Epidemiological Evidence for MDMAEcstasy 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

5
(No Transcript)
6
(No Transcript)
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)

8
(No Transcript)
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,
  n185) 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 (12)
(N305)
(N305)
Subjects receive RBA SAM
Subjects receive RBA SAM
(SCAN) Clinical Interview (N295)
30
Characteristics of Tri-City Study of Ecstasy
Dependence
31
Sir Bradford Hills 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 Hills 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
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 (12)
(N150)
(N150)
Subjects receive RBA SAM
Subjects receive RBA SAM
Random assignment (13)
Random assignment (13)
(SCAN) Clinical Interview (N150)
(N25)
(N25)
Ethnographic Sub-study (N50)
39
Sir Bradford Hills 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
plt.0001
plt.0001
plt.0001
plt.0001
43
Adopted DSM-IV Dependence Criteria by Pill Use
p.0014
plt.0001
plt.0001
plt.0001
plt.0001
plt.0001
plt.0001
44
Sir Bradford Hills 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

46
(No Transcript)
47
(No Transcript)
48
(No Transcript)
49
(No Transcript)
50
(No Transcript)
51
Focus Group Responses

• 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

52

• 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 dont
  think they cook it like heroin, but Im not sure.
  There are fillers that are dangerous, cause you
  dont know what else is in it, but thats what
  your livers for. 33 y/o male
• I can use drugs professionally. Im a
  professional drug user in the fact that Ive used
  drugs since I was 16, and Ive 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 youll restore your
  serotonin. 24 y/o female

53

• I think that from everyone that Ive known that
  has done ecstasy and myself, Ive 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)
  

54
Sir Bradford Hills 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

55
Table 3. Mean number of Physical Conditions in
Young, Low-Income Women (n 696) Wu et al, CPDD
Poster Presentation. 2006
56
Specificity of Ecstasy Dependence
57

• 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

58
Figure 2. Latent class conditional probabilities
for THREE cluster model.
59
Additional Findings

• 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

60
How do we know it is Ecstasy?

• 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

61
Design of Club Drugs Study in Taipei
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 (12)
(N75)
(N75)
Subjects receive no clinical interview (all
given opportunity to receive clinical SAM)
Subjects receive Clinical SAM at
Tri-Service General Hospital
(MRI) Clinical Interview (N75 )
62
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.