Epidemiological Evidence for MDMA/Ecstasy Dependence

1. Epidemiological Evidence for MDMA/Ecstasy Dependence Linda B. Cottler, Ph.D Department of Psychiatry Director, Epidemiology & Prevention Research Group Washington University School of Medicine St. Louis 23 January, 2007

2. Acknowledgements • NIDA T32, R01s, R21, Single Source Contract (Taiwan) • NIAAA • NINR • Fogarty International Center Training Grant

3. Disclosures • No pharmaceutical or other COI

4. Ecstasy 3,4-methylene dioxy-N-methyl amphetamine MDMA

7. History • Developed in Germany in early 1900s to synthesize other pharmaceuticals • Used in 1970s by psychiatrists as a psychoactive tool (called “penicillin for the soul”) • 1980s used on the street; 1990s at raves • 2000 approved by FDA for use in RCT for PTSD • Both a stimulant and psychedelic • Taken orally, effect lasts 3 to 6 hours • Average dose is 1 to 2 tablets (each 60 to 120 mg)

9. Scheduling • Schedule I. (A) The drug or other substance has a high potential for abuse. (B) The drug or other substance has no currently accepted medical use in treatment in the United States. (C) There is a lack of accepted safety for use of the drug or other substance under medical supervision. The substance has a high potential for abuse. • Examples: MDMA, Heroin, Marijuana, LSD, Mescaline, Peyote

10. Scheduling • Schedule II. (A) The drug or other substance has a high potential for abuse. (B) The drug or other substance has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions. (C) Abuse of the drug or other substances may lead to severe psychological or physical dependence. • Examples: Amphetamine, Cocaine, Ritalin, Methadone, Oxycodone

11. Scheduling • Schedule III. (A) The drug or other substance has a potential for abuse less than the drugs or other substances in schedules I and II.(B) The drug or other substance has a currently accepted medical use in treatment in the United States. (C) Abuse of the drug or other substance may lead to moderate or low physical dependence or high psychological dependence. • Examples: Anabolic steroids, Codeine, Ketamine

12. Scheduling • Schedule IV. (A) The drug or other substance has a low potential for abuse relative to the drugs or other substances in schedule III.(B) The drug or other substance has a currently accepted medical use in treatment in the United States. (C) Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in schedule III. • Examples: Xanax, Librium, Valium, Rohypnol, Provigil, Ambien, Ativan

13. Scheduling • Schedule V. (A) The drug or other substance has a low potential for abuse relative to the drugs or other substances in schedule IV. (B) The drug or other substance has a currently accepted medical use in treatment in the United States. (C) Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in schedule IV. • Examples: Robitussin C, Lomotil

14. For Today • Whether there is epidemiological evidence for MDMA/Ecstasy dependence • Whether the evidence might suggest a separate category in the DSM

15. In the Future • Realization that this is only part of the evidence • Efforts are still under way and many investigators have puzzle pieces

16. Review of Criteria--DSM-IV Abuse-- Recurrent use resulting in failure to meet role obligations at work, home or school Recurrent use in situations when it is likely to be physically hazardous Legal problems resulting from recurrent use Continued use despite knowledge that it is causing social/interpersonal problems At least one of the above is required for the disorder Dependence must not have been met

17. Review of Criteria--DSM-IV Dependence-- • Tolerance • Withdrawal • Taking substance for longer time or larger amounts than intended • Persistent desire or unsuccessful efforts to quit or cut down • Great deal of time spent in activities to obtain or recover from the effects of the drug • Important social or occupational activities given up in order to use • Continued use despite knowledge of physical/ psychological problems caused by substance • Maladaptive pattern of use, evidenced by at least 3 of the above in any one 12 month period

18. The DSM Category • There is no separate category for Ecstasy and its isomers. • Currently, Ecstasy is lumped with hallucinogens.

19. Use of Ecstasy among 8th,10th and 12th graders--Monitoring the Future Data //

20. Perceived Harmfulness of Obtaining EcstasyReported by 12th Graders (MTF Data)

21. “Research in animals indicates that MDMA is neurotoxic; whether or not this is also true in humans is currently an area of intense investigation. MDMA can also be dangerous to health and, on rare occasions, lethal.”

22. What the Public has been told aboutthe Risks of Ecstasy • It damages brain cells, even in occasional users. • Causes increased heart rate, blood pressure, body temperature. • Not benign. • Alan Leshner, former Director, NIDA (2002); current CEO of AAAS (publisher of Science)

23. What the Public has been told aboutthe Risks of Ecstasy • “…it is a drug that is far from benign. For example, MDMA can cause a dangerous increase in body temperature that can lead to kidney failure. MDMA can also increase heart rate, blood pressure, and heart wall stress. Animal studies show that MDMA can damage specific neurons in the brain. In humans, the research is not conclusive at this time; however, a number of studies show that long-term, heavy MDMA users suffer cognitive deficits, including problems with memory.” Nora Volkow, Director, NIDA (2002)

