, 40, 35, 40, 25, 20, 15, 10, 5, 4, 3, 2, or 1 minutes of one another). In certain embodiments, the opiate is administered before the 5HT2 agonist and / or 5HT releasing agent are administered. In other embodiments, the opiate is administered after the 5HT2 agonist and / or 5HT releasing agent are administered.

[0116] As used herein, the terms “ring structure” and “ring” are used interchangeably. As used herein, the term “substituent” refers a functional group (e.g., an alkyl, amide, ether, halogen, etc. group) that is present in a molecule (or portion thereof) where a hydrogen atom might otherwise be found. For example, in the case of benzene, a clorine atom (a halogen) may be bound to one of the ring carbons where a hydrogen atom would otherwise be. In such a situation, the chlorine atom is a substituent of the benzene ring. The term “substituted” similarly refers to the presence of a functional group in a chemical structure where a hydrogen atom might otherwise be found. Atoms present in the described structures have been given their standard abbreviations. Accordingly, as used herein, “C” refers to a carbon atom; “H” refers to a hydrogen atom, “O” refers to an oxygen atom, “N” refers to a nitrogen atom, “Cl” refers to a chlorine atom, “F” refers to a florine atom, etc. As used herein, an atom or a portion of a molecule that is “bound directly” or “directly bound” to another atom or another portion of the molecule is connected by a single chemical bond.

[0117] As used herein, a compound is a “derivative” of another compound if the two compounds share significant structural similarities (e.g., if both have a benzene ring or an indole structure); a compound does not have to be synthetically derived from the other compound to be a derivative. Derivatives include, for example, enantiomers or enantiomeric mixtures thereof.

[0118] As used herein, the term “analog” when used in reference to a chemical compound includes any salt formed by such compound. As one example, the term analog encompasses the hydrochloride salt of oxycodone, as well as any other salt form of oxycodone. An another example, the term analog encompases the hydrochloride salt of fenfluramine, as well as any other salt form of fenfluramine.

[0119] As used herein, the term “about” when used in reference to a value, shall be understood to mean within + / -5% of the specified value, optionally within + / -2% of the specified value.

[0120] The scope of the disclosure encompasses combination therapies comprising the administration of opiates and secondary agents, 5HT2 agonists and / or serotonin-releasing agents, which secondary agents ameliorate, prevent, inhibit, delay, or otherwise reduce the addictive or abuse potential of the administered opiates. The scope of the disclosure may encompass treatments and associated pharmaceutical compositions wherein a reduction in addictive or abuse potential of administered opioids is achieved relative to that expected or observed by administration of the opioids without the secondary 5HT2 agonists and / or serotonin-releasing agents. The reduction in addictive potential may encompass any relevant measure, including, for example, measures of craving, drug liking, reward, or withdrawal symptoms, or other measures of addictive potential or addiction, for example, as measured by visual analog scales (VAS), the Addiction Severity Instrument (ASI), the Substance Dependence Severity Scale (SDSS), the Severity of Opiate Dependence Questionnaire (SODQ), the Substance Use Involvement Index (SUII), the Severity of Dependence Scale (SDS), or the Global Appraisal of Individual Needs (GAIN).

[0121] The conditioned place preference (CPP) behavioral assay is a common and reproducible rodent behavior designed to quantify the rewarding / reinforcing effects of a drug, as well as assess individual craving following the administration of a drug. Drugs that are commonly abused by humans, such as cocaine, morphine, and amphetamines, etc., are known to be able to condition a place preference in mice. As shown herein, it is possible to block theformation of opioid-induced CPP by co-administering morphine with selective serotonin type 2c agonists, WAY163909 (FIGS. 1A and IB) and lorcaserin (FIG. 5), a serotonin type 2a / c agonist, psilocin (FIGS. 2A and 2B), or the 5HT releasing agent fenfluramine (FIG. 3). This effect was not dependent of the specific opioid used, as the 5HT releasing agent fenfluramine was also able to effectively block the acquisition of fentanyl and oxycodone CPP (FIGS. 4 and 6). Accordingly, drugs having activity at two different receptors can independently lower the rewarding effects of an opioid analgesic. Also shown is that none of these drugs negatively affects the analgesic properties of morphine (FIG. 5).

[0122] The present disclosure also provides a pharmaceutical formulation using an opioid analgesic combined with (i) a 5HT2 agonist, e.g., a 5HT2a, 5HT2c, and / or 5HT2a / c agonist, or (ii) a 5HT releasing agent, to produce a drug that has a lower addictive liability than the opioid alone. This would represent a first in class drug combination for this purpose and could be administered directly to patients. A key use case would be post-procedural opioid prescriptions which are routinely prescribed, but have also been linked to development of opioid use disorders in formerly drug-naive patients (Sun, Darnall et al, 2016 JAMA Internal Medicine).II. DESCRIPTION OF THE EMBODIMENTS

[0123] The present disclosure provides compositions, including pharmaceutical compositions, comprising (i) an opioid and (ii) a serotonin receptor type 2 (5HT2) agonist, particularly a 5HT2c agonist. The 5HT2c agonist can be a selective 5HT2c agonist. As used herein, a “selective” 5HT2c agonist has at least 2-times greater agonist activity with respect to 5HT2c receptors as compared with 5HT2a receptors, optionally at least 5-times greater, at least 10-times greater, at least 15-times greater, at least 20-times greater, or more, 5HT2c agonist activity as compared to 5HT2a agonist activity. The opioid can be any opioid disclosed herein, including any of the opioids described in section II.B, below. The 5HT2 agonist can be any 5HT2 agonist disclosed herein, including any of the 5HT2 agonists described in section II.C, below.

[0124] The present disclosure also provides compositions, including pharmaceutical compositions, comprising (i) an opioid and (ii) a serotonin (5HT) releasing agent. The opioid can be any opioid disclosed herein, including any of the opioids described in section II.B, below. The 5HT releasing agent can be any 5HT releasing agent disclosed herein, including any of the 5HT releasing agents described in section II. D, below.A. Methods

[0125] The present disclosure further provides methods of treating a subject. Exemplary methods are set forth, for example, in Embodiments 500-632, and elsewhere herein.

[0126] In some embodiments, the methods and associated pharmaceutical compositions of the disclosure are utilized in the treatment of conditions typically treated by opioids and / or for achieving therapeutic effects typically induced by opioids. In some embodiments, an effective amount of an opioid is administered, wherein the amount is an amount sufficient to achieve one or more selected therapeutic effects in a subject. In a primary embodiment, the scope of the disclosure encompasses methods (and related pharmaceutical compositions) for the prevention of opioid abuse in a subject. By way of example, and not intending to be limiting, the methods can: reduce the addictive liability (e.g., the psychological addictiveness) of an opioid administered to a subject reduce the rewarding effect (e.g., euphoria, intoxication, or the like) experienced by the subject when the opioid is administered; eliminate or substantially reduce the tendency for the subject to develop physical dependence, tolerance, and / or withdrawal symptoms with respect to the opioid; and / or eliminate or substantially reduce the tendency for the subject to use opioids in ways not prescribed, take opioids more often or in larger amounts than prescribed, and / or use opioids recreationally. In some embodiments, the methods (and related pharmaceutical compositions) do not diminish the analgesic properties of the opioid in the subject.

[0127] The methods disclosed herein can make use of any opioid disclosed herein, including any of the opioids described in section II.B, below, along with (i) any 5HT2 agonist disclosed herein, including any of the 5HT2 agonists described in section II. C, below, and / or (ii) any 5HT releasing agent disclosed herein, including any of the 5HT releasing agents described in section II.D, below. The methods disclosed herein can make use of any of the compositions, including pharmaceutical compositions, disclosed herein.

[0128] In some embodiments, the subject is a human (e.g., a patient). In other embodiments, the subject a non-human, such as a mammal. The subject can be, for example, a pet (e.g., dog, cat, pig, rabbit, rodent, bird, etc.); a farm animal (e.g., horse, cow, pig, sheep, chicken, goose, duck, etc.); an animal living in captivity (e.g., primate, monkey, tiger, lion, jaguar, leopard, cougar (or puma), cheetah, bear, boar, zebra, hyena, otter, ruminant, rodent, reptile, etc.); or a wild animal (e.g., primate, monkey, tiger, lion, jaguar, leopard, cougar (or puma), cheetah, cat, bear, boar, pig, zebra, horse, hyena, dog, otter, ruminant, rodent, reptile, bird, etc.).B. Opioids

[0129] In some embodiments, the opioid comprises (or is) a compound selected from the group consisting of morphine, codeine, buprenorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone, diacetylmorphine, nicomorphine, desomorphine, dihydrocodein, ethylmorphine, fentanyl, alfentanil, sufentanil, remifentanil, pethidine, ketobemidone, methadone, dezocine, pentazocine, butorphanol, nalbuphine, levorphanol, levomethorphan, meptazinol, tilidine, tramadol, analogs thereof, derivatives thereof, and combinations thereof. See, for example, Compounds I-XXVIII of Table 1.

[0130] In some embodiments, the opioid comprises (or is) selected from the group consisting of morphine, codeine, hydrocodone, hydromorphone, oxycodone, fentanyl, and tramadol, and combinations thereof.

[0131] In some embodiments, the opioid comprises, consists essentially of, or consists of morphine. In some embodiments, the opioid comprises, consists essentially of, or consists of fentanyl. In some embodiments, the opioid comprises, consists essentially of, or consists of oxycodone. In some embodiments, the opioid comprises, consists essentially of, or consists of hydrocodone. In some embodiments, the opioid comprises, consists essentially of, or consists of hydromorphone.C. 5HT2 Agonists

[0132] The 5HT2 agonists can be any 5HT2 agonist known in the art. 5HT2 agonists have been extensively studied and described, for example, in EP0572863, EP0863 136, EP1213017, U.S. Pat. No. 3,253,989, U.S. Pat. No. 3,676,558, U.S. Pat. No. 3,652,588, U.S. Pat. No.4,082,844, U.S. Pat. No. 4,971,969, U.S. Pat. No. 5,494,928, U.S. Pat. No. 5,646,173, U.S. Pat. No. 6,310,208, U.S. Pat. No. 6,503,900, U.S. Pat. No. 6,953,787, U.S. Pat. No. 7,045,545, U.S. Pat. No. 7,129,237, U.S. Pat. No. 10,407,381, WO97 / 42183, WO98 / 30546, WO98 / 30548, WO98 / 33504, WO99 / 02159, WO99 / 43647 (U.S. Pat. No. 6,281.243), WOOO / 12475 (U.S. Pat. No. 6,380.238), WO00 / 12502 (U.S. Pat. No. 6,365,598), WO00 / 12510 (U.S. Pat. No.6,433,175), WOOO / 12475, WOOO / 12481 (U.S. Pat. No. 6,552,062), WOOO / 12482, WO00 / 12502, WOOO / 16761, WO00 / 17170, WOOO / 28993, WOOO / 35922 (U.S. Pat. No.6,372.745), WOOO / 44737, WOOO / 44753, WOOO / 64899, WO00 / 77001, WO00 / 77002, WO00 / 77010, WOOO / 76984 (U.S. Pat. No. 6,465,467), WO01 / 09111, W001 / 09122, W001 / 09123 (U.S. Pat. No. 6,638,936), W001 / 09126, W001 / 12602, W001 / 12603 (U.S. Pat. No. 6,706,750), W001 / 40183, WOOl / 66548 (U.S. Pat. No. 6,583,134), W001 / 70207,W001 / 70223, WOOl / 72752 (U.S. Pat. No. 6,734.301), WOOl / 83487, W002 / 04456, W002 / 04457, W002 / 08178, W002 / 10169, W002 / 24700, W002 / 24701, WO02 / 36596, W002 / 40456, W002 / 40457, W002 / 42304, WO02 / 44152 (U.S. Pat. No. 6.479,534), WO02 / 48124, WO02 / 51844 (U.S. Pat. No. 6,610,685), WO02 / 59124, WO02 / 59127, WO02 / 59129, WO02 / 72584, WO02 / 74746, WO02 / 83863, W002 / 98350, W002 / 98400, W002 / 98860, W003 / 00663, W003 / 00666, W003 / 04501, W003 / 06466, WO03 / 11281, WO03 / 14118, WO03 / 14125, WO03 / 24976, WO03 / 28733, WO03 / 33497, WO03 / 57161, WO03 / 57213, WO03 / 57673, WO03 / 57674, W003 / 62205, WO03 / 64423, W003 / 86306, W003 / 87086, W003 / 89409, W003 / 91250, WO03 / 91251, WO03 / 91257, WO03 / 97636, W004 / 00829, W004 / 00830 (U.S. Pat. No. 6,667,303), WO04 / 56324, WOO4 / 78718, W004 / 81010, WOO4 / 087.156, WOO4 / 87662, WOO4 / 87692, WOO4 / 89897, WOO4 / 0961.96, WOO4 / 96201, WOO4 / 112769, US2004 / 192754, W005 / 00849, W005 / 03096, EP1500391, W005 / 16902, W005 / 19180, US2005 / 080074, W005 / 40146, WO05 / 41856, W005 / 42490, WO05 / 42491, WO05 / 44812, WO05 / 082859, W005 / 000309, W005 / 019179, WO05 / 121113, WO05 / 049.623, W005 / 105082, W005 / 109987, WO05 / 121113, WO05 / 113535, US2006 / 003990, US2006 / 014777, US2006 / 014778, W006 / 000.902, W006 / 028961, W006 / 020817, W006 / 020049, W006 / 019940, W006 / 004931, US2006 / 025601, WO06 / 044762, W006 / 047032, W006 / 050007, WO06 / 052887, W006 / 077025, W006 / 065600, W006 / 103511, WO06 / 116165, WO06 / 047228, WO06 / 117304, US2006 / 241172, US2006 / 241176, WO06 / 116136, WO06 / 116148, WO06 / 116151, WO06 / 116171, WO06 / 116170, WO06 / 116218, WO06 / 116169, W006 / 077025, US2007 / 032481, W007 / 025,144, W007 / 028,082, W007 / 028,132, W007 / 028,131, W007 / 028,083, W007 / 030,150, US2007 / 0049613, US2013 / 0267500, US2023 / 0293546.

[0133] In some embodiments, the 5HT2 agonist comprises a 5HT2a agonist, 5HT2c agonist, or 5HT2a / 2c agonist. In some embodiments, the 5HT2 agonist comprises a 5HT2c agonist. In some embodiments, the 5HT2 agonist comprises (or is) a selective 5HT2c agonist (e.g., it preferentially agonizes 5HT2c receptors over 5HT2a receptors). In some embodiments, the 5HT2 agonist selectively agonizes 5HT2c receptors at least about 2-times greater than 5HT2a receptors (e.g., at least about 3-times, at least about 4-times greater than 5HT2a receptors). In certain embodiments, the 5HT2 agonist selectively agonizes 5HT2c receptors at least about 5-times greater than 5HT2a receptors (e.g., at least about 6-times, at least about 7-times, at least about 8-times, at least about 9-times greater than 5HT2a receptors). In certain embodiments,the 5HT2 agonist selectively agonizes 5HT2c receptors at least about 10-times greater than 5HT2a receptors (e.g., at least about 11 -times, at least about 12-times, at least about 13 -times, at least about 14-times greater than 5HT2a receptors). In still other embodiments, the 5HT2 agonist selectively agonizes 5HT2c receptors at least about 15-times greater than 5HT2a receptors (e.g., at least about 16-times, at least about 17-times, at least about 18-times, at least about 19-times, at least about 20-times greater than 5HT2a receptors).

[0134] In some embodiments, the 5HT2 agonist comprises, consists essentially of, or consists of a compound according to any one of Embodiments 1-155 and 200-215 disclosed herein, or a mixture of two or more such compounds. In particular embodiments, the 5HT2 agonist comprises, consists essentially of, or consists of a compound according to Embodiments 138-140 disclosed herein. In other particular embodiments, the 5HT2 agonist comprises, consists essentially of, or consists of a compound according to Embodiments 141-142 disclosed herein. In other particular embodiments, the 5HT2 agonist comprises, consists essentially of, or consists of a compound according to Embodiments 143-145 disclosed herein. In other particular embodiments, the 5HT2 agonist comprises, consists essentially of, or consists of a compound according to Embodiments 146-150 disclosed herein. In still other particular embodiments, the 5HT2 agonist comprises, consists essentially of, or consists of a compound according to Embodiments 151-155 disclosed herein. In some embodiments, the 5HT2 agonist is part of a pharmaceutical composition that comprises, for example, a pharmaceutically acceptable carrier.

[0135] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 1 to 50 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound comprising at least a first ring structure A and a second ring structure B, and wherein the first ring A is a 6-member aromatic ring, optionally a heterocycle, and optionally substituted; the second ring B is a 5- to 9-member ring, optionally a heterocycle, optionally aromatic, and optionally substituted; wherein the first ring A is fused to the second ring B and the compound has 5HT2c receptor agonist activity, and, optionally, wherein the compound comprises 5HT2c agonist activity (e.g., selective 5HT2c agonist activity).

[0136] In some embodiments, ring A comprises a benzene ring. In some embodiments, ring A comprises a diazine ring (e.g., a pyrimidine ring). In some embodiments, ring A comprises one or more substituents. In some embodiments, the one or more substituents to ring A include an electron withdrawing (EW) group. In some embodiments, the EW group comprises ahalogen, an amide, an ether, a phenyl, a halo-phenyl, a benzyl, or a halo-benzyl group. In some embodiments, the one or more substituents to ring A include an alkyl group (e.g., a C1-C6 alkyl, such as a methyl or ethyl group), an amine group (e.g., an alkylamine), a cycloalkane group, or a heterocycle group (e.g., a nitrogen-containing heterocycle, such as azetidine, piperidine, or azepine).

[0137] In some embodiments, ring B comprises a 7-member heterocycle. In some embodiments, ring B comprises an azepine or diazepine ring. In some embodiments, wherein ring B comprises a 5-member heterocycle. In some embodiments, ring B comprises a pyrrole, pyrazole, imidazole, cyclopentene, or cyclopentadiene ring. In some embodiments, ring B comprises a 6-member heterocycle. In some embodiments, ring B comprises a piperazine, dihydropyran, or dihydromorpholine ring. In some embodiments, ring B comprises one or more substituents. In some embodiments, the one or more substituents to ring B include an alkyl group (e.g., a C1-C6 alkyl, such as a methyl or ethyl group) or an amine group (e.g., a C1-C6 alkylamine, such as methylamine, ethylamine, propylamine, or the like). In some embodiments, the one or more substituents to ring B include a phenyl, a halo-phenyl, a benzyl, or a halo-benzyl group.

