Methods of treating substance abuse

Abstract

The disclosure provides a method of treating a substance use disorder in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising R(−)-ketamine or a pharmaceutically acceptable salt thereof, wherein the composition is substantially free of S(+)-ketamine or a pharmaceutically acceptable salt thereof.

What is claimed is: 
     
         1 . A method of treating a substance use disorder in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising R(−)-ketamine or a pharmaceutically acceptable salt thereof, wherein the composition is substantially free of S(+)-ketamine or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the substance use disorder comprises abuse of alcohol, marijuana, synthetic cannabinoids, opioids, stimulants, barbiturates, benzodiazepines, dextromethorphan (DXM), a sleep medication, khat, synthetic cathinones, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), phencyclidine (PCP), lysergic acid diethylamide (LSD), psilocybin, an inhalant, Rohypnol, gamma-hydroxybutyric acid (GHB), N,N-Dimethyltryptamine (DMT), ayahuasca, mescaline, salvia, or nicotine. 
     
     
         3 . The method of  claim 1  or  2 , wherein the therapeutically effective amount of the composition comprising R(−)-ketamine does not cause anhedonia or negative affect in the subject. 
     
     
         4 . The method of  claim 1  or  3 , wherein the substance use disorder comprises abuse of opioids. 
     
     
         5 . The method of  claim 1  or  3 , wherein the substance use disorder comprises abuse of alcohol. 
     
     
         6 . The method of any one of claims  claim 2 - 4 , wherein the opioid comprises Heroin, Codeine, Fentanyl, Hydrocodone (Dihydrocodeinone), Hydromorphone, Meperidine, Methadone, Morphine, Oxycodone or Oxymorphone. 
     
     
         7 . The method of  claim 2  or  3 , wherein the stimulant comprises Amphetamine, Amphetamine sulfate, Methamphetamine, Dextroamphetamine, Levoamphetamine, Lisdexamfetamine, Atomoxetine, Methylphenidate, Dexmethylphenidate, Oxymetazoline, Pseudoephedrine, Phenylephrine or a combination thereof. 
     
     
         8 . The method of  claim 2  or  3 , wherein the benzodiazepine comprises Aprazolam, Chlorodiazepoxide, Diazepam, Lorazepam or Triazolam. 
     
     
         9 . The method of  claim 2  or  3 , wherein the barbiturate comprises Phenobarbital, Pentobarbital, Methohexital, Secobarbital, Butabarbital or Butalbital. 
     
     
         10 . The method of  claim 2  or  3 , wherein the sleep medication comprises Eszopiclone, Zaleplon or Zolpidem. 
     
     
         11 . The method of any one of  claims 1 - 10 , wherein administering the composition reduces a symptom of withdrawal or prevents a relapse of the substance use disorder in the subject. 
     
     
         12 . The method of any one of  claims 1 - 10 , wherein administering the composition reduces tolerance to a substance of the substance use disorder in the subject. 
     
     
         13 . The method of any one of  claims 1 - 10  or  12 , wherein administering the composition reduces dependence on a substance of the substance use disorder in the subject. 
     
     
         14 . The method of any one of  claims 1 - 10 , wherein administering the composition improves adherence to a treatment for the substance use disorder in the subject. 
     
     
         15 . The method of any one of  claims 1 - 10 , wherein administering the composition reduces a preference for a substance of the substance use disorder or decreases liking for a substance the substance use disorder in the subject. 
     
     
         16 . The method of any one of  claims 1 - 10 , wherein administering the composition increases abstinence from a substance of the substance use disorder in the subject. 
     
     
         17 . The method of any one of  claims 11 - 16 , wherein the method further comprises an additional pharmacotherapy for substance abuse. 
     
     
         18 . The method of  claim 17 , wherein the additional pharmacotherapy comprises a gradually reducing regimen, a substitution therapy or a medication assisted treatment. 
     
     
         19 . The method of  claim 17  or  18 , wherein the method further comprises a behavioral therapy. 
     
     
         20 . The method of  claim 19 , wherein the behavioral therapy comprises counseling, a contingency management system, a mindfulness based therapy, a cognitive-behavioral therapy, a digitally administered behavioral therapy or a virtual reality based behavioral therapy. 
     
     
         21 . The method of  claim 20 , wherein the counseling is in person or digitally administered. 
     
     
         22 . The method of any one of  claims 19 - 21 , wherein the method reduces the amount behavioral therapy required compared behavioral therapy without the administration of the composition. 
     
     
         23 . The method of  claim 18 , wherein the substance use disorder comprises abuse of an opioid, and wherein the substitution therapy comprises Methadone or Buprenorphine. 
     
     
         24 . The method of  claim 18 , wherein the substance use disorder comprises abuse of an opioid, and wherein the medication assisted treatment comprises Naltrexone. 
     
