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WO2022150525A1 - Mdma dans le traitement d'un trouble de consommation d'alcool - Google Patents

Mdma dans le traitement d'un trouble de consommation d'alcool Download PDF

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Publication number
WO2022150525A1
WO2022150525A1 PCT/US2022/011511 US2022011511W WO2022150525A1 WO 2022150525 A1 WO2022150525 A1 WO 2022150525A1 US 2022011511 W US2022011511 W US 2022011511W WO 2022150525 A1 WO2022150525 A1 WO 2022150525A1
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Prior art keywords
mdma
subject
psychotherapy
alcohol
assisted
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WO2022150525A9 (fr
Inventor
Ben SESSA
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Awakn Life Sciences
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Awakn Life Sciences
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Priority to CA3204457A priority Critical patent/CA3204457A1/fr
Publication of WO2022150525A1 publication Critical patent/WO2022150525A1/fr
Publication of WO2022150525A9 publication Critical patent/WO2022150525A9/fr
Priority to US18/219,057 priority patent/US20240122895A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse

Definitions

  • compositions of MDMA and methods of their use in MDMA- assisted psychotherapy for the treatment of patients with alcohol use disorder including physically dependent alcohol use disorder (“dependent use” or “alcohol addiction”) and non- physically dependent alcohol use disorder (“harmful use”).
  • compositions of MDMA and their use in methods of MDMA-assisted psychotherapy to treat patients with alcohol use disorder. Such compositions and methods have various advantages over current treatments, as further discussed herein.
  • the method further comprises an alcohol detoxification course prior to the MDMA-assisted psychotherapy regimen.
  • the method further comprises a pre-detoxification motivational group therapy course prior to the alcohol detoxification course.
  • the method further comprises a group therapy preparation course prior to the MDMA-assisted psychotherapy regimen.
  • the reduced alcohol intake is maintained for at least 1 month after the subject has completed the MDMA-assisted psychotherapy regimen. In some embodiments of the invention, the reduced alcohol intake is maintained for at least 3 months after the subject has completed the MDMA-assisted psychotherapy regimen. In some embodiments of the invention, the reduced alcohol intake is maintained for at least 6 months after the subject has completed the MDMA-assisted psychotherapy regimen. In some embodiments of the invention, the reduced alcohol intake is maintained for at least 9 months after the subject has completed the MDMA-assisted psychotherapy regimen. In some embodiments of the invention, the reduced alcohol intake is maintained for at least 12 months after the subject has completed the MDMA-assisted psychotherapy regimen.
  • alcohol intake is reduced by at least 50%. In some embodiments of the invention, alcohol intake is reduced by at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In some embodiments of the invention, the subject remains completely abstinent from alcohol.
  • kits for preventing relapse into alcohol use in a subject diagnosed with AUD comprising facilitating an MDMA-assisted psychotherapy regimen, wherein the regimen comprises one or more MDMA-assisted psychotherapy sessions and one or more non-drug psychotherapy sessions.
  • the relapse into alcohol use is prevented for at least 1 month after the subject has completed the MDMA-assisted psychotherapy regimen. In some embodiments of the invention, the relapse into alcohol use is prevented for at least 3 months after the subject has completed the MDMA-assisted psychotherapy regimen. In some embodiments of the invention, the relapse into alcohol use is prevented for at least 6 months after the subject has completed the MDMA-assisted psychotherapy regimen. In some embodiments of the invention, the relapse into alcohol use is prevented for at least 9 months after the subject has completed the MDMA-assisted psychotherapy regimen. In some embodiments of the invention, the relapse into alcohol use is prevented for at least 12 months after the subject has completed the MDMA-assisted psychotherapy regimen.
  • the comorbid psychiatric disorder is any of post- traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, a depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, phobia disorders, binge disorders, body dysmorphic disorder, a mood disorder related to another health condition, disruptive behavior disorders, eating disorders, impulse control disorders, obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorders, attachment disorders, dissociative disorders, and substance- related disorders including substance use disorder (SUD).
  • PTSD post- traumatic stress disorder
  • adjustment disorder affective disorder
  • depression atypical depression
  • postpartum depression postpartum depression
  • catatonic depression catatonic depression
  • a depressive disorder due to a medical condition premenstrual dysphoric disorder
  • seasonal affective disorder dysthymia
  • anxiety, phobia disorders binge disorders
  • the comorbid psychiatric disorder is depression or anxiety. In some embodiments of the invention, the comorbid psychiatric disorder is depression, and the symptoms are treated as demonstrated by a reduction in a PHQ-9 depression score. In some embodiments of the invention, the comorbid psychiatric disorder is anxiety, and the symptoms are treated as demonstrated by a reduction in a GAD-7 anxiety score.
  • the comorbid psychiatric disorder is a behavioral addiction, including any of pathological gambling, kleptomania, pyromania, compulsive buying, compulsive sexual behaviour, Internet addiction, pornography, and binge eating disorder.
  • the subject has dependent use AUD.
  • the subject has harmful use AUD.
  • the subject has alcohol abuse, alcohol dependence, alcohol addiction, or alcoholism.
  • the subject has demonstrated motivation to reduce their alcohol intake.
  • the subject has successfully completed the alcohol detoxification course prior to the MDMA-assisted psychotherapy regimen.
  • the subject has successfully completed the pre-detoxification motivational group therapy course prior to the alcohol detoxification course.
  • the subject has successfully completed the group therapy preparation course prior to the MDMA-assisted psychotherapy regimen.
  • the subject is diagnosed with AUD as defined by a version of the Diagnostic and Statistical Manual of Mental Disorders (DSM), comprising scoring above the diagnostic threshold for AUD.
  • DSM Diagnostic and Statistical Manual of Mental Disorders
  • the severity of AUD is determined using one or more questionnaires.
  • the one or more questionnaire(s) comprise the Severity of Alcohol Questionnaire (SADQ) and/or the Short Inventory of Problems for Alcohol (SIP) questionnaire.
  • the one or more questionnaire(s) comprise the Severity of Alcohol Questionnaire (SADQ).
  • the severity of AUD is scored on the SADQ as mild (score of less than 16), moderate (score of 16-30), or severe (score of greater than or equal to 31). In some embodiments of the invention, the severity of AUD is mild (score of less than 16). In some embodiments of the invention, the severity of AUD is moderate (score of 16-30). In some embodiments, the severity of AUD is severe (score of greater than or equal to 31).
  • the method results in one or more of a reduction of alcohol use, a reduction of alcohol cravings, a promotion of alcohol abstinence, a prevention of relapse into alcohol use, or an improvement of at least one symptom of alcohol use disorder.
  • the method results in one or more of an increase in quality of life, an increase in psychosocial functioning, a decrease in use or frequency of a prescription medication, a decrease in use or frequency of a recreational drug, a decrease in obsessive compulsive thoughts, a decrease in suicidality, an increase in feelings of empathy, or an increase in self-compassion.
  • the method results in one or more of an increase in physical functioning, a decrease in role limitations due to physical health, an increase in emotional well-being, a decrease in role limitations due to emotional problems, an increase in energy, a decrease in fatigue, an increase in social functioning, a decrease in pain, or an increase in general health.
  • the increase and/or the decrease is demonstrated by a patient-reported measure on a Short Form (36) Health Survey.
  • the results are measured at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year from the end of detoxification, if detoxification is completed, from baseline, from the first psychotherapy session, or from the completion of the MDMA-assisted psychotherapy regimen.
  • the MDMA-assisted psychotherapy regimen comprises one or more non-drug psychotherapy sessions prior to and after administration of MDMA in conjunction with psychotherapy. In some embodiments of the invention, the MDMA-assisted psychotherapy regimen comprises more than one non-drug psychotherapy session prior to and after the one or more MDMA-assisted psychotherapy sessions. In some embodiments of the invention, the MDMA-assisted psychotherapy regimen comprises administering one or more doses of MDMA during the one or more MDMA-assisted psychotherapy sessions. In some embodiments of the invention, the MDMA-assisted psychotherapy regimen comprises repeated MDMA-assisted psychotherapy sessions.
  • the MDMA-assisted psychotherapy regimen comprises an initial MDMA-assisted psychotherapy session and a subsequent MDMA-assisted psychotherapy session.
  • the MDMA-assisted psychotherapy regimen comprises one, two, three, or four non-drug psychotherapy sessions prior to a first dose of MDMA in conjunction with psychotherapy.
  • the MDMA-assisted psychotherapy regimen comprises two non-drug psychotherapy sessions prior to a first MDMA-assisted psychotherapy session.
  • the MDMA-assisted psychotherapy regimen comprises one or more non-drug psychotherapy session(s) after the first MDMA-assisted psychotherapy session.
  • the MDMA-assisted psychotherapy regimen comprises one, two, three, four, five, or six non-drug psychotherapy sessions after the first MDMA- assisted psychotherapy session and prior to a subsequent MDMA-assisted psychotherapy session.
  • the MDMA-assisted psychotherapy regimen comprises three non-drug psychotherapy sessions after the first MDMA-assisted psychotherapy session and prior to the subsequent MDMA-assisted psychotherapy session.
  • the subsequent MDMA-assisted psychotherapy session is a second, a third, a fourth, or a fifth MDMA-assisted psychotherapy session.
  • the subsequent MDMA-assisted psychotherapy session is a second MDMA-assisted psychotherapy session.
  • the MDMA-assisted psychotherapy regimen comprises two MDMA-assisted psychotherapy sessions and eight non-drug psychotherapy sessions.
  • the MDMA-assisted psychotherapy regimens comprises three MDMA-assisted psychotherapy sessions and 11 psychotherapy non-drug sessions.
  • the one or more MDMA-assisted psychotherapy sessions comprise administering one single dose of MDMA.
  • the first and the subsequent MDMA-assisted psychotherapy sessions each comprise administering one single dose of MDMA.
  • the one or more MDMA-assisted psychotherapy sessions comprise administering two doses of MDMA, an initial dose and a booster dose.
  • the first and the subsequent MDMA-assisted psychotherapy sessions each comprise two doses of MDMA, an initial dose and a booster dose.
  • the booster dose is less than the initial dose. In some embodiments of the invention, the booster dose is about 10% to about 90% of the amount of the initial dose.
  • the booster dose is about 25%, about 50%, or about 75% of the amount of the initial dose. In some embodiments of the invention, the booster dose is about 10%, 15%, 20%, 25%, 30%, 35%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% of the amount of the initial dose. In some embodiments of the invention, the booster dose is administered about 30 minutes, one hour, two hours, three hours, or four hours after the initial dose. In some embodiments of the invention, the booster dose is administered two hours following the initial dose, or at such time as to extend peak subjective effects or to optimize the plasma concentration-time profile.
  • the MDMA-assisted psychotherapy regimen comprises between 5 and 20 psychotherapy sessions, inclusive, during which at least two of said psychotherapy sessions the subject is administered MDMA.
  • a total dose of about 40 mg to 200 mg of MDMA is administered, wherein the range is inclusive.
  • a total dose of about 40 mg to 100 mg, about 100 mg to 150 mg, about 150 to 200 mg, about 175 mg to 200 mg, about 180 mg to 190 mg, about 180 to 200 mg, or about 185 to 200 mg of MDMA is administered, wherein each range is inclusive.
  • a total dose of about 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, or 190 mg of MDMA is administered. In some embodiments of the invention, a total dose of about 187.5 mg of MDMA is administered.
  • MDMA is administered as a pharmaceutically acceptable salt, as a free base, or as a polymorph of MDMA.
  • MDMA is administered as a racemate.
  • MDMA is administered as an enantiomerically enriched mixture of A-MDMA and L'-MDMA having an enantiomeric excess in any amount greater than 0%.
  • MDMA is administered as a pure or substantially pure individual enantiomer of R- MDMA or A-MDMA having an enantiomeric excess greater than 90%.
  • the psychotherapy in MDMA-assisted and non drug sessions comprises motivational interviewing.
  • the psychotherapy in MDMA-assisted and non-drug sessions comprises cognitive behavioral therapy.
  • the psychotherapy in MDMA-assisted and non-drug sessions comprises motivational interviewing and cognitive behavioral therapy.
  • the cognitive behavioral therapy is a modified form of cognitive behavioral therapy comprising elements of Acceptance and Commitment Therapy (ACT).
  • the MDMA-assisted and drug-free psychotherapy sessions comprise one or more of supporting subjects to maintain and/or improve a reduction in alcohol consumption, preventing relapse into heavy drinking, and developing skills to lead a fulfilling life without problematic drinking.
  • a subj ect for MDMA-assisted psychotherapy comprising identifying a subject who meets one or more of the following criteria: has an AUD diagnosis, wherein the severity of AUD is mild, moderate, or severe; has completed detoxification of alcohol prior to administration of MDMA-assisted psychotherapy; and has tapered off of medications known to interact with or attenuate the effects of MDMA prior to administration of MDMA-assisted psychotherapy; wherein the subject does not experience adverse events associated with administration of MDMA.
  • methods of minimizing or eliminating the risk of adverse events related to MDMA-assisted psychotherapy in a subject having AUD comprising: selecting a subject who has been diagnosed with AUD, wherein the severity of AUD is mild, moderate, or severe; facilitating detoxification of alcohol prior to administration of MDMA-assisted psychotherapy; and tapering off medications known to interact with or attenuate the effects of MDMA prior to administration of MDMA-assisted psychotherapy; wherein the subject does not experience adverse events associated with administration of MDMA.
  • detoxification comprises gradually cutting down alcohol consumption over many weeks and/or is a medically assisted detoxification regime.
  • the method further comprises facilitating a pre detoxification motivational group therapy course prior to facilitating the detoxification of alcohol.
  • identifying a subject who meets one or more of the following criteria comprising identifying a subject who meets one or more of the following criteria: has an AUD diagnosis, wherein the severity of AUD is mild, moderate, or severe; has completed a group therapy preparation course prior to administration of MDMA-assisted psychotherapy; and has tapered off of medications known to interact with or attenuate the effects of MDMA prior to administration of MDMA-assisted psychotherapy; wherein the subject does not experience adverse events associated with administration of MDMA.
  • the methods comprise monitoring the subject having AUD for adverse events during administration of MDMA.
  • the adverse events during administration of MDMA comprise one or more of hyperthermia, hypertension, and elevated heart rate.
  • the subject diagnosed with AUD does not display adverse events during administration of MDMA.
  • the methods comprise monitoring the subject having AUD for adverse events after administration of MDMA.
  • the adverse events after administration of MDMA comprise mood disturbances and/or depressed affect.
  • the subject does not report a disturbance in mood or a depressed affect after administration of MDMA-assisted psychotherapy.
  • the subject does not report a disturbance in mood or a depressed affect within about one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, or ten days after administration.
  • the subject diagnosed with AUD does not display adverse events after administration of MDMA-assisted psychotherapy.
  • the methods comprise monitoring the subject having AUD for adverse events both during and after administration of MDMA.
  • the adverse events during administration of MDMA comprise one or more of hyperthermia, hypertension, and elevated heart rate
  • the adverse events after administration of MDMA comprise mood disturbances and/or depressed affect.
  • the subject diagnosed with AUD does not display or report adverse events during or after administration of MDMA-assisted psychotherapy.
  • the subject does not display adverse events during administration of MDMA, or report adverse events after administration of MDMA, including within about one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, or ten days after administration.
  • the methods comprise evaluating the severity of anxiety and/or depression in a subject diagnosed with AUD prior to MDMA-assisted psychotherapy.
  • the severity of anxiety and/or depression are assessed using questionnaires.
  • the severity of anxiety and/or depression are assessed using the Generalised Anxiety Disorder Assessment (GAD-7) and/or the Patient Health Questionnaire-9 (PHQ-9) questionnaire(s).
  • the severity of anxiety and/or depression are also assessed after MDMA-assisted psychotherapy, and are reduced after the MDMA-assisted psychotherapy in comparison to levels preceding said MDMA-assisted psychotherapy.
  • AUD is diagnosed as defined by a version of the Diagnostic and Statistical Manual of Mental Disorders (DSM), wherein diagnosis comprises scoring above the diagnostic threshold for AUD.
  • DSM Diagnostic and Statistical Manual of Mental Disorders
  • the subject has dependent use AUD.
  • the subject has harmful use AUD.
  • the subject has alcohol abuse, alcohol dependence, alcohol addiction, or alcoholism.
  • a method of treating an alcohol use disorder (AUD) subject comprising: confirming the subject has alcohol use disorder; conducting a screening visit; confirming the subject meets all inclusion criteria; confirming the subject does not meet any exclusion criteria; conducting a plurality of psychotherapy sessions as part of a treatment protocol, wherein at least three of the plurality of psychotherapy sessions include at least one dose of MDMA (MDMA-assisted psychotherapy sessions); and evaluation of results at predetermined intervals after the subject completes the treatment protocol.
  • AUD alcohol use disorder
  • the treatment protocol includes between 5 and 20 sessions or between 10 and 15 sessions. In some embodiments of the invention, the treatment protocol includes 14 sessions. In some embodiments of the invention, the treatment protocol includes 3 MDMA-assisted psychotherapy sessions, and 11 non-drug psychotherapy sessions. In some embodiments of the invention, the MDMA-assisted psychotherapy sessions comprise at least one MDMA administration. In some embodiments of the invention, the at least one MDMA administration comprises an initial dose and optionally a booster dose. In some embodiments of the invention, the initial dose is between about 100 mg to about 150 mg, and wherein the optional booster dose is half of the initial dose. In some embodiments of the invention, the optional booster dose is administered between about 90 minutes to about 120 minutes after the initial dose.
  • the third, seventh, and eleventh sessions are MDMA-assisted psychotherapy sessions.
  • the MDMA-assisted psychotherapy sessions last from between about 360 minutes to about 480 minutes.
  • the evaluation of results occurs at 3 months, 6 months, and 9 months after a subject successfully completes the treatment protocol.
  • the subject prior to conducting a plurality of psychotherapy sessions, the subject completes a group therapy preparation course.
  • the group therapy preparation course includes a plurality of sessions.
  • each of the plurality of sessions last for about 60 minutes.
  • each of the plurality of sessions includes a discussion surrounding a specific topic.
  • the plurality of sessions includes a first session, a second session, a third session, and a fourth session.
  • the specific topic of the first session is building confidence; the specific topic of the second session is resources, barriers, and goal setting; the specific topic of the third session is increasing rewarding activities and building support; the specific topic of the fourth session is building the foundations for recovery.
  • the subject prior to conducting a plurality of psychotherapy sessions, the subject completes a detoxification course.
  • AUD alcohol use disorder
  • determining the amount of alcohol consumed by the subject prior to completing the method conducting a treatment protocol comprising 14 psychotherapy sessions, wherein 3 of the 14 psychotherapy sessions are MDMA-assisted psychotherapy sessions, and each of the MDMA-assisted psychotherapy sessions includes an initial dose, and optionally a booster dose, wherein the initial dose is between about 100 mg to about 150 mg, and the optional booster dose is about half of the initial dose; measuring the amount of alcohol consumed of the subject three months, six months, and nine months after the final psychotherapy session; verifying that the amount of alcohol consumed by the subject nine months after the final psychotherapy session is less than the amount consumed by the subject as determined prior to completing the method.
  • AUD alcohol use disorder
  • the amount of alcohol consumed by the subject nine months after the final psychotherapy session is at least 50% less than the amount consumed by the subject as determined prior to completing the method. In some embodiments of the invention, the amount of alcohol consumed by the subject nine months after the final psychotherapy session is at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% less than the amount consumed by the subject as determined prior to completing the method.
  • AUD alcohol use disorder
  • the method comprising: completing an 11 week psychotherapy regimen comprising 14 psychotherapy sessions, wherein 3 of the 14 psychotherapy sessions are about 360 minute to about 480 minute long MDMA-assisted psychotherapy sessions comprising the administration of two doses of MDMA, the two doses including an initial dose and a booster dose, the initial dose comprising between about 100 mg to about 150 mg of MDMA, and the booster dose, administered between about 90 minutes to about 120 minutes after the initial dose, comprising about half of the initial dose, and wherein 11 of the 14 psychotherapy sessions are non-drug psychotherapy sessions lasting about 60 minutes.
  • 3 of the 14 psychotherapy sessions are about 360 minute to about 480 minute long MDMA-assisted psychotherapy sessions comprising the administration of two doses of MDMA, the two doses including an initial dose and a booster dose, the initial dose comprising between about 100 mg to about 150 mg of MDMA, and the booster dose, administered between about 90 minutes to about 120 minutes after the initial dose, comprising about half of the initial dose, and wherein 11 of the
  • the MDMA-assisted psychotherapy sessions occur once every 3 weeks for 9 weeks of the psychotherapy regimen, and the non-drug psychotherapy sessions occur once every week for all 11 weeks of the psychotherapy regimen, so that a non-dosing psychotherapy session follows an MDMA dosing session on weeks where the MDMA dosing session occurs.
  • AUD alcohol use disorder
  • a psychotherapy treatment protocol comprising the steps of: conducting a screening visit, wherein the screening visit confirms the subject meets all inclusion criteria and does not meet any exclusion criteria; completion of a plurality of psychotherapy sessions as part of a treatment protocol conducted under the supervision of a dyadic therapy team, the plurality of psychotherapy sessions including: a first session, wherein the dyadic therapy pair introduces the therapy program to the subject, prepares the subject for the treatment protocol, and discusses the subject’s personal story; a second session, wherein the dyadic therapy team teaches and practices a relaxation technique with the subject and reviews the subject’s current recovery plan; a third session, wherein the subject is administered at least one dose of MDMA, wherein the at least one dose of MDMA is between about 100 mg to about 150 mg; a fourth session, wherein the dyadic therapist team guides the subject through a mindfulness routine, and the subject optionally provides
  • MDMA for use in a method of treating alcohol use disorder (AUD) in a subject diagnosed therewith, comprising a psychotherapy treatment protocol comprising the steps of: conducting a screening visit, wherein the screening visit confirms the subject meets all inclusion criteria and does not meet at least one exclusion criteria; completion of a plurality of psychotherapy sessions as part of a treatment protocol conducted under the supervision of a dyadic therapy team, the plurality of psychotherapy sessions including: a first session, wherein the dyadic therapy pair introduces the therapy program to the subject, prepares the subject for the treatment protocol, and discusses the subject’s personal story; a second session, wherein the dyadic therapy team teaches and practices a relaxation technique with the subject and reviews the subject’s current recovery plan; a third session, wherein the subject is administered at least one dose of MDMA, wherein the at least one dose of MDMA is between about 100 mg to about 150 mg; a fourth session, wherein the dyadic therapist team guides the subject through
  • methods of reducing the units of alcohol consumed per week in a subject diagnosed with alcohol use disorder (AUD) by between about 70% to about 100% after completing the method comprising: determining the amount of alcohol consumed by the subject in units per week prior to completing the method; conducting a treatment protocol comprising 14 psychotherapy sessions, wherein 3 of the 14 psychotherapy sessions are MDMA-assisted psychotherapy sessions, and each of the MDMA-assisted psychotherapy sessions includes an initial dose, and optionally a booster dose, wherein the initial dose is between about 100 mg to about 150 mg, and the optional booster dose is about half of the initial dose; measuring the amount of alcohol consumed of the subject in units per week three months, six months, and nine months after completing the 14 psychotherapy sessions; verifying that the amount of alcohol consumed by the subject nine months after completing the 14 psychotherapy sessions is between about 70% to about 100% less than the amount consumed by the subject as determined prior to completing the method.
  • AUD alcohol use disorder
  • the subject has a genetic variation associated with a substance use disorder, such as alcohol use disorder, and including a genetic variation in mGluR5 or or FKBP5.
  • the subject is administered one or more therapeutic agents in addition to MDMA.
  • the subject is also administered a therapeutically effective amount of an additional active agent selected from the group consisting of: an opioid antagonist (e.g., nalmefene, naltrexone), a CB1 antagonist (e.g., rimonabant), a CRH1 receptor antagonist (e.g., verucerfont, pexacerfont), a NK1R antagonist (e.g., tradipitant), an OTR agonist (e.g., oxytocin), a GABA agent (e.g., topiramate, baclofen, a benzodiazepine, such as alprazolam, diazepam or lorazepam), a voltage-gated sodium channel inhibitor (e.g., oxacarbazepine, valproic acid, zonisamide), a voltage-dependent opioid antagonist (e.g., nalmefene,
  • compositions of MDMA for use in the method of the invention, wherein said composition comprises a substantially pure MDMA compound having a chromatographic purity of greater than 95% as measured by HPLC.
  • the substantially pure MDMA is substantially free of impurities or adulterants.
  • compositions of MDMA for use in the method of the invention which is a pure or substantially pure individual enantiomer of A-MDMA or S- MDMA having an enantiomeric excess greater than 90%, or an enantiomerically enriched mixture having an enantiomeric excess in any amount greater than 0%.
  • compositions of MDMA for use in the method of the invention, wherein said MDMA is in unit dosage form.
  • the unit dosage form is an immediate release, controlled release, sustained release, extended release, or modified release formulation.
  • MDMA for use in a method of reducing the units of alcohol consumed per week in a subject diagnosed with alcohol use disorder (AUD) by between about 70% to about 100% after completing the method, the method comprising: determining the amount of alcohol consumed by the subject in units per week prior to completing the method; completion by the subject of a preparation group course; conducting a treatment protocol comprising 14 psychotherapy sessions, wherein 3 of the 14 psychotherapy sessions are MDMA-assisted psychotherapy sessions, and each of the MDMA-assisted psychotherapy sessions includes an initial dose, and optionally a booster dose, wherein the initial dose is between about 100 mg to about 150 mg, and the optional booster dose is about half of the initial dose; measuring the amount of alcohol consumed of the subject in units per week three months, six months, and nine months after completing the 14 psychotherapy sessions; verifying that the amount of alcohol consumed by the subject nine months after completing the 14 psychotherapy sessions is between about 70% to about 100% less than the amount consumed by the subject as determined prior to completing the method.
  • AUD alcohol use disorder
  • MDMA for use in a method of decreasing the daily alcohol consumption in a subject diagnosed with alcohol use disorder, the method comprising: completing an 11 week psychotherapy regimen comprising 14 psychotherapy sessions, wherein 3 of the 14 psychotherapy sessions are about 360 minute to about 480 minute long MDMA-assisted psychotherapy sessions comprising the administration of two doses of MDMA, the two doses including an initial dose and a booster dose, the initial dose comprising between about 100 mg to about 150 mg of MDMA, and the booster dose, administered between about 90 minutes to about 120 minutes after the initial dose, comprising about half of the initial dose, and wherein 11 of the 14 psychotherapy sessions are non-drug psychotherapy sessions lasting about 60 minutes.
  • AUD alcohol use disorder
  • the AUD subject has dependent use AUD, harmful use AUD, alcohol abuse, alcohol dependence, alcohol addiction, or alcoholism.