[0138] In some embodiments, the compound described herein further comprises a third ring structure C, optionally a heterocycle, optionally aromatic, and optionally substituted, wherein ring C is fused with ring A, ring B, or both. In some embodiments, ring C comprises a 5- to 7-member ring. In some embodiments, ring C comprises a 5-member ring. In some embodiments, ring C comprises a dihydropyrrole, pyrrole, pyrazole, or furan ring. In some embodiments, ring C comprises a 6-member ring. In some embodiments, ring C comprises a tetrahydropyridine, dihydropyrimidinone, dihydropyran, or cycloalkane ring. In some embodiments, ring C comprises a 7-member ring. In some embodiments, ring C comprises diazepine. In some embodiments, ring C comprises one or more substituents. In some embodiments, the one or more substituents to ring C include an alkyl group (e.g., a C1-C6 alkyl, such as a methyl or ethyl group) or an amine group (e.g., a C1-C6 alkylamine, such as methylamine, ethylamine, propylamine, or the like).

[0139] In some embodiments, the compound described herein further comprises a fourth ring structure D, optionally a heterocycle, optionally aromatic, and optionally substituted, wherein ring D is fused with ring C. In some embodiments, ring D is not fused with either ring A or ring B. In some embodiments, ring D is not bound directly to either ring A or ring B. In someembodiments, ring D comprises a 5- to 8-member ring. In some embodiments, ring D comprises a cycloalkane, cycloalkene, or a heterocycle. In some embodiments, ring D comprises at least one nitrogen ring atoms. In some embodiments, ring D comprises an azepine or piperidine ring. In some embodiments, ring D comprises one or more substituents. In some embodiments, the one or more substituents to ring D include an alkyl group (e.g., a C1-C6 alkyl, such as a methyl or ethyl group), an amine group (e.g., a C1-C6 alkylamine, such as methylamine, ethylamine, propylamine, or the like), or an amide group.

[0140] In some embodiments, the compound described herein further comprises a fourth ring structure D, optionally a heterocycle, optionally aromatic, and optionally substituted, wherein ring D is bound directly to ring A. In some embodiments, ring D is not fused to ring B. In some embodiments, ring D is not bound directly to ring B. In some embodiments, ring D comprises a 4- to 8-member ring. In some embodiments, ring D comprises a cycloalkane, cycloalkene, or a heterocycle. In some embodiments, ring D comprises at least one nitrogen ring atoms. In some embodiments, ring D comprises an azetidine ring. In some embodiments, ring D comprises one or more substituents. In some embodiments, the one or more substituents to ring D include an alkyl group (e.g., a C1-C6 alkyl, such as a methyl or ethyl group), an amine group (e.g., a C1-C6 alkylamine, such as methylamine, ethylamine, propylamine, or the like), or an amide group. In some embodiments, the compound comprises an indoline, indole, indazole, indane, or indene derivative.

[0141] In some embodiments, the compound comprises a benzazepine or benzodiazepine derivative. In some embodiments, the compound comprises an azepinoindole derivative. In some embodiments, the compound comprises a 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine derivative or a pyrimidino[3,4-d]azepine derivative. In some embodiments, the compound comprises a phenylpiperazine derivative. In some embodiments, the compound comprises a benzodihydropyran derivative.

[0142] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 51 to 137 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a compound comprising a first aromatic ring structure A and a second ring structure B according to the structure of Compound L:Compound Lwherein: R1is C; R2is NR2’, CH2, CHR2', CR2', or O; R3is, independently, CH2, CHR3’, CH, CR3’, or CH(CH3)C(O); R4is N, NH, NR4', CH2, C(CH3)2, CH, or CR4'; R5is, independently, CH2, CH, CH(CH3), or O; R6is C; R7is CH or N; R8is CH, CR8’, or N; R9is CH, CR9’, or NR9’; R10is CH, CR10’, or N; m is 0, 1 or 2; n is 0, 1 or 2; R2’ is a Ci-Ce alkyl, an alkylamine, or a benzyl group, or part of a third ring structure C; R3’ is a Ci-Ce alkyl or an alkylamine group, or part of a third ring structure C; R4’ is CH3or part of a third ring structure C; R8’ is an electron withdrawing (EW) group, or part of a third ring structure C; R9’ is a Ci-Ce alkyl or EW group, or part of a third ring structure C; R10’ is a Ci-Ce alkyl, amine, alkylamine, heterocycle, or EW group, or part of a third ring structure C; wherein ring C, if present, is fused to ring A, ring B, or both; is optionally a heterocycle; and optionally includes one or more substituents; and wherein the compound has 5HT2c receptor agonist activity and, optionally wherein the compound comprises 5HT2c agonist activity (e.g., selective 5HT2c agonist activity).

[0143] In some embodiments, the compound comprises a third ring structure C. In some embodiments, ring C is fused to both ring A and ring B. In some embodiments, ring C is a 5-or 6- member heterocycle. In some embodiments, R2is NR2’; R3is, independently, CH2 or CHR3’; R4is NH; R5is CH2; R7is CH; R8is CH or CR8’; R9is CH or CR9’; R10is CR10’; m is 2; n is 1; R2’ is part of ring C; R3’, if present, is a Ci-Ce alkyl (e.g., methyl) or an alkylamine group; R8’, if present, is an EW group; R9’ is an EW group; and R10’ is part of ring C. In some embodiments, R3is CH2; and R8is CH. In some embodiments, R9’ is an amide, optionally substituted with a Ci-Ce alkyl group or a Ci-Ce halo-alkyl group (e.g., difluoroethyl, dicloroethyl, or the like). In some embodiments, ring C comprises a pyrrole, optionally substituted. In some embodiments, ring C comprises a dihydropyrrole, optionally substituted. In some embodiments, ring C comprises a tetrohydropyridine, optionally substituted.

[0144] In some embodiments, the compound further comprises a fourth ring structure D, wherein ring D is a 5- to 8- member ring fused to ring C. In some embodiments, ring D is not fused or directly bound to ring A or ring B. In some embodiments, ring D comprises a cycloalkane or a cycloalkene, optionally substituted.

[0145] In some embodiments, the compound described herein comprises a third ring structure C which is a 5-member heterocycle. In some embodiments, R2is NR2’; R3is CH2; R4is CH2; R5is O; R7is CH; R8is CH or CR8’; R9is CH or CR9’; R10is CR10’; m is 1; n is 1; R2’ is part of ring C; R8’, if present, is an EW group; R9’, if present, is an EW group; and R10’ is part of ring C. In some embodiments, R8’ is a halogen (e.g., Cl or F); and / or R9’ is a halogen (e.g., Cl or F) or an amide, optionally substituted with a Ci-Ce alkyl group or a Ci-Ce halo-alkyl group (e.g., difluoroethyl, dicloroethyl, or the like). In some embodiments, R8’ is CH; and R9’ is CH. In some embodiments, ring C comprises a pyrrole, optionally substituted. In some embodiments, the compound further comprises a fourth ring structure D, wherein ring D is a 5- to 8- member ring fused to ring C. In some embodiments, ring D is not fused or directly bound to ring A or ring B. In some embodiments, ring D comprises an azepine, optionally substituted.

[0146] In some embodiments, the compound described herein comprises a third ring structure C which is a 6-member ring. In some embodiments, R2is CR2’; R3is CH; R4is NH; R7is CH; R8is CH or CR8’; R9is CH or CR9’; R10is CR10’; m is 1; n is 0; R2’ is an alkylamine (e.g., ethylamine, oc-methyl ethylamine, or the like); R8’, if present, is an EW group; R9’, if present, is an EW group; and R10’ is part of ring C. In some embodiments, R8’ is a halogen (e.g., Cl or F); and / or R9’ is a halogen (e.g., Cl or F) or an amide, optionally substituted with a Ci-Ce alkyl group or a Ci-Ce halo-alkyl group (e.g., difluoroethyl, dicloroethyl, or the like). In some embodiments, R8’ is CH; and R9’ is CH. In some embodiments, ring C comprises cyclohexene, optionally substituted. In some embodiments, the compound further comprises a fourth ring structure D, wherein ring D is a 5- to 8- member ring fused to ring C. In some embodiments, ring D is not fused or directly bound to ring A or ring B. In some embodiments, ring D comprises a piperidine, optionally substituted. In some embodiments, ring D comprises an amide substituent.

[0147] As disclosed herein, the compound comprises a ring C which is fused to ring A but not ring B. In some embodiments, ring C is a 5-member heterocycle. In some embodiments, R2is NR2’; R4is N; R5is CH; R7is CH; R8is CH or CR8’; R9is CR9’; R10is CR10’; m is 0; nis 1; R2’ is an alkylamine (e.g., ethylamine, oc-methyl ethylamine, or the like); R8’, if present, is an EW group; R9’ is an EW group that is part of ring C; and R10’ is part of ring C. In some embodiments, R8’ is a halogen (e.g., Cl or F). In some embodiments, R8’ is CH; and / or R9’ is an O. In some embodiments, ring C comprises furan, optionally substituted. In some embodiments, ring C comprises a Ci-Ce alkyl group (e.g., an ethyl group) substituent.

[0148] In some embodiments, ring C is a 6-member heterocycle, wherein R2is CR2’; R3is CH; R4is NH or NR4’; R7is CH; R8is CH or CR8’; R9is CR9’; R10is CR10’; m is 1; n is 0; R2’ is an alkylamine (e.g., ethylamine, oc-methyl ethylamine, or the like); R4’ is CH3; R8’, if present, is an EW group; R9’ is part of ring C; and R10’ is part of ring C. In some embodiments, R8’ is a halogen (e.g., Cl or F). In some embodiments, R8’ is CH; and / or R9’ is an O. In some embodiments, ring C comprises dihydropyran, optionally substituted. In some embodiments, ring C comprises a Ci-Ce alkyl group (e.g., an ethyl group) substituent.

[0149] In some embodiments, ring C is a 6-member heterocycle, wherein R2is NR2’; R4is N; R5is CH; R7is CH; R8is CH or CR8’; R9is CR9’; R10is CR10’; m is 0; n is 1; R2’ is an alkylamine (e.g., ethylamine, oc-methyl ethylamine, or the like); R8’, if present, is an EW group; R9’ is part of ring C; and R10’ is part of ring C. In some embodiments, R8’ is a halogen (e.g., Cl or F). In some embodiments, R8’ is CH; and / or R9’ is an O. In some embodiments, ring C comprises dihydropyran, optionally substituted. In some embodiments, ring C comprises a Ci-Ce alkyl group (e.g., an ethyl group) substituent.

[0150] In some embodiments, ring C is a 5-member heterocycle, wherein R2is CH2; R3is CH2; R4is NH; R5is, independently, CH2 or CH(CH3); R7is N; R8is CR8’; R9is NR9’; R10is CR10’ ; m is 1 ; n is 2; R8’ is part of ring C; R9’ is part of ring C; and R10’ is an amine, alkylamine, or a nitrogen-comprising heterocycle, optionally substituted. In some embodiments, R10’ comprises azetidine, optionally substituted. In some embodiments, the azetidine comprises a amide substituent. In some embodiments, ring C comprises pyrazole, optionally substituted.

[0151] As disclosed herein, the compound may comprise a ring C which is fused to ring B but not ring A. In some embodiments, ring C is a 6-member heterocycle. In some embodiments, R2is NR2’; R3is CH(R3’)C(O); R4is NH; R7is CH; R8is CR8’; R9is CR9’; R10is CH; m is 1; n is 0; R2’ is part of ring C; R3’ is part of ring C; R8’ is an EW group; and R9’ is an EW group. In some embodiments, R8’ is a halogen (e.g., Cl or F); and / or R9’ is a halogen (e.g., Cl or F). In some embodiments, ring C comprises piperazine, optionally substituted.

[0152] In some embodiments, ring C is a 5-member heterocycle. In some embodiments, R2is CR2’; R3is CR3’; R4is C(CH3)2; R7is CH; R8is CH or CR8’; R9is CR9’; R10is CR10’; m is 1; n is 0; R2’ is part of ring C; R3’ is part of ring C; R8’ is an EW group; and R9’ is a Ci-Ce alkyl group (e.g., a methyl group). In some embodiments, R8’ is CH; and / or R9’ is a methyl group. In some embodiments, ring C comprises pyrrole, optionally substituted. In some embodiments, ring C comprises an alkylamine substituent (e.g., ethylamine, oc-methyl ethylamine, or the like).

[0153] In some embodiments, ring C is a 5-member heterocycle, wherein R2is NR2’; R4is CR4’; R5is CH; R7is CH; R8is CH or CR8’; R9is CH or CR9’; R10is CH or CR10’; m is 0; n is 1; R2’ is part of ring C; R3’ is part of ring C; R8’, if present, is an EW group; R9’, if present, is an EW group; and R10’, if present, is a Ci-Ce alkyl, amine, alkylamine, heterocycle, or EW (e.g., ether, phenyl) group. In some embodiments, R8’ is CH; and / or R9’ is CH; and / or R10’ is CH. In some embodiments, ring C comprises diazapine, optionally substituted.

[0154] In certain embodiments, the compound described herein comprises a first aromatic ring structure A and a second ring structure B according to the structure of Compound L, wherein R2is CHR2'; R3is CH2or CHR3’; R4is NH; R5is CH2; R7is CH; R8is CH or CR8’; R9is CR9’; R10is CH or CR10’; m is 1; n is 2; R2’ is a Ci-Ce alkyl (e.g., methyl) group; R3’, if present, is a Ci-Ce alkyl (e.g., methyl) or an alkylamine group; R8’, if present, is an EW group (e.g., a halogen); R9’ is an EW group (e.g., a halogen, amide, phenyl, halo-phenyl, benzyl, or halo-benzyl group); and R10’ is a Ci-Ce alkyl, amine, alkylamine, heterocycle, or EW group. In some embodiments, R3is CH2; R8is CH; and / or R10is CH. In some embodiments, R2’ is a methyl group; and / or R9’ is a halogen (e.g., Cl). In some embodiments, R3is CH2; R8is CH; R10is CH; R2’ is a methyl group; and R9’ is a halogen (e.g., Cl).

[0155] In certain embodiments, the compound described herein comprises a first aromatic ring structure A and a second ring structure B according to the structure of Compound L, wherein R2is NR2'; R3is CR3’;R4is N; R7is CH; R8is CH or CR8’; R9is CH or CR9’; R10is CH or CR10’; m is 1; n is 0; R2’ is a benzyl group, optionally a halo-benzyl group (e.g., cloro benzyl); R3’ is an alkylamine group (e.g., n-methyl pyrrolidine); R8’, if present, is an EW group (e.g., a halogen); R9’, if present, is an EW group (e.g., a halogen, amide, phenyl, halo-phenyl, benzyl, or halo-benzyl group); and R10’, if present, is a Ci-Ce alkyl, amine, alkylamine, heterocycle, or EW group. In certain embodiments, R8is CH; R9is CH; and / or R10is CH. In certain embodiments, R2’ is a halo-benzyl group (e.g., cloro benzyl); and / or R3’ is n-methylpyrrolidine, optionally substituted. In certain embodiments, R8is CH2; R9is CH; R10is CH; R2’ is a cloro benzyl group; and R9’ is n-methyl pyrrolidine.

[0156] In certain embodiments, the compound described herein comprises a first aromatic ring structure A and a second ring structure B according to the structure of Compound L, wherein: R2is CH2 or CHR2'; R3is CH2 or CHR3’; R4is CH2; R7is CH; R8is CH or CR8’; R9is CR9’; R10is CH or CR10’; m is 1; n is 0; R2’, if present, is a Ci-Ce alkyl (e.g., methyl) or an alkylamine group; R3’, if present, is a Ci-Ce alkyl (e.g., methyl) or an alkylamine group; R8’, if present, is an EW group (e.g., a halogen); R9’ is an EW group (e.g., an ether, such as an alkyl ether); and R10’ is an EW group (e.g., an ether, such as a pyrrolidine ether). In certain embodiments, R2is CH2; R3is CH2; and / or R8is CH. In certain embodiments, R9’ is an ether (e.g., an alkyl ether); and / or RIO’ is an ether (e.g., a pyrrolidine ether). In certain embodiments, R2is CH2; R3is CH; R8is CH; R9’ is an alkyl ether (e.g., methyl ether); and R9’ is a pyrrolidine ether, optionally substituted.

[0157] In certain embodiments, the compound described herein comprises a first aromatic ring structure A and a second ring structure B according to the structure of Compound L, wherein: R2is O; R3is CHR3’; R4is CH2; R5is CH2; R7is CH; R8is CH or CR8’; R9is CH; R10is CR10’; m is 1; n is 1; R3’ is an alkylamine group (e.g., methylamine); R8’, if present, is an EW group (e.g., a halogen); and R10’ is an EW group (e.g., a phenyl group, such as a halo-phenyl group). In some embodiments, R8is CH; and / or R10is a phenyl group. In some embodiments, R3’ is methylamine; and R10’ is a halo-phenyl (e.g., dicloro-phenyl). In some embodiments, R2is NR2'; R3is CH; R4is CH; R7is CH; R8is CR8’; R9is CR9’; R10is CH or CR10’; m is 1; n is 0; R2’ is an alkylamine group (e.g., oc-methyl ethylamine); R8’ is an EW group (e.g., a halogen); R9’ is an EW group (e.g., a halogen); and R10’, if present, is a Ci-Ce alkyl, amine, alkylamine, heterocycle, or EW group. In some embodiments, R10is CH; R2is oc-methyl ethylamine; R8is a halogen (e.g., F or Cl); and / or R9is a halogen (e.g., Cl or F). In some embodiments, R3’ is methylamine; and R10’ is a halo-phenyl (e.g., dicloro-phenyl).

[0158] In certain embodiments, the compound described herein comprises a first aromatic ring structure A and a second ring structure B according to the structure of Compound L, wherein: R2is CH2; R3is CH2; R4is NH; R5is CH2; R7is CH; R8is N; R9is CR9’; R10is N; m is 1; n is 2; and R9’ is an EW group (e.g., a halogen or a benzyl group, optionally a halo-benzyl group). In some embodiments, R9is a halogen (e.g., Cl or F). In some embodiments, R9is a benzyl group, optionally a halo-benzyl group.