     
         25 . The method of  claim 18 , wherein the substance use disorder comprises alcohol abuse, and wherein the medication assisted treatment comprises Disulfiram, Acamprosate or Naltrexone. 
     
     
         26 . The method of any one of  claims 17 - 25 , wherein the composition is administered prior to the additional therapy. 
     
     
         27 . The method of any one of  claims 17 - 25 , wherein the composition is administered at the same time as the additional therapy. 
     
     
         28 . The method of any one of  claims 17 - 25 , wherein the composition is administered after the additional therapy. 
     
     
         29 . The method of any one of  claims 1 - 28 , wherein the composition is administered every day, every 2 days, every 3 days, every 4 days, every 7 days, every 10 days, every 14 days or every 30 days. 
     
     
         30 . The method of any one of  claims 1 - 29 , wherein composition further comprises a pharmaceutically acceptable carrier. 
     
     
         31 . The method of  claim 30 , wherein the composition comprises about 0.01 mg to about 500 mg of R(−)-ketamine or a pharmaceutically acceptable salt thereof. 
     
     
         32 . The method of  claim 30 , wherein the composition comprises about 0.1 mg to about 500 mg of R(−)-ketamine or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method of  claim 30 , wherein the composition comprises about 0.1 mg to about 100 mg of R(−)-ketamine or a pharmaceutically acceptable salt thereof. 
     
     
         34 . The method of any one of  claims 30 - 33 , wherein the pharmaceutically acceptable salt of R(−)-ketamine is R(−)-ketamine hydrochloride. 
     
     
         35 . The method of any one of  claims 30 - 34 , wherein the composition is formulated for intravenous, intramuscular, sublingual, subcutaneous, transnasal, oral, rectal or transdermal administration. 
     
     
         36 . A method of treating at least one substance use withdrawal symptom in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising R(−)-ketamine or a pharmaceutically acceptable salt thereof, wherein the composition is substantially free of S(+)-ketamine or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The method of  claim 36 , wherein the at least one substance use withdrawal symptom comprises a symptom of withdrawal from alcohol, marijuana, synthetic cannabinoids, opioids, stimulants, barbiturates, benzodiazepines, dextromethorphan (DXM), a sleep medication, khat, synthetic cathinones, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), phencyclidine (PCP), lysergic acid diethylamide (LSD), psilocybin, an inhalant, Rohypnol, gamma-hydroxybutyric acid (GHB), N,N-Dimethyltryptamine (DMT), ayahuasca, mescaline, salvia, or nicotine. 
     
     
         38 . The method of  claim 36  or  37 , wherein the therapeutically effective amount of the composition comprising R(−)-ketamine does not cause anhedonia or negative affect in the subject. 
     
     
         39 . The method of  claim 36  or  38 , wherein the at least one substance use withdrawal symptom comprises a symptom of withdrawal from opioids. 
     
     
         40 . The method of  claim 36  or  38 , wherein the at least one substance use withdrawal symptom comprises a symptom of withdrawal from alcohol. 
     
     
         41 . The method of  claim 37 , wherein the opioid comprises Heroin, Codeine, Fentanyl, Hydrocodone (Dihydrocodeinone), Hydromorphone, Meperidine, Methadone, Morphine, Oxycodone or Oxymorphone. 
     
     
         42 . The method of  claim 41 , wherein the stimulant comprises Amphetamine, Amphetamine sulfate, Methamphetamine, Dextroamphetamine, Levoamphetamine, Lisdexamfetamine, Atomoxetine, Methylphenidate, Dexmethylphenidate, Oxymetazoline, Pseudoephedrine, Phenylephrine or a combination thereof. 
     
     
         43 . The method of  claim 37 , wherein the benzodiazepine comprises Aprazolam, Chlorodiazepoxide, Diazepam, Lorazepam or Triazolam. 
     
     
         44 . The method of  claim 37 , wherein the barbiturate comprises Phenobarbital, Pentobarbital, Methohexital, Secobarbital, Butabarbital or Butalbital. 
     
     
         45 . The method of  claim 37 , wherein the sleep medication comprises Eszopiclone, Zaleplon or Zolpidem. 
     
     
         46 . The method of any one of  claims 36 - 45 , wherein the at least one substance use withdrawal symptom comprises a physical symptom of withdrawal, a psychological symptom of withdrawal or a combination thereof. 
     
     
         47 . The method of  claim 46 , wherein the physical symptom of withdrawal comprises tremors, insomnia, disturbed sleep, headache, sweating, nausea, vomiting, muscle pain, muscle stiffness, hypertension, irregular heart rate, elevated heart rate, heart palpitations, dizziness, shakiness, tremors, seizures, dehydration, shallow breathing, fatigue, loss of appetite, clammy skin, loss of color or a combination thereof. 
     