  • Disclosed herein are uses of MDMA in conjunction with psychotherapy to treat an alcohol use disorder (AUD) subject, according to the methods of the invention.
  • uses of MDMA for the manufacture of a medicament for a treatment to reduce alcohol use by an AUD subject, according to the methods of the invention.
  • uses of MDMA for the manufacture of a medicament for a treatment to prevent relapse into alcohol use by an AUD subject, according to the methods of the invention.
  • uses of MDMA for the manufacture of a medicament for a treatment to promote alcohol abstinence by an AUD subject according to the methods of the invention.
  • MDMA for the manufacture of a medicament for the treatment of the symptoms of depression or anxiety associated with AUD, according to the methods of the invention.
  • the psychiatric disorder comorbid with AUD is any of post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, a depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, phobia disorders, binge disorders, body dysmorphic disorder, a mood disorder related to another health condition, disruptive behavior disorders, eating disorders, impulse control disorders, obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorders, attachment disorders, dissociative disorders, or substance-related disorders including substance use disorder (SUD).
  • PTSD post-traumatic stress disorder
  • adjustment disorder affective disorder
  • depression depression
  • atypical depression depression
  • postpartum depression postpartum depression
  • catatonic depression catatonic depression
  • a depressive disorder due to a medical condition premenstrual dysphoric disorder
  • seasonal affective disorder dysthymia
  • anxiety, phobia disorders bin
  • the psychiatric disorder comorbid with AUD is a behavioral addiction, including any of pathological gambling, kleptomania, pyromania, compulsive buying, compulsive sexual behaviour, Internet addiction, pornography, and binge eating disorder.
  • the use of MDMA comprises monitoring adverse events during MDMA-assisted psychotherapy.
  • the adverse events comprise one or more of hyperthermia, hypertension, and elevated heart rate.
  • adverse events are not observed during MDMA- assisted psychotherapy.
  • the use of MDMA comprises monitoring for adverse events after administration of MDMA-assisted psychotherapy.
  • the adverse events after MDMA-assisted psychotherapy comprise mood disturbances and/or depressed affect.
  • a mood disturbance and/or depressed affect after administration of MDMA-assisted psychotherapy are not observed and/or reported.
  • mood disturbances and/or depressed affect are not observed and/or reported within about one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, or ten days after MDMA- assisted psychotherapy.
  • adverse events after administration of MDMA-assisted psychotherapy are not observed or reported.
  • the use of MDMA comprises monitoring for adverse events both during and after administration of MDMA.
  • the adverse events during administration of MDMA comprise one or more of hyperthermia, hypertension, and elevated heart rate
  • the adverse events after administration of MDMA comprise mood disturbances and/or depressed affect.
  • no adverse events are observed or reported during or after administration of MDMA- assisted psychotherapy.
  • no adverse events are observed or reported during administration of MDMA, or reported after administration of MDMA, including within about one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, or ten days after administration.
  • the subject has a genetic variation associated with a substance use disorder, such as alcohol use disorder, and including a genetic variation in mGluR5 or or FKBP5.
  • the subject is administered one or more therapeutic agents in addition to MDMA.
  • the subject is also administered a therapeutically effective amount of an additional active agent selected from the group consisting of: an opioid antagonist (e.g., nalmefene, naltrexone), a CB1 antagonist (e.g., rimonabant), a CRH1 receptor antagonist (e.g., verucerfont, pexacerfont), a NK1R antagonist (e.g., tradipitant), an OTR agonist (e.g., oxytocin), a GABA agent (e.g., topiramate, baclofen, a benzodiazepine, such as alprazolam, diazepam or lorazepam), a voltage-gated sodium channel inhibitor (e.g., oxacarbazepine, valproic acid, zonisamide), a voltage-dependent opioid antagonist (e.g., nalmefene,
  • FIG. 2 illustrates drinking behavior outcomes for the Outcomes patients undergoing a community alcohol detoxification (as measured by TLFB) up to nine months (reproduced from Sessa et al. 2020). Specifically, the average weekly alcohol consumption for all 12 patients up to 9 months post-detox as shown in FIG. 1 is illustrated.
  • FIG. 3 illustrates the results of the PHQ-9 assessment of outcome measures (see TABLE 2 and discussion below), in table and graph form, demonstrating high levels of depression among the population of Outcomes patients, levels of depression that remained significantly high throughout the 9 months of the study (reproduced from Sessa et al. 2020).
  • FIG. 4 illustrates the results of the PHQ-9 assessment of outcome measures (see TABLE 2 and discussion below), in table and graph form, demonstrating high levels of anxiety among the population of Outcomes patients, levels of anxiety that remained significantly high throughout the 9 months of the study (reproduced from Sessa et al. 2020).
  • FIG. 5 illustrates the results of the SF-36 outcome measure (see TABLE 2 and discussion below), in table and graph form, suggesting that for those who provided results to 9 months, despite the majority of patients relapsing to high levels of drinking by 3 months (and continuing high rates of drinking, even if they had second or third detoxes) their overall level of psychosocial functioning appears to have improved over the course of 9 months (although an incomplete dataset at 9 months is noted) (reproduced from Sessa et al. 2020).
  • FIG. 6 illustrates the results of the Severity of Alcohol Dependence Questionnaire (SAD-Q) measure of alcohol dependency, from the patients who received MDMA-assisted psychotherapy as in Example 8. A score of 31 or higher indicates severe alcohol dependence, a score of 16-30 indicates moderate dependence (light grey area), anything lower than 16 indicates mild dependence (dark grey area). Also illustrated are the results of the Short Inventory of Problems for Alcohol (SIP), a 15 question measure of self-noted consequences of drinking. Both observed at screening. Four SAD-Q questions were unanswered, in which case, mean substitution was applied using the average row value for the relevant time period and participant. B05, B16, B20 and B21 had one question missing each.
  • SAD-Q Severity of Alcohol Dependence Questionnaire
  • FIG. 7 illustrates pooled data of Blood Pressure, Temperature, Heart Rate, Observed Drug Effects, and Subjective Units of Distress (SUDS) observed over the duration of the MDMA sessions in patients who underwent MDMA-assisted psychotherapy in the study of Example 8.
  • SUDS and Drug Effects observed over 8 hours, physiological data observed over 6 hours following dosing. Mean data for each session is used, except in the case of missing data, where available session data is applied. Error bars (where applied) indicate +/- SEM.
  • FIG. 8 illustrates the results of the Timeline Follow Back (TLFB), which assesses drinking behavior prior to, and following the study of Example 8. Data is collected daily by self-reporting and reviewed at one month prior to detox, immediately following detox and at 1, 3, 6 and 9 months follow-up. A full dataset was not available for three of the participants. One participant dropped out of the study at three months and two patients failed to provide data at the nine month follow-up. Two participants had a second detox since starting the study. For these participants, TLFB drinking behavior data was carried forward from the point of drinking levels pre- second detox.
  • FIG. 9 illustrates the results of the Profile of Mood States (POMS), individual composite scores of mood disturbance observed daily over a week following dosing, obtained from the patients in the study of Example 8. Mean data shown for both MDMA sessions. In the case of absent data for either session the available data for the remaining session is used.
  • POMS Profile of Mood States
  • FIG. 10 illustrates the results of General Anxiety Disorder 7 (GAD-7) and Patient Health Questionnaire 9 (PHQ-9) obtained from the patients in the study of Example 8. These are self-report scales for anxiety and depression, respectively (as shown for Outcomes patients in FIGS. 3 and 4). Recording was at screening, baseline, week 10, then 3, 6 and 9 months follow-up. Greater scores report indication of heightened anxiety/depression. Error bars indicate +/- SEM.
  • FIG. 11 illustrates TLFB showing the percentage of patients consuming more than the 14 recommended daily units of alcohol, and comparing the results of the patients in the study of Example 8 with the results of the Outcomes patients reported in Sessa et al. 2020.
  • FIG. 12 illustrates an embodiment of the invention comprising a therapy protocol useful in the treatment of non-physically dependent (harmful use) AUD.
  • FIG. 13 illustrates an embodiment of the invention comprising a therapy protocol useful in the treatment of physically dependent (dependent use) AUD.
  • FIG. 14 illustrates an exemplary detoxification course, according to some embodiments of the invention.
  • FIG. 15 illustrates an overview of an exemplary treatment protocol useful in treating a patient diagnosed with AUD, according to some embodiments of the invention.
  • FIG. 16 illustrates an exemplary treatment protocol useful in treating a patient diagnosed with AUD, according to some embodiments of the invention.
  • FIG. 17 illustrates the study procedure for the 13 -week study course, including assessments completed, according to some embodiments of the invention.
  • Alcohol use disorder (AUD) (DSM-5, APA 2013), which includes what are sometimes referred to as alcohol abuse, alcohol dependence, alcohol addiction, and colloquially “alcoholism,” is a psychiatric disorder in which individuals present with a cluster of symptoms of varying severity, that cause psychological and physical harms and social dysfunction due to the use of alcohol.
  • drinking alcohol is a widely socially acceptable behavior and many people consume alcohol without experiencing any problems, a growing number of people drink in a harmful manner. Approximately 24% of the adult population of England consume alcohol in a way that is potentially or actually harmful, i.e., “harmful use” (McManus et al 2009).
  • Alcohol dependence or “dependent use” is a less common, more severe form of AUD.
  • the prevalence of physical alcohol dependence is about 4%, with 6% of men and 2% of women meeting criteria for this psychiatric disorder.
  • alcohol dependence is characterized by: often serious withdrawal symptoms on cessation of alcohol, or drinking to avoid withdrawal symptoms, tolerance and the persistent desire to drink, and continuing drinking despite negative consequences (NICE Guidelines on Alcohol Use Disorders, 2011).
  • Harmful use of alcohol by contrast, is defined in the World Health Organization (WHO)’s International Classification of Diseases, 10th Revision (The ICD-10 Classification of Mental and Behavioural Disorders) as: “[A] pattern of psychoactive substance use that is causing damage to health. The damage may be physical (e.g., hepatitis) or mental (e.g., depressive episodes secondary to heavy alcohol intake). Harmful use commonly, but not invariably, has adverse social consequences; social consequences in themselves, however, are not sufficient to justify a diagnosis of harmful use” (ICD-10; WHO, 1992).
  • WHO World Health Organization
  • Licensed pharmacological options for treating AUD include acamprosate, disulfiram, naltrexone, and nalmefene.
  • the U.S. Food and Drug Administration (FDA) has approved only disulfiram, naltrexone, and acamprosate for the treatment of AUD, and the European Medicines Agency (EMA) has approved, in addition, nalmefene.
  • FDA Food and Drug Administration
  • EMA European Medicines Agency
  • Acamprosate a glutamate antagonist, reduces NMDA activity associated with alcohol withdrawal and reduces relapse rates (Rosner et al. 2010).
  • Disulfiram is used as an agent to deter relapse by preventing the elimination of acetaldehyde, which results in an unpleasant physical reaction if alcohol is used together (Krampe et al. 2006).
  • Naltrexone is a competitive opioid antagonist which decreases cravings from alcohol (Soyka and Rosner 2008).
  • Nalmefene is an opioid antagonist, similar to naltrexone but with a longer half-life and lower risk of toxicity than naltrexone. This can be given to patients while still drinking in order to reduce cravings (Paille and Martini 2014).
  • Benzodiazepines are commonly prescribed as a time-limited course as part of alcohol detoxification program (Lingford-Hughes et al. 2012).
  • opioid antagonists e.g., nalmefene
  • CBi antagonists e.g., rimonabant
  • CRHi receptor antagonists e.g., verucerfont, pexacerfont
  • NKIR antagonists e.g., tradipitant
  • OTR agonists e.g., oxytocin
  • GABA agents e.g., topiramate, baclofen, benzodiazepines
  • voltage gated sodium channel inhibitors e.g., oxacarbazepine, valproic acid, zonisamide
  • voltage- dependent calcium channel agonists e.g., gabapentin, pregabalin
  • on nicotinic acetylcholine receptor agonists e.g., gabapentin, pregabalin
  • MDMA 3,4-Methylenedioxymethamphetamine
  • MDMA has been included in over 5,000 academic articles and administered to over 1,100 human volunteers. Twelve clinical trials have been completed globally under sponsorship of MAPS, investigating MDMA-assisted psychotherapy for PTSD, anxiety related to advanced- stage illness, social anxiety in autistic adults, and an ongoing study of healthy subjects via an MDMA therapist training program.
  • MDMA is a ring-substituted phenethylamine. It exerts its effects primarily through promoting raised levels of monoamine neurotransmitters in the brain, in particular serotonin, but also dopamine and noradrenaline. Increased activity at 5-HT I A and 5-HT IB receptors reduces feelings of depression and anxiety, reduces the amygdala fear response and increases levels of self-confidence (Brunner 1997). Furthermore, the effect of raised serotonin at 5-HT 2A receptors provides alterations in the perceptions of meanings and facilitates new ways of thinking about old experiences (Nash et al. 1994).
  • MDMA produces elevated mood, increased sociability and feelings of closeness to others, slight alterations in perception that facilitate imagination and memory (Harris et al. 2002), greater compassion, feelings of sociability, closeness and increased empathy for others and themselves (Hysek et al. 2013).
  • the effects of MDMA at reducing activity in the amygdala results in users experiencing a reduced fear response, and greater activity in the reward pathways in the Ventral Tegmental Area (VTA) in comparison to placebo, associated with less activity in the left amygdala after viewing angry faces, suggesting less reactivity to anger and improved prosocial behavior.
  • Subjects receiving MDMA showed a better ability to detect positive facial expressions and a greater difficulty detecting negative facial expressions (Hysek et al. 2012a).
  • OCD obsessive compulsive disorder
  • MDMA is generally more easily tolerated than the classical psychedelics, with less perceptually disturbing effects compared to LSD and psilocybin. But whether this in fact offers an alternative opportunity for enhanced psychotherapy was not before demonstrated. Indeed, given that the depth of the mystical experience is strongly associated with maintained abstinence from substance use, it would have been logical to presume that MDMA-assisted therapy for AUD would have less success in treating patients than LSD- or psilocybin-assisted therapy ( cf. McCulloch et al. 2021).
  • compositions of MDMA and their use in treating AUD, including both “dependent use” AUD and “harmful use” AUD.
  • the psychotherapeutic processes involved in the treatment of AUD are not only enhanced and intensified, but are improved in novel, unexpected, and surprising ways.
  • the unique effects of MDMA given in a psychotherapeutic context disclosed and using the compositions and methods of the invention, reduce avoidance of emotionally distressing thoughts, images, or memories while increasing empathy for the self and others.
  • the compositions and methods of the invention herein also address symptoms of other conditions that are frequently comorbid with substance abuse, particularly those symptoms associated with a history of psychological trauma. Additionally, as taught herein, the compositions and methods of the invention can lead to reductions in alcohol cravings, problematic consumption, and rates of relapse.
  • compositions of MDMA and methods of their use in MDMA-assisted psychotherapy for the treatment of patients with AUD including physically dependent alcohol use disorder (“dependent use” or “alcohol addiction”) and non-physically dependent alcohol use disorder (“harmful use”).
  • MDMA-assisted psychotherapy may involve the careful screening of patients, such as through specific inclusion and exclusion criteria on which the success of treatment may depend.
  • the therapeutic program involves both non-MDMA and MDMA-assisted sessions which are all delivered by trained healthcare professionals, in a safe and supportive setting. Visits involving MDMA dosing typically last 6- 8 hours during which patients are carefully monitored.
  • MDMA-assisted psychotherapy can be safely delivered, can be well tolerated, and can enhance and intensify the psychotherapeutic processes in the treatment of patients with AUD.
  • MDMA given in the psychotherapeutic context described by Applicant, can reduce avoidance of emotionally distressing thoughts, images, or memories of alcohol misuse, while increasing empathy for the self and others. It can also address symptoms of other conditions that are frequently comorbid with substance abuse, particularly those symptoms associated with a history of psychological trauma. Further, patients treated with the compositions and methods of the invention can reduce their alcohol consumption over the long term, resulting in reduced rates of relapse, and producing benefits not only to the individual patients treated, but to their friends, family, and society at large.
  • MDMA-assisted psychotherapy is a superior method of treating patients with AUD, with numerous significant improvements over prior art methods. As shown below, MDMA-assisted psychotherapy has significant advantages over standard psychotherapy or other existing treatments for AUD, offering patients a potential new approach to a devastating, chronic, and relapsing condition.
  • the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
  • AUD Alcohol use disorder
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
  • AUD refers to a problematic pattern of alcohol use accompanied by clinically significant impairment or distress (Kranzler and Soyka, 2018).
  • AUD refers to a disease characterized by a loss of control over alcohol drinking accompanied by changes in brain regions related to the execution of motivated behaviors and to the control of stress and emotionality (e.g., the midbrain, the limbic system, the prefrontal cortex, and the amygdala) (Witkiewitz, Litten, and Leggio, 2019).
  • compositions and methods of the invention are equally applicable to patients having the equivalent underlying disorder, whether that disorder is diagnosed based on the criteria in DSM-5 or in DSM-IV (which described two distinct disorders — “alcohol abuse” and “alcohol dependence” — with specific criteria for each), whether the diagnosis is based on other clinically acceptable criteria (e.g., as “Alcohol Dependence Syndrome,” see Edwards, G. (1986), The Alcohol Dependence Syndrome: a concept as stimulus to enquiry. Brit. J. Addiction, 81 : 171-183), or whether the patient has not yet had a formal clinical diagnosis.
  • Alcohol dependence refers to the more severe form of AUD involving physical alcohol dependence.
  • Alcohol Dependence Syndrome e.g., Alcohol Dependence Syndrome
  • Alcohol dependence is characterized by (often serious) withdrawal symptoms on cessation of alcohol, or drinking to avoid withdrawal symptoms, tolerance and the persistent desire to drink, and continuing drinking despite negative consequences (NICE 2013).
  • “Harmful use of alcohol” or “harmful use” AUD refers to the definition in the WHO’s International Classification of Diseases, 10th Revision (ICD-10 Classification of Mental and Behavioural Disorders) (ICD-10; WHO, 1992): “[A] pattern of psychoactive substance use that is causing damage to health. The damage may be physical (e.g., hepatitis) or mental (e.g., depressive episodes secondary to heavy alcohol intake). Harmful use commonly, but not invariably, has adverse social consequences; social consequences in themselves, however, are not sufficient to justify a diagnosis of harmful use.”
  • the categories of mild, moderate, and severe may be diagnosed based on the symptoms as defined by the DSM-5, wherein “mild” refers to two or three symptoms, “moderate” refers to four or five symptoms, and “severe” refers to six or more symptoms.
  • AUD patients characterized as “harmful use,” refer to those engaging in “harmful alcohol use,” which is characterized by a pattern of use that causes damage to health, which may be physical or mental; and has adverse social consequences, including those affecting personal relationships, professional relationships, familial relationships, etc. (note, however, that adverse social consequences themselves do not justify a diagnosis of “harmful use”).
  • “harmful use” or “harmful alcohol use” refer to a condition where a patient scores between 0 and 15 on the SADQ.
  • “harmful use” or “harmful alcohol use” refer to a condition where a patient scores between 0 and 15 on the SADQ, and where the patient exhibits at least one of damage to health (e.g., physical, mental, or physical and mental health), and strained/damaged social relationships.
  • damage to health e.g., physical, mental, or physical and mental health
  • Alcohol use disorder patient or “AUD patient” refers to a patient diagnosed with AUD (such as dependent use AUD or harmful use AUD), as defined herein.
  • AUD patient refers to a patient diagnosed with AUD who is in abstinence from alcohol, for example, for at least 1 day, such as 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, or 7 days or more.
  • AUD patient in abstinence from alcohol refers to a patient diagnosed with AUD in abstinence from alcohol, i.e., having not consumed alcohol, for a given period of time, for example, for at least 1 day, such as 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, or 7 days or more.
  • AUD patient post-detox refers to a patient diagnosed with AUD after having undergone a detoxification course, wherein a “detoxification course” or simply “detoxification” refers, in some embodiments, to the abrupt cessation of alcohol intake in individuals that suffer from alcohol dependence.
  • detoxification includes the administration of drugs to prevent symptoms of “withdrawal,” which refers to a physiological response experienced by those having a physical dependence on alcohol, the symptoms of which include, but are not limited to, anxiety, shakiness, sweating, vomiting, fever, increased heart rate, seizures, hallucinations, and delirium tremens (National Clinical Guideline Centre, 2010).
  • a detoxification course may last for a given duration of time, for example, for at least 1 day, such as 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, or 7 days or more.
  • detoxification or a detoxification course will be as specifically disclosed herein.
  • “Binge drinking” refers to a pattern of drinking that brings a person’s blood alcohol concentration (BAC) to at least .08 g/dl.
  • a “binge drinker,” i.e., one who binge drinks, is referred to as an “alcohol abuser” or “abuser of alcohol,” wherein the act of binge drinking itself may be referred to as “alcohol abuse” or “abuse of alcohol.”
  • Abusers of alcohol may not drink on a consistent basis; for example, they may only drink once a week, but, when drinking, they may drink heavily, which may cause adverse health effects, such as, but not limited to, suffering from alcohol intoxication, unintentional injuries, such as car accidents, falls, bums, and alcohol poisoning; violence, including homicide, suicide, domestic violence, and sexual assault; sexually transmitted diseases; unintended pregnancy and poor pregnancy outcomes, including miscarriage and stillbirth; fetal alcohol spectrum disorders, sudden infant death syndrome, chronic diseases such as, but not limited to,
  • the frequency at which one binge drinks may determine whether or not the individual is considered a “heavy drinker” or “heavy alcohol user.” “Heavy drinker” refers to someone with a heavy alcohol use pattern.
  • the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the Substance Abuse and Mental Health Services Administration (SAMHSA) define “heavy alcohol use” as binge drinking on 5 or more days in the past month.
  • NIAAA defines binge drinking as a pattern of drinking that brings BAC levels to at least 0.08 g/dL. This typically occurs after 4 alcoholic drinks for women and 5 alcoholic drinks for men within a period of about 2 hours.
  • SAMHSA defines “binge drinking” as 5 or more alcoholic drinks for males or 4 or more alcoholic drinks for females on the same occasion (i.e., at the same time or within a couple of hours of each other) on at least 1 day in the past month.
  • Alcohol refers to ethyl alcohol (i.e., ethanol).
  • Alcohol craving refers to a conscious desire or urge to consume alcohol.
  • Alcohol use refers to alcohol consumption, and “alcohol consumption” refers to the standards known in the art, such as those of NIAAA or WHO.
  • “Reducing alcohol use” or “reduction of alcohol use” refers to reducing the amount or frequency of alcohol use, for example as assessed by urinalysis (e.g., by measuring metabolites of alcohol in urine, such as Ethyl Glucuronide (EtG)) or as assessed by using self-reported alcohol use with standardized tools like the Timeline Follow-Back self-report (Sobell & Sobell, 1996).
  • “reducing alcohol use” or “reduction of alcohol use” refers to a reduction in drinks per day, a reduction in drinks per drinking day, or a reduction in the frequency of drinking, such as a reduction in the percentage of drinking days or percentage of heavy drinking days.
  • reducing alcohol use” or the “reduction of alcohol use” refers to an increase in the time between consuming at least one drink of alcohol, such that less total units of alcohol are consumed within a given timeframe.
  • a “unit of alcohol” refers to a standard drink, which contains about 14 g of pure alcohol (ethanol). For typical alcoholic beverages, this refers to 12 ounces of 5% alcohol beer, 5 ounces of 12% wine, and 1.5 ounces of 40% distilled spirits (NIH). “Drinking,” “drinks,” or “alcoholic drinks,” is understood in the context of “standard drinks,” such as spirits or blends that are intended for human consumption, wherein a “standard drink” equals 12 g (15.2 mL) ethanol.
  • “Heavy drinking day” refers to a day with a total alcohol consumption >60 g (76.05 L) of ethanol for men and >40 g (50.7 mL) for women.
  • “reducing alcohol use” or the “reduction of alcohol use” refers to increasing the time to a “heavy drinking day,” wherein “heavy drinking day” refers to a given 24-hour period in which the pattern of drinking meets that of “binge drinking,” as defined herein.
  • Alcohol abstinence or “in abstinence from alcohol” refers to the cessation of alcohol consumption for an extended period of time, for example, for at least 1 day, such as 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, or 7 days or more.
  • promoting alcohol abstinence or “promotion of alcohol abstinence” refers to helping to maintain abstinence from alcohol use, in particular after at least 1 day of not drinking alcohol, for example maintaining abstinence from alcohol use for a period of days, including a period of a week or more, including more than one week, more than two weeks, more than three weeks, and a month or more, including more than one month, more than two months, more than three months, more than four months, more than five months, more than six months, more than seven months, more than eight months, more than nine months, more than 10 months, more than 11 months, and a year or more, including more than one year, more than two years, more than three years, more than four years, and more than five years, including values in between.
  • “promoting alcohol abstinence” or “promotion of alcohol abstinence” refers to helping to maintain abstinence from alcohol use, in particular after at least 1 day of not drinking alcohol, for example maintaining abstinence from alcohol use until at least the 3 month, 6 month, and/or 9 month follow-ups, as are disclosed within, or for longer than 9 months, or for longer than 1 year.
  • “Relapse into alcohol use” or “relapse into alcohol consumption” refers to alcohol intake (i.e., the consumption of alcohol or the “taking” of alcohol) following a period of alcohol abstinence, for example following a period of alcohol abstinence of at least 1 day or more, such as 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 9 months, 1 year, or greater than 1 year, and values in between.
  • “preventing relapse into alcohol use” or “preventing relapse into alcohol consumption” refers to the prevention of alcohol intake by an AUD patient after the patient has ceased the intake of alcohol for at least 24 hours.
  • “preventing relapse into alcohol use” or “preventing relapse into alcohol consumption” refers to the prevention of alcohol intake by an AUD patient after the patient has ceased the intake of alcohol for less than 24 hours. In some embodiments, “preventing relapse into alcohol use” or “preventing relapse into alcohol consumption” refers to the permanent cessation of alcohol intake. In some embodiments, wherein a subject is administered a composition of the invention, “preventing relapse into alcohol use” or “preventing relapse into alcohol consumption” refers to an increase in time prior to the resumption of alcohol intake as compared to the time prior to the resumption of alcohol intake by a subject who is not administered a compound of the invention.
  • the increase in time prior to the resumption can be, e.g., at least 1 day, such as 2 days or more, 3 days or more, 4 days or more, 5 days or more, 6 days or more, or a week or more, including more than one week, more than two weeks, more than three weeks, and a month or more, including more than one month, more than two months, more than three months, more than four months, more than five months, more than six months, more than seven months, more than eight months, more than nine months, more than 10 months, more than 11 months, and a year or more, including more than one year, more than two years, more than three years, more than four years, and more than five years, including values in between.