[0159] In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LI:Compound LIwherein: R1is -H or -CH3; R2is -H, -CH3, -CH2CH3, or -OH; and R3is -F, -Cl, -CF3, a clorophenyl group (e.g., orthoclorophenyl), -Br, or -I. In some embodiments, R1is -H; R2is -CH3; and R3is -Cl. In some embodiments, the compound comprises a stereocenter with an R configuration.

[0160] In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LIII:Compound LIIIwherein: R1is -H, -CH3, or a -C2-6 alkyl group; R2is -H, -F, -Cl, -CF3, or -CONHCH2CHF2; and R3is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. In some embodiments, R1is -H;R2is -H; and R3is -CH2CH2CH2-.

[0161] In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LV :Compound LVwherein: R1is -CH3, -CH2CH3; and R2is -H or -CH3; or R1 and R2 together are -CH2CH2CH2-. In some embodiments, R1is -CH3; and R2is -H. In some embodiments, the compound comprises a stereocenter with an R configuration.

[0162] In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LVII:wherein: R1 is -CH2CH2F, -CH2CHCH2, -CH2CH2CH2F, -CH2C(F)CH2; and R2 is -F or -Cl. In some embodiments, R1 is -CH2CH2F; and R2 is -F. In some embodiments, R1 is -CH2CHCH2; and R2 is -F. In some embodiments, R1 is -CH2CH2CH2F; and R2 is -Cl. In some embodiments, R1 is -CH2C(F)CH2; and R2 is -Cl.

[0163] In some embodiments, the 5HT2 agonist comprises (or is) a compound having a structure according to Compound LVIII:Compound LVIIIwherein: R1is -H or -CH3; R2is -H; R3is -H or -CF3; and R4is -H or -CF3. In some embodiments, R1is -H; R2is -H; R3is -CF3; and R4is -H. In some embodiments, the compound comprises a stereocenter with an S configuration. In some embodiments, the compound comprises a stereocenter with an R configuration. In some embodiments, the compound comprises a mixture of R and S enantiomers, optionally a racemic mixture.

[0164] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 200 to 215 disclosed herein. In some embodiments, the 5HT2 agonist is a compound comprising at least a first ring structure A and a second ring structure B, and wherein the first ring A is a 6-member aromatic ring, optionally a heterocycle, and optionally substituted; the second ring B is a 6-member ring, optionally a heterocycle, optionally aromatic, and optionally substituted; wherein the first ring A is directly bound to the second ring B and the compound has 5HT2c receptor agonist activity, and, optionally, wherein the compound comprises 5HT2c agonist activity (e.g., selective 5HT2c agonist activity).

[0165] In some embodiments, ring A is a heterocycle that comprises nitrogen. In some embodiments, ring A is a pyrazine. In some embodiments, ring A is a pyridine. In some embodiments, ring A comprises one or more substituents. In some embodiments, ring A comprises an electron withdrawing substituent. In some embodiments, ring A comprises a halogen (e.g., Cl or F) substituent and / or a halo-alkyl substituent (e.g., a halo-methyl group, such as tetrafluoro methyl group). In some embodiments, ring A comprises an ether substituent. In some embodiments, the ether substituent comprises an alkoxy group. In some embodiments, the ether substituent comprises a pyridine or a quanaldine group (e.g., linked through a secondary ether). In some embodiments, the ether substituent comprises a benzyl group (e.g., a halo-benzyl group).

[0166] In some embodiments, ring B comprises a piperazine. In some embodiments, ring B comprises one or more substituents. In some embodiments, ring B comprises a C1-C6 alkyl (e.g., methyl) substituent.

[0167] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 51 to 63 disclosed herein. In some embodiments, the 5HT2 agonist comprises a derivative of indoline or indole. In some embodiments, the 5HT2 agonist comprises a diazepine ring fused to an indoline or an indole. In some embodiments, the 5HT2 agonist comprises (or is) Compound LXI (WAY-162545), Compound LXII (WAY-163909),Compound LXIII (WAY-470), Compound LXIV (WAY-629), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing. In some embodiments, the 5HT2 agonist comprises a derivative of 1,4-benzodiazepine. In some embodiments, the 5HT2 agonist comprises (or is) Compound LIV (vabicaserin), Compound LVI (bexicaserin), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or any combination of the foregoing.

[0168] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 52 and 117 to 120 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a derivative of 3-benzazepine. In some embodiments, the 5HT2 agonist comprises (or is) Compound LII (lorcaserin), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0169] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 51 to 52, 81 to 82, and 100 to 103 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a derivative of pyrimidino azepine. In some embodiments, the 5HT2 agonist comprises (or is) Compound LXVI (BI-4752), Compound LXVII (BI-03234), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0170] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 51 and 135 to 137 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a derivative of 6,7,8,9-tetrahydro-5H-pyrimido[4,5-D]azepine. In some embodiments, the 5HT2 agonist comprises (or is) Compound LXV (PF-03246799), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0171] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 51 to 52, 104, 109, and 114 to 116 disclosed herein. In certain embodiments, the 5HT2 agonist comprises a compound of any one of Embodiments 51 to 53 and 64 to 71 disclosed herein. In some embodiments, the 5HT2 agonist comprises a derivative of azepinoindole. In some embodiments, the 5HT2 agonist comprises (or is) Compound LXVIII (PNU-181731), Compound LXIX (PNU-57378), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0172] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 51 to 52 and 81 to 87 disclosed herein. In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 51 and 121 to 124 disclosed herein. In certain embodiments, the 5HT2 agonist comprises (or is) a compound of any one of Embodiments 51 to 52, 81, and 94 to 99 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a derivative of indazole. In some embodiments, the 5HT2 agonist comprises (or is) Compound LXX (YM-348), Compound LXXI (clemizole), Compound LXXVIII (AL-38022A), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0173] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 200 to 215 disclosed herein. In some embodiments, the 5HT2 agonist comprises (or is) a derivative of piperazinylpyrazine or piperazinylpyridine. In some embodiments, the 5HT2 agonist comprises (or is) a derivative of piperazinylbenzene. In some embodiments, the 5HT2 agonist comprises (or is) Compound LXXX (PNU-243922), Compound LXXXII (PRX-00933), Compound LXXXIII (CP-809101), Compound LXXXIV (MK-212), Compound LXXXV (Org- 12962), Compound XC (mCPP), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0174] In certain embodiments, the 5HT2 agonist comprises (or is) a compound according to any one of Embodiments 51 and 125 to 128 disclosed herein. In some embodiments, the 5HT2 agonist comprises a derivative of indane. In certain embodiments, the 5HT2 agonist comprises a compound of any one of Embodiments 51 to 52, 104, and 109 to 113 disclosed herein. In some embodiments, the 5HT2 agonist comprises a derivative of indene. In some embodiments, the 5HT2 agonist comprises (or is) Compound LXXII (Org-37684), Compound LXXIII (Ro 60-0332), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0175] In certain embodiments, the 5HT2 agonist comprises (or is) a compound of any one of Embodiments 51 to 53 and 72 to 80 disclosed herein. In certain embodiments, the 5HT2 agonist comprises (or is) a compound of any one of Embodiments 51 to 52 and 88 to 93 disclosed herein. In some embodiments, the 5HT2 agonist comprises a derivative of tryptamine. In some embodiments, the 5HT2 agonist comprises (or is) Compound LXXVI (CP-132484), Compound LXXVII (dihydroergotamine), Compound LXXXI (PNU-22394), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0176] In certain embodiments, the 5HT2 agonist comprises (or is) a compound of any one of Embodiments 51 and 132 to 134 disclosed herein. In some embodiments, the 5HT2 agonist comprises a derivative of oc-methyl-lH-indole-l-ethanamine. In some embodiments, the 5HT2 agonist comprises Compound LXXIX (Ro 60-0175), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0177] In some embodiments, the 5HT2 agonist comprises (or is) Compound XCII (psilocybin), Compound XCIII (psilocin), Compound XCIV (LSD), Compound XCV (DMT), Compound XCVI (5-MeO-DMT), Compound XCI (mescaline), an analog thereof, or any combination of the foregoing. In some embodiments, the 5HT2 agonist does not comprise Compound XCII (psilocybin). In some embodiments, the 5HT2 agonist does not comprise Compound XCIII (psilocin). In some embodiments, the 5HT2 agonist does not comprise Compound XCIV (LSD). In some embodiments, the 5HT2 agonist does not comprise Compound XCV (DMT). In some embodiments, the 5HT2 agonist does not comprise Compound XCVI (5-MeO-DMT). In some embodiments, the 5HT2 agonist does not comprise Compound XCI (mescaline).

[0178] In some embodiments, the 5HT2 agonist comprises (or is) a non-selective 5HT2c agonist (e.g., Compound LXXI (clemizole) or Compound LXXVII (dihydroergotamine), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing). In certain embodiments, the 5HT2 agonist comprises (or is) a compound of any one of Embodiments 51 to 52 and 104 to 108 disclosed herein. In certain embodiments, the 5HT2 agonist comprises (or is) a compound of any one of Embodiments 51 and 129 to 131 disclosed herein. In some embodiments, the 5HT2 agonist comprises a compound selected from the group consisting of Compound LXXIV (WAY-161503), Compound LXXV (WAY-261240), Compound LXXX (PNU-243922), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing. In some embodiments, the 5HT2 agonist comprises a compound selected from the group consisting of Compound LXXXVI (ATHX-105), Compound LXXXVII (JJ-3-42B), Compound LXXXVIII (PF-04781340), Compound LCVIII (PF-4479745), Compound XCIX (PF-4522654), Compound LVII (BMB-101), and Compound LXXXIX (KB- 128), a derivativeor analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0179] In some embodiments, the 5HT2 agonist comprises (or is) a compound selected from the group consisting of Compounds L-XCIX of Table 2, a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing. In some embodiments, the 5HT2 agonist comprises (or is) a compound selected from the group consisting of Compounds L-XCIX of Table 2.

[0180] In some embodiments, the 5HT2 agonist comprises (or is) a 5HT2c agonist selected from the group consisting of Compound LII (lorcaserin), Compound LIV (vabicaserin), Compound LVI (bexicaserin), Compound LIX (norfenfluramine), Compound LX (dexnorfenfluramin), and Compound XCVII (CMY-16). In some embodiments, the 5HT2 agonist comprises (or is) Compound LII. In some embodiments, the 5HT2 agonist comprises (or is) Compound LIV. In some embodiments, the 5HT2 agonist comprises (or is) Compound LVI. In some embodiments, the 5HT2 agonist comprises (or is) Compound LIX. In some embodiments, the 5HT2 agonist comprises (or is) Compound LX. In some embodiments, the 5HT2 agonist comprises (or is) Compound XCVII.D. 5HT Releasing Agents

[0181] The 5HT releasing agent can be any 5HT releasing agent known in the art. Examples of 5HT releasing agents include, but not limited to, those described, in Richard B Rothman and Michael H Baumann, “Serotonin releasing agents: Neurochemical, therapeutic and adverse effects”, Pharmacology Biochemistry and Behavior, Volume 71, Issue 4, 2002, Pages 825-836, and in patents and patent applications, e.g. US Pat. No. 3,198,833A, US Pat. No. 11,673,852, and US20240238222A1, each of which is hereby incorporated by reference in its entirety. In some embodiments, the 5HT2 agonist comprises, consists essentially of, or consists of a compound according to any one of embodiments 300-332 disclosed herein, or a mixture of two or more such compounds. In particular embodiments, the 5HT2 agonist comprises, consists essentially of, or consists of a compound according to embodiments 328-332 disclosed herein. In some embodiments, the 5HT2 agonist is part of a pharmaceutical composition that comprises, for example, a pharmaceutically acceptable carrier.

[0182] In some embodiments, the 5HT releasing agent comprises (or is) a compound according to any one of Embodiments 300-332 disclosed herein, or a mixture of two or moresuch compounds. In some embodiments, the 5HT2 agonist is part of a pharmaceutical composition that comprises, for example, a pharmaceutically acceptable carrier.

[0183] In some embodiments, the 5HT releasing agent comprises a derivative of phenethylamine, a derivative of amphetamine, a derivative of indane and / or a derivative of 2-aminoindane.

[0184] In some embodiments, the 5HT releasing agent comprises a derivative of aminoindane. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CXXIV (MMAI), Compound CXXV (TAI), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0185] In some embodiments, the 5HT releasing agent comprises a derivative of phenethylamine. In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CII (fenfluramine), Compound CIII (dexfenfluramine), Compound CIV (chlorophentermine), Compound CV (cloforex), Compound CVI (etolorex), Compound CVII (flucetorex), Compound CVIII (tiflorex), Compound CXI (MDMA), Compound CXII (MDEA), Compound CXIII (MBDB), Compound CXIV (MDA), Compound CXV (2-methyl-MDA), Compound CXVI (MMA), Compound CXVII (EDMA), Compound CXVIII (PMA), Compound CXIX (PMEA), Compound CXX (PMMA), Compound CXXI (4-MTA), Compound CXXII (5-APDB), Compound CXXIII (5-APDI), Compound XCI (mescaline), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0186] In some embodiments, the 5HT releasing agent comprises (or is) a compound selected from the group consisting of Compound CIX (indeloxazine), Compound CX (carbamazepine), a derivative or analog thereof, including enantiomers or enantiomeric mixtures thereof, or a combination of any of the foregoing.

[0187] In certain embodiments, the 5HT releasing agent comprises, consists essentially of, or consists of a compound presented in Table 3 herein (i.e., Compounds C-CXXV), analogs thereof, derivatives thereof, and combinations of any of the foregoing. In some embodiments, the 5HT releasing agent comprises a compound selected from the group consisting of Compounds C-CXXV of Table 3.

[0188] In some embodiments, the 5HT releasing agent comprises (or is) a compound having a structure according to Compound C:Compound Cwherein: R2is -H or -CH3; R3is -H, -CH2CH2R4, or an electron withdrawing group; R4is -H, -CH3, -CH2-R3, or an electron withdrawing group; R5is -H; R6is -H or -CH2- (when R6=Ral); Ralis -H, an alkyl group, such as -CH3 or -CH2CH3, or -CH2- (when Ral= R6); Ra2is -H or -CH3; RNis -H, an alkyl group, such as -CH3 or -CH2CH3, an alcohol group, such as -CH2CH3OH, or a carbonyl-containing group, such as -CORN; and RNis an alkoxy group, such as -OCH2CH3, or an aromatic group, such as -CH2OC6H5, optionally substituted, wherein the compound comprises 5HT releasing activity. In some embodiments, each electron withdrawing group (EWG) is selected from the group consisting of a halogen, a haloalkyl-containing group, an alkoxy group, a dioxy group (e.g., involved in ring structure substituents to the primary aromatic ring), and an alkylthio group. In some embodiments, R3is an EWG. In some embodiments, R3is a haloalkyl-containing group (e.g., -CF3 or -SCF3), an alkoxy group (e.g., -OCH3), or an oxygen-containing group (e.g., -OCH2R4or -OCH2CH2R4). In some embodiments, R4is an EWG. In some embodiments, R4is a halogen (e.g., -Cl), an alkoxy group (e.g., -OCH3), an alkylthio group (e.g., -SCH3), or an oxygen-containing group (e.g., -OR3). In some embodiments, R2is -H. In some embodiments, R3is -CF3. In some embodiments, R3is -CF3, R4is -H, and optionally R2is -H. In some embodiments, R3is -OCH3. In some embodiments, R3is -OCH3, R4is -H, and optionally R2is -H. In some embodiments, R3and R4are part of a dioxy ring structure fused to the primary aromatic ring. In some embodiments, R3and R4together are -OCH2O- or -OCH2CH2O-. In some embodiments, R4is -OCH3. In some embodiments, R4is -OCH3, R3is -H, and optionally R2is -H. In some embodiments, Ralis -CH3 and Ra2is -H. In some embodiments, Ralis -CEE and Ra2is -CH3. In some embodiments, RNis -H. In some embodiments, RNis -CEE. In someembodiments, is -CH2CH3. In some embodiments, the compound is a derivative of phenethylamine. In some embodiments, the compound is a derivative of amphetamine. In some embodiments, the compound is a derivative of indane. In some embodiments, the compound is a derivative of 2-amino indane.

[0189] In some embodiments, the compound is a derivative of phenethyl amine and has 5HT releasing activity. In some embodiments, the compound is a derivative of amphetamine and has 5HT releasing activity. In some embodiments, the compound is a derivative of indane which has 5HT releasing activity. In some embodiments, the compound is a derivative of 2-amino indane which has 5HT releasing activity.

[0190] In some embodiments, the 5HT releasing agent comprises (or is) a compound having a structure according to Compound CI:Compound CIwherein: R1is -H or -CH3; R2is -H, -CH3, or a -C2-5 alkyl group; R3is -H or -CF3; and R4is -H or -CF3. In some embodiments, R1is -H; R2is -CH2CH3; R3is -CF3; and R4is -H. In some embodiments, the compound comprises a stereocenter with an S configuration. In some embodiments, the compound comprises a stereocenter with an R configuration. In some embodiments, the compound comprises a mixture of R and S enantiomers, optionally a racemic mixture.

[0191] In some embodiments, the 5HT releasing agent comprises, consists essentially of, or consists of Compound CII, Compound CIII, or combinations thereof.

[0192] In certain particular embodiments, the 5HT releasing agent is fenfluramine (Compound CII). In other particular embodiments, the 5HT releasing agent is dexfenfluramine (Compound CIII).D. Compositions

[0193] The present disclosure provides a composition comprising (i) an opioid and (ii) a serotonin receptor type 2 (5HT2) agonist or a serotonin (5HT) releasing agent. In some embodiments, the opioid is selected from the group listed in Table 1. In some embodiments,the 5HT2 agonist is selected from the group listed in Table 2. In some embodiments, the 5HTreleasing agent is selected from the group listed in Table 3.Table 1. Exemplary Opioid Compounds<> <"<<" ""Table 2. Exemplary 5HT2 Agonists" "<<""""<>"><" """"Table 3. Exemplary 5HT Releasing Agents""<<< "<"<<E. Pharmaceutical Compositions

[0194] The scope of the present disclosure encompasses pharmaceutical compositions comprising (i) one or more opioids, and (ii) one or more serotonin receptor type 2 (5HT2) agonists. The one or more opioids will typically be present in an amount effective for an opioid therapeutic effect in a subject. The opioid therapeutic effect can be, for example, any opioid therapeutic effect known in the art, including, but not limited to treatment of pain (e.g., reduction of pain), and / or serotonin (5HT) releasing agents, for example, provided in an amount effective to prevent opioid abuse in the subject. It will be understood that the opioids, 5HT2agonists and / or 5HT releasing agents can be provided as pharmaceutically acceptable salts, solvates, stereoisomers, or prodrug forms thereof.