     
         48 . The method of  claim 46 , wherein the psychological symptom of withdrawal comprises anxiety, irritability, difficulty concentrating, difficulty thinking clearly, mood swings, nightmares, depression, tension, panic attacks, short term memory loss, restlessness, a feeling of helplessness, stress-sensitivity, a heightened responsivity to substance-related cues, aberrant reward processing, a substance craving or a combination thereof. 
     
     
         49 . The method of any one of  claims 36 - 48 , wherein the method further comprises an additional pharmacotherapy for withdrawal. 
     
     
         50 . The method of  claim 49 , wherein the additional pharmacotherapy comprises a gradually reducing regimen, a substitution therapy or a medication assisted treatment. 
     
     
         51 . The method of  claim 49  or  50 , wherein the method further comprises a behavioral therapy. 
     
     
         52 . The method of  claim 51 , wherein the behavioral therapy comprises counseling, a contingency management system, a mindfulness based therapy, a cognitive-behavioral therapy, a digitally administered behavioral therapy or a virtual reality based behavioral therapy. 
     
     
         53 . The method of  claim 52 , wherein the counseling is in person or digitally administered. 
     
     
         54 . The method of any one of  claims 51 - 53 , wherein the method reduces the amount behavioral therapy required compared behavioral therapy without the administration of the composition. 
     
     
         55 . The method of  claim 50 , wherein the withdrawal symptom comprises a symptom of withdrawal from an opioid, and wherein the substitution therapy comprises Methadone or Buprenorphine. 
     
     
         56 . The method of  claim 50 , wherein the withdrawal symptom comprises a symptom of withdrawal from an opioid, and wherein the medication assisted treatment comprises Naltrexone. 
     
     
         57 . The method of  claim 50 , wherein the withdrawal symptom comprises a symptom of withdrawal from alcohol, and wherein the medication assisted treatment comprises Disulfiram, Acamprosate or Naltrexone. 
     
     
         58 . The method of any one of  claims 36 - 57 , wherein the composition is administered prior to the onset of the at least one withdrawal symptom in the subject. 
     
     
         59 . The method of any one of  claims 36 - 57 , wherein the composition is administered at the same time as the onset of the at least one withdrawal symptom in the subject. 
     
     
         60 . The method of any one of  claims 36 - 57 , wherein the composition is administered after the onset of the at least one withdrawal symptom in the subject. 
     
     
         61 . The method of any one of  claims 36 - 60 , wherein the composition is administered every 24 hours, 2 days, every 3 days, every 4 days, every 7 days, every 10 days, every 14 days or every 30 days. 
     
     
         62 . The method of any one of  claims 36 - 61 , wherein composition further comprises a pharmaceutically acceptable carrier. 
     
     
         63 . The method of  claim 62 , wherein the composition comprises about 0.01 mg to about 500 mg of R(−)-ketamine or a pharmaceutically acceptable salt thereof. 
     
     
         64 . The method of  claim 62 , wherein the composition comprises about 0.1 mg to about 500 mg of R(−)-ketamine or a pharmaceutically acceptable salt thereof. 
     
     
         65 . The method of  claim 62 , wherein the composition comprises about 0.1 mg to about 100 mg of R(−)-ketamine or a pharmaceutically acceptable salt thereof. 
     
     
         66 . The method of any one of  claims 62 - 65 , wherein the pharmaceutically acceptable salt of R(−)-ketamine is R(−)-ketamine hydrochloride. 
     
     
         67 . The method of any one of  claims 62 - 66 , wherein the composition is formulated for intravenous, intramuscular, sublingual, subcutaneous, transnasal, oral, rectal or transdermal administration. 
     
     
         68 . The method of any one of  claims 36 - 67 , wherein the composition reduces or eliminates the at least one substance use withdrawal symptom in the subject. 
     
     
         69 . A method of treating a psychological symptom associated with a substance use disorder in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising R(−)-ketamine or a pharmaceutically acceptable salt thereof, wherein the composition is substantially free of S(+)-ketamine or a pharmaceutically acceptable salt thereof. 
     
     
         70 . The method of  claim 69 , wherein the psychological symptom comprises a psychological symptom of withdrawal from alcohol, marijuana, synthetic cannabinoids, opioids, stimulants, barbiturates, benzodiazepines, dextromethorphan (DXM), a sleep medication, khat, synthetic cathinones, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), phencyclidine (PCP), lysergic acid diethylamide (LSD), psilocybin, an inhalant, Rohypnol, gamma-hydroxybutyric acid (GHB), N,N-Dimethyltryptamine (DMT), ayahuasca, mescaline, salvia, or nicotine. 
     