  • AUD associated with high risk drinking for acute problems refers to AUD associated with daily alcohol consumption >60 g/day (76.05 mL/day) of ethanol for men and 340 g/day (50.7 mL/day) for women (International Guide for Monitoring Alcohol Consumption and Related Harm, WHO/MSD/MSB/00.4; WHO 2000, p. 51).
  • Psychosocial or behavioral therapy refers to, but is not limited to, such therapies other than the MDMA-assisted psychotherapy of the invention, e.g., 12-step facilitation therapy (e.g., NIAAA, Project MATCH Monograph Series. Volume 1, NIH Publication No. 94-3722, (1995) reprinted 1999), cognitive behavioral therapy (e.g., as described in Arch. Gen. Psychiatry 1999; 56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav 2009; 23(1): 168-174), contingency management based therapy (e.g., as described in Psychol Addict Behav 2009; 23(1): 168-174; in J. Consul. Clin. Psychol.
  • 12-step facilitation therapy e.g., NIAAA, Project MATCH Monograph Series. Volume 1, NIH Publication No. 94-3722, (1995) reprinted 1999
  • cognitive behavioral therapy e.g., as described in Arch. Gen. Psychiatry 1999;
  • Standardized psychological treatment or “standardized psychological support” refers to standardized sessions, which may be, e.g., once a week, twice a week, once every two weeks, once a month, and the like, in particular psychological treatment, support, or other counseling focused on alcohol consumption.
  • “Mental health disorder,” “mental illness,” or “psychiatric disorder” refer to a disease condition in a mammal, and preferably in a human, that generally involves negative changes in emotion, mood, thinking, and/or behavior. In some embodiments, “mental health disorder,” “mental illness,” or “psychiatric disorder” refer to a behavioral or mental pattern that causes distress or impairment of personal functioning (Bolton, 2008).
  • Mental health disorders include post-traumatic stress disorder (PTSD), adjustment disorder, affective disorder, depression, atypical depression, postpartum depression, catatonic depression, a depressive disorder due to a medical condition, premenstrual dysphoric disorder, seasonal affective disorder, dysthymia, anxiety, phobia disorders, binge disorders, body dysmorphic disorder, a mood disorder related to another health condition, disruptive behavior disorders, eating disorders, impulse control disorders, obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), personality disorders, attachment disorders, dissociative disorders, and substance- related disorders, including alcohol or drug abuse or dependence disorders like AUD and SUDs (see Merck Manual of Diagnosis & Therapy, 20th Ed. (2018)).
  • Behavioral addictions refer to non-substance addictions that are characterised by an inability to resist an urge to perform a behavior resulting in actions that are harmful to oneself or others (Grant, Schreiber, & Odlaug, 2013). Although behavioral addictions share some at least surface similarities with alcohol and substance abuse, they are separate and distinct categories and classifications. Examples of behavioral addictions include pathological gambling, kleptomania, pyromania, compulsive buying, compulsive sexual behaviour, Internet addiction, pornography, and binge eating disorder.
  • MDMA refers to 3,4-methylenedioxymethamphetamine, i.e., l-(l,3-benzodioxol- 5- yl)-A-methylpropan-2-ainine (IUPAC), whether as a racemate, as pure or substantially pure individual enantiomers, or as an enantiomerically enriched mixture in any amount greater than 0%, and whether in salt or freebase form, and includes polymorphs.
  • MDMA as used herein therefore will be understood to encompass all salt forms of MDMA, such as MDMA hydrochloride salt (3,4-MDMA HC1, available from, e.g., Cayman Chemical Co., Ann Arbor, MI, with purity > 98%, as Item No.
  • MDMA will include the hydrochloride salt in all hydrated crystalline forms, such as quarter-hydrate, hemihydrate, three-quarter hydrate, and monohydrate [see, e.g., Shulgin 1986, and references cited). It includes MDMA HC1 “forms I-IP” (see Nair 2021). It includes MDMA base, generally a colourless oil insoluble in water.
  • MDMA as a racemic mixture (i.e., A, / ⁇ ( ⁇ )-3 ,4- methyl enedi oxymethamphetami ne) (CAS 69610-10-2), as an enantiomerically enriched mixture (of whatever proportions), or as individual enantiomers (i.e., pure or substantially pure A-MDMA or L'-MDMA). Both enantiomers function as monoamine releasers (Hiramatsu and Cho, 1990; Johnson et al. 1986; Setola et al.
  • A-MDMA being a more potent dopamine releaser
  • “MDMA” thus may refer to racemic MDMA or to enantiomerically enriched compositions (e.g., to balance the individual therapeutic effects of A-MDMA and A-MDMA, or to minimize certain negative effects, such as the suggested greater neurotoxicity of the S-(+ ) enantiomer) or compositions of individual MDMA enantiomers.
  • the dosage may be adjusted accordingly based on the known differences in potency, and may be done so based on the teachings herein in combination with the general knowledge in the art.
  • MDMA monomethylenedioxy- amphetamine
  • HMMA 4-hydroxy-3-methoxymethamphetamine
  • HMA 4- hydroxy-3- methoxyamphetamine
  • HHA 3,4-dihydroxyamphetamine
  • HHMA 3,4- dihydroxy- methamphetamine
  • the terms “subject,” “user,” “patient,” and “individual” are used interchangeably, and refer to any mammal although preferably a human.
  • the terms “subject,” “user,” “patient,” and “individual” refer to any mammal, although preferably a human, who has an indication for which a compound, composition, or method described herein may be efficacious, or who otherwise may benefit by the invention.
  • all of the compounds, compositions, and methods of the invention will be appreciated to work for all individuals, although individual variation is to be expected, and will be understood.
  • the terms “subject,” “user,” “patient,” and “individual” includes one who has a mental health disorder, or a condition related to a mental health disorder for which similar treatment may be efficacious; in embodiments herein, unless otherwise specified, a “mental health disorder” shall refer to an alcohol use disorder. In embodiments herein, unless otherwise specified, an “alcohol use disorder” shall refer to both “harmful use” and “dependent use” AUD. When a “subject,” “user,” “patient,” or “individual” is participating in a course of therapy as described below, the term “participant” also may be used.
  • these terms also shall refer to patients in need of treatment for such a disorder, persons predisposed to such a disorder, and subjects whether or not diagnosed with such a disorder. Moreover, these terms shall likewise refer to persons who have received treatment or therapy for a mental health disorder, are currently receiving therapy or treatment for a mental health disorder, or who may receive therapy or treatment for such a disorder in the future. In some embodiments, the disclosed methods also can be used to improve mental health and improve psychological functioning in non-disease states, i.e., in an individual without a diagnosed mental health disorder, or specific symptoms thereof.
  • compositions and methods of the invention will be appreciated to work for all individuals, although individual variation is to be expected, and will be understood. Where there is variation between individuals, modification to the compositions and methods will be understood based on the teachings herein in combination with the general knowledge of the art. In some instances, certain personalized approaches (i.e., “personalized” or “precision” medicine) may be utilized, based on individual characteristics, including drug metabolism (e.g., CYP2D6 or CYP3A4) or individual genetic variation.
  • drug metabolism e.g., CYP2D6 or CYP3A4
  • genetic variation refers to a change in a gene sequence relative to a reference sequence (e.g., a commonly-found and/or wild-type sequence).
  • Genetic variation may be recombination events or mutations such as substitution/deletion/insertion events like point and splice site mutations.
  • the genetic variation is a genetic variation in metabotropic glutamate receptor type 5 (mGluR5), which has been implicated in mood and anxiety symptoms in humans, as well as playing a direct role in the pathogenesis of AUD, showing involvement in the development of behavioral sensitization towards ethanol in animal models.
  • the genetic variation is one or more single nucleotide polymorphisms (SNPs) in the FKBP5 gene that are associated with elevated levels of FKBP51 protein relative to persons lacking such SNPs.
  • SNPs single nucleotide polymorphisms
  • the genetic variation is a genetic variation in one or more cytochrome P450 (CYP or CYP450) enzymes that affects drug metabolism, including metabolism of a composition of the invention, and including CYP1A2, CYP2C9, CYP2D6, CYP2C19, CYP3A4 and CYP3A5.
  • cytochrome P450 CYP or CYP450
  • CYP enzymes include CYPIAI, CYPIBI, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYPl lAl, CYP11B2, CYP 17, CYP 19, CYP21, CYP24, CYP26A1, CYP26B1,
  • a composition of the invention is taken together with a compound that is metabolized by the same CYP enzyme(s) as the composition of the invention, so as to permit a lower dose to be taken, increase the effective bioavailability of one or both, or otherwise affect drug metabolism or pharmacokinetics.
  • the dose of a composition of the invention is adjusted when administered to a subject known to be a “poor metabolizer” of the active agent in composition (e.g., having a genetic variation in CYP2D6, known to be the major metabolizer of the methylenedioxy moiety of MDMA).
  • a genetic variation (or a genetic marker signifying a variation) is an exclusion criteria for the administration of a compound of the invention.
  • the genetic variation is a genetic variation in metabotropic glutamate receptor type 5 (mGluR5), which has been implicated in mood and anxiety symptoms in humans.
  • the genetic variation is one or more single nucleotide polymorphisms (SNPs) in the FKBP5 gene that are associated with elevated levels of FKBP51 protein relative to persons lacking such SNPs.
  • SNPs single nucleotide polymorphisms
  • the genetic variation is a genetic variation such as a SNP in a membrane transporter, such as SERT, DAT, NET, or VMAT.
  • the mammal being treated has altered epigenetic regulation of a gene the expression of which is associated with a mental health condition or susceptibility to a mental health treatment, such as the SIGMARl gene for the non-opioid sigma- 1 receptor.
  • any modification to the compositions and methods of the invention are determined by the age of the patient, the weight of the patient, whether the patient has any comorbidities (i.e., any other medical conditions simultaneously present within a patient), other medications the patient is taking (routinely or presently), any patient-specific aspects that could affect the way in which the compositions of the invention interact with the patient, such as, but not limited to, variations in metabolism and variations in patient response, and any other such natural variations that would be apparent to one of skill.
  • “Therapist” refers to a person who treats a patient using the compositions and methods of the invention, whether that person is a psychiatrist, clinical psychologist, clinical therapist, psychotherapist, or other trained counselor, facilitator, or guide, and who may or may not be a trained addiction specialist or counselor, substance abuse specialist or counselor, or alcohol abuse specialist or counselor.
  • the therapist will be certified in the use of the treatment manual for the MDMA-assisted psychotherapy administered, and will have completed the appropriate training in delivering that form of MDMA-assisted psychotherapy. This will enable a therapist to respond in a safe and supportive manner during the non-MDMA and MDMA sessions.
  • Treating” or “treatment” of a disorder includes: (i) inhibiting the disorder, i.e., arresting or reducing the development or progression of the disorder or its clinical symptoms; or (ii) relieving the disorder, i.e., causing regression of the disorder or its clinical symptoms. Inhibiting the disorder, for example, would include prophylaxis.
  • a therapeutic amount necessary to effect treatment for purposes of this invention will, for example, be an amount that provides for objective indicia of improvement in patients having clinically-diagnosable symptoms.
  • objective indicia will be those recognized by clinicians who diagnose and treat patients having the condition, and therefore readily appreciated in the art.
  • objective indicia may include, but are not limited to, an improvement in weight, body temperature, heart rate (HR), respiratory rate, blood oxygenation, blood pressure (BP) and its variables, including, but not limited to: systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP); continuous non-invasive beat-by-beat blood pressure (CNIBP); measurements from an electrocardiogram (ECG), including, but not limited to, RR interval or its variability, QT interval or its variability, heart rate variability (HRV) (or measured by devices other than an ECG); hemodynamic response (HR), and levels of glucose, cortisol, serotonin, dopamine, cholesterol; electroencephalography (EEG) measures such as quantitative EEG (qEEG); electrocochleogram (ECochG), electromyography (EMG), electrooculography (EOG), magnetoencephalography (MEG); electrocorticography (ECoG); magnetic resonance imaging (MRI); functional MRI (fMRI); compute
  • EEG electrocardi
  • the objective indicia of improvement may be an improvement in one’s psychological state, wherein “psychological state” may refer to the condition or state of one’s mind including, but limited to, its physiological and subjective characteristics.
  • psychological state is synonymous with the terms or phrases “mental condition,” “mental state,” “psychological condition,” “neural status,” “cognitive state,” “state of mind,” “frame of mind,” “emotional state,” etc.
  • psychological state broadly refers to the condition of the nervous system and its components, including, but not limited to, the brain and its subunits, non-limiting examples of which include the frontal lobe, temporal lobe, brain stem, cerebellum, occipital lobe, parietal lobe, and cerebral cortex.
  • the effect, or improvement may be prophylactic in terms of completely or partially preventing a disorder or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disorder, an adverse effect attributable to the disorder, and/or a comorbidity simultaneously present with the disorder.
  • a “comorbidity” present with AUD includes psychiatric disorders such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive compulsive disorder, binge eating disorder, and PTSD.
  • treatment covers any treatment of a disorder in a mammal, and preferably in a human, and includes: (a) preventing a disorder from occurring in a subject who may be predisposed to the disorder but has not yet been diagnosed with it; (b) inhibiting a disorder, i.e., arresting its development; (c) relieving a disorder, i.e., causing regression thereof; (d) protection from or relief of a symptom or pathology caused by or related to a disorder; (e) reduction, decrease, inhibition, amelioration, or prevention of onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with a disorder; and (f) prevention or inhibition of a worsening or progression of symptoms or pathologies associated with a disorder or comorbid with a disorder.
  • Other such measurements, benefits, and surrogate or clinical endpoints, alone or in combination, would be understood to one of skill based on the teachings herein and general knowledge in the art.
  • any of the disclosed methods can be used in combination with one or more therapeutically beneficial activities, where such participation follows or is in conjunction with the administration of the composition, including breathing exercises, meditation and concentration practices, focusing on an object or mantra, listening to music, physical exercise, stretching or bodyworkjournaling, grounding techniques, positive self-talk, or engaging with a pet or animal, and it should be understood that such participation can occur with or without the participation or guidance of a therapist or other professional.
  • An exemplary treatment protocol is outlined in FIG. 15, and is further detailed as follows.
  • a patient will first be assessed to see if they meet the inclusion protocol, which contains criteria outlined in TABLE 1 (1501). If not (1503), the patient is excluded from the treatment protocol (1504). If all inclusion criteria are met (1502), however, the patient is further assessed to determine if any of the exclusion criteria (also listed in TABLE 1) are met (1505). Unlike inclusion criteria, in which all must be met, only one exclusion criteria need be present (1506) to exclude the patient from participating in the treatment protocol or method of the invention (1508). If no exclusion criteria are found to be met (1507), however, the patient may participate in the treatment protocol/method of the invention (1509).
  • the patient While participating in a treatment protocol or method of the invention, the patient will further be assessed for withdrawal criteria (1510), also listed in TABLE 1, as with exclusion criteria, if one is met (1511), the patient is withdrawn from the treatment protocol or method of the invention (1513). So long as no withdrawal criteria are met (1512), the patient may continue with the treatment protocol or method of the invention, and it thus be determined as to whether or not the patient satisfies the requirements of the particular treatment protocol or method of the invention (1514). If so (1515), the patient thereby completes the treatment protocol (1518). However, if the patient does not satisfy the requirements of the particular treatment protocol/method of the invention (1516), the patient is withdrawn from the treatment protocol, or method of the invention (1517).
  • withdrawal criteria also listed in TABLE 1, as with exclusion criteria, if one is met (1511), the patient is withdrawn from the treatment protocol or method of the invention (1513). So long as no withdrawal criteria are met (1512), the patient may continue with the treatment protocol or method of the invention, and it thus be determined as to whether
  • patients undergoing MDMA-assisted psychotherapy may be withdrawn prior to or during a course of therapy if certain withdrawal criteria were to occur.
  • patients after patients have completed a course of therapy (e.g., an exemplary 8-week course or 13- week course of MDMA-assisted psychotherapy as in embodiments below, including those of Examples 4 and 8) they generally are not withdrawn based on these criteria. Patients are always free to withdraw at any time from treatment without giving reasons and without prejudicing further treatment.
  • drugs will be required to taper and stop any medications with a known or suspected risk of drug interaction with MDMA.
  • Drug interaction refers to a case wherein two or more drugs react with one another in the body and, as a result, either potentiate the effects of one or both of the drugs (i.e., increase the strength with which the drugs act in the body such that their effects are greater than would be expected on their own), or cause unexpected, and often adverse, side effects.
  • drug interactions also refer to drug and food, or drug and beverage interactions, wherein the drug administered to the patient interacts with a given food or beverage (namely, the compounds within the food or beverage), to cause an unexpected, often adverse reaction.
  • drug interactions also refer to drug and condition interactions, wherein administration of a drug may worsen a diagnosed, or undiagnosed medical condition.
  • a drug or substance being “tapered,” or “tapering” a drug or substance refers to the process of slowly decreasing the amount of the drug or substance being taken over a given period of time. Meaning, the subject is administered smaller, and smaller amounts of the drug or substance to avoid or limit withdrawal symptoms, which would likely occur if the subject were to quit taking the drug or substance “cold turkey,” (i.e., without tapering).
  • tapering may be completed through direct tapering, which involves slowly reducing the amount of the drug or substance taken over a given amount of time (which is dependent upon the drug or substance taken, the individual, the length of use and other such metrics that would be known to those of skill); substitution tapering, wherein the drug or substance is replaced with a drug or substance that, in some embodiments, causes a similar physiological response, but has a longer half-life, so tapering is more effective; and titration tapering, wherein the drug or substance is dissolved in a specific amount of a fluid, generally but not necessarily water, so that the “strength” of each dose, or amount of the drug or substance in each dose administered to the patient, may be less than the previous dose (Coalition Recovery, 2019).
  • the washout period of medications to be stopped will be dependent on the half-life of that particular medication. In some embodiments, a sufficient washout period of 2 weeks (5 weeks for fluoxetine) must be allowed prior to the first MDMA session and, in such embodiments, medications should not be restarted until completion of the final MDMA session unless clinically required.
  • Exemplary psychotropic medication that generally will be excluded include: any drugs inhibiting the liver enzyme CYP2D6, antidepressants of the serotonin and/or noradrenaline reuptake inhibitor type (SSRI/SNRI), Mirtazapine, Ritonavir and regular use of benzodiazepines.
  • exemplary medications that generally will be permitted include: pregabalin, gabapentin, occasional benzodiazepines and Z-hypnotics (e.g., zolpidem, zopiclone, zaleplon, or eszopiclone).
  • Commonly used medications during and after the detoxification processes that generally will be permitted include baclofen, acamprosate, naltrexone, and disulfiram.
  • CYP3A4 activity evidence suggests there is an apparent decrease in CYP3A4 activity after a single dose of MDMA of 1.5mg/kg (Yubero-Lahoz 2011), and in some embodiments certain CYP3A4 medications therefore may be contraindicated. Adjustments may also be made for patients who are considered “slow” or “fast” metabolizers, e.g, for CYP2D6 and/or CYP3A4 (see, e.g., Zanger 2013).
  • “Assessment” refers to any means or method used with a patient, whether before, during, after, or unrelated in time to a specific treatment protocol, to measure, estimate, or evaluate a nature, ability, symptom, disorder, or other characteristic of the patient, whether qualitatively or quantitatively, and whether performed by the therapist or other clinician (e.g., an interview), by the patient his or herself (e.g., a self-reported questionnaire), by a third-party human or by a medical or other device (e.g., a medical sensor or biosensor, a watch or fitness tracker), and whether graded by a human decision-maker or an artificial intelligence (AI), using machine learning, or with a computer algorithm.
  • assessments include those in TABLE 2 below.
  • An assessment may be computer-assisted, and other computer-assisted assessments may be performed besides the assessments above.
  • the term “computer-assisted” in “computer- assisted assessment” means an assessment comprising the use of electronic tools such as online tools, smartphones, wireless devices, or health apps (in some such examples, also known as “digital phenotyping”).
  • Computer-assisted assessment may include use of an electronic psychiatric notes system, where relevant clinical information is recorded for the duration of the therapy by a therapist interacting face-to-face with a patient, and will also include the use of computer systems where the therapist and patient interact virtually (either synchronously or asynchronously), as well as where a patient only interacts with a computer (“computer” broadly meaning any electronic tool suitable for such purposes, including desktop, laptop, and notebook computers; tablets, smartphones, and other mobile devices; watches, fitness trackers, and personal electronic devices; and the like).
  • “Computer-assisted” may refer to one or more aspects of a psychosocial, behavioral, or MDMA-assisted therapy.
  • “Therapeutic effect” or “therapeutic efficacy,” as used herein, means the response(s) in a mammal, and preferably a human, after treatment that are judged to be desirable and beneficial. Hence, depending on the disorder to be treated, or improvement in physiological or psychological functioning sought, and depending on the particular constituent(s) in the compositions of the invention under consideration, those responses shall differ, but would be readily understood by those of ordinary skill. For AUD, including for both “harmful use” AUD and “dependent use” AUD, those responses will be understood based on the teachings herein and the general knowledge in the art.
  • Measures of therapeutic effect includes any outcome measure, endpoint, effect measure, or measure of effect within clinical or medical practice or research which is used to assess the effect, both positive and negative, of an intervention or treatment, whether patient- reported, gathered through laboratory tests such as blood work, urine samples etc., or through medical examination.
  • therapeutic effect may include the collection of objective measures, including but not limited to weight, body temperature, heart rate, respiratory rate, blood oxygenation, BP and its variables, including SBP, SBP, MAP, and PP; CNIBP; ECG measurements, including, but not limited to, RR interval or its variability, QT interval or its variability, HRV (including measured by devices other than an ECG); hemodynamic response, and levels of glucose, cortisol, serotonin, dopamine, cholesterol; EEG measures; BDNF; genetic markers including relating to CYP enzymes or drug metabolism; genetic variation in mGluR5 or FKBP5; and numerous more, as will be readily appreciated by those of skill.
  • objective measures including but not limited to weight, body temperature, heart rate, respiratory rate, blood oxygenation, BP and its variables, including SBP, SBP, MAP, and PP
  • CNIBP CNIBP
  • ECG measurements including, but not limited to, RR interval or its variability, QT interval or its variability, HRV (including measured by devices other than
  • Measures of therapeutic effect for purposes of the invention will be understood to include, as non-limiting examples: (1) Weekly units of alcohol consumed post-detox (i.e., counting from the last day of an alcohol detoxification course), or post “baseline” as defined herein, wherein a unit of alcohol refers to a standard drink that contains about 14 g of pure alcohol (ethanol), or other measure of relapse status; (2) Quality of life, including subjective sleep; (3) Psychosocial functioning; (4) Prescribed medication use; (5) Number and frequency of recreational drugs (if any); (6) Cravings relating to MDMA and any subsequent use of illicit ecstasy; and (7) Symptoms of AUD or any comorbid disorder(s).
  • a therapeutic effect may be shown by one or more of: (a) a reduction of alcohol use, (b) a reduction of alcohol cravings, (c) a promotion of alcohol abstinence, (d) a prevention of relapse into alcohol use, or (e) an improvement of at least one symptom of alcohol use disorder.
  • a therapeutic effect may be shown by one or more of: (a) an increase in quality of life, (b) an increase in psychosocial functioning, (c) a decrease in use or frequency of a prescription medication, (d) a decrease in use or frequency of a recreational drug, (e) a decrease in obsessive compulsive thoughts, (f) a decrease in suicidality, (g) an increase in feelings of empathy, or (h) an increase in self-compassion.
  • a therapeutic effect may be shown by an improvement of at least one symptom of a comorbid psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive compulsive disorder, binge eating disorder, or PTSD.
  • a measure of therapeutic effect may be “durable,” e.g., where shown after a specific period of time, for example at least 1 month, at least 3 months, at least 6 months, at least 9 months, at least 1 year, or greater than 1 year, where such time is from the end of detoxification, if detoxification is completed, from baseline, or from the first psychotherapy session.
  • a measure of therapeutic effect will be shown for a period of time measured from when the subject has completed the MDMA- assisted psychotherapy regimen (i.e., measured from the last MDMA-assisted or non-drug assisted psychotherapy session).
  • an “effective amount,” a “therapeutically effective amount,” a “therapeutically effective dose,” or a “pharmacologically effective amount,” refers to an amount of an active agent that is non-toxic and sufficient to provide the desired therapeutic effect with performance at a reasonable benefit/risk ratio attending any medical treatment.
  • the effective amount will vary depending upon the subject and the disease condition being treated or health benefit sought, the weight and age of the subject, the severity of the disease condition or degree of health benefit sought, the manner of administration, and the like, all of which can readily be determined by one of skill.
  • “therapeutically effective amount” refers to the amount of a compound of the invention (i.e., MDMA) sufficient to effect treatment when administered to a subject in need of such treatment.
  • Administration of a composition in a “therapeutically effective amount” or an “effective amount” to a subject means administration of an amount of the composition of the invention in a manner as disclosed herein, sufficient to achieve the desired effect.
  • a “therapeutically effective amount,” or an “effective amount,” thus would be the amount sufficient to cause a measurable modulation which, in some embodiments, refers to the exertion of a modifying or controlling influence on something which, as it relates to the invention, may be a neurotransmitter system (such as, but not limited to, the serotonergic, dopaminergic, and/or noradrenergic system), where that measurable modulation is known to result in or is shown to result in treatment of a disorder.
  • an “effective amount” means an amount effective in treating the stated disorder itself, or in the symptoms thereof in a subject
  • “therapeutic effect” would be understood to mean the responses(s) in the subject after treatment judged to be desirable and beneficial.
  • “Pharmacovigilance” refers to any efforts to monitor the physiological, psychological, or other effects associated with MDMA or any other active agent of the invention, especially in order to identify and evaluate adverse events or adverse reactions. For example, at every visit during a treatment period patients may be asked open-ended questions about how they are feeling and any side effects or adverse events documented. Therapists will have access to a check-list of common side effects to aid documentation.
  • AE Advanced adverse event
  • An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational medicinal product (IMP), whether or not considered related to the IMP.
  • IMP investigational medicinal product
  • a moderate rise in pulse and blood pressure is common when taking MDMA.
  • MDMA at doses of 100-125 mg has been associated with increases in heart rate of 26-30 bpm and blood pressure (diastolic 14.4-25 mmg) (Harris 2002, Mas 1999, Mithoefer et al. 2011).
  • blood pressure and pulse can be measured throughout a MDMA-assisted session, starting at baseline before the drug is given and hourly thereafter for six hours.
  • BP systolic BP
  • DBP diastolic BP
  • the upper age range of patients may be limited, e.g., to 65 years, and patients may be screened for cardiac abnormalities.
  • AR adverse reaction
  • PVCs ventricular extrasystoles
  • UAR Unexpected adverse reaction
  • SmPC summary of product characteristics
  • SES Serious adverse event
  • SAR seerious adverse reaction
  • results in death results in death; is life-threatening (i.e., an event in which the subject was at risk of death at the time of the event, but not an event which hypothetically might have caused death if it were more severe); requires hospitalization, or prolongation of existing inpatients’ hospitalization; results in persistent or significant disability or incapacity; or is a congenital anomaly or birth defect.