[0195] The pharmaceutical compositions will comprise at least one pharmaceutically acceptable excipient. In some embodiments, opioid-5HT2 agonists are combined with a pharmaceutically suitable (or acceptable) carrier (also referred to herein as a pharmaceutically suitable or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier selected on the basis of a chosen route of administration, e.g., oral administration, and standard pharmaceutical practice.

[0196] Examples of suitable aqueous and non-aqueous carriers which are employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof; vegetable oils, such as olive oil; and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin; by the maintenance of the required particle size, in the case of dispersions; and by the use of surfactants.

[0197] In some embodiments, the pharmaceutical combinations of the disclosure further comprise one or more excipients. Non-limiting examples of excipients include binders (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose), fillers (e.g., lactose, starch), disintegrants (e.g., croscarmellose sodium, sodium starch glycolate), lubricants (e.g., magnesium stearate, stearic acid), coatings (e.g., enteric coating materials, polymers), and / or stabilizers (e.g., antioxidants, preservatives).

[0198] In some embodiments, the formulation of the oxycodone and fenfluramine combination further comprises a solvent, such as water for injection, ethanol, or another solvent suitable for the formulation.

[0199] As disclosed herein, the formulation of the oxycodone and fenfluramine combination may be administered in various dosage forms. In one implementation, the pharmaceutical compositions of the disclosure are formulated in an oral dosage form. Exemplary oral dosage forms, include but are not limited to: tablets, for example immediate-release and controlled-release formulations; capsules, for example hard and soft gelatin capsules; lozenges formulated for oral transmucosal delivery; and liquid formulations, for example syrup, for example, opioid-based cough suppressant formulations. Other dosage forms of the compositions of the disclosure include rectal suppositories, or injectable solutions or suspensions for intravenous or intramuscular administration, for example packaged in vials, bottles, or I V. solutions bags.

[0200] In some embodiments, the pharmaceutical compositions of the disclosure comprise additional active ingredients. In one embodiment, the pharmaceutical composition comprises non-opioid active agents. In one embodiment, the pharmaceutical compositions of the disclosure comprise acetaminophen, for example 300 or 325 mg acetaminophen. In one embodiment, the pharmaceutical composition comprises a cough suppressant and further comprises promethazine.F. Exemplary Compositions.

[0201] Oxycodone and Fenfluramine. In some embodiments, the pharmaceutical composition comprises active ingredients oxycodone hydrochloride (5 mg, 10 mg, or 20 mg) and fenfluramine hydrochloride (20 mg), with a fenfluramine concentration of about 2-10% w / w.

[0202] Hydrocodone and Fenfluramine. In some embodiments, the pharmaceutical composition comprises active ingredients hydrocodone hydrochloride (5 mg, 10 mg, 20 mg, or 40 mg) and fenfluramine hydrochloride (20 mg), with a fenfluramine concentration of about 2-10% w / w.

[0203] Hydromorphone and Fenfluramine. In some embodiments, the pharmaceutical composition comprises active ingredients hydromorphone hydrochloride (4 mg, 8 mg, or 16 mg) and fenfluramine hydrochloride (20 mg), with a fenfluramine concentration of about 2-10% w / w.

[0204] Oxycodone and Dexfenfluramine . In some embodiments, the pharmaceutical composition comprises active ingredients oxycodone hydrochloride (5 mg, 10 mg, or 20 mg) and dexfenfluramine hydrochloride (15 mg), with a dexfenfluramine concentration of about 2-10% w / w.

[0205] Hydrocodone and Dexfenfluramine. In some embodiments, the pharmaceutical composition comprises active ingredients hydrocodone hydrochloride (5 mg, 10 mg, 20 mg, or 40 mg) and dexfenfluramine hydrochloride (15 mg), with a dexfenfluramine concentration of about 2-10% w / w.

[0206] Hydromorphone and Dexfenfluramine . In some embodiments, the pharmaceutical composition comprises active ingredients hydromorphone hydrochloride (4 mg, 8 mg, or 16 mg) and dexfenfluramine hydrochloride (15 mg), with a dexfenfluramine concentration of about 2-10% w / w.

[0207] Oxycodone and Lorcaserin. In some embodiments, the pharmaceutical composition comprises active ingredients oxycodone hydrochloride (5 mg, 10 mg, or 20 mg) and lorcaserin hydrochloride hemihydrate (10 mg), with a lorcaserin concentration of about 2-10% w / w.

[0208] Hydrocodone and Lorcaserin. In some embodiments, the pharmaceutical composition comprises active ingredients hydrocodone hydrochloride (5 mg, 10 mg, 20 mg, or 40 mg) and lorcaserin hydrochloride hemihydrate (10 mg), with a lorcaserin concentration of about 2-10% w / w.

[0209] Hydromorphone and Lorcaserin. In some embodiments, the pharmaceutical composition comprises active ingredients hydromorphone hydrochloride (4 mg, 8 mg, or 16 mg) and lorcaserin hydrochloride hemihydrate (10 mg), with a lorcaserin concentration of about 2-10% w / w.

[0210] Oxycodone and Vabicaserin. In some embodiments, the pharmaceutical composition comprises active ingredients oxycodone hydrochloride (5 mg, 10 mg, or 20 mg) and vabicaserin hydrochloride hemihydrate (100 mg), with a vabicaserin concentration of about 2-10% w / w.

[0211] Hydrocodone and Vabicaserin. In some embodiments, the pharmaceutical composition comprises active ingredients hydrocodone hydrochloride (5 mg, 10 mg, 20 mg, or 40 mg) and vabicaserin hydrochloride hemihydrate (100 mg), with a vabicaserin concentration of about 2-10% w / w.

[0212] Hydromorphone and Vabicaserin. In some embodiments, the pharmaceutical composition comprises active ingredients hydromorphone hydrochloride (4 mg, 8 mg, or 16 mg) and vabicaserin hydrochloride hemihydrate ( 100 mg), with a vabicaserin concentration of about 2-10% w / w.

[0213] Oxycodone and Bexicaserin. In some embodiments, the pharmaceutical composition comprises active ingredients oxycodone hydrochloride (5 mg, 10 mg, or 20 mg) and bexicaserin hydrochloride hemihydrate (10 mg), with a bexicaserin concentration of about 2-10% w / w.

[0214] Hydrocodone and Bexicaserin. In some embodiments, the pharmaceutical composition comprises active ingredients hydrocodone hydrochloride (5 mg, 10 mg, 20 mg, or 40 mg) and bexicaserin hydrochloride hemihydrate (10 mg), with a bexicaserin concentration of about 2-10% w / w.

[0215] Hydromorphone and Bexicaserin. In some embodiments, the pharmaceutical composition comprises active ingredients hydromorphone hydrochloride (4 mg, 8 mg, or 16 mg) and bexicaserin hydrochloride hemihydrate (10 mg), with a bexicaserin concentration of about 2-10% w / w.

[0216] Oxycodone and Norfenfluramine. In some embodiments, the pharmaceutical composition comprises active ingredients oxycodone hydrochloride (5 mg, 10 mg, or 20 mg) and norfenfluramine hydrochloride (20 mg), with a norfenfluramine concentration of about 2-10% w / w.

[0217] Hydrocodone and Norfenfluramine . In some embodiments, the pharmaceutical composition comprises active ingredients hydrocodone hydrochloride (5 mg, 10 mg, 20 mg, or 40 mg) and norfenfluramine hydrochloride (20 mg), with a norfenfluramine concentration of about 2-10% w / w.

[0218] Hydromorphone and Norfenfluramine . In some embodiments, the pharmaceutical composition comprises active ingredients hydromorphone hydrochloride (4 mg, 8 mg, or 16 mg) and norfenfluramine hydrochloride (20 mg), with a norfenfluramine concentration of about 2-10% w / w.

[0219] Oxycodone and Dexnorfenfluramine . In some embodiments, the pharmaceutical composition comprises active ingredients oxycodone hydrochloride (5 mg, 10 mg, or 20 mg) and dexnorfenfluramine hydrochloride (15 mg), with a dexnorfenfluramine concentration of about 2-10% w / w.

[0220] Hydrocodone and Dexnorfenfluramine . In some embodiments, the pharmaceutical composition comprises active ingredients hydrocodone hydrochloride (5 mg, 10 mg, 20 mg, or 40 mg) and dexnorfenfluramine hydrochloride (15 mg), with a dexnorfenfluramine concentration of about 2-10% w / w.

[0221] Hydromorphone and Dexnorfenfluramine . In some embodiments, the pharmaceutical composition comprises active ingredients hydromorphone hydrochloride (4 mg, 8 mg, or 16 mg) and dexnorfenfluramine hydrochloride (15 mg), with a dexnorfenfluramine concentration of about 2-10% w / w.III. EXEMPLARY EMBODIMENTS