     
         71 . The method of  claim 69  or  70 , wherein administering to the subject a therapeutically effective amount of the composition comprising R(−)-ketamine does not cause anhedonia or negative affect in the subject. 
     
     
         72 . The method of any one of  claims 69 - 71 , wherein the psychological symptom comprises a psychological symptom of a mood disorder that is comorbid with the substance use disorder. 
     
     
         73 . The method of  claim 71 , wherein the mood disorder comprises major depressive disorder, bipolar disorder, post traumatic stress disorder, obsessive compulsive disorder or dementia. 
     
     
         74 . The method of  claim 70 , wherein the opioid comprises Heroin, Codeine, Fentanyl, Hydrocodone (Dihydrocodeinone), Hydromorphone, Meperidine, Methadone, Morphine, Oxycodone or Oxymorphone. 
     
     
         75 . The method of  claim 70 , wherein the stimulant comprises Amphetamine, Amphetamine sulfate, Methamphetamine, Dextroamphetamine, Levoamphetamine, Lisdexamfetamine, Atomoxetine, Methylphenidate, Dexmethylphenidate, Oxymetazoline, Pseudoephedrine, Phenylephrine or a combination thereof. 
     
     
         76 . The method of  claim 70 , wherein the benzodiazepine comprises Aprazolam, Chlorodiazepoxide, Diazepam, Lorazepam or Triazolam. 
     
     
         77 . The method of  claim 70 , wherein the barbiturate comprises Phenobarbital, Pentobarbital, Methohexital, Secobarbital, Butabarbital or Butalbital. 
     
     
         78 . The method of  claim 70 , wherein the sleep medication comprises Eszopiclone, Zaleplon or Zolpidem. 
     
     
         79 . The method of any one of  claims 69 - 78 , wherein the psychological symptom comprises anxiety, irritability, difficulty concentrating, difficulty thinking clearly, mood swings, nightmares, depression, tension, panic attacks, short term memory loss, restlessness, a feeling of helplessness, stress-sensitivity, a heightened responsivity to substance-related cues, aberrant reward processing, a substance craving or a combination thereof. 
     
     
         80 . The method of any one of  claims 69 - 79 , wherein the method further comprises an additional pharmacotherapy. 
     
     
         81 . The method of  claim 80 , wherein the additional pharmacotherapy comprises a gradually reducing regimen, a substitution therapy or a medication assisted treatment. 
     
     
         82 . The method of  claim 80  or  81 , wherein the method further comprises a behavioral therapy. 
     
     
         83 . The method of  claim 82 , wherein the behavioral therapy comprises counseling, a contingency management system, a mindfulness based therapy, a cognitive-behavioral therapy, a digitally administered behavioral therapy or a virtual reality based behavioral therapy. 
     
     
         84 . The method of  claim 83 , wherein the counseling is in person or digitally administered. 
     
     
         85 . The method of any one of  claims 82 - 84 , wherein the method reduces the amount behavioral therapy required compared behavioral therapy without the administration of the composition. 
     
     
         86 . The method of any one of  claims 69 - 85 , wherein the composition is administered prior to the onset of the at least one psychological symptom in the subject. 
     
     
         87 . The method of any one of  claims 69 - 85 , wherein the composition is administered at the same time as the onset of the at least one psychological symptom in the subject. 
     
     
         88 . The method of any one of  claims 69 - 85 , wherein the composition is administered after the onset of the at least one psychological symptom in the subject. 
     
     
         89 . The method of any one of  claims 69 - 88 , wherein the composition is administered every 24 hours, 2 days, every 3 days, every 4 days, every 7 days, every 10 days, every 14 days or every 30 days. 
     
     
         90 . The method of any one of  claims 69 - 89 , wherein the composition further comprises a pharmaceutically acceptable carrier. 
     
     
         91 . The method of  claim 90 , wherein the composition comprises about 0.01 mg to about 500 mg of R(−)-ketamine or a pharmaceutically acceptable salt thereof. 
     
     
         92 . The method of  claim 90 , wherein the composition comprises about 0.1 mg to about 500 mg of R(−)-ketamine or a pharmaceutically acceptable salt thereof. 
     
     
         93 . The method of  claim 90 , wherein the composition comprises about 0.1 mg to about 100 mg of R(−)-ketamine or a pharmaceutically acceptable salt thereof. 
     
     
         94 . The method of any one of  claims 90 - 93 , wherein the pharmaceutically acceptable salt of R(−)-ketamine is R(−)-ketamine hydrochloride. 
     
     
         95 . The method of any one of  claims 90 - 93 , wherein the composition is formulated for intravenous, intramuscular, sublingual, subcutaneous, transnasal, oral, rectal or transdermal administration. 
     
     
         96 . The method of any one of  claims 69 - 95 , wherein the composition reduces or eliminates the at least one psychological symptom in the subject.