  • this list is non exclusive, and medical judgment will be exercised in deciding whether an AE or AR is serious in other situations. Important AEs or ARs that are not immediately life-threatening or do not result in death or hospitalization but may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the definition above, also should be considered serious.
  • SUSAR Sespected unexpected serious adverse reaction
  • MDMA refers to MDMA that is pure or substantially pure, or a composition containing such pure or substantially pure MDMA (e.g., such MDMA plus an excipient, wherein “excipient,” in some embodiments, refers to a substantially “inactive” substance that serves as the vehicle or medium for a drug or other substantially “active” substance, and an “inactive” substance refers to a substance that exerts substantially no effects on the body, while an “active” substance exerts observable — through, among other metrics, objective measurements as disclosed herein — effects on the body).
  • Set and setting may play a role in the development of some ecstasy -related adverse events, such as vigorous physical exertion, lack of attention to somatic cues, and too little or too much hydration resulting in hyperthermia or hyponatremia.
  • the term “set and setting” is commonly attributed to Timothy Leary, a psychologist well known for promoting psychedelics and psychedelic research in the 1960s. While consideration of set and setting is traced further back to use of plant-based psychedelics in Native cultures, it continues to be considered to be crucial in modern use of psychedelic-assisted therapies in clinical settings and research trials (Hartogsohn, 2017).
  • set refers to the internal aspects of the person undergoing a psychedelic experience such as their personality, mood, intentions and expectations (Metzer and Leary, 1967). “Setting” encompasses the physical, social and cultural environment in which the psychedelic experience takes place (Hartogsohn, 2017).
  • “Causality” and “causal relationship” for an AE also may be assessed, i.e., an AE may be assessed as to whether or not there is a reasonable possibility of a causal relationship to the composition and/or its administration or method of use (e.g., a protocol of MDMA-assisted psychotherapy).
  • a protocol of MDMA-assisted psychotherapy e.g., a protocol of MDMA-assisted psychotherapy.
  • a large number of AEs are expected due to the nature of the patients’ condition.
  • the intervention is composed of psychotherapy sessions as well as MDMA-assisted psychotherapy sessions, those performing the methods herein will in some embodiments document causality according to intervention where possible.
  • the assignment of the causality may be made by the physician, investigator, clinical psychologist, or other member of the medical or treatment team responsible for the care of the patient using the definitions in TABLE 3 below. On occasion, doubt about the causality may exist. In such circumstances, all members of the medical or treatment team can speak together or with other knowledgeable clinicians. In the case of continued discrepant views, additional outside clinicians can be asked to advise.
  • Psychedelic-assisted psychotherapy refers to a range of related approaches that involve at least one session where the patient ingests a “psychedelic” and is monitored, supported, and/or otherwise engaged by one or more trained mental health professionals while under the effects of the drug (see, e.g., Schenberg 2018). Protocols have been developed for the standardization of procedures which emphasize a high degree of care (see, e.g, Johnson 2008), such as the therapeutic approach used by MAPS to treat patients with PTSD using MDMA (e.g., described in Mithoefer 2017).
  • the drug compound in the psychotherapy need not be a “psychedelic” as the class is sometimes understood (e.g., the class of “classic” psychedelics), but also may include drugs having “entactogenic” or “empathogenic” effects like MDMA, or drugs having “dissociative” effects such as ketamine and esketamine.
  • “Additional therapeutic effects” that may be increased in some embodiments of the invention include, but are not limited to, antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti- PTSD, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, entactogenic, empathogenic, entheogenic, euphoric, psychedelic, sedative, and stimulant effects.
  • “Synergistic effects” will be understood as including increases in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect (including one or more additional therapeutic effects), that are greater than the additive contributions of the components acting alone, and/or are greater than the contribution of the isolated compounds on their own.
  • “synergistic” refers to a pharmaceutical composition or combination therapy that is more effective than the additive effects of any two or more single agents. A synergistic effect, for example, permits the effective treatment of a disease using lower amounts (doses) of individual therapy.
  • the lower doses result in lower toxicity without reduced efficacy.
  • a synergistic effect may additionally result in improved efficacy, including an improved avoidance or reduction of disease as compared to any single therapy.
  • “Synergistic effects” will also be understood to include increases in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect (including one or more additional therapeutic effects), that are greater than the additive contributions of the components acting alone, and/or are greater than the contribution of the isolated compounds on their own.
  • Such additional active compounds may include any one or more of amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, other entactogens and empathogens, entheogens, psychedelics, monoamine oxidase inhibitors, sedatives, stimulants, and vitamins.
  • These ingredients may be in ion, freebase, or salt form, include polymorphs, and may be isomers.
  • an additional active agent may be any one or more of an opioid antagonist (e.g., nalmefene, naltrexone), a CBi antagonist (e.g., rimonabant), a CRHi receptor antagonist (e.g., verucerfont, pexacerfont), a NKIR antagonist (e.g., tradipitant), an OTR agonist (e.g., oxytocin), a GABA agent (e.g., topiramate, baclofen, a benzodiazepine, such as alprazolam, diazepam or lorazepam), a voltage-gated sodium channel inhibitor (e.g., oxacarbazepine, valproic acid, zonisamide), a voltage-dependent calcium channel agonist (e.g., gabapentin, pregabalin), an a7 nicotinic acetylcholine receptor agonist
  • an opioid antagonist e
  • the compounds described herein may contain one or more asymmetric centers and give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the invention is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms.
  • chiral compounds will be understood to refer to racemic mixtures, as well as any of the individual enantiomers, and all enantiomerically enriched mixtures thereof, in any proportions.
  • Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • Various methods are known in the art for preparing optically active forms and determining activity. Such methods include standard tests described herein and other similar tests which are well known in the art.
  • the compounds of the invention may be provided in a composition that is enantiomerically enriched, such as a mixture of enantiomers in which one enantiomer is present in excess, including an enantiomeric excess in any amount greater than 0%, and in some embodiments in an enantiomeric excess of at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.9%, up to (and including) 100%.
  • a composition that is enantiomerically enriched such as a mixture of enantiomers in which one enantiomer is present in excess, including an enantiomeric excess in any amount greater than 0%, and in some embodiments in an enantiomeric excess of at least about 50%, at least about 55%, at least about 60%, at least
  • enantiomerically enriched mixtures in an enantiomeric excess of less than about 50%, such as less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, including less than about 1%, less than about 0.5%, and up to 0%.
  • the compound will be MDMA.
  • compounds, e.g., MDMA which are present in a composition or used in a method, and which are a pure or substantially pure individual enantiomer, such as a mixture having an enantiomeric excess of greater than about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or preferably above about 90%, such as about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9%, and up to about 100% and including 100%.
  • any compounds described herein contain
  • compositions of the invention will be understood to also encompass pharmaceutically acceptable salts of such compounds.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, and which may be synthesized by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base forms of these agents with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable.
  • Exemplary salts include, but are not limited to, 2 -hydroxy ethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2- naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, dig
  • compositions of each drug in each group including solvates, salts, esters, enantiomers, isomers (stereoisomers and/or constitutional, including, but not limited to, ones based on substituting deuterium or a halogen, such as bromine, chlorine, fluorine, and iodine; for any hydrogen), derivatives or prodrugs of the compounds of the invention.
  • Prodrugs of the active agents also will be appreciated to be within the scope of the invention.
  • the term “prodrug” refers to a precursor of a biologically active pharmaceutical agent. Prodrugs undergo a chemical or a metabolic conversion to become a biologically active pharmaceutical agent.
  • a prodrug can be converted ex vivo to the biologically active pharmaceutical agent by chemical transformative processes.
  • a prodrug is converted to the biologically active pharmaceutical agent by the action of a metabolic process, an enzymatic process or a degradative process that removes the prodrug moiety, such as a glycoside or acetyl group, to form the biologically active pharmaceutical agent.
  • Other examples include addition of hydroxy groups (Tsujikawa et al. 2011. Xenobiotica, 41(7), 578-584; Yamamoto et al. 1984. Xenobiotica, 14(11), 867-875), acyloxyalkoxycarbonyl derivatives, amino acids, or peptides (Vig et al. 2013.
  • Types of prodrugs contemplated to be within the scope and spirit of the invention therefore include compounds that are transformed in various organs or locations in the body (e.g., liver, kidney, G.I., lung, tissue) to release the active agent.
  • liver prodrugs will include active agents conjugated with a polymer or chemical moiety that is not released until acted upon by liver cytochrome enzymes; CYP metabolism includes dealkylation, dehydrogenation, reduction, hydrolysis, oxidation, and the breakdown of aromatic rings.
  • Kidney prodrugs will include active agents conjugated to L-gamma-glutamyl or N-acetyl-L- gamma glutamic moieties so that they are metabolized by gamma-glutamyl transpeptidase before they are bioactive; alternatively, they may be conjugated to alkylglucoside moieties to create glycosylation-based prodrugs. Digestive or G.I.
  • prodrugs will include those where an active agent is, e.g., formulated into microspheres or nanospheres that do not degrade until the spheres are subjected to an acidic pH; formulated with an amide that will resist biochemical degradation until colonic pH is achieved; or conjugated with a linear polysaccharide such as pectin that will delay activation until the pharmaceutical composition reaches the bacteria in the colon.
  • an active agent e.g., formulated into microspheres or nanospheres that do not degrade until the spheres are subjected to an acidic pH
  • an amide that will resist biochemical degradation until colonic pH is achieved
  • conjugated with a linear polysaccharide such as pectin that will delay activation until the pharmaceutical composition reaches the bacteria in the colon.
  • pectin a linear polysaccharide
  • many others will be known to one of skill.
  • physiologically functional derivatives refers to physiologically tolerated chemical derivatives of the compound having the same physiological function thereof, for example by being convertible in the body thereto, and which on administration to a mammal such as a human is able to form (directly or indirectly) the compound or an active metabolite thereof (acting therefore, like a prodrug), or by otherwise having the same physiological function, despite one or more structural differences.
  • physiologically functional derivatives may include esters (including diacid hemiesters), amides, carbamates, ureas, and heterocycles.
  • the compounds of the invention are synthetic.
  • “Synthetic” means a compound which is manufactured artificially in a laboratory, by means of chemical synthesis (e.g., by a series of chemical processes or reactions using chemical substrates, reagents, and optionally one or more catalysts) or biosynthesis (e.g., from a bioengineered organism, and thus including those compounds also referred to as “biosynthetic” or as involving “synthetic biology” or “synbio”).
  • bacteria, yeast, and other host cells can be bioengineered to produce synthetic compounds by inserting genes that produce appropriate enzymes and/or by altering the natural metabolic pathway to achieve the production of the desired compound(s), e.g., from sugars, the main carbon source available to yeast, or from other precursor molecules.
  • Cell-free protein synthesis (CFPS) and in vitro protein synthesis are also contemplated. These compounds can then be obtained and purified.
  • the individual compounds of the invention shall be administered as part of a pharmaceutical composition or formulation, but will be prepared for inclusion in such composition or formulations as isolated or purified compounds.
  • a compound of the invention is in a substantially pure or isolated preparation.
  • isolated refers to material that is substantially or essentially free from components that normally accompany the material when the material is synthesized, manufactured, or otherwise produced, according to a particular degree of purity, and when measured by a method described herein or of general knowledge in the art. Any compound of the disclosure can be purified.
  • a compound (or a composition comprising a compound) as described herein will generally be at least about 90% pure, including at least about 95% pure, at least about 96% pure, at least about 97% pure, at least about 98% pure, at least about 99% pure, at least about 99.1% pure, at least about 99.2% pure, at least about 99.3% pure, at least about 99.4% pure, at least about 99.5% pure, at least about 99.6% pure, at least about 99.7% pure, at least about 99.8% pure, at least about 99.9% pure, or up to 100% pure.
  • a “substantially pure” compound may be defined as a compound or composition having a chromatographic purity (of the desired compound) of greater than about 90%, more preferably greater than about 95%, more preferably greater than about 96%, more preferably greater than about 97%, more preferably greater than about 98%, more preferably greater than about 99%, more preferably greater than about 99.25%, more preferably greater than about 99.50%, more preferably greater than about 99.75%, and most preferably greater than about 99.90%, greater than about 99.95%, or greater than about 99.99%, as determined by area normalization of HPLC profile or other similar detection method.
  • a substantially pure compound of the invention is, preferably, substantially free of any other active agents which are not intended to be administered to a subject.
  • substantially free can be taken to mean that no impurities, adulturants, or active agent(s) other than the active agent intended to be administered to a subject are detectable by HPLC or other similar detection method, or are below a desired threshold of detection such as defined above.
  • active agents that may be found in a compound that is not substantially pure include those known in the art to be present in recreational or non-clinical MDMA, such as by products and side-products of non-GMP synthesis, or compounds sold as or with “MDMA” while not in fact MDMA (e.g., other phenethylamines, cathinones, etc.) (see, e.g., Saleemi 2017).
  • the composition of the invention therefore will comprise less than about 5% impurities or adulterants, including additional (undesired) active agents such as described above, and in some embodiments will comprise less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1%, less than 0.05%, less than 0.025%, or less than 0.01% impurities or adulterants, including in some embodiments no measurable impurities or adulterants.
  • compositions are compositions comprising disclosed compound(s) together in an amount (for example, in a unit dosage form) with a pharmaceutically acceptable carrier, diluent, or excipient. It should be understood that some embodiments do not have a single carrier, diluent, or excipient alone, but include multiple carriers, diluents, and/or excipients.
  • Compositions can be prepared by standard pharmaceutical formulation techniques such as disclosed in Remington: The Science and Practice of Pharmacy (2005) 21 th ed., Mack Publishing Co., Easton, Pa.; The Merck Index (1996) 12 th ed., Merck Publishing Group, Whitehouse, N.J.; Pharm.
  • “Pharmaceutically acceptable” as used in connection with one or more ingredients means that the ingredients are generally safe and, within the scope of sound medical judgment, suitable for use in contact with the cells of humans and other animals without undue toxicity, irritation, allergic response, or complication, and commensurate with a reasonable risk/benefit ratio.
  • compositions can be prepared as formulations suitable for administration by a variety of routes, non-limiting examples of which include enteral means, wherein “enteral means” or “enteral administration means” includes, but is not limited to oral solid and oral liquid dosage forms, sublingual, and buccal administration means; as well as parenteral means, wherein “parenteral means” or “parenteral administration means” includes but is not limited to, intravenous, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, intracerebroventricular, rectal, vaginal, ocular, nasal, cutaneous, topical, otic, ocular, transdermal, and subcutaneous administration means.
  • the compounds employed in the methods of the invention are effectively administered as oral solid and oral liquid dosage forms; sublingually or buccally; as injections, including intravenous, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, and intracerebroventricular; rectally, vaginally, ocularly, nasally, cutaneously, topically, oticly, transdermally, and subcutaneously.
  • the compounds employed in the methods of the invention are effectively administered via other means, and prepared as any acceptable compositions known to those of skill. Such compositions may be prepared in any manner known in the pharmaceutical arts that comprise at least one active agent (Sheth et ah, 1980).
  • the active ingredients are often mixed with an excipient, diluted by an excipient, or enclosed within such a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft or hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • Different embodiments include immediate, delayed, extended, and controlled release forms. Many other variations are possible and known to those skilled in the art.
  • ERTAIN routes of administration are multiple routes of administration, which may differ between patients according to patient preferences, comorbidities, side effect profiles, pharmacokinetic and pharmacodynamic considerations, and other factors.
  • the presence of other substances with the active agents known to those skilled in the art, such as fillers, carriers, gels, skin patches, lozenges, or other modifications in the preparation to facilitate absorption through various routes (e.g., gastrointestinal, transdermal, etc.), to extend the effect of the drugs, and/or attain higher or more stable serum levels or enhance the therapeutic effect of the active agents in the combination.
  • Excipients may include, but are not limited to, fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity -increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof.
  • compositions described herein can be formulated into any suitable dosage form, including aqueous oral dispersions, aqueous oral suspensions, solid dosage forms including oral solid dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, self-emulsifying dispersions, solid solutions, liposomal dispersions, lyophilized formulations, tablets, capsules, pills, powders, delayed- release formulations, immediate-release formulations, modified release formulations, extended-release formulations, pulsatile release formulations, multi particulate formulations, and mixed immediate release and controlled release formulations.
  • aqueous oral dispersions aqueous oral suspensions
  • solid dosage forms including oral solid dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, self-emulsifying dispersions, solid solutions, liposomal dispersions, lyophilized formulations, tablets, capsules, pills, powders, delayed- release formulations, immediate-release formulations, modified release formulations
  • the compositions are formulated in a unit dosage form.
  • unit dosage form refers to a physically discrete unit suited as unitary dosages for the subject to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect(s), in association with a suitable pharmaceutical carrier, diluent, or excipient.
  • Unit dosage forms are often used for ease of administration and uniformity of dosage.
  • Unit dosage forms can contain a single or individual dose or unit, a sub dose, or an appropriate fraction thereof (e.g., one half a “full” dose), of the pharmaceutical composition administered.
  • Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampules and vials, which may include a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo.
  • Unit dosage forms also include ampules and vials with liquid compositions disposed therein.
  • Unit dosage forms further include compounds for transdermal administration, such as “patches” that contact the epidermis of a subject for an extended or brief period of time.
  • compositions of the invention are formulated in a pharmaceutically acceptable oral dosage form.
  • Oral solid dosage forms may include but are not limited to, lozenges, troches, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, and/or any combinations thereof.
  • Oral solid dosage forms may be formulated as immediate release, controlled release, sustained release, extended release, or modified release formulations.
  • the oral solid dosage forms of the invention may be in the form of a tablet (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol.
  • a tablet including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid- disintegration tablet, an effervescent tablet, or a caplet
  • a pill including a sterile packaged powder
  • the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including a fast-melt tablet. Additionally, pharmaceutical formulations of the invention may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, three, four, or more capsules or tablets.
  • Oral solid dosage forms may contain pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof.
  • Oral solid dosage forms also can comprise one or more pharmaceutically acceptable additives such as a compatible carrier, complexing agent, ionic dispersion modulator, disintegrating agent, surfactant, lubricant, colorant, moistening agent, plasticizer, stabilizer, wetting agent, anti foaming agent, alone or in combination, as well as supplementary active agent(s).
  • Supplementary active agents include preservatives, antioxidants, antimicrobial agents including biocides and biostats such as antibacterial, antiviral and antifungal agents.
  • the pharmaceutical composition may be an “immediate release formulation,” wherein a therapeutically effective amount of the pharmaceutical composition is administered to the subject in a way that facilitates rapid release.
  • Immediate-release formulations may be prepared by combining a superdisintegrant such as croscarmellose sodium and different grades of microcrystalline cellulose in different ratios.
  • sodium starch glycolate may be added to aid disintegration.
  • Tablets of the invention can be prepared by methods well known in the art.
  • Various methods for the preparation of the immediate release, modified release, controlled release, and extended-release dosage forms e.g., as matrix tablets having one or more modified, controlled, or extended-release layers
  • a tablet may be made by compression or molding.
  • Compressed tablets may be prepared by compressing, in a suitable machine, an active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Molded tablets may be produced by molding, in a suitable apparatus, a mixture of powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide a slow or controlled release of the active ingredient therein.
  • Generally recognized compendia of methods include Remington 2020 and Sheth et al. 1980.
  • solid dosage forms are prepared by mixing the active agents of the invention with one or more pharmaceutical excipients to form a “bulk blend” composition.
  • the bulk blend composition is homogeneous, i.e., the active agents are dispersed evenly throughout so that the bulk blend may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.
  • the individual unit dosages may also comprise film coatings, which disintegrate upon oral ingestion or upon contact with diluents. These formulations can be manufactured by conventional pharmaceutical techniques.
  • Conventional pharmaceutical techniques for preparation of solid dosage forms include, but are not limited to, the following methods, which may be used alone or in combination: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion (see, e.g., Lachman et al. 1986).
  • Other methods include spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tableting, and extruding.
  • oral solid dosage forms may be prepared as immediate release formulations, or as modified release formulations, such as controlled release, extended release, sustained release, or delayed release.
  • the release profile is determined by obtaining objective measurements from a patient, the objective measurements including but are not limited to, weight, body temperature, heart rate, respiratory rate, blood oxygenation, BP and its variables, including, but not limited to: SBP, SBP, MAP, and PP; CNIBP; ECG measurements, including RR interval or its variability, QT interval or its variability, HRV (including measured by devices other than an ECG); hemodynamic response, and levels of glucose, cortisol, serotonin, dopamine, cholesterol; EEG measures; BDNF; genetic markers including relating to CYP enzymes or drug metabolism; genetic variation in mGluR5 or FKBP5; and numerous more, as will be readily appreciated by those of skill.
  • the half-life compared to the half-life of an immediate release formulation is greater by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 50%, at least 75%, at least 100%, or values in between.
  • the formulations are designed to result in a comparable “area under the curve,” or AUCo-24, and a similar safety and efficacy profile, but having a delayed time to maximum concentration (t max ) of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 50%, at least 75%, at least 100%, or values in between, as would be appreciated by one of skill.
  • t max delayed time to maximum concentration
  • a formulation is designed to be a product with a specific time course based on an optimum “therapeutic window,” such as less than about 30 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, and greater than 8 hours, including lengths of time in between.
  • optimum “therapeutic window” such as less than about 30 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, and greater than 8 hours, including lengths of time in between.
  • oral solid dosage forms are formulated as a delayed release dosage form by utilizing an enteric coating to affect release in the small intestine of the gastrointestinal tract.
  • An enteric-coated oral dosage form may be a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated.
  • the enteric-coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.
  • enteric coatings may be used to prepare other controlled release dosage forms, including but not limited to extended release and pulsatile release dosage forms.
  • Pulsatile release dosage forms may be formulated using techniques known in the art, such as those described in U.S. Pat. Nos. 5,011,692, 5,017,381, 5,229,135, and 5,840,329. Other suitable dosage forms are described in U.S. Pat. Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040, 5,567,441 and 5,837,284.
  • the controlled release dosage form is a pulsatile release solid oral dosage form comprising at least two groups of particles, each containing active agents of the invention.
  • “Particles” refers to homogenous groupings of substantially the same active agent.
  • the first group of particles upon ingestion by a subject, provides a substantially immediate dose of the active agents of the invention, and may either be uncoated, or comprise a coating and/or sealant.
  • a single unit dosage form can provide both a first and a second dosage amount in the single form (i.e., a first dosage amount in an immediate release form, and a second dosage amount in a delayed release form).
  • gastroretentive sustained release tablets are formulated by using a combination of hydrophilic polymer (e.g., hydroxypropyl methylcellulose), together with at least one swelling agent (e.g., crospovidone, sodium starch glycolate, and croscarmellose sodium), and an effervescent substance (e.g., sodium bicarbonate).
  • hydrophilic polymer e.g., hydroxypropyl methylcellulose
  • at least one swelling agent e.g., crospovidone, sodium starch glycolate, and croscarmellose sodium
  • an effervescent substance e.g., sodium bicarbonate
  • Coatings for providing a controlled, delayed, or extended release may be applied to the compositions of the invention or to a core containing the compositions, and may comprise a pharmaceutically acceptable ingredient in an amount sufficient to provide a delayed release from, for example, about 1 hour to about 7 hours following ingestion before release of the active agents.
  • Suitable coatings include one or more differentially degradable coatings including pH-sensitive coatings (enteric coatings), or non-enteric coatings having variable thickness to provide differential release of the active agents. Many other types of modified release systems will be known to those of skill.
  • Non-limiting examples of additional delivery systems include both polymer- and nonpolymer-based systems, silastic systems, peptide-based systems, wax coatings, bioerodible dosage forms, and compressed tablets using conventional binders (see, e.g, Liberman et al. 1990; Singh et al. 2002; U.S. Pat. Nos. 4,327,725; 4,624,848; 4,968,509; 5,461,140; 5,456,923; 5,516,527; 5,622,721; 5,686,105; 5,700,410; 5,977,175; 6,465,014; and 6,932,983).
  • compositions of the invention are formulated as a pharmaceutically acceptable oral liquid form.
  • Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like. These oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those of skill for the preparation of liquid dosage forms, and with solvents, diluents, carriers, excipients, and the like chosen as appropriate to the solubility and other properties of the active agents and other ingredients.
  • Solvents may be, e.g., water, glycerin, simple syrup, alcohol, medium chain triglycerides (MCT), and combinations thereof.
  • Oral liquid dosage forms are especially advantageous in treating geriatric and pediatric populations, as the liquid formulation is much easier to swallow.
  • the liquid formulation is also absorbed more rapidly than a solid dosage form, as it need not be dissolved by the digestive system before it is available for absorption.
  • Oral liquid dosage forms may be monophasic or biphasic, the former being a substantially homogenous solution dissolved in water or non-aqueous solvent, while the latter refers to oral liquid dosage forms in which the active ingredients do not fully dissolve in common solvents.
  • the solid particles i.e., the active agents
  • examples of monophasic liquid forms include syrups, linctuses, spirits/essences, elixirs, and fluid extracts.
  • Examples of biphasic liquid forms include oral suspensions, oral emulsions, and mixtures.
  • Liquid dosage forms for oral administration may be prepared as liquid suspensions or solutions using a sterile liquid, such as but not limited to, an oil, water, an alcohol, combinations of pharmaceutically suitable surfactants, suspending agents, and emulsifying agents.
  • a sterile liquid such as but not limited to, an oil, water, an alcohol, combinations of pharmaceutically suitable surfactants, suspending agents, and emulsifying agents.
  • Liquid formulations also may be prepared as single dose or multi-dose beverages.
  • Suspensions may include oils. Such oils include, but are not limited to peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suitable oils also include carrier oils such as MCT and long chain triglyceride (LCT) oils.
  • Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides.
  • Suspension formulations may include alcohols, such as ethanol, isopropyl alcohol, hexadecyl alcohol; glycerol, and propylene glycol.
  • Ethers such as polyethylene glycol; petroleum hydrocarbons, such as mineral oil and petrolatum; and water may also be used in suspension formulations.
  • Suspension can thus include an aqueous liquid or a non-aqueous liquid, an oil-in-water liquid emulsion, or a water-in-oil emulsion.
  • Dosage forms for oral administration may be aqueous suspensions such as aqueous oral dispersions, emulsions, solutions, and syrups (see, e.g., Singh et al. 2002).
  • the liquid dosage forms may comprise additives, such as one or more (a) disintegrating agents, (b) dispersing agents, (c) wetting agents, (d) preservatives, (e) viscosity enhancing agents, (f) sweetening agents, and/or (g) flavoring agents.