[0222] Exemplary embodiments provided in accordance with the presently disclosed subject matter include, but are not limited to, the following embodiments 1-155 and 200-215, which present exemplary 5HT2c agonist compounds suitable for use in the methods and compositions disclosed herein:1. A compound comprising at least a first ring structure A and a second ring structure B, wherein:the first ring A is a 6-member aromatic ring, optionally a heterocycle, and optionally substituted;the second ring B is a 5- to 9-member ring, optionally a heterocycle, optionally aromatic, and optionally substituted;wherein the first ring A is fused to the second ring B and the compound has 5HT2c receptor agonist activity, and, optionally,wherein the compound comprises 5HT2c agonist activity (e.g., selective 5HT2c agonist activity).2. The compound of embodiment 1, wherein ring A comprises a benzene ring.3. The compound of embodiment 1, wherein ring A comprises a diazine ring (e.g., a pyrimidine ring).4. The compound of embodiment 2 or 3, wherein ring A comprises one or more substituents.5. The compound of embodiment 4, wherein the one or more substituents to ring A include an electron withdrawing (EW) group.6. The compound of embodiment 5, wherein the EW group comprises a halogen, an amide, an ether, a phenyl, a halo-phenyl, a benzyl, or a halo-benzyl group.7. The compound of embodiments 4 to 6, wherein the one or more substituents to ring A include an alkyl group (e.g., a C1-C6 alkyl, such as a methyl or ethyl group), an amine group (e.g., an alkylamine), a cycloalkane group, or a heterocycle group (e.g., a nitrogen-containing heterocycle, such as azetidine, piperidine, or azepine).8. The compound of any one of embodiments 1 to 7, wherein ring B comprises a 7- member heterocycle.The compound of embodiment 8, wherein ring B comprises an azepine or diazepine ring.The compound of any one of embodiments 1 to 7, wherein ring B comprises a 5-member heterocycle.The compound of embodiment 10, wherein ring B comprises a pyrrole, pyrazole, imidazole, cyclopentene, or cyclopentadiene ring.The compound of any one of embodiments 1 to 7, wherein ring B comprises a 6-member heterocycle.The compound of embodiment 12, wherein ring B comprises a piperazine, dihydropyran, or dihydromorpholine ring.The compound of any one of embodiment 1 to 13, wherein ring B comprises one or more substituents.The compound of embodiment 14, wherein the one or more substituents to ring B include an alkyl group (e.g., a C1-C6 alkyl, such as a methyl or ethyl group) or an amine group (e.g., a C1-C6 alkylamine, such as methylamine, ethylamine, propylamine, or the like).The compound of embodiment 14 or 15, wherein the one or more substituents to ring B include a phenyl, a halo-phenyl, a benzyl, or a halo-benzyl group.The compound of any one of embodiments 1 to 16 further comprising:a third ring structure C, optionally a heterocycle, optionally aromatic, and optionally substituted, wherein ring C is fused with ring A, ring B, or both.The compound of embodiment 17, wherein ring C comprises a 5- to 7-member ring. The compound of embodiment 17 or 18, wherein ring C comprises a 5-member ring. The compound of embodiment 19, wherein ring C comprises a dihydropyrrole, pyrrole, pyrazole, or furan ring.The compound of embodiment 17 or 18, wherein ring C comprises a 6-member ring. The compound of embodiment 21, wherein ring C comprises a tetrahydropyridine, dihydropyrimidinone, dihydropyran, or cycloalkane ring.The compound of embodiment 17 or 18, wherein ring C comprises a 7-member ring.The compound of embodiment 23, wherein ring C comprises diazepine.The compound of any one of embodiments 17 to 24, wherein ring C comprises one or more substituents.The compound of embodiment 25, wherein the one or more substituents to ring C include an alkyl group (e.g., a C1-C6 alkyl, such as a methyl or ethyl group) or an amine group (e.g., a C1-C6 alkylamine, such as methylamine, ethylamine, propylamine, or the like).The compound of any one of embodiments 17 to 26 further comprising:a fourth ring structure D, optionally a heterocycle, optionally aromatic, and optionally substituted, wherein ring D is fused with ring C.The compound of embodiment 27, wherein ring D is not fused with either ring A or ring B.The compound of embodiment 27 or 28, wherein ring D is not bound directly to either ring A or ring B.The compound of any one of embodiments 27 to 29, wherein ring D comprises a 5- to 8-member ring.The compound of any one of embodiments 27 to 30, wherein ring D comprises a cycloalkane, cycloalkene, or a heterocycle.The compound of any one of embodiments 27 to 31, wherein ring D comprises at least one nitrogen ring atoms.The compound of embodiment 32, wherein ring D comprises an azepine or piperidine ring.The compound of any one of embodiments 27 to 33, wherein ring D comprises one or more substituents.The compound of embodiment 34, wherein the one or more substituents to ring D include an alkyl group (e.g., a C1-C6 alkyl, such as a methyl or ethyl group), an amine group (e.g., a C1-C6 alkylamine, such as methylamine, ethylamine, propylamine, or the like), or an amide group.The compound of any one of embodiments 17 to 26 further comprising:a fourth ring structure D, optionally a heterocycle, optionally aromatic, and optionally substituted, wherein ring D is bound directly to ring A.The compound of embodiment 36, wherein ring D is not fused to ring B.The compound of embodiment 36 or 37, wherein ring D is not bound directly to ring B.The compound of any one of embodiments 36 to 38, wherein ring D comprises a 4- to 8-member ring.The compound of any one of embodiments 36 to 39, wherein ring D comprises a cycloalkane, cycloalkene, or a heterocycle.The compound of any one of embodiments 36 to 40, wherein ring D comprises at least one nitrogen ring atoms.The compound of embodiment 41, wherein ring D comprises an azetidine ring.The compound of any one of embodiments 36 to 42, wherein ring D comprises one or more substituents.The compound of embodiment 34, wherein the one or more substituents to ring D include an alkyl group (e.g., a C1-C6 alkyl, such as a methyl or ethyl group), an amine group (e.g., a C1-C6 alkylamine, such as methylamine, ethylamine, propylamine, or the like), or amide group.The compound of any one of embodiments 1 to 44, where the compound comprises an indoline, indole, indazole, indane, or indene derivative.The compound of any one of embodiments 1 to 44, where the compound comprises a benzazepine or benzodiazepine derivative.The compound of any one of embodiments 1 to 44, where the compound comprises an azepinoindole derivative.The compound of any one of embodiments 1 to 44, where the compound comprises a 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine derivative or a pyrimidino[3,4-d]azepine derivative.The compound of any one of embodiments 1 to 44, where the compound comprises a phenylpiperazine derivative.The compound of any one of embodiments 1 to 44, where the compound comprises a benzodihydropyran derivative.The compound having a first aromatic ring structure A and a second ring structure B according to the structure of Compound L:Compound Lwherein:R1is C;R2is NR2’, CH2, CHR2', CR2', or O;R3is, independently, CH2, CHR3’, CH, CR3’, or CH(CH3)C(O);R4is N, NH, NR4', CH2, C(CH3)2, CH, or CR4';R5is, independently, CH2, CH, CH(CH?), or O;R6is C;R7is CH orN;R8is CH, CR8’, orN;R9is CH, CR9’, or NR9’;R10is CH, CR10’, orN;m is 0, 1 or 2;n is 0, 1 or 2;R2’ is a Ci-Ce alkyl, an alkylamine, or a benzyl group, or part of a third ring structure C;R3’ is a Ci-Ce alkyl or an alkylamine group, or part of a third ring structure C;R4’ is CH? or part of a third ring structure C;R8’ is an electron withdrawing (EW) group, or part of a third ring structure C;R9’ is a Ci-Ce alkyl or EW group, or part of a third ring structure C;R10’ is a Ci-Ce alkyl, amine, alkylamine, heterocycle, or EW group, or part of a third ring structure C;wherein ring C, if present:is fused to ring A, ring B, or both;is optionally a heterocycle; andoptionally includes one or more substituents; andwherein the compound has 5HT2c receptor agonist activity and, optionally, wherein the compound comprises 5HT2c agonist activity (e.g., selective 5HT2c agonist activity).The compound of embodiment 51 comprising the third ring structure C.The compound of embodiment 52, wherein ring C is fused to both ring A and ring B The compound of embodiment 52 or 53, wherein ring C is a 5- or 6- member heterocycle.The compound of embodiment 54, wherein:R2isNR2’;R3is, independently, CEE or CHR3’;R4is NH;R5is CH2;R7is CH;R8is CH or CR8’;R9is CH or CR9’;R10is CR10’;m is 2;n is 1;R2’ is part of ring C;R3’, if present, is a Ci-Ce alkyl (e.g., methyl) or an alkylamine group;R8’, if present, is an EW group;R9’ is an EW group; andR10’ is part of ring C.The compound of embodiment 55, wherein:R3is CH2; andR8is CH.The compound of embodiment 55 or 56, wherein:R9’ is an amide, optionally substituted with a Ci-Ce alkyl group or a Ci-Ce halo-alkyl group (e.g., difluoroethyl, dicloroethyl, or the like).The compound of any one of embodiments 52 to 57, wherein:ring C comprises a pyrrole, optionally substituted.The compound of any one of embodiments 52 to 57, wherein:ring C comprises a dihydropyrrole, optionally substituted.The compound of any one of embodiments 52 to 57, wherein:ring C comprises a tetrohydropyridine, optionally substituted.The compound of any one of embodiments 52 to 60 further comprising a fourth ring structure D, wherein ring D is a 5- to 8- member ring fused to ring C.The compound of embodiment 61, wherein ring D is not fused or directly bound to ring A or ring B.The compound of embodiment 61 or 62, wherein ring D comprises a cycloalkane or a cycloalkene, optionally substituted.The compound of embodiment 52 or 53, wherein ring C is a 5-member heterocycle. The compound of embodiment 64, wherein:R2isNR2’;R3is CH2;R4is CH2;R5is O;R7is CH;R8is CH or CR8’;R9is CH or CR9’;R10is CR10’;m is 1;n is 1;R2’ is part of ring C;R8’, if present, is an EW group;R9’, if present, is an EW group; andR10’ is part of ring C.The compound of embodiment 65, wherein:R8’ is a halogen (e.g., Cl or F); and / orR9’ is a halogen (e.g., Cl or F) or an amide, optionally substituted with a Ci-Ce alkyl group or a Ci-Ce halo-alkyl group (e.g., difluoroethyl, dicloroethyl, or the like).The compound of embodiment 65, wherein:R8’ is CH; andR9’ is CH.The compound of any one of embodiments 64 to 67, wherein ring C comprises a pyrrole, optionally substituted.The compound of any one of embodiments 64 to 68 further comprising a fourth ring structure D, wherein ring D is a 5- to 8- member ring fused to ring C.The compound of embodiment 69, wherein ring D is not fused or directly bound to ring A or ring B.The compound of embodiment 69 or 70, wherein ring D comprises an azepine, optionally substituted.The compound of embodiment 52 or 53, wherein ring C is a 6-member ring.The compound of embodiment 72, wherein:R2is CR2’;R3is CH;R4is NH;R7is CH;R8is CH or CR8’;R9is CH or CR9’;R10is CR10’;m is 1;n is 0;R2’ is an alkylamine (e.g., ethylamine, oc-methyl ethylamine, or the like);R8’, if present, is an EW group;R9’, if present, is an EW group; andR10’ is part of ring C.The compound of embodiment 73, wherein:R8’ is a halogen (e.g., Cl or F); and / orR9’ is a halogen (e.g., Cl or F) or an amide, optionally substituted with a Ci-Ce alkyl group or a Ci-Ce halo-alkyl group (e.g., difluoroethyl, dicloroethyl, or the like). The compound of embodiment 73, wherein:R8’ is CH; andR9’ is CH.The compound of any one of embodiments 72 to 75, wherein ring C comprises cyclohexene, optionally substituted.The compound of any one of embodiments 72 to 76 further comprising a fourth ring structure D, wherein ring D is a 5- to 8- member ring fused to ring C.The compound of embodiment 69, wherein ring D is not fused or directly bound to ring A or ring B.The compound of embodiment 69 or 70, wherein ring D comprises a piperidine, optionally substituted.The compound of embodiment 79, wherein ring D comprises an amide substituent. The compound of embodiment 52, wherein ring C is fused to ring A but not ring B. The compound of embodiment 81, wherein ring C is a 5-member heterocycle.The compound of embodiment 82, wherein:R2isNR2’;R4is N;R5is CH;R7is CH;R8is CH or CR8’;R9is CR9’;R10is CR10’;m is 0;n is 1;R2’ is an alkylamine (e.g., ethylamine, oc-methyl ethylamine, or the like);R8’, if present, is an EW group;R9’ is an EW group that is part of ring C; andR10’ is part of ring C.The compound of embodiment 83, wherein:R8’ is a halogen (e.g., Cl or F).The compound of embodiment 83, wherein:R8’ is CH; and / orR9’ is an O.The compound of any one of embodiments 82 to 85, wherein ring C comprises furan, optionally substituted.The compound of embodiment 86, wherein ring C comprises a Ci-Ce alkyl group (e.g., an ethyl group) substituent.The compound of embodiment 81, wherein ring C is a 6-member heterocycle.The compound of embodiment 88, wherein:R2is CR2’;R3is CH;R4isNH orNR4’;R7is CH;R8is CH or CR8’;R9is CR9’;R10is CR10’;m is 1;n is 0;R2’ is an alkylamine (e.g., ethylamine, oc-methyl ethylamine, or the like);R4’ is CH3;R8’, if present, is an EW group;R9’ is part of ring C; andR10’ is part of ring C.The compound of embodiment 89, wherein:R8’ is a halogen (e.g., Cl or F).The compound of embodiment 89, wherein:R8’ is CH; and / orR9’ is an O.The compound of any one of embodiments 88 to 91, wherein ring C comprises dihydropyran, optionally substituted.The compound of embodiment 92, wherein ring C comprises a Ci-Ce alkyl group (e.g., an ethyl group) substituent.The compound of embodiment 81, wherein ring C is a 6-member heterocycle.The compound of embodiment 94, wherein:R2isNR2’;R4is N;R5is CH;R7is CH;R8is CH or CR8’;R9is CR9’;R10is CR10’;m is 0;n is 1;R2’ is an alkylamine (e.g., ethylamine, oc-methyl ethylamine, or the like);R8’, if present, is an EW group;R9’ is part of ring C; andR10’ is part of ring C.The compound of embodiment 95, wherein:R8’ is a halogen (e.g., Cl or F).The compound of embodiment 95, wherein:R8’ is CH; and / orR9’ is an O.The compound of any one of embodiments 94 to 97, wherein ring C comprises dihydropyran, optionally substituted.The compound of embodiment 98, wherein ring C comprises a Ci-Ce alkyl group (e.g., an ethyl group) substituent.The compound of embodiment 82, wherein:R2is CH2;R3is CH2;R4is NH;R5is, independently, CH2 or CH(CHs);R7is N;R8is CR8’;R9isNR9’;R10is CR10’;m is 1;n is 2;R8’ is part of ring C;R9’ is part of ring C; andR10’ is an amine, alkylamine, or a nitrogen-comprising heterocycle, optionally substituted.The compound of embodiment 100, wherein:R10’ comprises azetidine, optionally substituted.The compound of embodiment 101, wherein the azetidine comprises a amide substituent.The compound of any one of embodiments 100 to 103, wherein ring C comprises pyrazole, optionally substituted.The compound of embodiment 52, wherein ring C is fused to ring B but not ring A. The compound of embodiment 104, wherein ring C is a 6-member heterocycle.The compound of embodiment 105, wherein:R2is NR2’;R3is CH(R3’)C(O);R4is NH;R7is CH;R8is CR8’;R9is CR9’;R10is CH;m is 1;n is 0;R2’ is part of ring C;R3’ is part of ring C;R8’ is an EW group; andR9’ is an EW group.The compound of embodiment 106, wherein:R8’ is a halogen (e.g., Cl or F); and / orR9’ is a halogen (e.g., Cl or F).The compound of any one of embodiments 104 to 107, wherein ring C comprises piperazine, optionally substituted.The compound of embodiment 104, wherein ring C is a 5-member heterocycle.The compound of embodiment 109, wherein:R2is CR2’;R3is CR3’;R4is C(CH3)2;R7is CH;R8is CH or CR8’;R9is CR9’;R10is CR10’;m is 1;n is 0;R2’ is part of ring C;R3’ is part of ring C;R8’ is an EW group; andR9’ is a Ci-Ce alkyl group (e.g., a methyl group).The compound of embodiment 110, wherein:R8’ is CH; and / orR9’ is a methyl group.The compound of any one of embodiments 109 to 111, wherein ring C comprises pyrrole, optionally substituted.The compound of embodiment 112, wherein ring C comprises an alkylamine substituent (e.g., ethylamine, oc-methyl ethylamine, or the like).The compound of embodiment 109, wherein:R2is NR2’;R4is CR4’;R5is CH;R7is CH;R8is CH or CR8’;R9is CH or CR9’;R10is CH or CR10’;m is 0;n is 1;R2’ is part of ring C;R3’ is part of ring C;R8’, if present, is an EW group;R9’, if present, is an EW group; andR10’, if present, is a Ci-Ce alkyl, amine, alkylamine, heterocycle, or EW (e.g., ether, phenyl) group.The compound of embodiment 114, wherein:R8’ is CH; and / orR9’ is CH; and / orR10’ is CH.The compound of embodiment 114 or 115, wherein ring C comprises diazapine, optionally substituted.The compound of embodiment 51, wherein:R2is CHR2';R3is CH2or CHR3’;R4is NH;R5is CH2;R7is CH;R8is CH or CR8’;R9is CR9’;R10is CH or CR10’;m is 1;n is 2;R2’ is a Ci-Ce alkyl (e.g., methyl) group;R3’, if present, is a Ci-Ce alkyl (e.g., methyl) or an alkylamine group;R8’, if present, is an EW group (e.g., a halogen);R9’ is an EW group (e.g., a halogen, amide, phenyl, halo-phenyl, benzyl, or halo-benzyl group); andR10’ is a Ci-Ce alkyl, amine, alkylamine, heterocycle, or EW group.The compound of embodiment 117, wherein:R3is CH2;R8is CH; and / orR10is CH.The compound of embodiment 117 or 118, wherein:R2’ is a methyl group; and / orR9’ is a halogen (e.g., Cl).The compound of embodiment 117, wherein:R3is CH2;R8is CH;R10is CH;R2’ is a methyl group; andR9’ is a halogen (e.g., Cl).The compound of embodiment 51, wherein:R2isNR2';R3is CR3’;R4is N;R7is CH;R8is CH or CR8’;R9is CH or CR9’;R10is CH or CR10’;m is 1;n is 0;R2’ is a benzyl group, optionally a halo-benzyl group (e.g., cloro benzyl);R3’ is an alkylamine group (e.g., n-methyl pyrrolidine);R8’, if present, is an EW group (e.g., a halogen);R9’, if present, is an EW group (e.g., a halogen, amide, phenyl, halo-phenyl, benzyl, or halo-benzyl group); andR10’, if present, is a Ci-Ce alkyl, amine, alkylamine, heterocycle, or EW group. The compound of embodiment 121, wherein:R8is CH;R9is CH; and / orR10is CH.The compound of embodiment 121 or 122, wherein:R2’ is a halo-benzyl group (e.g., cloro benzyl); and / orR3’ is n-methyl pyrrolidine, optionally substituted.The compound of embodiment 121, wherein:R8is CH2;R9is CH;R10is CH;R2’ is a cloro benzyl group; andR9’ is n-methyl pyrrolidine.The compound of embodiment 51, wherein:R2is CH2or CHR2';R3is CH2or CHR3’;R4is CH2;R7is CH;R8is CH or CR8’;R9is CR9’;R10is CH or CR10’;m is 1;n is 0;R2’, if present, is a Ci-Ce alkyl (e.g., methyl) or an alkylamine group;R3’, if present, is a Ci-Ce alkyl (e.g., methyl) or an alkylamine group;R8’, if present, is an EW group (e.g., a halogen);R9’ is an EW group (e.g., an ether, such as an alkyl ether); andR10’ is an EW group (e.g., an ether, such as a pyrrolidine ether).The compound of embodiment 125, wherein:R2is CH2;R3is CH2; and / orR8is CH.The compound of embodiment 125 or 126, wherein:R9’ is an ether (e.g., an alkyl ether); and / orRIO’ is an ether (e.g., a pyrrolidine ether).The compound of embodiment 125, wherein:R2is CH2;R3is CH;R8is CH;R9’ is an alkyl ether (e.g., methyl ether); andR9’ is a pyrrolidine ether, optionally substituted.The compound of embodiment 51, wherein:R2is O;R3is CHR3’;R4is CH2;R5is CH2;R7is CH;R8is CH or CR8’;R9is CH;R10is CR10’;m is 1;n is 1;R3’ is an alkylamine group (e.g., methylamine);R8’, if present, is an EW group (e.g., a halogen); andR10’ is an EW group (e.g., a phenyl group, such as a halo-phenyl group). The compound of embodiment 129, wherein:R8is CH; and / orR10is a phenyl group.The compound of embodiment 129 or 130, wherein:R3’ is methylamine; andR10’ is a halo-phenyl (e.g., dicloro-phenyl).The compound of embodiment 51, wherein:R2isNR2';R3is CH;R4is CH;R7is CH;R8is CR8’;R9is CR9’;R10is CH or CR10’;m is 1;n is 0;R2’ is an alkylamine group (e.g., oc-methyl ethylamine);R8’ is an EW group (e.g., a halogen);R9’ is an EW group (e.g., a halogen); andR10’, if present, is a Ci-Ce alkyl, amine, alkylamine, heterocycle, or EW group.The compound of embodiment 132, wherein:R10is CH;R2is oc-methyl ethylamine;R8is a halogen (e.g., F or Cl); and / orR9is a halogen (e.g., Cl or F).The compound of embodiment 129 or 130, wherein:R3’ is methylamine; andR10’ is ahalo-phenyl (e.g., dicloro-phenyl).The compound of embodiment 51, wherein:R2is CH2;R3is CH2;R4is NH;R5is CH2;R7is CH;R8is N;R9is CR9’;R10is N;m is 1;n is 2; andR9’ is an EW group (e.g., a halogen or a benzyl group, optionally a halo-benzyl group).The compound of embodiment 135, wherein R9is a halogen (e.g., Cl or F).The compound of embodiment 135, wherein R9is a benzyl group, optionally a halo-benzyl group.A compound having a structure according to Compound LI:Compound LIwherein:R1is -H or -CH3;R2is -H, -CH3, -CH2CH3, or -OH; andR3is -F, -Cl, -CF3, a clorophenyl group (e.g., orthoclorophenyl), -Br, or -I.The compound of embodiment 138, wherein:R1is -H;R2is -CH3; andR3is -Cl.The compound of embodiment 139 having a stereocenter with an R configuration. A compound having a structure according to Compound LIII:Compound LIIIwherein:R1is -H, -CH3, or a -C2-6 alkyl group;R2is -H, -F, -Cl, -CF3, or -CONHCH2CHF2; andR3is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.The compound of embodiment 141, wherein:R1is -H;R2is -H; andR3is -CH2CH2CH2-.A compound having a structure according to Compound LV:Compound LVwherein:R1is -CH3, -CH2CH3; andR2is -H or -CH3;orR1 and R2 together are -CH2CH2CH2-.The compound of embodiment 143, wherein:R1is -CH3; andR2is -H.The compound of embodiment 144 having a stereocenter with an R configuration. A compound having a structure according to Compound LVII:Compound LVIIwherein:R1 is -CH2CH2F, -CH2CHCH2, -CH2CH2CH2F, -CH2C(F)CH2; and R2 is -F or -Cl.The compound of embodiment 146, wherein:R1 is -CH2CH2F; andR2 is -F.The compound of embodiment 146, wherein:R1 is -CH2CHCH2; andR2 is -F.The compound of embodiment 146, wherein:R1 is -CH2CH2CH2F; andR2 is -Cl.The compound of embodiment 146, wherein:R1 is -CH2C(F)CH2; andR2 is -Cl.A compound having a structure according to Compound LVIII:Compound LVIIIwherein:R1is -H or -CH3;R2is -H;R3is -H or -CF3; andR4is -H or -CF3.The compound of embodiment 151, wherein:R1is -H;R2is -H;R3is -CF3; andR4is -H.The compound of embodiment 152 having a stereocenter with an S configuration. The compound of embodiment 152 having a stereocenter with an R configuration. The compound of embodiment 152 comprising a mixture of R and S enantiomers, optionally a racemic mixture.A compound comprising at least a first ring structure A and a second ring structure B, wherein:the first ring A is a 6-member aromatic ring, optionally a heterocycle, and optionally substituted;the second ring B is a 6-member ring, optionally a heterocycle, optionally aromatic, and optionally substituted;wherein the first ring A is directly bound to the second ring B and the compound has 5HT2c receptor agonist activity, and, optionally,wherein the compound comprises 5HT2c agonist activity (e.g., selective 5HT2c agonist activity).The compound of embodiment 200, wherein ring A is a heterocycle that comprises nitrogen.The compound of embodiment 201, wherein ring A is a pyrazine.The compound of embodiment 201, wherein ring A is a pyridine.The compound of any one of embodiments 200 to 203, wherein ring A comprises one or more substituents.The compound of embodiment 204, wherein ring A comprises an electron withdrawing substituent.206. The compound of embodiment 204, wherein ring A comprises a halogen (e.g., Cl or F) substituent and / or a halo-alkyl substituent (e.g., a halo-methyl group, such as tetrafluoro methyl group).207. The compound of embodiment 204, wherein ring A comprises an ether substituent. 208. The compound of embodiment 207, wherein the ether substituent comprises an alkoxy group.209. The compound of embodiment 207, wherein the ether substituent comprises a pyridine or a quanaldine group (e.g., linked through a secondary ether).210. The compound of embodiment 207, wherein the ether substituent comprises a benzyl group (e.g., a halo-benzyl group).211. The compound of any one of embodiments 200 to 210, wherein ring B comprises a piperazine.212. The compound of embodiment 211, wherein ring B comprises one or more substituents.213. The compound of embodiment 212, wherein ring B comprises a C1-C6 alkyl (e.g., methyl) substituent.214. The compound of any one of embodiments 200 to 213, wherein the compound comprises a piperazinylpyrazine derivative.215. The compound of any one of embodiments 200 to 213, wherein the compound comprises a piperazinylpyridine derivative.

