Epidemiological evidence for mdma ecstasy dependence
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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. Acknowledgements.

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Epidemiological evidence for mdma ecstasy dependence
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


Acknowledgements
Acknowledgements

  • NIDA T32, R01s, R21, Single Source Contract (Taiwan)

  • NIAAA

  • NINR

  • Fogarty International Center Training Grant


Disclosures
Disclosures

  • No pharmaceutical or other COI


Ecstasy

Ecstasy

3,4-methylene dioxy-N-methyl amphetamine

MDMA


History
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)


Scheduling
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


Scheduling1
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


Scheduling2
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


Scheduling3
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


Scheduling4
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


For today
For Today

  • Whether there is epidemiological evidence for MDMA/Ecstasy dependence

  • Whether the evidence might suggest a separate category in the DSM


In the future
In the Future

  • Realization that this is only part of the evidence

  • Efforts are still under way and many investigators have puzzle pieces


Review of criteria dsm iv abuse
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


Review of criteria dsm iv dependence
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


The dsm category
The DSM Category

  • There is no separate category for Ecstasy and its isomers.

  • Currently, Ecstasy is lumped with hallucinogens.



Perceived harmfulness of obtaining ecstasy reported by 12th graders mtf data
Perceived Harmfulness of the Future DataObtaining EcstasyReported by 12th Graders (MTF Data)



What the public has been told about the risks of ecstasy
What the Public has been told about 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.”the 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)


What the public has been told about the risks of ecstasy1
What the Public has been told about 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.”the 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)


March 2006 printed
March 2006, printed 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.”


What is known about ecstasy
What is known about Ecstasy 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.”

  • 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%)


Opportunity
Opportunity 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.”

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)


Miami collaborators
Miami collaborators 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.”

  • Jim Inciardi, PhD

  • Hilary Surratt, PhD

  • Steve Kurtz, PhD


Sydney collaborators
Sydney collaborators 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.”

  • Jan Copeland, PhD, Maree Teesson, PhD

    • National Drug and Alcohol Research Center, NSW


Design
Design: 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.”

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)


Characteristics of tri city study of ecstasy dependence
Characteristics of Tri-City Study of Ecstasy Dependence 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.”


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


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


Adopted dsm iv criteria for ecstasy abuse
“Adopted” DSM-IV Criteria for Ecstasy Abuse be Used to Decide on Acceptance of Revisions to Criteria


Adopted dsm iv criteria for ecstasy dependence
“Adopted” DSM-IV Criteria for Ecstasy Dependence be Used to Decide on Acceptance of Revisions to Criteria


Adopted dsm iv ecstasy use disorder
“Adopted” DSM-IV Ecstasy Use Disorder be Used to Decide on Acceptance of Revisions to Criteria


Tolerance and ecstasy
Tolerance and Ecstasy be Used to Decide on Acceptance of Revisions to Criteria

  • 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


Test re test
Test/Re-test be Used to Decide on Acceptance of Revisions to Criteria

  • Abuse criteria: kappas between 0.58 and 0.77

  • Dependence criteria: kappas between 0.51 and 0.75.


St louis design
St. Louis Design: be Used to Decide on Acceptance of Revisions to Criteria

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)


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


How to obtain dosage
How to Obtain Dosage be Used to Decide on Acceptance of Revisions to Criteria

  • 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?”


Patterns of lifetime ecstasy use
Patterns of Lifetime Ecstasy Use be Used to Decide on Acceptance of Revisions to Criteria


Adopted dsm iv abuse criteria by pill use
be Used to Decide on Acceptance of Revisions to CriteriaAdopted” DSM-IV Abuse Criteria by Pill Use

p<.0001

p<.0001

p<.0001

p<.0001


Adopted dsm iv dependence criteria by pill use
be Used to Decide on Acceptance of Revisions to CriteriaAdopted” DSM-IV Dependence Criteria by Pill Use

p=.0014

p<.0001

p<.0001

p<.0001

p<.0001

p<.0001

p<.0001


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


Effects
Effects be Used to Decide on Acceptance of Revisions to Criteria

  • 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


Focus group responses
Focus Group Responses be Used to Decide on Acceptance of Revisions to Criteria