  • liquid formulations of the invention may also comprise inert diluents commonly used in the art such as water or other solvents, solubilizing agents, emulsifiers, flavoring agents, and/or sweeteners. Co-solvents and adjuvants also may be added to a formulation.
  • effervescent powders containing the compositions of the invention may be prepared.
  • Effervescent salts are used to disperse medicines in water for oral administration.
  • Effervescent salts also may be packaged as single dose or multi-dose drink mixes, alone or in combination with other ingredients, such as vitamins or electrolytes.
  • Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate and sodium carbonate, citric acid, and/or tartaric acid.
  • salts of the invention When salts of the invention are added to water, the acids and the base react to liberate carbon dioxide gas, thereby causing “effervescence.” Any acid-base combination that results in the liberation of carbon dioxide may be used, as long as the ingredients are suitable for pharmaceutical use, and result in a pH of about 6.0 or higher.
  • compositions of the invention are formulated in a pharmaceutically acceptable transdermal application, and delivered transdermally.
  • transdermal delivery involves contacting the formulations of the invention with a subject’s skin under conditions effective for the active agent(s) to penetrate the skin and cause an effect.
  • Formulations may be prepared as ointments, creams, suspensions, lotions, pastes, gels, sprays, foams, oils, and the like, and any combination thereof.
  • transdermal delivery form is a transdermal “patch” which contains the pharmaceutical compositions.
  • Transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the invention in controlled amounts. Such patches may be constructed for continuous, gradual, pulsatile, or on demand delivery of pharmaceutical agents.
  • a “patch” within the meaning of the invention may be simply a medicated adhesive patch, i.e., a patch impregnated with a composition of the invention for application onto the skin.
  • a patch may be a single-layer or multi-layer drug-in-adhesive patch, wherein the one or more adhesive layers also contain the active agents.
  • a patch may also be a “matrix” (or “monolithic”) patch, wherein the adhesive layer surrounds and overlays the drug layer (wherein a solution or suspension of the active agents is in a semisolid matrix).
  • a “reservoir” patch may also be used, comprising a drug layer, typically as a solution or suspension of the active agents in a liquid compartment (i.e., the reservoir), separate from an adhesive layer.
  • a patch also may be part of a delivery system, for instance used with an electronic device communicatively coupled to the mobile device of a user, and coupled with a mobile application (e.g., to control the delivery rate from the reservoir, and optionally to provide information about delivery back to the application or user).
  • a mobile application e.g., to control the delivery rate from the reservoir, and optionally to provide information about delivery back to the application or user.
  • Various transdermal patch technologies may be accordingly utilized.
  • compositions of the invention may also be prepared as formulations designed for subcutaneous, intravenous, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, or intracerebroventricular, injection.
  • injection formulations may be prepared by dissolving, suspending, or emulsifying the active agent(s) in an aqueous or nonaqueous solvent, non-limiting examples of which include oils, such as vegetable oil, synthetic aliphatic acid glycerides, and esters of higher aliphatic acids or propylene glycol; and may also contain additives such as solubilizers, stabilizers, and suspending, preserving, wetting, emulsifying, dispensing, and isotonic agents.
  • compositions of the invention are formulated in a pharmaceutically acceptable nanostructured formulation, such as a nanoemulsion, a nanocapsule, a nanoparticle conjugate, or a nano-encapsulated oral or nasal spray.
  • a pharmaceutically acceptable nanostructured formulation such as a nanoemulsion, a nanocapsule, a nanoparticle conjugate, or a nano-encapsulated oral or nasal spray.
  • Preparations of the compositions of the invention as certain nanostructured formulations may be done by reference to the general knowledge of the art (see, e.g., Jaiswal 2015).
  • nano as used in the terms describing various embodiments of a nanostructured formulation denotes a size range in the nanometer (“nm”) scale. Accordingly, sizes of such nanoparticle delivery vehicles include those in the range of about 1 to about 100 nm, about 100 to about 200 nm, about 200 to about 400 nm, about 400 to about 600 nm, about 600 to about 800 nm, and about 800 to about 1000 nm, as well as “microparticles” in the range of about 1000 to about 2000 nm (1-2 micrometer (“pm”) scale).
  • lipid-based nanoparticles such as liposomes, solid lipid nanoparticles (SLN), or nanostructured lipid carriers (NLC) are used.
  • compositions of the invention are prepared as pharmaceutically acceptable formulations suitable as oral solid or oral liquid dosage forms, administered sublingually, buccally, topically, rectally, vaginally, ocularly, oticly, nasally, cutaneously, topically, and transdermally; or as intravenous, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, intracerebroventricular, and subcutaneous injection, wherein such injections comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • composition of the invention therefore may be administered via enteral or parenteral means, wherein enteral means includes, but is not limited to, oral solid and oral liquid dosage forms, sublingual, and buccal administration; and parenteral administration means includes, but is not limited to, intravenous, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, intracerebroventricular, rectal, vaginal, ocular, nasal, cutaneous, topical, otic, transdermal, and subcutaneous administration; in addition to other equivalent means known to those of skill.
  • enteral means includes, but is not limited to, oral solid and oral liquid dosage forms, sublingual, and buccal administration
  • parenteral administration means includes, but is not limited to, intravenous, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, intracerebroventricular, rectal, vaginal, ocular, nasal, cutaneous, topical, otic, transdermal, and subcutaneous administration; in addition to other equivalent means known to those of skill
  • administering broadly refers to providing a compound or pharmaceutical composition of the invention to a subject suffering from, or at risk of, the diseases or conditions to be treated or prevented.
  • the terms “subject,” “user,” “patient,” and “individual” are used interchangeably, and refer to any mammal although preferably a human. Such terms will be understood to include one who has an indication for which a compound, composition, or method described herein may be efficacious, or who otherwise may benefit by the invention. In general, all of the compounds, compositions, and methods of the invention will be appreciated to work for all individuals, although individual variation is to be expected, and will be understood.
  • a “route of administration” is the path by which the compound or composition is taken into the body. Routes of administration may be generally classified by the location at which the substance is applied. Common examples may include oral and intravenous administration. Routes can also be classified based on where the target of action is. Action may be topical (local), enteral (system-wide effect, but delivered through the gastrointestinal tract), or parenteral (systemic action, but delivered by routes other than the GI tract).
  • Enteral administration includes administration involving any part of the gastrointestinal tract.
  • the examples may include those by mouth (orally), including oral solid and oral liquid dosage forms, and may be preferably formulated as tablets or capsules.
  • Parenteral administration refers to administration from any means not involving the gastrointestinal tract, including intravenous (into a vein), intra-arterial (into an artery), intraosseous infusion (into the bone marrow), intramuscular, intracerebral (into the brain parenchyma), intracerebroventricular (into cerebral ventricular system), intrathecal (an injection into the spinal canal), otic (through the ear), ocular (through the eye), rectal, vaginal, and subcutaneous (under the skin).
  • parenteral administration may include sublingual and/or buccal administration.
  • a pharmaceutical composition may be administered to a subject via injection.
  • a pharmaceutical composition may be administered to a subject via nasal systems or the mouth through, for example, an oral solid and/or oral liquid dosage forms; inhalation, via a nasal spray or oral inhaler; nebulization, from a “nebulizer,” which is a small machine that turns liquid medicine into a mist; or buccally/sublingually.
  • a pharmaceutical composition may be administered to a subject via a combination of administration means.
  • the pharmaceutical composition may be administered to a subject via one or more enteral administration means.
  • the pharmaceutical composition may be administered to a subject via one or more parenteral administration means.
  • the pharmaceutical composition may be administered to a subject via at least one enteral administration means, and at least one parenteral administration means. In some embodiments, an equivalent route of administration known to one of skill is utilized.
  • EXAMPLE 1 Formulation of capsules with 125 mg or 62.5 mg MDMA Gelatin capsules, containing the below milligram amounts of MDMA are made as follows:
  • MDMA is synthesized through known methods or commercially sourced.
  • the MDMA, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into size 4 hard or soft gelatin capsules in 200 mg or 100 mg quantities as above.
  • EXAMPLE 2 Formulation of tablets with 125 mg or 62.5 mg MDMA Tablets, containing the below milligram amounts of MDMA, are made as follows:
  • the components are blended and compressed into tablets, weighing 300 mg or 150 mg total.
  • any of the compounds may be substituted with the same compound in a different dosage amount (e.g., 120 mg, 115 mg, 110 mg, 105 mg, 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 15 mg, 10 mg, 5 mg, and values in between).
  • a different dosage amount e.g., 120 mg, 115 mg, 110 mg, 105 mg, 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 15 mg, 10 mg, 5 mg, and values in between.
  • racemic MDMA may be substituted with an enantiomerically enriched composition of MDMA, in an enantiomeric excess in any amount greater than 0%, or a pure or substantially pure individual enantiomer, such as an enantiomer in an enantiomeric excess of greater than about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, or preferably above about 90%, such as about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9%, and up to about 100% and including 100%, as well as values in between.
  • a pure or substantially pure individual enantiomer such as an enantiomer in an enantiomeric excess of greater than about 75%, about 76%, about 77%, about 78%, about 7
  • a compound of the invention as used, e.g., in a composition or method of the invention is MDMA
  • a compound will be another therapeutic entactogen.
  • a “therapeutic entactogen” refers to any member of the class of psychoactive compounds that produce distinctive entactogenic effects similar to those of MDMA. Examples of therapeutic entactogens will be known to those in the art, and may for example include substances derived from the 1,3-benzodioxole, cathinone, benzofuran, aminoindane, indole, and amphetamine classes (see, e.g., Oeri 2021).
  • a therapeutic entactogen may be, as non-limiting examples, 1-(1,3- benzodioxol-5-yl)-2-butanamine (BDB); l-(l,3-benzodioxol-5-yl)-N-methyl-2- butanamine (MBDB); 3,4-methylenedioxyamphetamine (MDA); 3,4-methylenedioxy-N- ethyl- amphetamine (MDEA).
  • BDB 1-(1,3- benzodioxol-5-yl)-2-butanamine
  • MBDB l-(l,3-benzodioxol-5-yl)-N-methyl-2- butanamine
  • MDA 3,4-methylenedioxyamphetamine
  • MDEA 3,4-methylenedioxy-N- ethyl- amphetamine
  • a therapeutic entactogen may be 3- methylmethcathinone (3-MMC), mephedrone (4-MMC), methylone, a-ethyltryptamine (aET), a-methyltryptamine (aMT), 5-iodo-2-aminoindane (5-IAI), methylene- dioxyaminoindane (MDAI), methylone, ethylone, butylone, 5-(2-Aminopropyl)-2,3- dihydro- lH-indene (5- APDI, lAP), 6-(2-Aminopropyl)benzofuran (6-APB) (benzofury), 5-(2- aminopropyl)benzofuran (5-APB), 5-MAPB, MDAI, MDOH, or 4-FA (see, e.g., Oeri 2021 and works cited).
  • a therapeutic entactogen of the invention is any substituted methylenedioxy- phenethylamine or “MDxx” compound, as will be understood by those in the art.
  • a therapeutic entactogen is an analog or derivative of an MDxx compound, such as a compound where the methylenedioxyphenyl ring is retained but the phenethyl portion is modified, or a compound which retains the 3,4-cyclised amphetamine core common to the MDxx compounds, but has the 1,3-benzodioxole ring replaced by related heterocycles.
  • a therapeutic entactogen is a “2C-x” compound with entactogenic or primarily entactogenic effects.
  • a therapeutic entactogen will be any other compound generally known to those of ordinary skill in the art as producing “entactogenic” or “empathogenic” effects, and which may also be used in “psychedelic”-assisted therapy, further including single enantiomers and enantiomeric mixtures; salts and solid forms such as polymorphs, hydrates, solvates, and co-crystals; amorphous forms; deuterated and halogenated versions; and prodrugs, metabolites, analogs, and derivatives of any of the above, including combinations thereof, and further including novel chemical compounds or NCEs having similar structures and/or effects, which may be modified to retain one or more entactogenic effects, but have one or more other novel effects (e.g., minimized side effects, reduced neurotoxicity, optimized onset or course of action, optimized pharmacokinetic or pharmacodynamic properties, and the like).
  • novel effects e.g., minimized side effects, reduced neurotoxicity, optimized onset or course of action, optimized pharmacokinetic or
  • compositions within the scope of the invention should be understood to be open-ended and may include additional active or inactive compounds and ingredients. In some embodiments, the composition will contain one or more additional compounds that provide a synergistic effect.
  • the type of formulation employed for the administration of the compounds employed in the methods of the invention generally are dictated by the compound(s) employed, the type of pharmacokinetic profile desired from the route of administration and the compound(s), and the state of the patient. It will be readily appreciated that any of the above embodiments and classes of embodiments can be combined to form additional embodiments and formulations.
  • the invention as disclosed herein provides methods for using therapeutically effective amounts of the pharmaceutical compositions and formulations of the invention in a mammal, and preferably a human. Such methods include those for modulating neurotransmission and for treating a disorder such as a mental health or psychiatric disorder, and specifically AUD.
  • compositions disclosed herein comprise therapeutic amounts of MDMA and/or other active or inactive ingredients.
  • a pharmaceutical composition includes MDMA, it may be present in an amount so that a single dose is (whether or not such dose is present in a unit dosage form), 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg
  • a patient may be administered an initial dose of between 1 mg to 200 mg of MDMA, including 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72
  • the booster dose of MDMA will be 1 ⁇ 2 of the initial dose of MDMA, such that, in an exemplary embodiment, if a subject were administered 100 mg of MDMA in an initial dose, the second such dose administered to the subject would be 50 mg.
  • capsules may be prepared as in Example 1 (or tablets as in Example 2), but with amounts of the active and inactive ingredients adjusted accordingly.
  • the booster dose of MDMA is greater than 100 mg, such as 125 mg, 150 mg, and 175 mg, and including up to 200 mg.
  • a subject is only administered a single dose of MDMA, wherein the single dose of MDMA is between 1 mg to 200 mg of MDMA, including 1 mg to 200 mg of MDMA, including 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg,
  • a single dose of MDMA will be between 25 mg and 175 mg, preferably between 50 mg and 150 mg, and more preferably between 62.5 mg and 125 mg, inclusive.
  • a MDMA-assisted psychotherapy regime of two doses of MDMA is used, with an “initial dose” of 125 mg and a “booster dose” two hours later of 62.5 mg.
  • a MDMA-assisted psychotherapy regime of two doses of MDMA is used, with an initial dose of 100 mg and a “booster” dose two hours later of 50 mg.
  • a MDMA-assisted psychotherapy regime of two doses of MDMA is used, with an initial dose of 80 mg and a “booster” dose two hours later of 40 mg.
  • the booster dose will be 0.5x (1 ⁇ 2) or about 0.5x (1 ⁇ 2) of the initial dose (see, e.g., Sessa et al. 2021).
  • the booster dose will be chosen based on objective or subjective patient measures, based on patient selection or choice at or preceding the time of administration, or based on the exercise of clinical judgment at or preceding the time of administration.
  • participants may receive a third or further dose (i.e., a second or further booster dose), which may be the same, a greater, or a lesser dose than the first booster dose.
  • dosages may vary depending upon the treatment protocol itself, the onset, progression, severity, frequency, duration, probability of, or susceptibility of the symptom to which treatment is directed, clinical endpoint desired, previous, simultaneous or subsequent treatments, general health, age, gender, and race of the subject, bioavailability, potential adverse systemic, regional, or local side effects, the presence of other disorders or diseases in the subject, and other factors that will be appreciated by the skilled artisan (e.g., medical or familial history).
  • the upper age range of subjects may be limited, e.g., to 65 years, and patients may be screened for cardiac abnormalities, and for medications that may affect the metabolism of MDMA (e.g., through CYP2D6 or CYP3A4), or genetic variations that may affect metabolism of MDMA.
  • MDMA metabolism of MDMA
  • Dose amount, frequency or duration may be increased or reduced, as indicated by the clinical outcome desired, status of the pathology or symptom, any adverse side effects of the treatment or therapy, or concomitant medications.
  • MDMA at doses of 1 GO- 125 mg has been associated with increases in heart rate (of 26-30 bpm) and blood pressure (of diastolic 14.4-25 mmg) (Harris 2002, Mas 1999, Mithoefer et al. 2011) these may be carefully monitored following the regime disclosed elsewhere (Oehen et al. 2013, Chabrol & Oehen 2013), and patients experiencing particular symptoms may not receive a booster dose.
  • the skilled artisan with the teaching of this disclosure in hand will appreciate the factors that may influence the dosage, frequency, and timing required to provide an amount sufficient or effective for providing a therapeutic effect or benefit, and to avoid or minimize adverse effects.
  • the dose actually administered will be determined by a physician, in light of the relevant circumstances, the method of delivery, (i.e., methods that are systemic and that are not subject to first pass effect will require less of a dose than those which are metabolised prior to entering the bloodstream; the age of the patient, the weight of the patient, whether the patient has any comorbidities (i.e., any other medical conditions simultaneously present within a patient), other medications the patient is taking (routinely or presently), and any patient-specific aspects that could affect the way in which the pharmaceutical composition interacts with the patient, such as variations in metabolism, variations in patient response, etc., and therefore any dosage ranges disclosed herein are not intended to limit the scope of the invention.
  • the method of delivery i.e., methods that are systemic and that are not subject to first pass effect will require less of a dose than those which are metabolised prior to entering the bloodstream; the age of the patient, the weight of the patient, whether the patient has any comorbidities (i.e., any other medical conditions simultaneously
  • dosage levels below the lower limit of a disclosed range may be more than adequate, while in other cases doses above a range may be employed without causing any harmful side effects, provided for instance that such larger doses also may be divided into several smaller doses for administration, either taken together or separately.
  • the pharmaceutical compositions may be administered and dosed in accordance with good medical practice, taking into account the method and scheduling of administration, prior and concomitant medications and medical supplements, the clinical condition of the individual patient and the severity of the underlying disease, the patient’s age, sex, body weight, and other such factors relevant to medical practitioners, and knowledge of the particular compound(s) used.
  • Dosage levels thus may differ from patient to patient, for individual patients across time, and for different pharmaceutical compositions and formulations, but shall be able to be determined with ordinary skill. Determination of appropriate dosing shall include not only the determination of single dosage amounts, but also the determination of the number and timing of doses, and the time(s) of day or time(s) during a psychotherapeutic session preferable for their administration.
  • suggested dosage amounts shall be known by reference to the format of the preparation itself.
  • suggested dosage amounts may be known by reference to the means of administration or by reference to the packaging and labeling, package insert(s), marketing materials, training materials, or other information and knowledge available to those of skill or the public.
  • Another aspect of this disclosure therefore provides pharmaceutical kits containing a pharmaceutical composition or formulation of the invention, suggested administration guidelines or prescribing information therefor, and a suitable container. Individual unit dosage forms can be included in multi-dose kits or containers. Pharmaceutical formulations also can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.
  • compositions disclosed herein are shown to be useful in methods for treating AUD, as in the exemplary treatment methods now described.
  • a patient prior to beginning a therapy protocol, a patient will be enrolled in a preparation group.
  • a person is first assessed to determine whether they are eligible for treatment at screening (i.e., whether they meet all inclusion criteria, as defined herein, and do not meet any exclusion criteria, as defined herein). If so, the person may participate in the preparation group.
  • the preparation group will span four weeks and include content such as “building confidence” which includes discussing problems drinking has caused in the patient’s family, job, social life, health, etc.; why change is necessary (completing a cost benefit analysis worksheet), discussing when something went well for the patient, completing a drinking diary, where drinking is monitored daily for one week; and completing “homework” tasks, such as the drinking diary and a worksheet detailing the patient’s strengths and weaknesses; “resources, barriers, and goal setting” which includes discussing goal setting as it relates to drinking, reviewing potential barriers and resources that may aid in the reduction of alcohol consumption, such as discussing the patient’s strengths and qualities, and identifying social and community support outlets; completing homework tasks, such as setting a goal related to alcohol consumption, completing a daily diary, and completing a worksheet that details social and community support outlets; “increasing rewarding activities and building support” which includes identifying challenges that may hinder the accomplishment of goals, and discussing how those challenges were/would be managed; reviewing the social and community support worksheet, and working
  • a patient successfully completes the preparation group course may refer to, e.g., the patient successfully reducing their alcohol intake as compared to their alcohol intake prior to the start of the preparation group course and/or the patient actively participating in the preparation group, such that the patient readily collaborates with the other members of the preparation group and fully or substantially completes each task required in the preparation group), and the patient remains eligible for treatment (e.g., meets all required “inclusion criteria” and does not meet at least one “exclusion criteria,”) the patient may begin a treatment protocol.
  • the methods of the invention may reduce relapse rates (wherein “relapse” refers to a resumption of drinking at a level that is above the threshold of “harmful use” as quantified by the ICD-10).
  • the methods of the invention may reduce relapse rates by increasing the participant’s “psychological flexibility,” wherein psychological flexibility refers to a person’s ability to be responsive and adaptive to situations as they arise, to shift perspectives (as opposed to being rigid or ‘stuck’) and to act mindfully in accordance with core values (rather than reacting impulsively or on ‘auto-pilot’).
  • the methods of the invention will include therapy sessions employing acceptance and commitment therapy (ACT), an enhanced form of cognitive behavioral therapy (CBT), which focuses upon an individual’s relationship with their internal experiences (e.g., thoughts, emotions, physical sensations, memories) rather than the content of these experiences, and uses mindfulness as one of the cornerstones from which to explore this.
  • ACT acceptance and commitment therapy
  • CBT cognitive behavioral therapy
  • the main purpose of ACT is to increase psychological flexibility via six core processes of being mindfully present, stepping back and being willing to accept all internal experiences, defusing thoughts, taking an observer's perspective, awareness of values (e.g., what’s important), and acting in accordance with those values.
  • the methods of the invention are useful in helping an individual achieve a more fulfilling and meaningful life (via increased psychological flexibility).
  • a reduction in the levels of distress are typically a welcome by-product of ACT interventions (Harris, 2009).
  • ACT can be seen as supporting and building upon the core mechanism of psychedelic-assisted therapies which enhance psychological flexibility, alongside enhancing the relapse prevention objective in supporting people to achieve a more fulfilling life without alcohol.
  • Relapse prevention can be an integral part of alcohol treatment. This intervention typically involves supporting individuals to develop greater insight regarding the potential triggers and high risk situations for using alcohol, identifying early warning signs and, crucially, developing effective coping skills and enhanced self-efficacy to manage these situations (Hendershot et al., 2011). Mindfulness-based relapse prevention (Marlatt et ah, 2011) incorporates core elements of mindfulness skills into this intervention.
  • Mindfulness can be defined as “paying attention in a particular way: on purpose, in the present moment, and non-judgmentally” (Kabat-Zinn, 1994) and has been embedded across a range of therapeutic interventions including CBT for depression (Teasdale et al., 2000) and stress-reduction (Kabat- Zinn et al., 1992).
  • CBT depression
  • Kabat- Zinn et al., 1992 stress-reduction
  • mindfulness-based principles can be incorporated via helping individuals to pay attention to their internal experiences (e.g., thoughts and emotions) and their potential role in relapse and practice in incorporating mindfulness practices into daily life (Bowen et al., 2009).
  • the methods of the invention employ one or more elements of mindfulness skills, for example in mindfulness-based relapse prevention, or otherwise employ mindfulness-based principles or mindfulness practices, including for purposes of relapse prevention, or to provide or support one or more other therapeutic effects, including: (a) reducing alcohol use, (b) reducing alcohol cravings, (c) promoting alcohol abstinence,
  • the one or more elements of mindfulness skills, or employment of mindfulness-based principles or mindfulness practices will provide or support one or more of: (a) increasing quality of life, (b) increasing psychosocial functioning, (c) decreasing use or frequency of a prescription medication, (d) decreasing use or frequency of a recreational drug,
  • the methods of the invention employ motivational interviewing (MI), a technique used to enhance motivation to change behavior that is widely used in addiction services.
  • MI motivational interviewing
  • Miller & Rollnick (1991) describe a key element of this process as coming alongside the individual to explore ambivalence and elicit the person’ s own ideas about change.
  • MI is characterized by therapists’ unconditional acceptance of where the individual finds themselves and their perspective.
  • a therapist’s role is to work in partnership and collaboration (not to act as the expert, to lecture or argue), to be genuinely curious and ask questions that provide opportunities for the individual to hear themselves talk about change and to have compassion for the individual (to prioritise their needs and an authentic regard for their well-being).
  • the treatment flow can be conceived in phases as follows, and are specifically outlined in FIG. 12: screening and initial eligibility check (1201); pre-MDMA course preparatory group therapy course, e.g., a four-week course of weekly sessions (1202); Baseline visit and eligibility confirmation (1203); an MDMA-assisted psychotherapy course, e.g., over eight or 13 weeks (1204); follow-up and data collection, e.g., at 3 months, 6 months, and 9 months (1205).
  • Potential patients will be invited to a screening visit where their eligibility for MDMA- assisted psychotherapy using the methods of the invention will be determined.
  • the screening visit will include informed consent, medical, psychiatric and substance use history, prescribed medication use, basic physiological observations and alcohol breath test, urine drugs, and pregnancy screen as clinically indicated.
  • they can be asked about their use of, or desire to use, illicit ecstasy, e.g., with standard questions such as those used by MAPS in MDMA-assisted therapy studies.
  • a psychiatric assessment is sought. In such embodiments, it will be performed by a trained psychiatrist. Assessments may include, e.g.: (1) the Mini International Neuropsychiatric Interview 5 (MINI 5) (Sheehan et al. 1998) to screen for comorbid psychiatric disorders; (2) diagnostic evaluation of the presence of Alcohol Use Disorder according to DSM-5 (assessed using SCID-5-CT (Clinical Trials Version) (First et al. 2015)); (3) diagnostic evaluation of the presence of AUD in the absence of physical dependence, as guided by the SADQ; and (4) clinical risk assessment for suicidality using the Columbia Suicide Severity Rating Scale (C-SSRS) (Mundt2013). Clinical data collection may include years of alcohol use and any dependence, complications/consequences, and previous therapeutic inputs provided including any previous in-patient or community alcohol detox programs. Other questionnaires may also be completed, as will be appreciated.
  • MINI 5 Mini International Neuropsychiatric Interview 5
  • SCID-5-CT C
  • information about alcohol consumption for the three months previous to the screening visit is assessed using the Alcohol Timeline Follow Back (TLFB) method, the gold-standard in self-report substance use, which utilizes a calendar method and memory aids to collect retrospective estimates of daily drinking to obtain accurate daily estimates of the quantity of alcohol consumption (Sobell 2001). Patients may receive the same calendar to take away to track their drinking behavior for the duration of the therapy.
  • TLFB Alcohol Timeline Follow Back
  • participant will attend weekly sessions of group therapy, which will be run by a trained professional with expertise in addiction treatment.
  • participants will attend weekly sessions of group therapy for four weeks, although shorter or longer courses may also be used, and in some embodiments the preparatory group therapy course may be skipped entirely.