24. March 2006, printed

25. What is known about Ecstasy • Topp and colleagues (1997) did the first study of DSM-IV abuse/dependence on Ecstasy (Sydney, n=185) and found that: • problems from Ecstasy use exist • reliability and validity of these criteria were needed • 64% met criteria for dependence, 21% met criteria for abuse • the most prevalent criteria reported were withdrawal, tolerance, and unsuccessful efforts to stop use • Cottler and colleagues (2001), using the SAM, found that: • reports of criteria were reliable • 43% met criteria for dependence • 34% met criteria for abuse • the most prevalent criteria reported were withdrawal (59%), physically hazardous use (43%), and continuing to use despite knowledge of harm (63%)

26. Opportunity NIDA-funded study focuses on: • Reliability (test-retest) and validity (clinical evaluation) of club drug use disorders • Revision to the Composite International Diagnostic Interview-- Substance Abuse Module (CIDI-SAM) • New Risk Behavior Assessment specific to club drugs • 2 sites: St. Louis, Miami (3rd site added with an international supplement: Sydney; 4th site added with a contract: Taipei and included MRI) • + Qualitative methods • + STD testing and drug testing (via hair)

27. Miami collaborators • Jim Inciardi, PhD • Hilary Surratt, PhD • Steve Kurtz, PhD

28. Sydney collaborators • Jan Copeland, PhD, Maree Teesson, PhD • National Drug and Alcohol Research Center, NSW

29. Design: Time I (N = 637) Subjects receive: RBA, SAM, CES-D Eligibility: 18 to 35 years of age; recruited via flyers, newspaper, respondent driven methods; used XTC at least 5 x LT; once in past 12 months Time II Random assignment (1:2) (N=305) (N=305) Subjects receive: RBA SAM Subjects receive: RBA SAM (SCAN) Clinical Interview (N=295)

30. Characteristics of Tri-City Study of Ecstasy Dependence

31. Sir Bradford Hill’s Criteria for Causal Inference Should be Used to Decide on Acceptance of Revisions to Criteria • Consistency of findings, replicability • Strength of the association • Dose-response or biological gradient • Temporal sequence • Biological plausibility • Specificity of findings

32. Sir Bradford Hill’s Criteria for Causal Inference Should be Used to Decide on Acceptance of Revisions to Criteria • Consistency of findings, replicability • Strength of the association • Dose-response or biological gradient • Temporal sequence • Biological plausibility • Specificity of findings

33. “Adopted” DSM-IV Criteria for Ecstasy Abuse

34. “Adopted” DSM-IV Criteria for Ecstasy Dependence

35. “Adopted” DSM-IV Ecstasy Use Disorder

36. Tolerance and Ecstasy • 31% found in Verduin et al study. • 50% found in Tri-city study, Bradford et al study. (9% tolerance only; 49% along with withdrawal) • Subtype with both tolerance and withdrawal most prevalent (41%); w/d only 28%; neither 22% and tolerance only 9%. • Those with both were more likely to meet criteria for dependence (+/- abuse); least likely to meet abuse only, use more pills lifetime and have youngest age of onset of Ecstasy use

37. Test/Re-test • Abuse criteria: kappas between 0.58 and 0.77 • Dependence criteria: kappas between 0.51 and 0.75.

38. St. Louis Design: Sub-study Group B (St. Louis): Do not meet withdrawal criteria from SAM (time 1) interview, N=75 Sub-study A (St. Louis): Meet withdrawal criteria from SAM (time 1) interview, N=75 Time I (N = 300) Subjects receive: RBA SAM Eligibility: 18 to 35 years of age; recruited via flyers, newspaper, chain referral methods Time II Random assignment (1:2) (N=150) (N=150) Subjects receive: RBA SAM Subjects receive: RBA SAM Random assignment (1:3) Random assignment (1:3) (SCAN) Clinical Interview (N=150) (N=25) (N=25) Ethnographic Sub-study (N=50)

39. Sir Bradford Hill’s Criteria for Causal Inference Should be Used to Decide on Acceptance of Revisions to Criteria • Consistency of findings, replicability • Strength of the association • Dose-response or biological gradient • Temporal sequence • Biological plausibility • Specificity of findings

40. How to Obtain Dosage • RBA questions: • “If you were to add up all of the ecstasy pills you have used since you first started using ecstasy, about how many pills would that be?” • “How many days have you used ecstasy in the last 30 days?” • “During these days [when you used], how many times a day did you usually use ecstasy or MDMA?”

41. Patterns of Lifetime Ecstasy Use

42. “Adopted” DSM-IV Abuse Criteria by Pill Use p<.0001 p<.0001 p<.0001 p<.0001

43. “Adopted” DSM-IV Dependence Criteria by Pill Use p=.0014 p<.0001 p<.0001 p<.0001 p<.0001 p<.0001 p<.0001

44. Sir Bradford Hill’s Criteria for Causal Inference Should be Used to Decide on Acceptance of Revisions to Criteria • Consistency of findings, replicability • Strength of the association • Dose-response or biological gradient • Temporal sequence • Biological plausibility • Specificity of findings

45. Effects • Positive: mental stimulation, emotional warmth, empathy towards others, general sense of well-being, decreased anxiety • Negative/Undesirable: anxiety, agitation, recklessness, nausea, chills, sweating, muscle cramping, blurred vision, jaw clenching, dehydration, high blood pressure, heart failure, kidney failure, arrhythmia, loss of consciousness, seizures, hyperthermia