[0223] Exemplary embodiments provided in accordance with the presently disclosed subject matter include, but are not limited to, the following embodiments 300-332, which present exemplary 5HT releasing agent compounds suitable for use in the methods and compositions disclosed herein:300. A compound having a structure according to Compound C:Compound Cwherein:R2is -H or -CEE;R3is -H, -CH2CH2R4, or an electron withdrawing group;R4is -H, -CH3, -CH2-R3, or an electron withdrawing group;R5is -H;R6is -H or -CH2- (when R6=Ral);group, such as -CH3 or -CH2CH3, or -CH2- (when R“1=R6);R“2is -H or -CEE;RNis -H, an alkyl group, such as -CH3 or -CH2CH3, an alcohol group, such as -CH2CH3OH, or a carbonyl-containing group, such as -CORN; andRNis an alkoxy group, such as -OCH2CH3, or an aromatic group, such as -CH2OC6H5, optionally substituted,wherein the compound comprises 5HT releasing activity.The compound of embodiment 300, wherein each electron withdrawing group (EWG) is selected from the group consisting of a halogen, a haloalkyl-containing group, an alkoxy group, a dioxy group (e.g., involved in ring structure substituents to the primary aromatic ring), and an alkylthio group.The compound of embodiment 300 or 301, wherein R3is an EWG.The compound of embodiment 302, wherein R3is a haloalkyl-containing group (e.g., -CF3 or -SCF3), an alkoxy group (e.g., -OCH3), or an oxygen-containing group (e.g., -OCH2R4or -OCH2CH2R4).The compound of any one of embodiments 300 to 303, wherein R4is an EWG.The compound of embodiment 304, wherein R4is a halogen (e.g., -Cl), an alkoxy group (e.g., -OCH3), an alkylthio group (e.g., -SCH3), or an oxygen-containing group (e.g., -OR3).The compound of any one of embodiments 300 to 305, wherein R2is -H.The compound of any one of embodiments 300 to 306, wherein R3is -CF3.The compound of any one of embodiments 300 to 303, wherein R3is -CF3, R4is -H, and optionally R2is -H.The compound of any one of embodiments 300 to 306, wherein R3is -OCH3.The compound of any one of embodiments 300 to 303, wherein R3is -OCH3, R4is -H, and optionally R2is -H.The compound of any one of embodiments 300 to 306, wherein R3and R4are part of a dioxy ring structure fused to the primary aromatic ring.The compound of any one of embodiments 300 to 306, wherein R3and R4together are -OCH2O- or -OCH2CH2O-.The compound of any one of embodiments 300 to 307, wherein R4is -OCH3.The compound of any one of embodiments 300 to 303, wherein R4is -OCH3, R3is -H, and optionally R2is -H.The compound of any one of embodiments 300 to 314, wherein Ralis -CH3 and R“2is -H.The compound of any one of embodiments 300 to 314, wherein Ralis -CH3 and R“2is -CH3.The compound of any one of embodiments 300 to 316, wherein RNis -H.The compound of any one of embodiments 300 to 316, wherein RNis -CH3.The compound of any one of embodiments 300 to 316, wherein is -CH2CH3.The compound of embodiment 300 which is a derivative of phenethylamine.The compound of embodiment 300 which is a derivative of amphetamineThe compound of embodiment 300 which is a derivative of indaneThe compound of embodiment 300 which is a derivative of 2-amino indane.324. A compound which is a derivative of phenethylamine and has 5HT releasing activity.325. A compound which is a derivative of amphetamine and has 5HT releasing activity. 326. A compound which is a derivative of indane which has 5HT releasing activity.327. A compound which is a derivative of 2-amino indane which has 5HT releasing activity.328. A compound having a structure according to Compound CI:Compound CIwherein:R1is -H or -CEE;R2is -H, -CH3, or a -C2-5 alkyl group;R3is -H or -CF3; andR4is -H or -CF3.329. The compound of embodiment 328, wherein:R1is -H;R2is -CH2CH3;R3is -CF3; andR4is -H.330. The compound of embodiment 329 having a stereocenter with an S configuration. 331. The compound of embodiment 329 having a stereocenter with an R configuration. 332. The compound of embodiment 329 comprising a mixture of R and S enantiomers, optionally a racemic mixture.

[0224] Exemplary embodiments provided in accordance with the presently disclosed subject matter include, but are not limited to, the following embodiments 400-434, which present exemplary pharmaceutical compositions comprising an opioid and a serotonin receptor type 2 (5HT2) agonist, any one of which is suitable for use in the methods disclosed herein:A pharmaceutical composition comprising (i) an opioid and (ii) a serotonin receptor type 2 (5HT2) agonist.The pharmaceutical composition of embodiment 400, wherein the 5HT2 agonist comprises a 5HT2a agonist, 5HT2c agonist, or 5HT2a / 2c agonist.The pharmaceutical composition of embodiment 400, wherein the 5HT2 agonist comprises a selective 5HT2c agonist.The pharmaceutical composition of embodiment 400, wherein the 5HT2 agonist comprises a compound as described in any one of Embodiments 1-155 or 200-215. The pharmaceutical composition of embodiment 400, wherein the 5HT2 agonist comprises a compound selected from the group consisting of Compounds L-XCIX of Table 2, analogs thereof, derivatives thereof, and any combination of the foregoing. The pharmaceutical composition of embodiment 400, wherein the 5HT2 agonist comprises a chemical structure according to Compound LI, wherein R1is -H or -CH3, R2is -H, -CH3, -CH2CH3, or -OH, and wherein R3is -F, -Cl, -CF3, a chlorine substituted phenyl group (e.g., ortho-clorophenyl group), -Br, or -I.The pharmaceutical composition of embodiment 400, wherein the 5HT2 agonist comprises Compound LII (lorcaserin).The pharmaceutical composition of embodiment 400, wherein the 5HT2 agonist comprises a chemical structure according to Compound LIII, wherein R1is -H, -CH3, or a -C2-6 alkyl group, R2is -H, -F, -Cl, -CF3, or -C(O)NHCH2CHF2, and R3 is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.The pharmaceutical composition of embodiment 400, wherein the 5HT2 agonist comprises Compound LIV (vabicaserin).The pharmaceutical composition of embodiment 400, wherein the 5HT2 agonist comprises a chemical structure according to Compound LV, wherein R1is (S)-CH3, (R)-CH3, (S)-CH2CH3, (R)-CH2CH3, (S)-CH2CF3, or (R)-CH2CF3, and R2is -H, or -CH3., or wherein R1and R2together are -CH2CH2CH2-.The pharmaceutical composition of embodiment 400, wherein the 5HT2 agonist comprises Compound LVI (bexicaserin).The pharmaceutical composition of embodiment 400, wherein the 5HT2 agonist comprises a chemical structure according to Compound LVII, wherein R1is -CH2CH2F, -CH2CH2CH2F, -CH2CHCH2, or -CH2CH2C(F)CH2, and R2is -F, or -Cl.The pharmaceutical composition of embodiment 400, wherein the 5HT2 agonist comprises a chemical structure according to Compound LVIII, wherein R1is -H, or -CH3, R2is -H, -CH3, or a -C2-5 alkyl group, R3is -H, or -CF3, and R4is -H, or -CF3. The pharmaceutical composition of embodiment 400, wherein the 5HT2 agonist comprises Compound LIX (norfenfluramine).The pharmaceutical composition of embodiment 400, wherein the 5HT2 agonist comprises Compound LX (dexnorfenfluramine).The pharmaceutical composition of any one of embodiments 400 to 414, wherein the composition comprises an amount of the 5HT2 agonist effective to prevent opioid abuse in a subject in need thereof.The pharmaceutical composition of any one of embodiments 400 to 415 comprising about 1 mg to about 100 mg (e.g., about 2 mg to about 50 mg, or about 3 mg to about 25 mg) of the 5HT2 agonist.The pharmaceutical composition of any one of embodiments 400 to 416, wherein the opioid comprises a compound selected from the group consisting of Compounds I-XXVIII of Table 1, analogs thereof, derivatives thereof, and any combination of the foregoing.The pharmaceutical composition of any one of embodiments 400 to 416, wherein the opioid comprises a compound selected from Compound II (morphine), Compound I (codeine), Compound IV (hydrocodone), Compound V (hydromorphone), Compound VI (oxycodone), Compound XIII (fentanyl), and Compound XXVIII (tramadol). The pharmaceutical composition of any one of embodiments 400 to 416, wherein the opioid comprises Compound VI.The pharmaceutical composition of any one of embodiments 400 to 416, wherein the opioid comprises Compound II.The pharmaceutical composition of any one of embodiments 400 to 416, wherein the opioid comprises Compound XIII.The pharmaceutical composition of any one of embodiments 400 to 416, wherein the opioid comprises Compound IV.The pharmaceutical composition of any one of embodiments 400 to 416, wherein the opioid comprises Compound V.The pharmaceutical composition of any one of embodiments 400 to 423, wherein the composition comprises an amount of the opioid effective for an opioid therapeutic effect in a subject in need thereof.The pharmaceutical composition of embodiment 424, wherein the opioid therapeutic effect includes reduction of pain, anesthetic effect, antitussive effect, anti -diarrheal effect, sedative effect, or any combination thereof.The pharmaceutical composition of embodiment 424 or 425, wherein the opioid therapeutic effect includes reduction of pain.The pharmaceutical composition of embodiment 426, wherein the opioid therapeutic effect further includes anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof.The pharmaceutical composition of any one of embodiments 400 to 427 comprising about 1 mg to about 500 mg of opioid (e.g., about 2 mg to about 300 mg of opioid, or about 5 mg to about 200 mg of opioid).The pharmaceutical composition of any one of embodiments 400 to 428 comprising a ratio of opioid to 5HT2 agonist of about 5:1 to about 1:5 (e.g., about 3:1 to about 1:3, about 2: 1 to about 1 :2, or about 1:1).The pharmaceutical composition of any one of embodiments 400 to 429, wherein the composition is formulated for oral, intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalational, or topical delivery.The pharmaceutical composition of any one of embodiments 400 to 430, wherein the composition is formulated for oral delivery.The pharmaceutical composition of embodiment 431, wherein the composition is in the form of a tablet or capsule.433. The pharmaceutical composition of any one of embodiments 400 to 430, wherein the composition is formulated for intravenous or intramuscular delivery.434. The pharmaceutical composition of embodiment 433, wherein the composition is in the form of a solution or suspension.

[0225] Exemplary embodiments provided in accordance with the presently disclosed subject matter include, but are not limited to, the following embodiments 450-480, which present exemplary pharmaceutical compositions comprising an opioid and a serotonin (5HT) releasing agent, any one of which is suitable for use in the methods disclosed herein:450. A pharmaceutical composition comprising (i) an opioid and (ii) a serotonin (5HT) releasing agent.451. The pharmaceutical composition of embodiment 450, wherein the 5HT releasing agent comprises a compound as described in any one of embodiments 300-332 described herein.452. The pharmaceutical composition of embodiment 450, wherein the 5HT releasing agent comprises a compound selected from Compounds C-CXXV of Table 3, analogs thereof, derivatives thereof, and any combination of the foregoing.453. The pharmaceutical composition of embodiment 450, wherein the 5HT releasing agent comprises a chemical structure according to Compound CI, wherein R1is -H, or -CH3, R2is -H, -CH3, or a -C2-5 alkyl group, R3is -H, or -CF3, and R4is -H, or -CF3.454. The pharmaceutical composition of embodiment 450, wherein the 5HT releasing agent comprises Compound CII (fenfluramine).455. The pharmaceutical composition of embodiment 450, wherein the 5HT releasing agent comprises Compound CIII (dexfenfluramine).456. The pharmaceutical composition of any one of embodiments 450 to 455 comprising about 1 mg to about 100 mg (e.g., about 5 mg to about 60 mg, or about 10 mg to about 40 mg) of the 5HT releasing agent.457. The pharmaceutical composition of any one of embodiments 450 to 456, wherein the opioid comprises a compound selected from the group consisting of Compounds I- XXVIII of Table 1, analogs thereof, derivatives thereof, and any combination of the foregoing.The pharmaceutical composition of any one of embodiments 450 to 457, wherein the opioid comprises a compound selected from Compound II (morphine), Compound I (codeine), Compound IV (hydrocodone), Compound V (hydromorphone), Compound VI (oxycodone), Compound XIII (fentanyl), and Compound XXVIII (tramadol). The pharmaceutical composition any one of embodiments 450 to 457, wherein the opioid comprises Compound VI.The pharmaceutical composition any one of embodiments 450 to 457, wherein the opioid comprises Compound II.The pharmaceutical composition any one of embodiments 450 to 457, wherein the opioid comprises Compound XIII.The pharmaceutical composition any one of embodiments 450 to 457, wherein the opioid comprises Compound IV.The pharmaceutical composition any one of embodiments 450 to 457, wherein the opioid comprises Compound V.The pharmaceutical composition of any one of embodiments 450 to 463, wherein the composition comprises an amount of the opioid effective for an opioid therapeutic effect in a subject in need thereof.The pharmaceutical composition of embodiment 464, wherein the opioid therapeutic effect includes reduction of pain, anesthetic effect, antitussive effect, anti -diarrheal effect, sedative effect, or any combination thereof.The pharmaceutical composition of embodiment 465, wherein the opioid therapeutic effect includes reduction of pain.The pharmaceutical composition of embodiment 466, wherein the opioid therapeutic effect further includes anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof.The pharmaceutical composition of any one of embodiments 450 to 467 comprising about 1 mg to about 500 mg of opioid (e.g., about 2 mg to about 300 mg of opioid, or about 5 mg to about 200 mg of opioid).The pharmaceutical composition of any one of embodiments 450 to 468 comprising a ratio of opioid to 5HT releasing agent of about 5 : 1 to about 1 : 5 (e.g., about 3 : 1 to about 1:3, about 2: 1 to about 1 :2, or about 1:1).The pharmaceutical composition of any one of embodiments 450 to 469, wherein the composition is formulated for oral, intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalational, or topical delivery.The pharmaceutical composition of any one of embodiments 450 to 470, wherein the composition is formulated for oral delivery.The pharmaceutical composition of embodiment 471, wherein the composition is in the form of a tablet or capsule.The pharmaceutical composition of any one of embodiments 450 to 470, wherein the composition is formulated for intravenous or intramuscular delivery.The pharmaceutical composition of embodiment 473, wherein the composition is in the form of a solution or suspension.The pharmaceutical composition of any one of embodiments 450 to 474 for use in preventing opioid abuse in a subject.The pharmaceutical composition of any one of embodiments 450 to 475 for use in reducing the rewarding effect (e.g., euphoria, intoxication, or the like) of an opioid administered to a subject.The pharmaceutical composition of any one of embodiments 450 to 476 for use in reducing the addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject.The pharmaceutical composition of any one of embodiments 450 to 477 for use in eliminating or substantially reducing the tendency for a subject to develop physical dependence, tolerance, and / or withdrawal symptoms with respect to the opioid.The pharmaceutical composition of any one of embodiments 450 to 478 for use in eliminating or substantially reducing the tendency for a subject to use opioids in ways not prescribed, take opioids more often or in larger amounts than prescribed, and / or use opioids recreationally.480. The pharmaceutical composition of any one of embodiments 475 to 479, wherein the subject is a human (e.g., a patient).