  • the purpose of the group will be to provide psychosocial support to assist individuals to gradually reduce their alcohol intake prior to starting the course of MDMA-assisted therapy.
  • a reduction in daily or weekly alcohol consumption should form part of a structured, individualised care plan involving careful preparation (NICE Guidelines). Adequate preparation also benefits from consideration of a person’s support network, motivation and after-care planning to improve post-treatment outcomes (Kouimtsidis, 2017). Prior to being considered ready for the MDMA-assisted course, patients thus may attend weekly sessions of group therapy.
  • groups of between 5 and 10 participants can be facilitated by one or two trained staff with experience in delivering motivational interview style alcohol treatment group counseling.
  • the number of participants and instructors may vary and, in some embodiments, the number of participants may be greater than 10, including at least 12, at least 14, at least 16, at least 18, and at least 20. Likewise, the number of participants may be less than 5, including 4, 3, 2, or 1.
  • the number of trained staff with experience in delivering motivational interview-style alcohol treatment group counseling may, in some embodiments, be greater than 2, including 3, 4, 5, 6, 7, 8, 9, 10, or more than 10.
  • participant groups rather than participating in an in-person group therapy course, participants attend a synchronous virtual group therapy course (i.e., participants attend all sessions “live,” but remote, e.g., via computer).
  • participants attend an asynchronous virtual group therapy course (i.e., attend at selected times of their choosing, where less than all participants may attend at the same time), and wherein one or more portions of the course will be pre-recorded.
  • Participants attending a detoxification course may also attend a synchronous or asynchronous virtual course.
  • each weekly group therapy session will last for between about 30 minutes to about 120 minutes. In some embodiments, weekly group therapy sessions will last for about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, about 120 minutes, and values in between. In some embodiments, weekly group therapy sessions may last for greater than 120 minutes, or may take place in a residential (or “rehab”) facility. In some embodiments, groups are closed and confidential. In some embodiments, patients are enrolled into the groups on a rolling basis and will leave after a minimum (e.g., of four) weeks attendance to be enrolled into the MDMA-assisted psychotherapy course when deemed appropriate by the facilitators.
  • a patient is not deemed sufficiently engaged in the preparation phase (e.g., as deemed by the group facilitators) and/or has not managed to reduce their use of alcohol to zero, their enrollment into the MDMA-assisted psychotherapy course can be delayed until they are considered to be adequately prepared or otherwise ready to progress.
  • further preparation it may include attending further group sessions which, in some embodiments, requires repeating the entire course while, in other embodiments, merely repeating one or more weeks of the course.
  • the participant After a participant has successfully completed the pre-treatment preparation group therapy course, the participant will be assessed for eligibility to start the MDMA-assisted psychotherapy course. This is the “baseline” point. During this visit, continued consent is confirmed and vital signs reassessed (pulse, blood pressure, etc.). A brief physical examination and ECG is performed, and blood samples for routine laboratory tests (urea and electrolytes, full blood count, liver function tests and Gamma-GT) are also completed. A blood test is not required if the patient has had one in, e.g., the last three months.
  • a patient will receive ten total therapy sessions during the treatment phase: eight 60-minute psychotherapy sessions, and two 6-8 hour MDMA-assisted psychotherapy sessions. Sessions will take place approximately 1-2 weeks apart and start as soon as possible after baseline.
  • MDMA-assisted psychotherapy sessions may be run by a therapist pair, e.g., one male and one female, although they also may be run by two male or two female therapists, one male and one non-binary therapist, one female and one non-binary therapist, two nonbinary therapists, a single therapist, or more than two therapists.
  • a therapist pair e.g., one male and one female, although they also may be run by two male or two female therapists, one male and one non-binary therapist, one female and one non-binary therapist, two nonbinary therapists, a single therapist, or more than two therapists.
  • psychological support during each MDMA session preferably will be provided by two members comprising a “therapy team.”
  • “therapy team” is used herein, it will be appreciated that modifications can be made to accommodate more than two therapists, such as 3, 4, or 5 therapists; or use a single therapist, and in such embodiments “team” will refer to that therapist alone (or where appropriate in context, to that therapist and another therapist or clinician not necessarily present with the patient during an MDMA-assisted or other therapy session, but nevertheless a member of the patient’s overall care team).
  • a therapy team may comprise a psychiatrist and a co-therapist who is a clinical psychologist or psychotherapist, but either member may be a “therapist” as the term is defined above.
  • a dyadic male-female pair is used in some embodiments herein.
  • a dyadic male-female pair is a feature of certain MDMA-assisted therapy (Greer and Tolbert 1998); however, the co therapist pair herein need not necessarily be male-female; same-sex pairs, and pairs comprising at least one member not identifying as a male or a female are also appropriate.
  • a dyadic therapy pair is used, in some embodiments, a patient will get to know both therapists in the preparatory sessions before their first MDMA session. In such embodiments, a facilitative relationship is thereby developed, which will aim to reduce discomfort or difficulties that might arise during the course of therapy.
  • the patient will drive the psychotherapy sessions according to the patient’s individual needs.
  • the therapists guide the psychotherapy sessions.
  • the therapeutic approach may be guided in part with reference to the Manual for MDMA- Assisted Psychotherapy in the Treatment of PTSD (Mithoefer, 2017).
  • Sessions 1 and 2 Therapists will discuss MDMA, how it works, the expected effects, risks and review of the historical evidence of MDMA as a tool for psychotherapy.
  • the patient will be invited to share aspects of their life history that they feel important for the therapists to know, given that, without being bound by theory, thoughts, feelings, images and memories about past experiences may come to the patient’s mind during the MDMA session.
  • Discussion in some embodiments, will also include questions about the patient’s internal experiences (e.g., thoughts, emotions, imagery) and their understanding of this.
  • the patient will be invited to discuss their current coping responses and any goals/hopes for participating in the study, alongside any intentions for what they would like to explore during the MDMA session.
  • Session 3 (MDMA-assisted session ): Patients will arrive at an agreed time which, in some embodiments, is in the morning — for instance between approximately 8-9 am. However, the scheduled time need not be in the morning, and may instead be in the afternoon, the evening, or late at night. Regardless, continued consent will be registered and eligibility may be checked, including assessment of physical health, alcohol breath test and urine drugs screen for recreational drugs and pregnancy (if applicable). Vital sign measurements such as heart rate, blood pressure, and temperature may be taken at baseline before the MDMA is administered and before discharge (or more frequently if clinically indicated, including by use of medical sensors or biosensors that provide continuous, near-continuous, or periodic measurements).
  • patients will receive an initial dose of about 125 mg MDMA (e.g., two capsules or tablets of 62.5 mg each), as in the formulations of Examples 1 and 2 or the equivalent.
  • patients may receive an initial dose of another amount, e.g., 100 mg or 80 mg.
  • Patients will be invited to relax for about 90 minutes, lying down with eyeshades on if happy to do so. The patient may have the option to listen to music, either through headphones or into the room, and may continue to do so throughout the therapy session.
  • This initial phase of the effects of MDMA most patients prefer to have little communication but rather to acclimatize to the psychological and physical effects of the drug.
  • the patient may be given the option to receive a further supplemental dose of, in some embodiments, half the original dose (i.e., 62.5 mg MDMA, in this example; or, e.g., 50 mg or 40 mg).
  • the time of administration of the supplemental dose will be two hours following the administration of the initial dose.
  • the time of administration of the booster dose will be determined so as to extend peak subjective effects.
  • the time of administration of the booster dose will be determined so as to optimize the plasma concentration-time profile, e.g., by prolonging the time at higher plasma concentrations.
  • the purpose of this is to prolong the psychological and direct pharmacological effects of the drug to allow for further time for psychotherapy, and therefore such prolongation can be optimized or determined either by reference to the subjective (psychological) effects, or the pharmacokinetic (pharmacological) effects, or through other known methods in the art.
  • the patient may be required to remain in the facility until they are deemed fit to return home. They may, e.g., be assessed by the attendant doctor and signed off as medically fit for discharge. If not deemed ready to leave they may be required to remain in the therapy facility until deemed medically fit for discharge. The patient may then be met at the facility by their pre-arranged significant other, who can accompany them home. Generally, for safety reasons, a patient should not be permitted to leave on their own.
  • Session 4 The day following session 3, the patient may undertake a follow-up session with the therapy team. This generally will involve a 60-minute face-to-face follow-up session discussing aspects of MDMA-assisted psychotherapy undertaken the day before. Patients will be given the contact details of a clinical member of the therapy team whom they can contact if required for further telephone support during the week after each MDMA session. In some embodiments, patients will receive one or more remote or virtual follow-ups after session 4, for example daily phone calls or using another follow-up means as described further below.
  • Session 7 (MDMA-assisted session) . Same as session 3 above; outlined in TABLE 5.
  • Session 9 and 10 Same as sessions 5 and 6 above, as outlined in TABLE 5, wherein the patient has the opportunity to reflect upon the MDMA session and to explore the material that emerged, and to reflect on new insights or perspectives gained/how this may impact on the issues unpinning their addictive behaviors and/or other areas of difficulty, and discuss any intentions for the next MDMA session.
  • patients may be invited to consider any meaningful goals and/or values that they would like to focus on and move toward beyond the treatment phase.
  • THQ Trauma History Questionnaire
  • a patient will receive 16 total therapy sessions during the treatment phase: thirteen 60-minute psychotherapy sessions, and three 6-8 hour MDMA-assisted psychotherapy sessions. Sessions will take place approximately 1-2 weeks apart and start as soon as possible after baseline (generally, within approximately one to three weeks).
  • Phases one through four preceding this 13-week MDMA-assisted psychotherapy course generally are the same as those outlined in the 8-week course of TABLE 5.
  • the MDMA-assisted psychotherapy sessions may be run by a therapy team, wherein the team comprises a male and a female pair, or in alternative embodiments, two males, two females, or one or two individuals not identifying with either male or female.
  • the protocols for each therapeutic session are as generally described above, with modifications such as those in response to, or accommodation of, the overall longer course of treatment and the additional MDMA session, as will be appreciated by those of ordinary skill from the teachings herein and the general knowledge in the art.
  • Sessions 13-14 Generally, as sessions 3 and 4, and 7 and 8 of the eight-week course outlined in TABLE 5.
  • Sessions 15 and 16 Generally, the same as sessions 9 and 10 in the eight- week course outlined in TABLE 5. Patients may continue to consider any meaningful goals and/or values that they would like to focus on and move toward beyond the treatment phase.
  • session 16 the final session in this exemplary embodiment, the patient may complete outcome measures after the therapy session has ended, such as the Trauma History Questionnaire (THQ). The visit including the therapy session will take approximately 1.5 hours.
  • TQ Trauma History Questionnaire
  • treatment is either considered complete, or the patient progresses to the follow-up phase below.
  • one or more of sessions 10-12 are eliminated or made optional, as may be one or more other sessions, or one or more sessions in the eight week treatment protocol above (e.g., session 6 or 9).
  • “Follow-up” phase refers to the period following the last session of the MDMA-assisted psychotherapy course (e.g., session 10 or session 16 above) or, if a patient discontinued treatment, from two weeks after the final psychotherapy session to the final follow-up visit.
  • outcomes will be assessed at 3 months, 6 months, and 9 months after the end of baseline or the initial detoxification.
  • the final follow-up visit is thus at 9 months post baseline or detoxification completion.
  • a final follow-up visit may be 12 months or longer post baseline or detoxification.
  • Means of performing follow-up visits and gathering follow-up data include in-person visits, telemedicine and other virtual visits, phone calls, automated inquiries and check-ins (e.g., email questionnaires, mobile apps, etc.), and the like. Accordingly, it will be appreciated that a “visit” need not be an in-person or face-to-face visit with a member of the therapy team, or another clinician.
  • Audit data from clinical notes indicates that formal assessment data for patients seeking treatment for AUD (including for those who undergo community detoxification) is typically sparse and difficult to collect. Accordingly, in preferred embodiments herein, means are provided to not only collect high quality data about patient outcomes, but to do so in a way that increases compliance and successful data collection. Such means will ease the burdens of collecting follow-up data (to patients, caregivers, and others), minimize attrition rates (previously shown to be in the range of 10-35% by Hallgren KA, Witkiewitz 2013), and avoid the pitfalls of using statistical analysis to predict outcomes for those lost to follow-up by collecting good quality long term outcome data in these studies from the outset, e.g., by advantageously enhancing contact with patients or by using optimized means.
  • Follow-up telephone calls (estimated duration: 5-10 mins) also can be utilized to gather follow-up data to determine therapeutic efficacy and measure therapeutic effect.
  • Systematic efforts will be made to contact patients to collect follow-up data; however, because some patients may be difficult to contact, patients can be asked (as an eligibility criterion) to identify a significant other who can be contacted in the event that the therapy team is unable to contact the patient to collect outcome data.
  • patients can be asked (as an eligibility criterion) to identify a significant other who can be contacted in the event that the therapy team is unable to contact the patient to collect outcome data.
  • a significant other also may be asked to give information about outcome (drinking behavior etc.).
  • EXAMPLE 4 Open Label Within-Subject Safety and Tolerability Feasibility Study of MDMA-Assisted Psychotherapy in Patients with “ Harmful Use” AUD
  • the study of this Example is an open label within-subject safety and tolerability feasibility study, in patients with AUD. All patients will receive MDMA-assisted therapy.
  • the main outcome measures will be the number of patients completing the eight week psychotherapy course, the number accepting the second booster dose of MDMA on drug assisted days and adverse events.
  • Secondary outcome measures will include changes in drinking behavior (measured by “units per week consumed,” wherein a standard drink contains about 14 g of pure alcohol (ethanol), at 3 months, 6 months, and 9 months since baseline), measures of mental well-being, psycho-social functioning, quality of life and concomitant drug use.
  • patients After completing a group therapy preparation course, patients will receive an eight week course of abstinence-based therapy comprising 10 psychotherapy sessions (such as described in further detail above). On two of these sessions (session 3 and 7) patients will be dosed with open-label MDMA during a 6-8 hour assisted therapy session. The eight week therapeutic course will start as soon as possible after a patient has completed the preparation course (with a delay up to two weeks).
  • patients will receive 16 therapy sessions, comprising 13 60-minute non-drug psychotherapy sessions and three, 6-8 hour MDMA-assisted therapy sessions. MDMA-assisted sessions will take place between three and five weeks apart (the interval between drug sessions 1 and 2 is three weeks, and the interval between drug sessions 2 and 3 is five weeks). This 13 week therapeutic course also will start as soon as possible after a patient has completed the four week group preparation course (with a delay up to two weeks).
  • MDMA i.e., substantially pure racemic MDMA HC1
  • Sterling Pharmaceuticals Newcastle
  • RVMA substantially pure racemic MDMA HC1
  • the clinic holds a schedule one license for Home Office approved storage, prescribing, and dispensing of MDMA. It will be within the knowledge of one of skill as to how to obtain such a license, if it is still required.
  • a patient On each dosing session, patients will receive an initial oral dose of 125 mg MDMA (i.e., two capsules), followed two-hours later by an optional booster dose of 62.5 mg (i.e., one capsule).
  • the booster dose will serve to prolong the experience, allowing for greater time for psychotherapy under the influence of MDMA.
  • a patient may only receive a single initial dose of MDMA, while in some embodiments, a patient may receive two doses of MDMA, the first being an initial dose, and the second being a booster dose.
  • Other sessions i.e., sessions 1, 2, 4, 5, 6, and 8-10 will comprise one hour psychotherapy sessions, and employ aspects of Motivational Interviewing and “third wave” cognitive-behavioral approaches, for example, modified cognitive-behavioral approaches, such as Acceptance and Commitment Therapy. Patients will remain in the study for a duration of approximately 10 months.
  • AUD will be identified using the ICD-10 SCID questionnaire. Screening will comprise of written informed consent, an evaluation of the patient’s physical and mental health background, a psychiatric interview (MINI), assessments of depression and anxiety severity will be assessed using the PHQ-9 and GAD-7 questionnaires. Severity of AUD will be established using the SADQ and SIP questionnaires. Patients will receive a thorough physical health check comprising an electrocardiogram (ECG), routine blood tests, blood pressure, heart rate, and physical examination. Following screening, eligible patients will first receive a four- week course of supportive group therapy (motivational group meetings) in order to gradually reduce their intake of alcohol.
  • ECG electrocardiogram
  • EXAMPLE 5 Randomized Double-Blind Between-Subject Controlled Study of MDMA- Assisted Psychotherapy in Patients with “ Harmful Use” AUD
  • MDMA-assisted psychotherapy is an effective treatment for patients with AUD, who do not have physical dependence.
  • the study of this Example will show that MDMA-assisted psychotherapy is superior to placebo dose MDMA-assisted psychotherapy and can reduce use of alcohol in patients without physical alcohol dependence and improve quality of life in patients with AUD.
  • patients will first receive a four-week course of supportive group therapy (motivational group meetings) in order to gradually reduce their intake of alcohol. Once abstinent, they will enter a 13-week course of MDMA-assisted therapy, comprising 15 psychotherapy sessions (or, in an alternate aspect, an eight-week course as in the embodiment above). Patients are randomized to either subtherapeutic / active control (placebo) or therapeutic dose. On three psychotherapy sessions (sessions 3, 7 and 13) patients will be given either active control (20 mg + 10 mg subtherapeutic) dose of MDMA or active therapeutic (125 mg + 62.5 mg) dose MDMA during the 6-8 hour assisted therapy sessions. Patients may optionally stay overnight, or go home after their MDMA session. Other sessions (1, 2, 4-6, 8-12, 14 and 15) will comprise non-drug-assisted 1 -hour psychotherapy sessions.
  • the pharmaceutical compositions of the invention are used to improve the symptoms of a mental health disorder, wherein the mental health disorder is a substance abuse disorder.
  • the mental health disorder is a substance abuse disorder.
  • that substance use disorder is AUD, and specifically non-physically dependent “harmful use” AUD.
  • the symptoms of the mental health disorder to be treated e.g., the symptoms of non-physically dependent AUD
  • the pharmaceutical compositions of the invention (and their use in the methods of the invention) will produce a therapeutic effect, and such effect may be (1) an improvement in a symptom of a comorbid psychiatric disorder; (2) an increase in quality of life; (3) an increase in psychosocial functioning; (4) a decrease in use or frequency of prescription medication; (5) a decrease in use or frequency of recreational drugs; (6) a decrease in units of alcohol consumed; (7) a reduction of cravings relating to alcohol; (8) a prevention of relapse.
  • the treatment flow can be conceived in phases as follows, and is outlined in FIG. 13: screening and initial eligibility check (1301); pre-detox group therapy, e.g., a four-week course of weekly sessions (1302); an alcohol detoxification course, e.g., over two weeks (1303); baseline visit and eligibility confirmation (1304); an MDMA-assisted psychotherapy course, e.g., over eight or 13 weeks (1305); follow-up and data collection, e.g., at 3 months, 6 months, and 9 months (1306).
  • pre-detox group therapy e.g., a four-week course of weekly sessions (1302)
  • an alcohol detoxification course e.g., over two weeks (1303
  • an MDMA-assisted psychotherapy course e.g., over eight or 13 weeks (1305
  • follow-up and data collection e.g., at 3 months, 6 months, and 9 months (1306).
  • Clinical data collection may include years of alcohol dependence, complications/consequences, and previous therapeutic inputs provided including any previous in-patient or community alcohol detox programs.
  • Pre-detoxification baseline questionnaires also may be completed. Information about alcohol consumption for the three months previous to the screening visit may be assessed using the Alcohol Time Line Follow Back (TLFB) method (Sobell 2001). This is a validated assessment using a calendar method and memory aids to collect retrospective estimates of daily drinking. Patients also may be given the same calendar to take away to help track their drinking behavior for the duration of the therapy.
  • TLFB Alcohol Time Line Follow Back
  • Groups will be, e.g., between five and 10 patients and may be facilitated by one or two trained staff with experience in delivering pre-detox group counseling. Each group session may be for, e.g., 60 minutes and should take place at a predetermined location. In some embodiments, pre-detox group sessions will last for about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, about 80 minutes, about 85 minutes, about 90 minutes, about 95 minutes, about 100 minutes, about 105 minutes, about 110 minutes, about 115 minutes, about 120 minutes, and values in between.
  • pre-detox group sessions may last for greater than 120 minutes, or may take place in a residential (or “rehab”) facility.
  • groups are closed and confidential. Patients may be enrolled into the groups on a rolling basis, and will leave after a minimum (e.g., of four) weeks attendance to be enrolled into a detox course when deemed appropriate by the facilitators. If a patient fails to attend at least (in the example embodiment, four weeks) of pre-detox group counseling, their detox may be delayed until deemed ready to progress. Similarly, if a patient is not deemed sufficiently engaged in the preparation phase — generally, as deemed by the group facilitators — their detox may be delayed until they are considered to be adequately prepared (e.g., by attending further group sessions).
  • Alcohol detoxification may be achieved either by gradual reductions in daily alcohol use (which may begin from the start of the pre-detox group phase, with support from the group facilitators) and/or through a medical detox.
  • the medical detox procedure outlined in FIG 3., is disclosed in further detail as follows:
  • a patient will undergo a medical assessment (1401). Physical examination and baseline physiological measures, e.g., blood pressure, will be recorded.
  • physiological measures e.g., blood pressure
  • the patient may attend a clinic daily (1403) to be prescribed a sliding scale of benzodiazepine treatment (such as chlordiazepoxide) over the next 10-14 days.
  • benzodiazepine treatment such as chlordiazepoxide
  • Chlordiazepoxide or other pharmacotherapeutic treatment e.g., another benzodiazepine
  • Chlordiazepoxide or other pharmacotherapeutic treatment is prescribed according to good medical practice and dosing regimens known to those in the art.
  • the patient may be assessed by a specialist addictions nurse at each daily visit throughout the detoxification (1404).
  • Daily measurements of blood pressure may be performed.
  • Daily measurements of the Clinical Institute Withdrawal Assessment for Alcohol — Revised Version (CIWA-Ar) (Saitz et al. 1994) (detox assessment measure) may be used to assess response to benzodiazepine administration and progress of the detox.
  • the detox is found to be successful (1406)(1407), the detox is complete (1408) and the patient may proceed to treatment. If the detox is found to be incomplete, and thus not successful (1406)(1409) the clinical team may decide whether further interventions are required (1410) before progressing to MDMA-assisted psychotherapy, or whether the patient must return to a prior step (1411).
  • patients may attend a baseline visit to confirm eligibility for continuation into MDMA-assisted psychotherapy. During this visit, continued consent should be confirmed and vital signs can be reassessed. A brief physical examination and ECG may be performed, and blood samples for routine laboratory tests (urea and electrolytes, full blood count, liver function tests and Gamma-GT) also may be completed. A blood test may not be required if the patient has had one in, e.g., the last three months.
  • the MDMA-assisted therapy course may be an eight-week MDMA-assisted psychotherapy course with two MDMA sessions (as in TABLE 5) or a 13 -week MDMA- assisted psychotherapy course with three MDMA sessions (as in TABLE 6), or a modification of either, based on the teachings herein and the general knowledge in the art.
  • FIG. 16 outlines one embodiment of the protocol of this Example that is useful in treating alcohol use disorder in a patient in need thereof, and is further discussed below.
  • the protocol of this Example will be used with one or more individuals (the term used interchangeably with patients) who have harmful use AUD; in other embodiments, the protocol of this Example will be used with one or more individuals who have dependent use AUD; in other embodiments, the protocol of this Example will be used with multiple individuals, some having harmful use AUD, and some having dependent use AUD; in all such embodiments, modifications are made as will be readily appreciated by those in the art (e.g., substituting Pre-detox Group Therapy and Pre-MDMA Course Preparatory Group Therapy Course with Alcohol Detoxification Course).
  • a practitioner will first confirm the patient has alcohol use disorder (1601). This may be accomplished via assessing whether the individual meets at least 2 of the 11 listed criteria for AUD in the DSM-V during the same 12-month period, the criteria being whether the individual has: “(1) Had times when you [i.e., the patient] ended up drinking more, or longer, than you intended? (2) More than once wanted to cut down or stop drinking, or tried to, but cannot’t? (3) Spent a lot of time drinking? Or being sick or getting over other aftereffects? (4) Wanted a drink so badly you could’t think of anything else? (5) Found that drinking — or being sick from drinking — often interfered with taking care of your home or family? Or caused job troubles? Or school problems?
  • a screening visit is conducted (1602), wherein a determination will be made as to whether or not the individual is fit to undergo treatment. Whether or not the individual is fit to undergo treatment will be determined by obtaining objective measurements, such as using inclusion and exclusion criteria as discussed below and set forth herein, or additionally and optionally including any regarding the individual’s weight, body temperature, HR, respiratory rate, blood oxygenation, BP and its variables, including, but not limited to: SBP, SBP, MAP, and PP; CNIBP; ECG measurements, including RR interval or its variability, QT interval or its variability, HRV (including measured by devices other than an ECG); hemodynamic response, and levels of glucose, cortisol, serotonin, dopamine, cholesterol; EEG measures; BDNF; genetic markers including relating to CYP enzymes or drug metabolism; genetic variation in mGluR5 or FKBP5; and numerous more, as known to those in the art.
  • the screening visit will also include assessing whether or not the individual meets all inclusion criteria (1603).
  • the inclusion criteria include informed consent, a primary diagnosis of AUD, being between the ages of 18 and 65 years old, identifying an individual able to accompany the patient to at least one study visit if required and be contacted by the study team in the tevent the patient could not be contacted, being proficient in speaking and in reading English, and agreeing to comply with the requirements of the protocol.
  • inclusion criteria may be assessed by evaluating an individual’s medical, psychiatric, and substance misuse history; prescribed medication use, basic physiological observations and alcohol breath test, and urine drugs screen, or others as clinically indicated.
  • an individual in some embodiments will also not have not met at least one exclusion criteria, wherein the exclusion criteria include any one or more of lacking capacity, having a history of a primary psychotic disorder, bipolar affective disorder type 1, or a personality disorder; posing a serious suicide risk, having at least one abnormal clinical finding during the screening visit, being a regular user of ecstasy, currently taking medication likely to interact with MDMA, being a regular use of other drugs or having a dependence thereon (besides also alcohol), being pregnant, breastfeeding, having taken part in a study involving an investigational product in the last three months, having an immunological disease, havingunstable hypertension, havingsevere liver disease, having cardiac disease, having an active infection, and having had an infection within four weeks of MDMA administration.
  • the exclusion criteria include any one or more of lacking capacity, having a history of a primary psychotic disorder, bipolar affective disorder type 1, or a personality disorder; posing a serious suicide risk, having at least one abnormal clinical finding during the screening visit, being a regular
  • an individual may proceed as a patient and complete the four-week preparation group course (1605).
  • the four-week preparation group course may employ group-therapy tactics to enable an individual to lessen their reliance on alcohol; “reliance” may refer to using alcohol as a means to cope with negative experiences in daily life.