  • The low is as low as the high. 32 y/o Female

  • I have made a conscious effort not to drive when I am on X, but sometimes parties get busted and then people need to drive. 30 y/o male

  • Self-experience is the best way for knowledge. 25 y/o male


  • I know that E is used intravenously. They crush up a pill into powder form, put it into a spoon, mix it with water, you know, put it up. I don’t think they cook it like heroin, but I’m not sure. There are fillers that are dangerous, cause you don’t know what else is in it, but that’s what your liver’s for. 33 y/o male

  • I can use drugs professionally. I’m a professional drug user in the fact that I’ve used drugs since I was 16, and I’ve used quite a few. Even when I was 17, and 18, I felt that after I had initially gotten the gist of it that I knew what my boundaries were. I knew when and where to go to do it. I knew the effects that I was going to have so I would plan for what I was going to do. 24 y/o female

  • Just use 5HT on Monday, and you’ll restore your serotonin. 24 y/o female


  • I think that from everyone that I’ve known that has done ecstasy and myself, I’ve never known it to be an addictive drug. 24 y/o female

  • I was pretty sure I was getting MDMA because I always got it from the same person and he was like a chemical engineering major. He looked like he knew what he was doing. But he never put it in pills for us and put logos on it; he only did that when he packaged it to sell it to other people. We always got it as powder. 20 y/o male

  • I felt it on Suicide Tuesday– the day after the day I was recovering– was awful. (multiple users)


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


Table 3. Mean number of Physical Conditions in Young, Low-Income Women (n = 696)

Wu et al, CPDD Poster Presentation. 2006


Specificity of ecstasy dependence
Specificity of Ecstasy Dependence Low-Income Women (n = 696)


Latent Class Analysis of Ecstasy Abuse and Dependence Symptoms:

A Multi-site Study with Three Community Samples

Lawrence M. Scheier1

Arbi Ben Abdallah2, James A. Inciardi 3

Jan Copeland4 and Linda B. Cottler2

1 LARS Research Institute and Washington University School of Medicine, Department of Psychiatry, St. Louis, Missouri, USA

2 Washington University School of Medicine, Department of Psychiatry, St. Louis, Missouri, USA

3 University of Delaware Research Center, Miami, Florida, USA

4 National Drug and Alcohol Research Center, University of New South Wales, Sydney, Australia

National Institute of Drug Abuse

DA 14854



Additional findings
Additional Findings cluster model.

  • Presented last year comparisons of findings for Ecstasy users who also used hallucinogens– there were specific and unique findings for each drug

  • Presented comparisons for Ecstasy users who also used stimulants– there were specific and unique findings for each

  • Ecstasy users can distinguish their symptoms


How do we know it is ecstasy
How do we know it is Ecstasy? cluster model.

  • There are many adulterants in the pills. Users tell us they know when they are getting good stuff.

  • Even use Marquis reagent to test their own pills (DanceSafe)

  • Hair samples tested


Design of club drugs study in taipei
Design of Club Drugs Study in Taipei: cluster model.

Time I

(N = 150)

Subjects receive:

RBA, SAM and CES-D

Eligibility: 18 to 35 years of age; recruited via flyers, newspaper, respondent driven methods

Time II

Random assignment

(1:2)

(N=75)

(N=75)

Subjects receive:

no clinical interview

(all given opportunity to receive clinical SAM)

Subjects receive:

Clinical SAM at

Tri-Service General Hospital

(MRI) Clinical Interview (N=75 +)


Should ecstasy and its isomers be added separately to the dsm
Should Ecstasy and its isomers be added separately to the DSM?

  • Data indicate this to be the case.

  • But, we have just scratched the surface.


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