[0226] Exemplary embodiments provided in accordance with the presently disclosed subject matter include, but are not limited to, the following embodiments 500-632, which present exemplary methods for preventing opioid abuse, reducing the rewarding effect of an opioid, and / or reducing the addictive liability of an opioid:500. A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject.501. The method of embodiment 500, wherein the 5HT2 agonist comprises a 5HT2a agonist, 5HT2c agonist, or 5HT2a / 2c agonist.502. The method of embodiment 500, wherein the 5HT2 agonist comprises a selective 5HT2c agonist (e.g., the 5HT2 agonist preferentially binds to 5HT2c relative to 5HT2a).503. The method of embodiment 500, wherein the 5HT2 agonist comprises a compound as described in any one of Embodiments 1-155 or 200-215 disclosed herein.504. The method of embodiment 500, wherein the 5HT2 agonist comprises a compound selected from the group consisting of Compounds L-XCIX of Table 2, analogs thereof, derivatives thereof, and any combination of the foregoing.505. A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises a chemical structure according to Compound LI, wherein R1is -H or -CH3, R2is -H, -CH3, -CH2CH3, or -OH, and wherein R3is -F, -Cl, -CF3, a chlorine substituted phenyl group (e.g., ortho-clorophenyl group), -Br, or -I.506. A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotoninreceptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises Compound LII (lorcaserin). A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises a chemical structure according to Compound LIII, wherein R1is -H, -CH3, or a -C2-6 alkyl group, R2is -H, -F, -Cl, -CF3, or -C(O)NHCH2CHF2, and R3 is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises Compound LIV (vabicaserin). A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises a chemical structure according to Compound LV, wherein R1is -CH3, -CH2CH3, or -CH2CF3, and R2is -H, or -CH3, or wherein R1and R2together are -CH2CH2CH2-.A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises Compound LVI (bexicaserin). A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises a chemical structure accordingto Compound LVII, wherein R1is -CH2CH2F, -CH2CH2CH2F, -CH2CHCH2, or -CH2CH2C(F)CH2, and R2is -F or -Cl.A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject, wherein the serotonin receptor type 2 (5HT2) agonist has a chemical structure according to Compound LVIII, wherein R1is -H, or -CH3, R2is -H, -CH3, or a -C2-5 alkyl group, R3is -H or -CF3, and R4is -H or -CF3.A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises Compound LIX (norfenfluramine).A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises Compound LX (dexnorfenfluramine).The method of any one of embodiments 500 to 514, wherein the pain for which the subject is in need of treatment is perioperative pain, post-operative pain, acute pain, chronic pain, nociceptive pain, or neuropathic pain.The method of any one of embodiments 500 to 515, wherein the subj ect is not currently on opioid therapy.The method of any one of embodiments 500 to 516, wherein the subject is a human. The method of any one of embodiments 500 to 517, wherein the opioid comprises a compound selected from the group consisting of Compounds I-XXVIII of Table 1, analogs thereof, derivatives thereof, and any combination of the foregoing.The method of any one of embodiments 500 to 518, wherein the opioid comprises a compound selected from Compound I, Compound II, Compound IV, Compound V, Compound VI, Compound XIII, and Compound XXVIII.The method of any one of embodiments 500 to 518, wherein the opioid comprises Compound VI (oxycodone).The method of any one of embodiments 500 to 518, wherein the opioid comprises Compound II (morphine).The method of any one of embodiments 500 to 518, wherein the opioid comprises Compound XIII (fentanyl).The method of any one of embodiments 500 to 518, wherein the opioid comprises Compound IV (hydrocodone).The method of any one of embodiments 500 to 518, wherein the opioid comprises Compound V (hydromorphone).The method of any one of embodiments 500 to 524, wherein the amount of opioid administered to the subject is about 0.005 mg / kg to about 10 mg / kg body weight, optionally about 0.01 mg / kg to about 4 mg / kg or about 0.02 mg / kg to about 2 mg / kg body weight.The method of any one of embodiments 500 to 525, wherein the opioid therapeutic effect includes treatment of pain, anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof.The method of any one of embodiments 500 to 525, wherein the opioid therapeutic effect includes treatment of pain.The method of embodiment 527, wherein the opioid therapeutic effect further includes anesthetic effect, antitussive effect, anti -diarrheal effect, sedative effect, or any combination thereof.The method of any one of embodiments 500 to 528, wherein the amount of the 5HT2 agonist is about 0.01 mg / kg to about 5 mg / kg body weight, optionally about 0.02 mg / kg to about 4 mg / kg body weight, about 0.03 mg / kg to about 2 mg / kg body weight, or about 0.04 mg / kg to about 1 mg / kg body weight.The method of any one of embodiments 500 to 529, wherein the 5HT2 agonist reduces the addictive liability (e.g., the psychological addictiveness) of the opioid in the subject. The method of any one of embodiments 500 to 530, wherein the 5HT2 agonist reduces the rewarding effect (e.g., euphoria, intoxication, or the like) of the opioid in the subject. The method of any one of embodiments 500 to 531, wherein the 5HT2 agonist does not diminish the analgesic properties of the opioid in the subject.The method of any one of embodiments 500 to 532, wherein the method comprises coadministering the 5HT2 agonist and the opioid to the subject.The method of any one of embodiments 500 to 533, wherein the method comprises administering the 5HT2 agonist prior to the administration of the opioid.The method of any one of embodiments 500 to 534, wherein (i) the opioid and / or (ii) the 5HT2 agonist are administered orally, intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, by inhalation, or topical administration.The method of any one of embodiments 500 to 535, wherein (i) the opioid and / or (ii) the 5HT2 agonist are administered orally.The method of any one of embodiments 500 to 534, wherein (i) the opioid and (ii) the 5HT2 agonist are administered orally (e.g., in a combined formulation).A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin (5HT) releasing agent effective to prevent opioid abuse in the subject.The method of embodiment 538, wherein the 5HT releasing agent comprises a compound as described in any one of Embodiments 300-332 disclosed herein.The method of embodiment 538, wherein the 5HT releasing agent comprises a compound selected from the group consisting of Compounds C-CXXV of Table 3, analogs thereof, derivatives thereof, and any combination of the foregoing.A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effectivefor achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin (5HT) releasing agent effective to prevent opioid abuse in the subject, wherein the 5HT releasing agent comprises a chemical structure according to Compound CI, wherein R1is -H, or -CH3, R2is -H, -CH3, or a -C2-5 alkyl group, R3is -H, or -CF3, and R4is -H, or -CF3.A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin (5HT) releasing agent effective to prevent opioid abuse in the subject, wherein the 5HT releasing agent comprises Compound CII.A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising: administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin (5HT) releasing agent effective to prevent opioid abuse in the subject, wherein the 5HT releasing agent comprises Compound CIII.The method of any one of embodiments 538 to 543, wherein the pain for which the subject is in need of treatment is perioperative pain, post-operative pain, acute pain, chronic pain, nociceptive pain, or neuropathic pain.The method of any one of embodiments 538 to 544, wherein the subject is not currently on opioid therapy.The method of any one of embodiments 538 to 545, wherein the subject is a human. The method of any one of embodiments 538 to 546, wherein the opioid comprises a compound selected from the group consisting of Compounds I-XXVIII of Table 1, analogs thereof, derivatives thereof, and any combination of the foregoing.The method of any one of embodiments 538 to 547, wherein the opioid comprises a compound selected from Compound I, Compound II, Compound IV, Compound V, Compound VI, Compound XIII, and Compound XXVIII.The method of any one of embodiments 538 to 547, wherein the opioid comprises Compound VI (oxycodone).The method of any one of embodiments 538 to 547, wherein the opioid comprises Compound II (morphine).The method of any one of embodiments 538 to 547, wherein the opioid comprises Compound XIII (fentanyl).The method of any one of embodiments 538 to 547, wherein the opioid comprises Compound IV (hydrocodone).The method of any one of embodiments 538 to 547, wherein the opioid comprises Compound V (hydromorphone).The method of any one of embodiments 538 to 553, wherein the amount of opioid administered to the subject is about 0.005 mg / kg to about 10 mg / kg body weight, optionally about 0.01 mg / kg to about 4 mg / kg or about 0.02 mg / kg to about 2 mg / kg body weight.The method of any one of embodiments 538 to 554, wherein the opioid therapeutic effect includes treatment of pain, anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof.The method of any one of embodiments 538 to 554, wherein the opioid therapeutic effect includes treatment of pain.The method of embodiment 556, wherein the opioid therapeutic effect further includes anesthetic effect, antitussive effect, anti -diarrheal effect, sedative effect, or any combination thereof.The method of any one of embodiments 538 to 557, wherein the amount of the 5HT releasing agent is about 0.01 mg / kg to about 5 mg / kg body weight, optionally about 0.02 mg / kg to about 4 mg / kg body weight, about 0.03 mg / kg to about 2 mg / kg body weight, or about 0.04 mg / kg to about 1 mg / kg body weight.The method of any one of embodiments 538 to 558, wherein the 5HT releasing agent reduces the addictive liability (e.g., the psychological addictiveness) of the opioid in the subject.The method of any one of embodiments 538 to 559, wherein the 5HT releasing agent reduces the rewarding effect (e.g., euphoria, intoxication, or the like) of the opioid in the subject.The method of any one of embodiments 538 to 560, wherein the 5HT releasing agent does not diminish the analgesic properties of the opioid in the subject.The method of any one of embodiments 538 to 561, wherein the method comprises coadministering the 5HT releasing agent and the opioid to the subject.The method of any one of embodiments 538 to 562, wherein the method comprises administering the 5HT releasing agent prior to the administration of the opioid.The method of any one of embodiments 538 to 563, wherein (i) the opioid and / or (ii) the 5HT releasing agent are administered orally, intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, by inhalation, or topical administration.The method of any one of embodiments 538 to 564, wherein (i) the opioid and / or (ii) the 5HT releasing agent are administered orally.The method of any one of embodiments 538 to 563, wherein (i) the opioid and (ii) the 5HT releasing agent are administered orally (e.g., in a combined formulation).A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin receptor type 2 (5HT2) agonist in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject.A method for reducing the addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin receptor type 2 (5HT2) agonist in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject.The method of embodiment 567 or 568, wherein the 5HT2 agonist comprises a 5HT2a agonist, 5HT2c agonist, or 5HT2a / 2c agonist.The method of embodiment 567 or 568, wherein the 5HT2 agonist comprises a selective 5HT2c agonist (e.g., the 5HT2 agonist preferentially binds to 5HT2c relative to 5HT2a).The method of embodiment 567 or 568, wherein the 5HT2 agonist comprises a compound as described in any one of Embodiments 1-155 or 200-215 disclosed herein.IllThe method of embodiment 567 or 568, wherein the 5HT2 agonist comprises a compound selected from the group consisting of Compounds L-XCIX of Table 2, analogs thereof, derivatives thereof, and any combination of the foregoing.A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) and / or addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin receptor type 2 (5HT2) agonist in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises a chemical structure according to Compound LI, wherein R1is -H or -CH3, R2is -H, -CH3, -CH2CH3, or -OH, and wherein R3is -F, -Cl, -CF3, a chlorine substituted phenyl group (e.g., ortho-clorophenyl group), -Br, or -I.A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) and / or addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin receptor type 2 (5HT2) agonist in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises Compound LII (lorcaserin).A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) and / or addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin receptor type 2 (5HT2) agonist in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises a chemical structure according to Compound LIII, wherein R1is -H, -CH3, or a -C2-6 alkyl group, R2is -H, -F, -Cl, -CF3, or -C(O)NHCH2CHF2, and R3 is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) and / or addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin receptor type 2 (5HT2) agonist in combination with an opioid, wherein the opioid isadministered in an amount effective for achieving an opioid therapeutic effect in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises Compound LIV (vabicaserin).A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) and / or addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin receptor type 2 (5HT2) agonist in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises a chemical structure according to Compound LV, wherein R1is (S)-CH3, (R)-CH3, (S)-CH2CH3, (R)-CH2CH3, (S)-CH2CF3, or (R)-CH2CF3, and R2is -H, or -CH3., or wherein R1and R2together are -CH2CH2CH2-.A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) and / or addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin receptor type 2 (5HT2) agonist in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject, wherein the serotonin receptor type 2 (5HT2) agonist is Compound LVI (bexicaserin).A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) and / or addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin receptor type 2 (5HT2) agonist in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject, wherein the serotonin receptor type 2 (5HT2) agonist has a chemical structure according to Compound LVII, wherein R1is -CH2CH2F, -CH2CH2CH2F, -CH2CHCH2, or -CH2CH2C(F)CH2, and R2is -F, or -Cl.A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) and / or addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin receptor type 2 (5HT2) agonist in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in thesubject, wherein the serotonin receptor type 2 (5HT2) agonist comprises a chemical structure according to Compound LVIII, wherein R1is -H, or -CH3, R2is -H, -CH3, or a -C2-5 alkyl group, R3is -H, or -CF3, and R4is -H, or -CF3.A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) and / or addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin receptor type 2 (5HT2) agonist in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises Compound LIX (norfenfluramine).A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) and / or addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin receptor type 2 (5HT2) agonist in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject, wherein the serotonin receptor type 2 (5HT2) agonist comprises Compound LX (dexnorfenfluramine).The method of any one of embodiments 567 to 582, wherein the 5HT2 agonist reduces the rewarding effect of the opioid in the subject.The method of any one of embodiments 567 to 583, wherein the 5HT2 agonist reduces the addictive liability of the opioid in the subject.The method of any one of embodiments 567 to 584, wherein an amount of the 5HT2 agonist administered to the subject is about 0.01 mg / kg to about 5 mg / kg body weight, optionally about 0.02 mg / kg to about 4 mg / kg body weight, about 0.03 mg / kg to about 2 mg / kg body weight, or about 0.04 mg / kg to about 1 mg / kg body weight.The method of any one of embodiments 567 to 585, wherein the 5HT2 agonist does not diminish the analgesic properties of the opioid in the subject.The method of any one of embodiments 567 to 586, wherein the opioid comprises a compound selected from the group consisting of Compounds I-XXVIII of Table 1, analogs thereof, derivatives thereof, and any combination of the foregoing.The method of any one of embodiments 567 to 587, wherein the opioid comprises a compound selected from Compound I, Compound II, Compound IV, Compound V, Compound VI, Compound XIII, and Compound XXVIII.The method of any one of embodiments 567 to 587, wherein the opioid comprises Compound VI (oxycodone).The method of any one of embodiments 567 to 587, wherein the opioid comprises Compound II (morphine).The method of any one of embodiments 567 to 587, wherein the opioid comprises Compound XIII (fentanyl).The method of any one of embodiments 567 to 587, wherein the opioid comprises Compound IV (hydrocodone).The method of any one of embodiments 567 to 587, wherein the opioid comprises Compound V (hydromorphone).The method of any one of embodiments 567 to 593, wherein the amount of opioid administered to the subject is about 0.005 mg / kg to about 10 mg / kg body weight, optionally about 0.01 mg / kg to about 4 mg / kg or about 0.02 mg / kg to about 2 mg / kg body weight.The method of any one of embodiments 567 to 594, wherein the opioid therapeutic effect includes reduction of pain, anesthetic effect, antitussive effect, anti -diarrheal effect, sedative effect, or any combination thereof.The method of any one of embodiments 567 to 594, wherein the opioid therapeutic effect includes reduction of pain.The method of embodiment 596, wherein the opioid therapeutic effect further includes anesthetic effect, antitussive effect, anti -diarrheal effect, sedative effect, or any combination thereof.The method of any one of embodiments 595 to 597, wherein the pain being reduced is perioperative pain, post-operative pain, acute pain, chronic pain, nociceptive pain, or neuropathic pain.The method of any one of embodiments 567 to 598, wherein the method comprises coadministering the 5HT2 agonist and the opioid to the subject.The method of any one of embodiments 567 to 599, wherein the method comprises administering the 5HT2 agonist prior to the administration of the opioid.The method of any one of embodiments 567 to 600, wherein (i) the opioid and / or (ii) the 5HT2 agonist are administered orally, intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, by inhalation, or topical administration.The method of any one of embodiments 567 to 601, wherein (i) the opioid and / or (ii) the 5HT2 agonist are administered orally.The method of any one of embodiments 567 to 602, wherein (i) the opioid and (ii) the 5HT2 agonist are administered orally (e.g., in a combined formulation).A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin (5HT) releasing agent in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject.A method for reducing the addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin (5HT) releasing agent in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject.The method of embodiments 604 or 605, wherein the 5HT releasing agent comprises a compound as described in any one of Embodiments 300-332 disclosed herein.The method of embodiments 604 or 605, wherein the 5HT releasing agent comprises a compound selected from the group consisting of Compounds C-CXXV of Table 3, analogs thereof, derivatives thereof, or any combination of the foregoing.A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) and / or addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin (5HT) releasing agent in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject, wherein the5HT releasing agent comprises a chemical structure according to Compound CI, wherein R1is -H, or -CH3, R2is -H, -CH3, or a -C2-5 alkyl group, R3is -H, or -CF3, and R4is -H, or -CF3.A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) and / or addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin (5HT) releasing agent in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject, wherein the 5HT releasing agent comprises Compound CII (fenfluramine).A method for reducing the rewarding effect (e.g., euphoria, intoxication, or the like) and / or addictive liability (e.g., psychological addictiveness) of an opioid administered to a subject, the method comprising: administering to the subject a serotonin (5HT) releasing agent in combination with an opioid, wherein the opioid is administered in an amount effective for achieving an opioid therapeutic effect in the subject, wherein the 5HT releasing agent comprises Compound CIII (dexfenfluramine).The method of any one of embodiments 608 or 610, wherein the 5HT releasing agent reduces the rewarding effect of the opioid in the subject.The method of any one of embodiments 608 or 610, wherein the 5HT releasing agent reduces the addictive liability of the opioid in the subject.The method of any one of embodiments 604 to 612, wherein the amount of the 5HT releasing agent is about 0.01 mg / kg to about 5 mg / kg body weight, optionally about 0.02 mg / kg to about 5 mg / kg body weight, about 0.03 mg / kg to about 2 mg / kg body weight, or about 0.04 mg / kg to about 1 mg / kg body weight.The method of any one of embodiments 604 to 613, wherein the 5HT releasing agent does not diminish the analgesic properties of the opioid in the subject.The method of any one of embodiments 604 to 614, wherein the subject is not currently on opioid therapy.The method of any one of embodiments 604 to 615, wherein the subject is a human. The method of any one of embodiments 604 to 616, wherein the opioid comprises a compound selected from the group consisting of Compounds I-XXVIII of Table 1, analogs thereof, derivatives thereof, and any combination of the foregoing.The method of any one of embodiments 604 to 617, wherein the opioid comprises a compound selected from Compound I, Compound II, Compound IV, Compound V, Compound VI, Compound XIII, and Compound XXVIII.The method of any one of embodiments 604 to 617, wherein the opioid comprises Compound VI (oxycodone).The method of any one of embodiments 604 to 617, wherein the opioid comprises Compound II (morphine).The method of any one of embodiments 604 to 617, wherein the opioid comprises Compound XIII (fentanyl).The method of any one of embodiments 604 to 617, wherein the opioid comprises Compound IV (hydrocodone).The method of any one of embodiments 604 to 617, wherein the opioid comprises Compound V (hydromorphone).The method of any one of embodiments 604 to 623, wherein the amount of opioid administered to the subject is about 0.005 mg / kg to about 10 mg / kg body weight, optionally about 0.01 mg / kg to about 4 mg / kg or about 0.02 mg / kg to about 2 mg / kg body weight.The method of any one of embodiments 604 to 624, wherein the opioid therapeutic effect includes reduction of pain, anesthetic effect, antitussive effect, anti -diarrheal effect, sedative effect, or any combination thereof.The method of any one of embodiments 604 to 624, wherein the opioid therapeutic effect includes reduction of pain.The method of embodiment 626, wherein the opioid therapeutic effect further includes anesthetic effect, antitussive effect, anti -diarrheal effect, sedative effect, or any combination thereof.The method of any one of embodiments 604 to 627, wherein the method comprises coadministering the 5HT releasing agent and the opioid to the subject.The method of any one of embodiments 604 to 628, wherein the method comprises administering the 5HT releasing agent prior to the administration of the opioid.630. The method of any one of embodiments 604 to 629, wherein (i) the opioid and / or (ii) the 5HT releasing agent are administered orally, intravenously, intramuscularly, intradermally, intraperitoneally, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, by inhalation, or topical administration.631. The method of any one of embodiments 604 to 630, wherein (i) the opioid and / or (ii) the 5HT releasing agent are administered orally.632. The method of any one of embodiments 604 to 629, wherein (i) the opioid and (ii) the 5HT releasing agent are administered orally (e.g., in a combined formulation).IV. EXAMPLESExample 1: Materials and MethodsVon Frey Mechanical Sensitivity (analgesia) Assay

[0227] Mice were injected with lOul of complete Freund’s adjuvant (CFA) into the left hind paw. Mice were then injected with saline, morphine, morphine and psilocin, or morphine and WAY163909 IP and placed on a wire rack in an acrylic tube. Mice were allowed to habituate for 30 minutes. The plantar surface of the left hind paw was then stimulated using von Frey monofilament hairs. Responses were recorded and a von Frey mechanical threshold score was calculated using previously described methods. Chaplan, S. R., Bach, F. W., Pogrel, J. W., Chung, J. M. & Yaksh, T. L. Quantitative assessment of tactile allodynia in the rat paw. J. Neurosci. Methods 53, 55-63 (1994).Conditioned Place Preference (CPP)

[0228] The protocol used for CPP was adapted from previously described procedures. Cunningham, C. L., Gremel, C. M. & Groblewski, P. A. Drug-induced conditioned place preference and aversion in mice. Nat. Protoc. 1, 1662-1670 (2006). In brief, mice were habituated to handling 24 hours prior to the start of experiments. CPP was performed in custom built acrylic chambers, separated in half by a removable, clear, acrylic sheet to create two distinguishable chambers. These sides differed by floor texture, rough or smooth, and wall patterns, black circles or black stripes. All video capture and data processing was done using Biobserve or EthoVison software. On day 1, mice were tested for baseline preference by allowing them to freely explore both chambers for 20 minutes. Mice demonstrating a baseline preference greater than 75% for either chamber were excluded. For conditioning days, micewere given an intraperitoneal (IP) injection of saline and confined to one chamber of the box for 30 minutes in the morning. This was followed by an additional 30-minute conditioning session in the afternoon, following an IP injection of drug or drug combination. Drugs (morphine, psilocin, wayl63909, etc.) were always administered during the afternoon session each day to avoid prolonged drug effects in the afternoon session. Conditioning was repeated for 3 days, experimental days 2-4, before a final post-test assessment was performed on day 5. For the post-test, mice were allowed to freely explore both chambers for 20 minutes.