  • the exemplary course described here will broadly cover four separate topics, including confidence building; resources, barriers, and goal setting; increasing rewarding activities and building support, and building the foundations for recovery.
  • the patient then completes an 11 -week therapy protocol comprising 14 psychotherapy sessions (under the supervision of a therapist pair or “therapist team”), three of which are MDMA-assisted psychotherapy sessions (lasting from between about 360 minutes to about 480 minutes), wherein the patient is administered an initial dose of between about 100 mg to about 150 mg of MDMA, and optionally a booster dose of about half of the initial dose (thus, if the initial dose was about 100 mg, the booster dose is about 50 mg); and 11 of which are about 60 minute non-drug psychotherapy sessions (1606).
  • the booster dose is administered to prolong the MDMA experience.
  • the booster dose is administered to increase the time with which the patient and the therapist pair have to interact while the patient is under the effects of MDMA.
  • the patient is further assessed at a visit three months, six months, and nine months after the conclusion of the therapy protocol (1607), or otherwise following treatment as defined below. Patients may also be assessed at other times following treatment, such as at one month, at one year, at greater than one year, at times in between, and at points periodically, semi-continuously, or continuously (e.g., by mobile apps, fitness trackers, regular email correspondence, and the like). In some embodiments, the amount of alcohol consumed per patient at the three, six, and nine month visits will be less than the alcohol the patient consumed prior to beginning the protocol of this Example.
  • the amount of alcohol consumed per patient is reduced (i.e., measured at any one or more of the three, six, and/or nine month visits) will be less than the alcohol the patient consumed prior to the start of the preparation group or prior to the start of detox, or otherwise prior to undergoing the method of the invention (e.g., when measured at or before intake).
  • the amount of alcohol consumed per patient at the three, six, and/or nine month visits will be 50% or less of the alcohol the patient consumed prior to the start of the preparation group or prior to the start of detox, or otherwise prior to undergoing the method of the invention.
  • the amount of alcohol consumed per patient at the three, six, and nine month visits will be a reduction of at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, up to and including a reduction of 100%, i.e., a patient is no longer consuming alcohol.
  • Other therapeutic effects or outcomes which a patient may experience will be as discussed below.
  • Each session lasts for 60 minutes and draws on motivational interviewing approaches, as detailed herein. It is anticipated that participants will further benefit from the peer support elements offered by the group format. As mentioned, this will be a rolling group, meaning participants can join at any week and attend for at least 4 weeks.
  • the three MDMA-assisted psychotherapy sessions will be conducted at weeks 3, 6, and 9. As mentioned, these sessions will last for approximately 6 to 8 hours (360 to 480 minutes), while the non-dosing physiotherapy sessions (which occur all 11 weeks) will last for approximately 1 hour (60 minutes).
  • the therapy appointments prior to the participant’s drug assisted sessions will give the therapist team and participant the opportunity to develop a good therapeutic alliance, which is also benefited by the participant having the opportunity to tell their story. This helps to create a collaborative understanding of problem development and maintenance, alongside identification of resources and protective factors.
  • These early sessions give the participant an opportunity to ask any questions about the drug experience, to set an intention for what they would like to get from this experience, and for therapists to describe what they can expect in terms of practicalities and support on the day.
  • the drug-assisted session content is led by the participant, with the therapists in a supporting role and occasionally making gentle suggestions as appropriate.
  • Subsequent integration sessions i.e., non-drug psychotherapy sessions
  • the 14-week, 11-session therapy protocol (also an “MDMA-assisted psychotherapy course” or “MDMA-assisted psychotherapy regimen”) is disclosed in the table below:
  • the therapy sessions themselves there are a total of 14 sessions spanning 11 weeks, wherein 3 of the 14 sessions are MDMA-dosing sessions wherein a patient is administered an initial dose, and optionally a booster dose, the initial dose comprising between about 100 mg to about 150 mg, and the booster dose comprising about half of the initial dose, such that — if the initial dose is about 100 mg of MDMA, the booster dose would be about 50 mg of MDMA.
  • the proportion of the initial dose as compared to the booster dose is 2:1, wherein the initial dose is twice as much as the booster dose.
  • the booster dose is an “optional” dose, wherein the booster dose is not required and, in some embodiments of the invention, the therapy protocol includes three MDMA-assisted psychotherapy sessions, wherein the optional booster dose is not administered to the patient.
  • the optional booster dose is administered during one of the MDMA-assisted psychotherapy sessions; in some embodiments, the optional booster dose is administered during two of the MDMA-assisted psychotherapy sessions; and, finally, in some embodiments, the optional booster dose is administered during all of the MDMA- assisted psychotherapy sessions.
  • the optional booster dose is administered to prolong the subjective experience felt by the patient when administered an effective dose of MDMA. In some embodiments, the optional booster dose is administered to allow for additional time for the patient and therapist team to discuss and work through any internalized emotions or feelings that surface for the patient.
  • each of the 3 MDMA-assisted psychotherapy sessions will last for between about 360 minutes to about 480 minutes. In some embodiments, the non-dosing therapy sessions will last for about 60 minutes.
  • the first weekly session will serve as an introduction to the MDMA for AUD therapy protocol, and will cover the purpose of the study (i.e., whether MDMA-assisted psychotherapy is more effective for preventing relapse to harmful drinking compared to psychotherapy without MDMA), and will provide a general overview of the protocol, including that the sessions will focus on reduction strategies and promoting psychological flexibility.
  • the therapy team then discusses with the patient how MDMA works as an adjunct to psychotherapy, which aids in developing a collaborative “formulation,” which is a provisional explanation or hypothesis of how an individual comes to present with a certain difficulty or circumstance at a particular point in time (Weerasekera, 1996).
  • a formulation should be a collaborative process between the patient and therapist team that will be added to, and altered, as the therapeutic process unfolds. It can be considered as a “road map” that will inform the direction of the therapy.
  • the therapy team and patient will then work together to form a shared understanding of the formulation, which includes the identification of difficulties, and areas of strength and resource.
  • the therapy team and patient will also work to develop therapy goals for the patient, and introduce “intention setting,” where the patient sets an intention for the drug-assisted session.
  • it is useful to invite a patient to have a focus for the session but to hold this lightly so that they do not grip onto the intention so tightly it becomes restrictive and potentially disruptive to the natural process that unfolds. Rather, they have a focus in mind but are prepared to go with whatever comes up for them.
  • ACT encourages acceptance of internal and external discomfort and an ability to tolerate and fully experience them with openness, thereby decreasing the need to use coping strategies of experiential avoidance and unworkable actions.
  • the ultimate aim is to live a full, meaningful life, which will indirectly lead to a reduction in the mental health symptoms that they present with, as well as reducing other associated problematic behaviours.
  • the therapy protocol alternates between drug- assisted therapy sessions and ACT-informed integration sessions based on the hexaflex; specifically to: (a) be in the present moment; (b) develop a more flexible experience of the self (self-as-context) rather than be fused to a particular personal narrative (self-as-content); (c) disengage from attempts to control thoughts and emotions and instead, observe and accept them as they are (acceptance and defusion), (d) clarify values in the areas of their life they would like to prioritize; and (e) engage in committed action in line with their values.
  • the ACT-based interventions involve a combination of techniques that enhance the effects of the drug-assisted dosing sessions in order to achieve greater psychological flexibility. These techniques and processes involve a synthesis of several factors in line with ACT: theoretical explanations about ACT principles; metaphors to illustrate key concepts; the use of worksheets; experiential exercises within session; revisiting the ACT specific formulation; and homework tasks between sessions. A guide with suggested exercises and the order in which these processes may be delivered can be provided. A participant will be asked to bring along their recovery support map developed during the preparation group to session 2.
  • the second session will generally continue from the first, building on the topics introduced in week one. If the development of the collaborative formulation is not completed during session 1, it is done so in session two. The therapist team will also practice at least one support technique and discuss/practice the use of “interpersonal touch” with the patient during this session.
  • a key skill of psychedelic-assisted psychotherapy work is to establish excellent patient- therapist rapport as quickly as possible. This will help the patient to feel comfortable enough in their drug-assisted session to be present and interested in whatever comes up for them, rather than trying to avoid or turn away from it.
  • the therapist should spend a few minutes discussing supportive/grounding techniques during preparation; exploring whether the patient has any current ways of managing emotional discomfort that could be useful for the session.
  • make it clear to the patient that the aim of using a supportive technique is to help the patient to persevere through, rather than avoid, any challenging experiences as much as possible. Discuss the use of supportive touch and whether the patient would feel comfortable with this. Clarify boundaries, all touch is non-sexual and will be on the shoulder, arm or hand. Practice in preparation how the patient may reach out for supportive touch and disengage from the same. It is useful to have an agreement and practice beforehand in the event of challenging experiences arising that the patient would appreciate support with in order to remain in, rather than move away from, the experience.
  • the therapist team will also discuss supportive/grounding techniques with the patient, non-limiting examples of which include diaphragmatic breathing, wherein the patient is instructed to “take a long, full breath from your abdomen, rather than from your chest. In through your nose and out through your mouth. As you breathe, notice any sensations, thoughts, and images as they come and go as you gently breathe in and out from your tummy;” as well as imagery, wherein the patient is instructed to “close or lower your eyes. Invite a calm and relaxing scene to come to mind and try to make it as vivid as possible. Allow yourself to wander and fill in the details of the image.” The therapist may also utilize the following follow up prompts: “What can you see/sm ell/feel? How does it feel to you?
  • the practitioner may also instruct the patient to “breathe with me — in through the nose, out through your mouth. Think of a place where you feel safe (can make suggestions if needed), imagine how safe and relaxed you feel, think of it in as much detail as you can. Describe it to me if you like.” Regardless of the method applied, the most important aspect is to ensure the patient is grounded such that their immediate environment can be used if the patient’s distress appears to be overwhelming.
  • At least one of the therapist pair may use reassuring phrases, such as “you’re here with us and you're safe, we’re right here with you,” and may distract the patient, such that they are focused on external surroundings rather than internal feelings, including exemplary phrases such as “how does the couch feel as you lay on it?” “what can you see around the room?” “are there any noises you can hear?” Note, this technique should be used after other options such as supportive touch (e.g., hand holding), use of the breath, etc.
  • the therapist pair will then briefly introduce to the patient what is meant by “psychological flexibility” in terms of three key concepts: “open up” (defusion & acceptance), “be present” (contact with present moment & self as context), and “do what matters” (values & committed action).
  • the therapist pair is not required to spend extensive time explaining these concepts in detail, but can rather introduce them to the patient and explain how they are associated with reduced suffering and enhanced quality of life (rather than symptom reduction necessarily).
  • the therapist pair will then review the recovery plan developed in the preparation group with the patient, discussing key elements and requesting the patient discuss with them any misapprehended points.
  • the therapist pair will then inquire about what seems to be working well, anything that may be particularly challenging, anything the patient feels could be added, and/or anything the patient would like to develop/change at this point.
  • the therapist pair will ensure they have the opportunity to review and add to the recovery plan with the patient during the final session, when the patient will have learned and practiced skills that may be new to them, and that they may wish to continue developing as part of their ongoing recovery.
  • patients may be introduced to the concept of maintaining an experiential therapy journal where they are encouraged to write down anything they find significant during their experiential day. For example, any impactful emotions, perspectives, images, questions, or thoughts that arose. These can be discussed in integration sessions with the therapist pair.
  • the therapist pair will arrive in advance of the patient to ensure the setting is prepared. In total, the therapist pair will ensure the room is clean, airy and comfortable; that blankets, pillows, and sheets are on the bed; that an eye mask and headphones are available; that lighting is dim and comfortable; that all audio equipment is tested and is working (including headphones); that all medical equipment is available and working (BP machine, thermometer); that medication is collected from a pharmacy/stored on-site, and appropriate access has been organized; that rescue medication is accessible; and that therapists’ needs are taken care of.
  • the therapist pair will then conduct a pre-dosing checklist upon patient arrival, which includes reconfirming consent; obtaining blood pressure and pulse measurements; assessing suicide risk via C-SSRS; conducting a urine screen (for substances and pregnancy as appropriate); conducting an alcohol breath test; checking participant medications, (including any changes and what, if any, medication the patient has taken that day to ensure that, e.g., if hypertensive medication was taken that such is routine, etc.).
  • the patient will then be reminded of key information, including that they are expected to remain in the facility (and in the room) for at least 6 hours after the initial dose, that vital signs will be monitored at dosing, 1 hour after the initial dose, 2 hours after the initial dose (before offering the booster dose), 3 hours after the initial dose, and 6 hours after the initial dose (at the end of the session). That the patient can be supported to get to the bathroom as needed, and the patient is subsequently orientated to the default position of laying on the bed, while wearing eye shades and headphones. That the patient should embrace the experience as much as possible, to be open and curious to all experiences that airse. That the patient will never be on their own, and that at least one therapist will be with them at all times. The patient is also reminded about how to reach out and/or ask for support, and the intention set for the session is reviewed. Finally, the therapist pair asks for any questions, reflections, comments, or concerns the patient may wish to talk about at this point.
  • the therapist pair may gently inquire about how the participant is doing, and if they have been largely ‘inside’ during the session. A gentle touch on the arm (if they have consented to touch) and a question such as, ‘just checking in how you’re doing’ will usually be sufficient. Another point at which the participant may naturally wish to engage may come when the booster dose is offered. Here, the therapist pair may wish to inquire more about how the participant is progressing and where they currently find themselves. All communication is offered as a suggestion or invitation rather than an instruction. For example, ‘would you like to... ’, ‘might this be a good time to... ’ etc.
  • the therapist pair may also inquire about any sensations in the body associated with what the patient is describing, which can also be helpful to ensure the patient stays focused on their internal experience. Additionally, asking about imagery can support an internal focus. For example, ‘when you describe feeling afraid, do you notice any sensations in your body?’ and ‘are there any images in your mind when you talk about that?’
  • the therapist pair may offer verbal support and/or supportive touch. They may say, ‘see if you can stay with that feeling that’s coming up for healing as much as you can, we’re here with you’.
  • the therapist pair will be acutely aware of any signs that the patient is unable to maintain an internal focus.
  • the therapist pair may intervene with supportive actions, such as but not limited to reminding the patient of their presence e.g., ‘we are here with you’, you are safe,’ using supportive touch (if pre-agreed), encouraging the use of breath, ‘breathe into it,’ ‘remember to use your breathing,’ etc.
  • This instruction can become more directive as warranted (e.g., in accordance with levels of distress). For example, ‘breathe with me’ or ‘breathe in and out on my count’ may be used.
  • the therapist may make general inquiries about how the patient coped during the session, and how they are presently feeling. However, it is best to not press the patient for a full narrative of the experience at this time, as there may be on-going processing and/or the patient may wish to be quiet and have a period of reflection and introspection. If the patient does wish to talk about their experience at this point, the therapist may listen as a supportive presence but limit any interpretation at this stage while the patient may be in a phase of increased psychological flexibility, and processing may still be unfolding. Rather, it is recommended the therapist pair encourage the patient to have a quiet rest of the day, and to journal/make notes of the experience. Note, the patient may also wish to express their feelings in other ways, such as but not limited to art or music. Week 3, Session 4
  • the first session after a dosing session will be geared towards integrating the MDMA experience with the prior therapy sessions.
  • the therapist pair will discuss the purpose of the MDMA dosing session, and will have prompt questions for the patient. At this stage, the therapist pair will also introduce mindfulness techniques and practice the same.
  • the therapist team will instruct the patient how to respond to urges to drink, will aid the patient in “stepping out of automatic pilot,” (i.e., being more present), and will discuss “Seemingly Irrelevant Decisions,” (SIDS), which are a series of decisions made that, while appearing to be innocuous, lead a patient to a situation wherein alcohol may be freely consumed; “responding to lapses and relapses,” “developing self compassion,” and how to develop a “SOBER breathing space” with the patient.
  • SIDS Seemingly Irrelevant Decisions
  • a “SOBER breathing space” refers to an acronym useful in diagnosing, and responding to dangerous/tempting situations, wherein “S” refers to “stop,” so the patient is instructed to stop at a given “challenging point,” and make the choice to step out of automatic pilot.
  • ⁇ stands for “expand,” wherein the patient expands the awareness they now feel to include a sense of the entire body, heart, and mind — including any tightness or tension, present emotions, etc.
  • R stands for “respond,” wherein the patient applies the awareness they now feel to their current situation, to determine if the emotion, setting, or person the patient is with is dangerous for them and their recovery.
  • the patient examines the choices they have, and is aware that they are in control of what choice they ultimately make. They then choose the option that best fits what the patient wants in life, including who they wish to be, and what is truly important to them. The patient then visualizes making that choice, and follows through with the decision.
  • EXAMPLE 8 Open-Label, Within-Subjects, Safety and Tolerability Feasibility Study of MDMA-Assisted Psychotherapy in Patients with AUD
  • This Example details an open-label, within-subjects, safety and tolerability feasibility study that was conducted in 14 patients aged 18-65 years old diagnosed with AUD who had recently undergone detoxification, and received MDMA-assisted therapy.
  • the main outcome measures of this study were the number of patients completing the eight-week course, the number accepting the second booster dose of MDMA on drug-assisted days, and adverse events.
  • Secondary outcome measures included changes in drinking behavior (measured by units per week consumed at 3, 6 and 9 months since completion of detoxification), measures of mental well-being, psychosocial functioning, quality of life, and concomitant drug use.
  • sessions 1, 2, 4, 5, 6, 8, 9, and 10 comprised one-hour psychotherapy sessions, wherein aspects of motivational interviewing and “third-wave” cognitive-behavioral approaches were employed. In all, patients remained in the study for approximately 10 months.
  • Inclusion criteria and exclusion criteria included those as set forth in TABLE 1. If one of the exclusion criteria were met, an individual was not selected to take part in the study. To be considered as a patient, all individuals also had to meet all inclusion criteria.
  • AUD was identified using the DSM-IV SCID interview. Screening comprised of written informed consent, an evaluation of the patient’s physical and mental health background, a psychiatric interview (MINI), and assessments of depression and anxiety severity using the Patient Health Questionnaire-9 (PHQ-9) and Generalised Anxiety Disorder Assessment (GAD- 7) questionnaires. Severity of AUD was established using the Severity of Alcohol Questionnaire (S ADQ) and the Short Inventory of Problems for Alcohol (SIP) questionnaire. However, it should be noted, additional questionnaires/assessments equivalent to those mentioned (as would be apparent to one of skill) may also be used. Patients received a thorough physical health check comprising an electrocardiogram, routine blood tests, blood pressure, heart rate and physical examination.
  • S ADQ Severity of Alcohol Questionnaire
  • SIP Short Inventory of Problems for Alcohol
  • FIG. 11 demonstrates the success of the participants of the study of this Example in terms of alcohol consumption over 9 months, compared with current best treatments available locally. Only 21% of participants who had undergone MDMA-assisted psychotherapy were drinking in excess of 14 units of alcohol a week in comparison with the 75% observed in the Outcomes Study ( see FIG. 11).
  • EXAMPLE 9 Randomized Double-Blind Between-Subject Controlled Study of MDMA- Assisted Psychotherapy in Patients with “ Dependent Use” AUD
  • MDMA-assisted psychotherapy is an effective treatment for patients with AUD, who have physical dependence.
  • the study of this Example will show that MDMA-assisted psychotherapy is superior to placebo dose- assisted psychotherapy and can reduce use of alcohol in patients with physical alcohol dependence — and, in some embodiments, especially those who require a course of detoxification before they undergo drug-assisted therapy — and improve their quality of life.
  • Results are obtained as above, and through this Example, MDMA-assisted psychotherapy is further demonstrated to be useful in treating AEID, and in particular AEID in patients who are physically dependent on alcohol, and to have such other benefits as claimed.
  • the pharmaceutical compositions of the invention are used to improve the symptoms of a mental health disorder, wherein the mental health disorder is a substance abuse disorder.
  • the mental health disorder is a substance abuse disorder.
  • that substance use disorder is AUD, and specifically physically dependent alcohol addiction.
  • the symptoms of the mental health disorder to be treated e.g., the symptoms of AUD or physically dependent alcohol addiction
  • the pharmaceutical compositions of the invention (and their use in the methods of the invention) will produce a therapeutic effect, and such effect may be (1) an improvement in a symptom of a comorbid psychiatric disorder; (2) an increase in quality of life; (3) an increase in psychosocial functioning; (4) a decrease in use or frequency of prescription medication; (5) a decrease in use or frequency of recreational drugs, which can include illicit use of prescription drugs; (6) a decrease in units of alcohol consumed; (7) a reduction of cravings relating to alcohol; (8) a prevention of relapse.
  • the methods of the invention will provide one or more therapeutic effects for a patient or a subject diagnosed with or having AUD, or symptoms thereof, or otherwise in need of such treatment.
  • the methods of the invention will result in one or more of: (a) a reduction of alcohol use, (b) a reduction of alcohol cravings, (c) a promotion of alcohol abstinence, (d) a prevention of relapse into alcohol use, or (e) an improvement of at least one symptom of alcohol use disorder.
  • the methods of the invention will result in one or more of: (a) an increase in quality of life, (b) an increase in psychosocial functioning, (c) a decrease in use or frequency of a prescription medication, (d) a decrease in use or frequency of a recreational drug, (e) a decrease in obsessive compulsive thoughts, (f) a decrease in suicidality, (g) an increase in feelings of empathy, or (h) an increase in self-compassion.
  • the methods of the invention will result in an improvement of at least one symptom of a comorbid psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive compulsive disorder, binge eating disorder, or PTSD.
  • a comorbid psychiatric disorder such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive compulsive disorder, binge eating disorder, or PTSD.
  • the methods of the invention will provide one or more therapeutic effects for a patient or a subject diagnosed with or having AUD, or symptoms thereof, or otherwise in need of such treatment, and will result in one or more of: (a) an increase in physical functioning; (b) a decrease in role limitations due to physical health; (c) an increase in emotional well-being; (d) a decrease in role limitations due to emotional problems; (e) an increase in energy; (f) a decrease in fatigue; (g) an increase in social functioning; (h) a decrease in pain; or (i) an increase in general health.
  • the increase and/or the decrease will be demonstrated by a patient-reported measure on a Short Form (36) Health Survey, or as otherwise described in Sessa (2020) and shown here, for example, in FIG. 5 and accompanying description thereof.
  • the measurement of such therapeutic effects may be performed by a therapist or other clinician (e.g., an interview), by a patient his or herself (e.g., a self- reported questionnaire), by a third-party human or by a medical or other device (e.g., a medical sensor or biosensor, a watch or fitness tracker); such measurements may be graded by a human decision-maker or an AI, by using machine learning, or by a computer algorithm.
  • a therapist or other clinician e.g., an interview
  • a patient his or herself e.g., a self- reported questionnaire
  • a medical or other device e.g., a medical sensor or biosensor, a watch or fitness tracker
  • such measurements may be graded by a human decision-maker or an AI, by using machine learning, or by a computer algorithm.
  • any one or more of such therapeutic effects will be durable effects, which will be shown when measured at a time following treatment by at least one month, at least three months, at least six months, at least nine months, at least one year, or greater than one year, including when measured at times in between.
  • Such measurements “following treatment” may be measured, e.g., from the end of detoxification, if detoxification is completed, from baseline, from intake, or from the first psychotherapy session, and therefore “following treatment” may include a period measured from the start of treatment, or a point following the start of treatment, but before treatment is complete.
  • a measurement is from the conclusion of a therapy protocol, or after the conclusion of a certain or chosen phase of a therapy protocol.
  • a measurement is from the end of treatment, i.e., after treatment is complete, which in some embodiments will be from the completion of the MDMA-assisted psychotherapy regimen.
  • the methods of the invention will result in a reduction of alcohol use.
  • a reduction of alcohol use may be measured by a reduction in the units of alcohol consumed per week (compared to the units of alcohol consumed per week prior to undergoing the methods of the invention), wherein a unit of alcohol refers to a standard drink, which contains about 14 g of pure alcohol (ethanol). For typical alcoholic beverages, this refers to 12 ounces of 5% alcohol beer, 5 ounces of 12% wine, and 1.5 ounces of 40% distilled spirits (NIH).
  • the amount of alcohol consumed per patient is a durable effect, and will be shown at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year following treatment.
  • the amount of alcohol consumed per patient is reduced by about 5% to about 50%, including about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, and values in between. In some preferred embodiments, the amount of alcohol consumed per patient is reduced by 50% or more. In some preferred embodiments, the amount of alcohol consumed per patient is reduced by at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, up to and including by 100% (i.e., a patient is no longer consuming alcohol), and values in between.
  • the methods of the invention will result in a reduction in alcohol cravings.
  • a reduction in alcohol cravings may be measured by subjective patient reports, as well as questionnaires, such as but not limited to the alcohol craving experience questionnaire.
  • the reduction in alcohol cravings is a durable effect, and will be shown at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year following treatment.
  • alcohol cravings will be reduced by about 5% to about 100%.
  • alcohol cravings will be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, up to and including by 100% (i.e., the patient is no longer having alcohol cravings), and values in between.
  • the methods of the invention will result in a promotion of abstinence, wherein abstinence refers to a prolonged period of time — such as at least 1 day, at least 2 days, at least 3, at least 4 days, at least 5, at least 6 days, at least 7 days, or more than 7 days — wherein the patient does not consume alcohol.
  • a promotion of abstinence may be measured by measuring the average duration of abstinence (e.g., the average time between “heavy drinking days,” as defined herein), before undergoing the methods of the invention, and after undergoing the methods of the invention.
  • the promotion of abstinence is a durable effect, and will be shown at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year following treatment.
  • the promotion of abstinence will be illustrated by an average increase in time between “heavy drinking days,” as defined herein, by at least about 5%, preferably by at least 25%, more preferably by at least 50%, and most preferably by at least 100%.
  • the promotion of abstinence will be illustrated by an average increase in time between “heavy drinking days,” as defined herein, by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, and about 100%, and values in between.
  • the promotion of abstinence will be illustrated by an average increase in time between “heavy drinking days,” as defined herein, by at least 100%, such as at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 650%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, and, in some embodiments, the promotion of abstinence will be illustrated by an average increase in time between “heavy drinking days,” as defined herein, by more than about 1000%, as well as values in between.
  • the methods of the invention will result in a prevention of relapse into alcohol use.
  • a prevention of relapse into alcohol use may be assessed by measuring the amount of alcohol consumed after undergoing the methods of the invention, and identifying whether or not the amount of alcohol consumed — and frequency with which it is consumed — is above the threshold to qualify the person as a “heavy drinker,” as defined herein, wherein a “heavy drinker” refers to an individual who “binge drinks” at least 5 or more days in a given month, and “binge drinking” refers to a male consuming 5 or more alcoholic drinks on the same occasion, or a female consuming 4 or more drinks on the same occasion.
  • the prevention of relapse into alcohol use is a durable effect, and will be shown at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year following treatment.
  • a male patient will consume 5 or more drinks on the same occasion less than 5 times in a given month, for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months following the completion of the methods of the invention.
  • a female patient will consume 4 or more drinks on the same occasion less than 5 times in a given month, for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months following the completion of the methods of the invention.
  • a prevention of relapse into alcohol use will be a reduction in the rate of relapse or likelihood of relapse, for example, a reduction of about 5% to about 100%.
  • a reduction in rate or likelihood of relapse will be about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, up to and including 100% (i.e., complete prevention of relapse), and values in between.
  • an increase in quality of life may be measured by subjective reports from patients, questionnaires, such as, but not limited to, the Quality of Life Scale (QoLS), the Health Related Quality of Life (HRQoL) questionnaire, World Health Organization Quality of Life instruments, for example, WHOQOL-IOO and its abbreviated version, WHOQOL-BREF, the Kunststoff Quality-of-life Dimension List (MLDL), Medical Outcomes Study Short Form (SF-36), the Quality of Life Consumment and Satisfaction Questionnaire (Q-LES-Q), the EuroQoL-5D (EQ-5D), the Life Situation Survey (LSS), the Nottingham Health Profile (NHP), the Sleep Quality Scale (SQS), the Pittsburgh Sleep Quality Index (PSQI), and the Leeds Sleep Evaluation Questionnaire (LSEQ), as well as changes in mental health conditions, including but not limited to anxiety and depression (i.e., after completing the methods of the invention, confirming the severity of the
  • anxiety and/or depression are assessed using questionnaires, for example, the Patient Health Questionnaire (PHQ-9) or the Generalized Anxiety Disorder Assessment (GAD-7).
  • PHQ-9 Patient Health Questionnaire
  • GID-7 Generalized Anxiety Disorder Assessment
  • the increase in the patient’s quality of life is a durable effect, and will be shown at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year following treatment.
  • the patient’s quality of life will be increased by between about 5%, to about 100%.
  • the patient’s quality of life will be increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, and value in between.
  • the patient’s quality of life is determined by a reduction in depression
  • the patient’s depression may decrease by between about 5%, to about 100%.
  • the patient’s depression may decrease by between about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, and values in between (i.e., the patient no longer has quantifiable depression).
  • the patient’s quality of life is determined by a reduction in anxiety
  • the patient’s anxiety may decrease by between about 5%, to about 100%.
  • the patient’s anxiety may decrease by between about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, up to and including 100% (i.e., the patient no longer has quantifiable anxiety), and values in between.
  • the methods of the invention are effective in reducing mild, moderate, moderately severe, and severe depression.
  • 12 patients Prior to undergoing the methods of the invention, specifically during the screening session, 12 patients were assessed for levels of depression. It was found that one patient suffered from mild depression, two suffered from moderate depression, four suffered from moderately severe depression, and five suffered from severe depression.
  • baseline In FIG. 3, one patient had mild depression, two had moderate depression, zero had moderately severe depression, and two had severe depression (out of 11 patients remaining in the study).
  • the patients were then reassessed at 3, 6, and 9 months post-baseline (i.e., after completing a detoxification course, and prior to beginning the MDMA-assisted psychotherapy regimen), wherein it was discovered that, at 3 months, two had mild depression, one had moderate depression, three had moderately severe depression, and one had severe depression (out of 9 patients remaining in the study); at 6 months, no patients suffered from mild or moderate depression, two had moderate severe depression, and one had severe depression (out of 6 patients remaining in the study); finally, at 9 months, one patient had mild depression, one had moderate depression, and one had moderate severe depression, with none having severe depression.
  • the methods of the invention successfully reduce both the incidence and severity of depression in patients diagnosed with AUD.
  • the methods of the invention are effective in reducing mild, moderate, and severe anxiety. Prior to undergoing the methods of the invention, specifically during the screening session, 12 patients were assessed for levels of anxiety. It was found that four patients suffered from moderate anxiety, and eight patients suffered from severe anxiety. Directly after undergoing the detoxification process (noted as “baseline” in FIG.
  • the methods of the invention will result in an increase in psychosocial functioning, wherein “psychosocial functioning” refers to one’s ability to perform the activities of daily life.
  • an increase in psychosocial functioning may be measured by obtaining subjective evidence from patients in the form of surveys, questionnaires, and/or other psychosocial functioning assessments, as would be apparent to one of skill.
  • the increase in psychosocial functioning is a durable effect, and will be shown at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year following treatment.
  • the patient’s psychosocial functioning will improve by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, and about 100%, and values in between.
  • the patient’s psychosocial functioning will improve by at least 100%, such as at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 650%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, and, in some embodiments, psychosocial functioning will improve will increase by more than about 1000%, as well as values in between.
  • the methods of the invention will result in a decrease in use or frequency of a prescription medication.
  • a patient decreases the frequency with which the patient takes a given prescription medication while, in some embodiments, the patient is prescribed a fewer number of medications than the patient was prescribed prior to undergoing the methods of the invention. Additionally, in some embodiments, the patient is both prescribed a fewer number of medications than the patient was prescribed prior to undergoing the methods of the invention, and decreases the frequency with which the patient takes a given prescription medication.
  • a practitioner may ask the patient to provide information regarding the type, dosage, and frequency of administration of prescription medication.
  • the reduction in prescription medication use is a durable effect, and will be shown at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year following treatment.
  • the reduction in prescription medication use persists for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, or more than 12 months after completion of the methods of the invention.
  • the methods of the invention will result in a decrease in use or frequency of at least one recreational drug.
  • a recreational drug is prescription drug that is abused, misused, or used illicitly. Meaning, in some embodiments, a patient decreases the frequency with which the patient takes a given recreational drug, while, in some embodiments, the patient takes a fewer number of recreational drugs than the patient took prior to undergoing the methods of the invention. Additionally, in some embodiments, the patient both takes a fewer number of recreational drugs than the patient took prior to undergoing the methods of the invention, and decreases the frequency with which the patient takes a given recreational drug.
  • a decrease in use or frequency of a recreational drug may be measured by asking the patient to provide information regarding their usage of such substances.
  • a practitioner may conduct a screening for recreational drugs via blood and urine testing, as would be apparent to one of skill.
  • the reduction in recreational drug use is a durable effect, and will be shown at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year following treatment.
  • the reduction in recreational drug use persists for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, or more than 12 months after completion of the methods of the invention.
  • the methods of the invention will result in a reduction in obsessive compulsive thoughts.
  • the reduction in obsessive compulsive thoughts may be measured by obtaining subjective reports from a patient, wherein the patient discusses the frequency and severity of obsessive compulsive thoughts; by administering to the patient at least one questionnaire or survey, wherein the at least one questionnaire or survey assesses the frequency and/or severity of the patient’s obsessive compulsive thoughts; and/or having the patient log the frequency and severity of obsessive compulsive thoughts throughout the duration of the methods of the invention, so a practitioner may objectively determine whether or not the frequency and/or severity of such obsessive compulsive thoughts has reduced.
  • the reduction in obsessive compulsive thoughts is a durable effect, and will be shown at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year following treatment. In some embodiments, the reduction in obsessive compulsive thoughts will be reduced by between about 5%, to about 100%.
  • the reduction in obsessive compulsive thoughts will be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, up to and including 100% (i.e., the patient has substantially no obsessive compulsive thoughts), and values in between.
  • a decrease in suicidality may be measured by obtaining subjective reports from a patient, wherein the patient discusses the frequency with which they experience suicidal thoughts; by administering to the patient at least one questionnaire and/or survey, wherein the at least one questionnaire and/or survey is capable of quantifying the suicidality of the patient; administering a suicide risk assessment test, suicide ideation risk assessment, or a suiccide severity rating scale, such as the Columbia suicide severity rating scale (C-SSRS); and/or having the patient log the frequency of suicidal thoguhts prior to, during, and after completing the methods of the invention, so that a practitioner may objectibely determine weather or not the patient experienced a reduction in suicidality as a result of the methods of the invention.
  • C-SSRS Columbia suicide severity rating scale
  • the reduction in suicidality is a durable effect, and will be shown at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year following treatment.
  • suicidality will be reduced by between about 5%, to about 100%.
  • suicidality will be reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, up to and including 100% (i.e., the patient has substantially no suicidal thoughts), and values in between.
  • the methods of the invention will result in an increase in feelings of empathy.
  • the increase in feelings of empathy may be measured by obtaining subjective reports from a patient, wherein the patient discusses the changes in empathetic feelings and actions they have experienced since completing the methods of the invention; and/or by utilizing questionnaires and/or surveys, wherein the questionnaires and/or surveys assess the subject’s empathy through a series of questions.
  • a practitioner may assess the patient’s level of empathy prior to, during, and after undergoing the methods of the invention, to determine whether the patient has experienced an increase in feelings of empathy as a result of the methods of the invention.
  • the increase in feelings of empathy is a durable effect, and will be shown at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year following treatment.
  • feelings of empathy will increase by at least about 5%, preferably by at least 25%, more preferably by at least 50%, and most preferably by at least 100%.
  • feelings of empathy will increase by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, and about 100%, and values in between.
  • feelings of empathy will increase by at least 100%, such as at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 650%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, and, in some embodiments, self-compassion will increase by more than about 1000%, as well as values in between.
  • the methods of the invention will result in an increase in self compassion.
  • the increase in self-compassion may be measured by obtaining subjective reports from a patient, wherein the patient discusses the changes in self compassion that they have experienced since completing the methods of the invention; and/or by utilizing questionnaires and/or surveys, wherein the questionnaires and/or surveys assess the subj ecf s self-compassion through a series of questions.
  • a practitioner may assess the patient’s self-compassion prior to, during, and after undergoing the methods of the invention, to determine whether the patient has experienced an increase in self-compassion as a result of the methods of the invention.
  • the increase in self compassion is a durable effect, and will be shown at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year following treatment.
  • self compassion will increase by at least about 5%, preferably by at least 25%, more preferably by at least 50%, and most preferably by at least 100%.
  • self-compassion will increase by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, and about 100%, and values in between.
  • self-compassion will increase by at least 100%, such as at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, at least about 450%, at least about 500%, at least about 550%, at least about 600%, at least about 650%, at least about 700%, at least about 750%, at least about 800%, at least about 850%, at least about 900%, at least about 950%, at least about 1000%, and, in some embodiments, self compassion will increase by more than about 1000%, as well as values in between.
  • the methods of the invention will result in an improvement of at least one symptom of a comorbid psychiatric disorder, wherein the comorbid psychiatric disorder includes, but is not limited to, antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive compulsive disorder, binge eating disorder, and PTSD.
  • the comorbid psychiatric disorder includes, but is not limited to, antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive compulsive disorder, binge eating disorder, and PTSD.
  • the improvement of at least one symptom of a comorbid psychiatric disorder may be measured by obtaining subjective reports from a patient, wherein the patient discusses any changes in the at least one symptom of a comorbid psychiatric disorder that they have experienced since completing the methods of the invention; by utilizing questionnaires and/or surveys, wherein the questionnaires and/or surveys assess the severity of the at least one symptom of a comorbid psychiatric disorder through a series of questions; and/or obtaining objective measurements, as disclosed herein.
  • the improvement in at least one symptom of a comorbid psychiatric disorder is a durable effect, and will be shown at least 1 month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year following treatment. In some embodiments, at least one symptom of a comorbid psychiatric disorder will improve by between about 5%, to about 100%.
  • At least one symptom of a comorbid psychiatric disorder will improve by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, and values in between.
  • quality of life and/or psychosocial functioning are evaluated, monitored, or rated to assess therapeutic outcomes in response to a treatment intervention, such as MDMA-assisted psychotherapy.
  • quality of life and/or psychosocial functioning can be assessed at one or more points in time prior to, during, after completion of a treatment, such as MDMA-assisted psychotherapy.
  • quality of life and/or psychosocial functioning can be assessed using subject-reported and/or interviewer- reported questionnaires. Such questionnaires include inquiries related to one or more aspects of a subject’s physical, social, and emotional well-being.
  • quality of life and psychosocial functioning assessments can share commonalities, especially when related to a subject’s ability to perform the activities of daily living, a subject’s engagement in relationships and satisfaction associated with the same, and the interactions of the subject with their workplace and/or community.
  • quality of life and psychosocial functioning can be assessed by questions related to health or improvement of a condition, for example, AUD.
  • Examples of quality of life and psychosocial functioning questionnaires and their contents are described below for illustrative purposes and should not be construed as limiting. In some cases, the described questionnaires have been used in studies of subjects who display alcohol abuse and dependence (Ugochukwu, 2013). i. Quality of Life Scale (QoLS)
  • QoLS Quality of Life Scale
  • the QOLS may be self-administered or administered by an interviewer. If the interview format is chosen, subjects are provided with a copy of a scale to refer to when deciding on the most appropriate response. Updated versions of the QOLS employ a 7-point scale to rate subject satisfaction.
  • 1 corresponds to “terrible”
  • 2 corresponds to “unhappy”
  • 3 corresponds to “mostly dissatisfied”
  • 4 corresponds to “mixed”
  • 5 corresponds to “mostly satisfied”
  • 6 corresponds to “pleased”
  • 7 corresponds to “delighted” (Burckhardt, 2003).
  • the Health Related Quality of Life (HRQoL) questionnaire probes the impact of health on a subject’s quality of life and psychosocial functioning.
  • Subjects respond with graded, i.e. on a point scale, or non-graded responses to questions in three domains: healthy days, activity limitations, and healthy day symptoms (CDC, 2016). Examples of non-graded responses include providing the number of days physical health was not good, the number of days mental health was not good, and the number of days when health interfered with daily activities.
  • Questions related to activity limitations evaluate the ability to fulfill personal care needs and the demands of a subject’s routine. Healthy day symptoms include inquiries into pain, depression, anxiety, rest and sleep, and a general assessment of health and energy level (Stanford Sparqtools: Health-Related Quality of Life Scale). iii. World Health Organization Quality of Life
  • WHOQOL World Health Organization Quality of Life instruments
  • WHOQOL- 100 World Health Organization Quality of Life instruments
  • WHOQOL-BREF World Health Organization Quality of Life instruments
  • the WHOQOL was developed by fifteen international field centres to develop a ross-culturally applicable quality of life assessment. The surveys may be self-administered or interviewer- administered.
  • the WHOQOL-BREF prompts scoring of four domains related to quality of life: physical health, psychological, social relationships, and environment. It also includes overall quality of life and general health. Though abbreviated, results of the WHOQOL-BREF correlate highly to WHOQOL- 100 domain scores, as calculated on a four domain structure (Development of the World Health Organization WHOQOL-BREF quality of life assessment, 1998).
  • scoring of WHOQOL-BREF entails examining two items separately (an individual’s overall perception of quality of life and an individual’s overall perception of their health) in addition to examining the four domains.
  • the four domain scores denote an individual’s perception of quality of life in each particular domain.
  • Higher domain scores denote higher quality of life.
  • the average score of items within each domain is used to calculate the domain score. If it is desired to compare domain results to those of the WHOQOL-IOO, the mean scores are then multiplied by 4 (WHO, 1996). iv. Kunststoff Quality-of-life Dimension List (MLDL)
  • the Kunststoff Quality-of-life Dimension List allows a subject to self-assess the level of personal satisfaction in all basic areas of life.
  • the MLDL includes 19 different items relevant to quality of life, including mental, physical, social and everyday-life dimensions during the last week on one overall scale and four subscales using Likert scales ranging from 0 (very unsatisfied/very unimportant) to 10 (very satisfied/very important).
  • Exemplary quality of life domains that may be assessed include “overall,” “physical aspects,” “psychological aspects,” “social life,” and “everyday life.”
  • the scale In addition to rating one's satisfaction, the scale also prompts the respondent to evaluate the personal relevance of every item using Likert scales from 0 (very unimportant) to 10 (very important).
  • a calculation algorithm may be used to determine relevance-weighted satisfaction scores. In the absence of differences in relevance ratings in the group comparisons of interest, unweighted satisfaction scores have been used (Frischknecht, 2013).
  • SF-36 Medical Outcomes Study Short Form
  • the Medical Outcomes Study Short Form (SF-36) is an example of a questionnaire that can be used as a self-reported and an observer-reported survey.
  • the survey was designed for self-administration by persons 14 years of age and older, and for administration by a trained interviewer in person or by telephone.
  • the SF-36 evaluates eight health concepts on one multi item scale: 1) limitations in physical activities because of health problems; 2) limitations in social activities because of physical or emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health, e.g., psychological distress and well-being; 6) limitations in usual role activities because of emotional problems; 7) vitality, e.g., energy and fatigue; and 8) general health perceptions (Ware, 1992).
  • Subsequent versions of the SF-36 have been developed that vary in length, e.g., the SF-6D and the SF-12, and rating scale, for example, reducing six-level response scales to a five-level scale.
  • a high or relatively higher SF-36 score indicates a better health state.
  • items and scales are scored in three steps: 1) item recoding, for the 10 items that require recoding; 2) computing scale scores by summing across items in the same scale (raw scale scores); and 3) transforming raw scale scores to a 0-100 scale (transformed scale scores). It is recommended that recoding and scale scoring be performed by a computer using the appropriate algorithms (Ware, 1993). vi. Quality of Life Consumment and Satisfaction Questionnaire (Q-LES-Q)
  • Q-LES-Q Quality of Life Enjoyment and Satisfaction Questionnaire
  • the EuroQoL-5D assesses five domains: mobility, usual activities, self-care, pain or discomfort, and anxiety or depression. Responses in each domain are rated on a scale from 1 to 3, where 1 indicates no problems, 2 indicates moderate problems, and 3 indicates extreme problems. The ratings in each domain constitute the five-digit number collectively known as the EQ-5D self-reported health state (Gunther, 2007). viii. Life Situation Survey (LSS)
  • the Life Situation Survey is a generic scale that assesses an individual’s current functioning using 20 QoL indicators, including work, leisure, nutrition, sleep, social nurturance, earnings, health, love/affection, environment, self-esteem, security, public support, stress, mobility, autonomy, energy level, social support, mood/affect, outlook, and enjoyableitarianism. Variables are rated on a scale from 1 to 7, with total scores ranging from 20 to 140. Scores of less than 90 correspond to a poor quality of life, which can be defined as greater psychosocial impairment (Foster, 2000). ix. Nottingham Health Profile (NHP)
  • the Nottingham Health Profile is a self-evaluated questionnaire that measures a subject’s perceived physical health and emotional and social problems. This scale evaluates the domains of energy, physical functioning/mobility, pain, sleep, affective control, and social isolation. Each section is rated with a score from 0 to 100, where 100 represents the most severe psychosocial/health-related dysfunction (Hunt, 1980). x. Clinical Global Impression - Improvement Scale (CGI-I)
  • the Clinical Global Impression - Improvement Scale facilitates an interviewer’s or an observer’s, e.g., a clinician's, rating of a subject’s global functioning prior to and after initiating a treatment intervention. This facilitates tracking of clinical progress over time. All available information, including a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the subject’s ability to function can be considered when rating using the CGI-I.
  • the CGI-I comprises two companion one-item measures that evaluate the severity of psychopathology on a scale from 1 to 7 and changes from the initiation of treatment on a similar seven-point scale (Busner, 2007). xi. Sleep Quality Scale (SQS)
  • the Pittsburgh Sleep Quality Index is a self-rated questionnaire, which is used to assess sleep quality, including sleep disturbances, over a 1-month time interval.
  • PSQI Pittsburgh Sleep Quality Index
  • Nineteen individual items generate seven "component" scores in the areas of subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The scores across the seven components are added to yield one global score (Buysse, 1989).
  • xiii. Leeds Sleep Evaluation Questionnaire
  • the Leeds Sleep Evaluation Questionnaire uses ten 100 mm visual analogue scale items in four areas related to the ease of getting to sleep (GTS), the perceived quality of sleep (QOS), the ease of awakening from sleep (AFS), and the integrity of early-morning behavior following wakefulness (BFW).
  • GTS ease of getting to sleep
  • QOS perceived quality of sleep
  • AFS ease of awakening from sleep
  • BFW the integrity of early-morning behavior following wakefulness
  • a subject is instructed to answer each question by placing a vertical mark on a line, i.e., the “scale.” If no change was experienced, a subject would place a mark in the middle of the line. If a change was experienced, then the position of the subject’s mark indicates the nature and extent of the change, for example, large charges are represented as near the ends of the line and small changes near the middle of the line (Parrott, 1980).
  • use and/or cravings of alcohol and/or drugs are evaluated, monitored, or rated to assess therapeutic outcomes in response to a treatment intervention, for example, MDMA-assisted psychotherapy.
  • aspects of alcohol and drug use and cravings can be assessed at one or more points in time prior to, during, after completion of a treatment, such as MDMA-assisted psychotherapy.
  • alcohol and drug use and cravings are assessed using subject-reported and/or interviewer-reported questionnaires.
  • Alcohol- and drug-related inquiries include, but are not limited to, evaluations of alcohol use, alcohol cravings, use of prescribed medication(s), number and frequency of use of recreational drugs, cravings relating to MDMA, and use of illicit ecstasy following MDMA- assisted psychotherapy. Examples of instruments for monitoring or rating alcohol and drug use and cravings and their contents are described below for illustrative purposes and should not be construed as limiting. i. Alcohol Use and Cravings
  • alcohol acquisition and consumption can be evaluated using a variety of mediums, including interviewing or asking a subject about drinking behavior, administering a self-assessment on drinking behavior, e.g., a questionnaire, or detecting a level of alcohol, e.g., blood alcohol content, such as from a breath, body fluid, or tissue specimen.
  • cravings for alcohol include, for example, experiencing anticipation and/or desire for consuming alcohol.
  • alcohol cravings manifest as alcohol-seeking behavior.
  • cravings may be prompted or triggered by a variety of stimuli including, for example, alcohol withdrawal, the sight or smell of alcohol, interactions with people who are drinking, or even reliving a memory where drinking was involved.
  • alcohol use and/or alcohol cravings can be evaluated using the Severity of Alcohol Dependence Questionnaire (SADQ) (Stockwell, 1983), The Alcohol Dependence Syndrome section of the SCID-5-CT (Clinical Trials Version) (First, 2015), The Alcohol Timeline Follow Back (TLFB) (Sobell, 2001), The Clinical Institute Withdrawal Assessment for Alcohol — Revised Version (CIWA-Ar) (Saitz, 1994), The Penn Alcohol Craving Scale (PACS) (Flannery, 1999), and the Obsessive Compulsive Drinking Scale (OCDS) (Anton, 1995).
  • SADQ Severity of Alcohol Dependence Questionnaire
  • SSDQ Alcohol Dependence Questionnaire
  • SCID-5-CT Cosmetic Trials Version
  • TLFB Alcohol Timeline Follow Back
  • PES Penn Alcohol Craving Scale
  • OCDS Obsessive Compulsive Drinking Scale
  • drug use for example use of prescription or recreational drugs
  • prescription drug use can be evaluated using a variety of mediums, including interviewing or asking the subject’s prescribing physician about prescribed medications and/or interviewing or asking the subject about the same.
  • use of drugs, such as prescription drugs can be evaluated using measures of adherence and/or compliance.
  • measures of adherence and/or compliance include, for example, use of electronic medication packaging (EMP) devices, pill counting, clinician assessments, and self-report (Lam, 2015).
  • EMP electronic medication packaging
  • use of drugs, such as prescription drugs can be evaluated using self-reported or interviewer-reported questionnaires.
  • EMP electronic medication packaging
  • MAQ Medication Adherence Questionnaire
  • use of drugs can be evaluated using self-reported or interviewer-reported questionnaires.
  • the Drug Abuse Screening Test (DAST-10 and DAST-20) is a self-reported 20-item questionnaire that assesses the extent of the problems related to drug misuse, using yes or no responses.
  • the DAST total score is computed by summing all items (Villalobos-Gallegos, 2016).
  • cravings for drugs include, for example, experiencing anticipation and/or desire for consuming such substances.
  • cravings for drugs such as recreational drugs, manifest as drug-seeking behavior.
  • drug cravings are determined using self-reported questionnaires.
  • drug cravings can be identified or measured using reinforcement “proxies,” drug self-administration, psychophysiological responding, neurobiological responding, cognitive processing, and expressive behavior (Sayette, 2000).
  • use and/or cravings for MDMA or ecstasy are determined using one or more of the methods described herein.
  • use and/or cravings for MDMA or ecstasy are determined by asking a subject, such as a subject who will, is, or has participated in an MDMA-assisted psychotherapy treatment regimen, about their use of MDMA and cravings for the same.
  • use and/or cravings for MDMA or ecstasy are determined using a self-reported assessment.
  • use and/or cravings for MDMA or ecstasy are determined using other methods, for example, reinforcement “proxies,” drug self-administration, psychophysiological responding, neurobiological responding, cognitive processing, and expressive behavior (Sayette, 2000).
  • Ketamine psychedelic therapy (KPT): A review of the results of ten years of research. J. Psychoactive Drugs 29 (2), 165 - 183 Kurland, A.A., Unger, S., Shaffer, J.W., Savage, C., 1967. Psychedelic therapy utilizing LSD in the treatment of the alcoholic patient: a preliminary report. Am. J. Psychiatry 123 (10), 1202el209.
  • Alcohol-Use Disorders Diagnosis, Assessment and Management of Harmful Drinking and Alcohol Dependence. Leicester (UK): British Psychological Society; 2011. (NICE Clinical Guidelines, No. 115.) 2, ALCOHOL DEPENDENCE AND HARMFUL ALCOHOL USE. Available from: https://www.ncbi.nlm.nih.gov/books/NBK65500/ National Institute for Health and Care Excellence, NICE (June 2013) Alcohol-use disorder diagnosis and clinical management of alcohol-related physical complications CGI 00 Neff, KD. (2003). Development and validation of a scale to measure self-compassion. Self and Identity, 2, 223-250.
  • Sheehan DV Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. ;59 Suppl 20:22-33;quiz 34-57. Sheth et al. (1980). Compressed tablets, in Pharm. dosage forms, Vol. 1, Lieberman & Lachtman, eds., Dekker, NY. Shulgin, A. T. (1986).
  • Cytochrome P4502D6 Inhibition in Humans Clin Pharmacokinet, 2011. 50(5): p. 319-29. anger, U. M., & Schwab, M. (2013). Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacology & therapeutics, 138(1), 103-141. https://doi.Org/10.1016/j.pharmthera.2012.12.007.

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Abstract

L'invention divulgue des compositions de MDMA et des procédés d'utilisation de celles-ci dans la psychothérapie assistée par MDMA pour le traitement de patients atteints d'un trouble de consommation d'alcool (AUD) comprenant un trouble de consommation d'alcool dépendant physiquement (« consommation dépendante » ou « dépendance à l'alcool ») et un trouble de consommation d'alcool non dépendant physiquement (« consommation nocive »).
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Cited By (17)

* Cited by examiner, † Cited by third party
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