[0229] For the assessment of psilocybin CPP / CPA (conditioned place aversion), the above protocol was modified in the following ways. On conditioning days, psilocybin was administered IP and then the mice were returned to the home cage for 30 minutes, before being placed in the CPP box for 30 minutes. This was repeated for 4 conditioning days, before the final post-test on day 6.Drugs Used

[0230] All Drugs were administered as IP injections in saline at the following dosages: morphine 10 mg / kg, fentanyl 0.15 mg / kg, oxycodone 3 mg / kg, WAY163909 10 mg / kg, psilocin 2 mg / kg, fenfluramine 10 mg / kg, fenfluramine 5 mg / kg, and lorcaserin 7 mg / kg.Example 2: 5HT2c Agonists, 5HT2a / C Agonists, and 5HT Releasing Agents Block Morphine Conditioned Place Preference

[0231] We ran a conditioned place preference (CPP) assay to test whether a selective serotonin 2c agonist (5ht2c), WAY163909, could block the acquisition of morphine-induced place preference. Mice received either morphine 10 mg / kg alone (red) or co-administration of morphine 10 mg / kg and WAY163909 10 mg / kg (orange) during conditioning days. Mice that only received morphine showed strong place preference for the side of the chamber paired with morphine (positive control). As shown in FIGS. 1A and IB, this effect was completely abolished in the group that received both morphine and WAY163909 (test group). This experiment suggests that the co-administration of a selective 5HT2c agonist with an opioid can reduce / eliminate the rewarding and / or reinforcing effects of the opioid.

[0232] We also ran a conditioned place preference (CPP) assay to test whether a non-selective serotonin 2a / c agonist, psilocin, could block the acquisition of morphine-induced place preference. Mice received either morphine 10 mg / kg alone (red) or co-administration of morphine 10 mg / kg and psilocin 2 mg / kg (orange) during conditioning days. Mice that onlyreceived morphine showed strong place preference for the side of the chamber paired with morphine (positive control). As shown in FIGS. 2A and 2B, this effect was completely abolished in the group that received both morphine and psilocin (test group). This experiment suggests that the co-administration of a non-selective 5HT2a / c agonist (psychedelic) with an opioid can reduce / eliminate the rewarding and / or reinforcing effects of the opioid.

[0233] We further ran a conditioned place preference (CPP) assay to test whether a serotonin releasing agent, fenfluramine (fen), could block the acquisition of morphine-induced place preference. Mice received either morphine 10 mg / kg alone (red) or co-administration of morphine 10 mg / kg and fenfluramine 10 mg / kg (orange) during conditioning days. Mice that only received morphine showed strong place preference for the side of the chamber paired with morphine (positive control). As shown in FIG. 3, this effect was completely abolished in the group that received both morphine and fenfluramine (test group). This experiment suggests that the co-administration of a serotonin releasing agent with an opioid can reduce / eliminate the rewarding and / or reinforcing effects of the opioid.

[0234] We next conducted a conditioned place preference (CPP) assay to test whether a serotonin releasing agent, fenfluramine (fen), could block the acquisition of place preference typically induced by fentanyl, a fully synthetic opioid. Mice received either 0.15 mg / kg fentanyl (grey) or co-administration of fentanyl 0.15 mg / kg and fenfluramine 10 mg / kg (orange). Mice that only received fentanyl showed strong place preference for the side of the chamber paired with fentanyl (positive control). As shown in FIG. 4, this effect was completely abolished in the group that received both fentanyl and fenfluramine (test group). This experiment indicates that the co-administration of a serotonin releasing agent with a synthetic opioid can reduce / eliminate the rewarding and / or reinforcing effects of the opioid.

[0235] We next conducted a conditioned place preference (CPP) assay to test whether a selective 5HT2c agonist, lorcaserin, could block the acquisition of morphine induced place preference. During the same experiment, we also tested whether morphine CPP could be blocked by co-administration of 5 mg / kg fenfluramine (fen). Mice received either 10 mg / kg morphine (grey), co-administration of morphine 10 mg / kg and lorcaserin 7 mg / kg (red), or co-administration of morphine 10 mg / kg and fenfluramine 5 mg / kg (orange). Mice that received only morphine showed strong place preference for the side of the chamber paired with morphine (positive control). As shown in FIG. 5, this effect was completely abolished in the groups that received the combination of morphine and lorcaserin, and morphine andfenfluramine (test group). This experiment indicates that the co-administration of a 5HT2c agonist or a serotonin releasing agent with an opioid can reduce / eliminate the rewarding and / or reinforcing effects of the opioid.

[0236] Finally, we conducted a conditioned place preference (CPP) assay to test whether a serotonin releasing agent, fenfluramine (fen), could block the acquisition of place preference induced by oxycodone, a semi-synthetic opioid, at two different fenfluramine doses, 5 and 10 mg / kg. Mice received either 3 mg / kg oxycodone (grey) or co-administration of oxycodone 3 mg / kg and fenfluramine 10 mg / kg (red) or 5 mg / kg (orange). Mice that only received oxycodone showed strong place preference for the side of the chamber paired with oxycodone (positive control). As shown in FIG. 6, this effect was completely abolished in the groups that received both oxycodone and fenfluramine with both dosages (test group). This experiment indicates that the co-administration of a serotonin releasing agent with a semi-synthetic opioid can reduce / eliminate the rewarding and / or reinforcing effects of the opioid.Summary of CPP data

[0237] We have shown that selective 5HT2c agonists (WAY163909 and lorcaserin), non-selective 5HT2a / c agonists (psilocin), and broad serotonin releasing agents (fenfluramine) are all capable of eliminating the acquisition of conditioned place preference in mice. This behaviorally demonstrates that all of these drugs, regardless of specific mechanism, are capable of reducing the reward / reinforcing properties of an opiate, morphine, a semi -synthetic opioid, oxycodone, and a synthetic opioid, fentanyl.Example 3. 5HT2a / c Agonists Are Not Aversive and Do Not Affect Morphine Analgesia

[0238] FIG. 7 shows data from a control experiment. Mice were put through the conditioned place preference protocol, pairing psilocybin, a prodrug of psilocin, with one side of the chamber and saline with the other. The results show that mice show no preference or aversion to the side of the chamber paired with psilocybin, demonstrating that this drug is not producing conditioned place aversion (CPA).

[0239] FIG. 8 shows that neither WAY163909 (5ht2c selective agonist) nor psilocin (non-selective 5ht2 agonist) modify the analgesic properties of morphine, using the von Frey mechanical sensitivity assay.

[0240] Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Claims

1. WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising (i) an opioid and (ii) a serotonin (5HT) releasing agent, wherein the 5HT releasing agent comprises a chemical structure according to Compound CI4. 6.Compound CI7.wherein R1is -H, or -CH3, R2is -H, -CH3, or a -C2-5 alkyl group, R3is -H, or -CF3, and R4is -H, or -CF3.

2. The pharmaceutical composition of claim 1, wherein the 5HT releasing agent comprises fenfluramine (Compound CII of Table 3).

3. The pharmaceutical composition of claim 1, wherein the 5HT releasing agent comprises dexfenfluramine (Compound CIII of Table 3).

4. A pharmaceutical composition comprising (i) an opioid and (ii) a serotonin receptor type 2 (5HT2) agonist, wherein the 5HT2 agonist comprises a chemical structure according to Compound LI13. 15.Compound LI16.wherein R1is -H or -CH3, R2is -H, -CH3, -CH2CH3, or -OH, and wherein R3is -F, -Cl, -CF3, a chlorine substituted phenyl group (e.g., ortho-clorophenyl group), -Br, or -I.

5. The pharmaceutical composition of claim 4, wherein the 5HT2 agonist comprises lorcaserin (Compound LII of Table 2).

6. A pharmaceutical composition comprising (i) an opioid and (ii) a serotonin receptor type 2 (5HT2) agonist, wherein the 5HT2 agonist comprises a chemical structure according to Compound LIII19. 21.Compound LIII22.wherein R1is -H, -CFF, or a -C2-6 alkyl group, R2is -H, -F, -Cl, -CF3, or -C(O)NHCH2CHF2, and R3 is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

7. The pharmaceutical composition of claim 6, wherein the 5HT2 agonist comprises vabicaserin (Compound LIV of Table 2).

8. A pharmaceutical composition comprising (i) an opioid and (ii) a serotonin receptor type 2 (5HT2) agonist, wherein the 5HT2 agonist comprises a chemical structure according to Compound LV26. 28.Compound LV29.wherein R1is (S)-CH3, (R)-CH3, (S)-CH2CH3, (R)-CH2CH3, (S)-CH2CF3, or (R)-CH2CF3, and R2is -H, or -CH3., or wherein R1and R2together are -CH2CH2CH2-.

9. The pharmaceutical composition of claim 8, wherein the serotonin receptor type 2 (5HT2) agonist comprises bexicaserin (Compound LVI of Table 2).

10. A pharmaceutical composition comprising (i) an opioid and (ii) a serotonin receptor type 2 (5HT2) agonist, wherein the 5HT2 agonist comprises a chemical structure according to Compound LVII33. 35.Compound LVII36.wherein R1is -CH2CH2F, -CH2CH2CH2F, -CH2CHCH2, or -CH2CH2C(F)CH2, and R2is -F, or -Cl.

11. A pharmaceutical composition comprising (i) an opioid and (ii) a serotonin receptor type 2 (5HT2) agonist, wherein the 5HT2 agonist comprises a chemical structure according to Compound LVIII40. 42.Compound LVIII43.wherein R1is -H, or -CH3, R2is -H, -CH3, or a -C2-5 alkyl group, R3is -H, or -CF3, and R4is -H, or -CF3.

12. The pharmaceutical composition of claim 11, wherein the 5HT2 agonist comprises norfenfluramine (Compound LIX of Table 2).

13. The pharmaceutical composition of claim 11, wherein the 5HT2 agonist comprises dexnorfenfluramine (Compound LX of Table 2).

14. A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising:47.administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subject and (ii) an amount of a serotonin (5HT) releasing agent effective to prevent opioid abuse in the subject,48.wherein the 5HT releasing agent comprises a chemical structure according to Compound CI49. 51.Compound CI52.wherein R1is -H, or -CH3, R2is -H, -CH3, or a -C2-5 alkyl group, R3is -H, or -CF3, and R4is -H, or -CF3.

15. The method of claim 14, wherein the 5HT releasing agent comprises fenfluramine (Compound CII of Table 3).

16. The method of claim 14, wherein the 5HT releasing agent comprises dexfenfluramine (Compound CIII of Table 3).

17. A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising:56.administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subj ect and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject,57.wherein the 5HT2 agonist comprises a chemical structure according to Compound LI59. 61.Compound LI62.wherein R1is -H or -CH3, R2is -H, -CH3, -CH2CH3, or -OH, and wherein R3is -F, -Cl, -CF3, a chlorine substituted phenyl group, -Br, or -I.

18. The method of claim 17, wherein the 5HT2 agonist comprises lorcaserin (Compound LII in Table 2).

19. A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising:administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subj ect and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject,65.wherein the 5HT2 agonist comprises a chemical structure according to Compound LIII67. 69.wherein R1is -H, -CH3, or a -C2-6 alkyl group, R2is -H, -F, -Cl, -CF3, or -C(O)NHCH2CHF2, and R3 is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

20. The method of claim 19, wherein the 5HT2 agonist comprises vabicaserin (Compound LIV in Table 2).

21. A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising:72.administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subj ect and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject,73.wherein the 5HT2 agonist comprises a chemical structure according to Compound LV75. 77.Compound LV78.wherein R1is -CH3, -CFLCH3, or -CFLCF3, and R2is -H, or -CH3, or wherein R1and R2together are -CH2CH2CH2-.

22. The method of claim 21, wherein the 5HT2 agonist comprises bexicaserin (Compound LVI of Table 2).

23. A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising:80.administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subj ect and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject,81.wherein the 5HT2 agonist comprises a chemical structure according to Compound LVII83. 85.Compound LVII86.wherein R1is -CH2CH2F, -CH2CH2CH2F, -CH2CHCH2, or -CH2CH2C(F)CH2, and R2is -F or -Cl.

24. A method for preventing opioid abuse in a subject in need of treatment of pain, the method comprising:88.administering to the subject (i) an amount of an opioid effective for achieving an opioid therapeutic effect in the subj ect and (ii) an amount of a serotonin receptor type 2 (5HT2) agonist effective to prevent opioid abuse in the subject,89.wherein the 5HT2 agonist has a chemical structure according to Compound LVIII91. 93.Compound LVIII94.wherein R1is -H, or -CH3, R2is -H, -CH3, or a -C2-5 alkyl group, R3is -H or -CF3, and R4is -H or -CF3.

25. The method of claim 24, wherein the serotonin receptor type 2 (5HT2) agonist comprises norfenfluramine (Compound LIX of Table 2).

26. The method of claim 24, wherein the serotonin receptor type 2 (5HT2) agonist comprises dexnorfenfluramine (Compound LX of Table 2).

27. The pharmaceutical composition of any one of claims 1 to 3 comprising about 1 mg to about 100 mg of the 5HT releasing agent and / or about 1 mg to about 500 mg of opioid, optionally comprising a ratio of opioid to 5HT releasing agent of about 5:1 to about 1:5.

28. The pharmaceutical composition of any one of claims 4 to 13 comprising about 1 mg to about 100 mg of the 5HT2 agonist and / or about 1 mg to about 500 mg of opioid, optionally comprising a ratio of opioid to 5HT2 agonist of about 5:1 to about 1:5.

29. The pharmaceutical composition of any one of claims 1 to 13, wherein the composition is formulated for oral, intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, intranasal, epidural, sublingual, intracerebral, intravaginal, transdermal, rectal, inhalational, or topical delivery.

30. The pharmaceutical composition of any one of claims 1 to 13, wherein the composition is formulated for oral delivery.

31. The pharmaceutical composition of claim 30, wherein the composition is in the form of a tablet or capsule.

32. The pharmaceutical composition of any one of claims 1 to 13, wherein the composition is formulated for intravenous or intramuscular delivery.

33. The pharmaceutical composition of claim 32, wherein the composition is in the form of a solution or suspension.

34. The pharmaceutical composition of any one of claims 1 to 13 for use in: preventing opioid abuse in a subject; reducing the rewarding effect of an opioid administered to a subject; reducing the addictive liability of an opioid administered to a subject; eliminating or substantially reducing the tendency for a subject to develop physical dependence, tolerance, and / or withdrawal symptoms with respect to the opioid; and / or eliminating or substantially reducing the tendency for a subject to use opioids in ways not prescribed, take opioids more often or in larger amounts than prescribed, and / or use opioids recreationally.

35. The pharmaceutical composition of claim 34, wherein the subject is a human (e.g., a patient).

36. The method of any one of claims 14 to 26, wherein the pain for which the subject is in need of treatment is perioperative pain, post-operative pain, acute pain, chronic pain, nociceptive pain, or neuropathic pain.

37. The method of any one of claims 14 to 26, wherein the subject is not currently on opioid therapy.

38. The method of any one of claims 14 to 26, wherein the subject is a human.

39. The method of any one of claims 14 to 26, wherein the amount of opioid administered to the subject is about 0.005 mg / kg to about 10 mg / kg body weight, optionally about 0.01 mg / kg to about 4 mg / kg or about 0.02 mg / kg to about 2 mg / kg body weight.

40. The method of any one of claims 14 to 26, wherein the opioid therapeutic effect includes treatment of pain, anesthetic effect, antitussive effect, anti-diarrheal effect, sedative effect, or any combination thereof.

41. The method of any one of claims 14 to 26, wherein the opioid therapeutic effect includes treatment of pain.

42. The method of claim 39, wherein the opioid therapeutic effect further includes anesthetic effect, antitussive effect, anti -diarrheal effect, sedative effect, or any combination thereof.

43. The method of any one of claims 14 to 26, wherein the amount of 5HT releasing agent or 5HT2 agonist administered to the subject is about 0.01 mg / kg to about 5 mg / kg body weight.

44. The method of any one of claims 14 to 26, wherein the 5HT releasing agent or 5HT2 agonist reduces the addictive liability of the opioid in the subject and / or the rewarding effect of the opioid in the subject.

45. The method of any one of claims 14 to 26, wherein the 5HT releasing agent or 5HT2 agonist does not diminish the analgesic properties of the opioid in the subject.

46. The method of any one of claims 14 to 26, wherein the method comprises (i) co-administering the 5HT releasing agent and the opioid to the subject, or (ii) co-administering the 5HT2 agonist and the opioid to the subject.

47. The method of any one of claims 14 to 26, wherein the method comprises (i) administering the 5HT releasing agent prior to the administration of the opioid, or (ii) administering the 5HT2 agonist prior to the administration of the opioid.

48. The method of any one of claims 14 to 26, wherein (i) the opioid and the 5HT releasing agent are administered orally (e.g., in a combined formulation), or (ii) the opioid and the 5HT2 agonist are administered orally (e.g., in a combined formulation).

49. The pharmaceutical composition or method of any one of claim 1 to 26, wherein the opioid comprises oxycodone (Compound VI of Table 1).

50. The pharmaceutical composition or method of any one of claim 1 to 26, wherein the opioid comprises morphine (Compound II of Table 1).

51. The pharmaceutical composition or method of any one of claim 1 to 26, wherein the opioid comprises fentanyl (Compound XIII of Table 1).

52. The pharmaceutical composition or method of any one of claim 1 to 26, wherein the opioid comprises hydrocodone (Compound IV of Table 1).

53. The pharmaceutical composition or method of any one of claim 1 to 26, wherein the opioid comprises hydromorphone (Compound V of Table 1).

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