Transcript 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


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NIDA T32, R01s, R21, Single Source
Contract (Taiwan)
NIAAA
NINR
Fogarty International Center Training Grant
Disclosures

No pharmaceutical or other COI
Ecstasy
3,4-methylene dioxy-N-methyl
amphetamine
MDMA
History
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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

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
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
Scheduling
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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
Scheduling
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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
Scheduling
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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.
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Examples: Robitussin C, Lomotil
For Today
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Whether there is epidemiological evidence for
MDMA/Ecstasy dependence
Whether the evidence might suggest a
separate category in the DSM
In the Future
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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-
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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
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At least one of the above is required for the
disorder
Dependence must not have been met
Review of Criteria
--DSM-IV Dependence-
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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
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Maladaptive pattern of use, evidenced by at least 3 of the above in any
one 12 month period
The DSM Category
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There is no separate category for Ecstasy
and its isomers.
Currently, Ecstasy is lumped with
hallucinogens.
Use of Ecstasy among 8th,10th and 12th
graders--Monitoring the Future Data
12
10
8
8th
10th
12th
6
4
2
//
0
95
96
97
98
99
'00
'02
'05
Perceived Harmfulness of
Obtaining Ecstasy
Reported by 12th Graders (MTF Data)
80
70
60
50
% who
think
MDMA is
harmful
40
30
20
10
0
'00
'01
'02
'03
'04
'05
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“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.”
What the Public has been told about
the Risks of Ecstasy
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It damages brain cells, even in occasional
users.
Causes increased heart rate, blood pressure,
body temperature.
Not benign.
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Alan Leshner, former Director, NIDA (2002);
current CEO of AAAS (publisher of Science)
What the Public has been told about
the Risks of Ecstasy
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“…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
What is known about Ecstasy
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
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
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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
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Jim Inciardi, PhD
Hilary Surratt, PhD
Steve Kurtz, PhD
Sydney collaborators
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Jan Copeland, PhD,
Maree Teesson, PhD

National Drug and
Alcohol Research
Center, NSW
Design:
Time I
(N = 637)
Subjects receive:
RBA, SAM, CES-D
Time II
(N=305)
Subjects receive:
RBA
SAM
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
Random
assignment
(1:2)
(N=305)
Subjects receive:
RBA
SAM
(SCAN) Clinical Interview
(N=295)
Characteristics of Tri-City Study of Ecstasy
Dependence
Miami
(n=186)
St. Louis Sydney
(n=297) (n=154)
p value
Female
Mean Age
Caucasian
39%
23.6
31%
44%
23.3
73%
39%
23.0
79%
N/S
N/S
.0001
Ever Married
9%
8%
1%
.01
Employed (any in past 12m)
94%
91%
92%
N/S
Cannabis (LT)
98%
99%
94%
N/S
Stimulants (LT)
GHB (LT)
Rohypnol (LT)
Ketamine (LT)
Hallucinogens (LT)
46%
26%
29%
37%
76%
58%
14%
5%
32%
65%
89%
13%
4%
34%
44%
.0001
.001
.0001
N/S
.0001
Sir Bradford Hill’s Criteria for Causal
Inference Should be Used to Decide on
Acceptance of Revisions to Criteria
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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


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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
Miami
(n=186)
St. Louis
(n=297)
Sydney
(n=154)
p value
Use results in failure to
fulfill major role
obligations
24%
21%
38%
.0003
Use in hazardous
situations
51%
50%
54%
N/S
Substance-related legal
problems
7%
3%
4%
N/S
Use despite knowledge
it caused social
problems
29%
25%
32%
N/S
“Adopted” DSM-IV Criteria for Ecstasy
Dependence
Miami
(n=186)
St. Louis Sydney
(n=297) (n=154)
p value
Tolerance
Withdrawal
Takes substance in larger
amounts or over longer period
56%
68%
48%
43%
65%
37%
55%
77%
47%
.006
.03
.04
Inability to cut down or
control use
18%
14%
21%
N/S
Great deal of time is spent using
or recovering from use
62%
48%
62%
.002
Important activities are given
up for substance
25%
21%
35%
.005
Substance is used despite
knowledge it causes physical
or psychological harm
90%
85%
90%
N/S
“Adopted” DSM-IV Ecstasy Use
Disorder
Miami
(n=183)
St. Louis
(n=279)
Sydney
(n=143)
Neither
21%
32%
24%
Abuse Only
16%
16%
10%
Dependence
(+/- Abuse)
63%
52%
66%
X2=11.26 (4 df) p=.02
Tolerance and Ecstasy
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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
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Abuse criteria: kappas between 0.58 and
0.77
Dependence criteria: kappas between 0.51
and 0.75.
St. Louis Design:
Time I
(N = 300)
Subjects receive:
RBA
SAM
Time II
(N=150)
Subjects receive:
RBA
SAM
Eligibility: 18 to 35 years
of age; recruited via
flyers, newspaper, chain
referral methods
Random
assignment
(1:2)
(N=150)
Subjects receive:
RBA
SAM
(SCAN) Clinical Interview
(N=150)
Sub-study A
(St. Louis):
Meet withdrawal criteria
from SAM (time 1)
interview, N=75
Random
assignment
(1:3)
(N=25)
Sub-study Group B
(St. Louis):
Do not meet withdrawal
criteria from SAM (time 1)
interview, N=75
Random
assignment
(1:3)
(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



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Consistency of findings, replicability
Strength of the association
Dose-response or biological gradient
Temporal sequence
Biological plausibility
Specificity of findings
How to Obtain Dosage
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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
Lifetime # of pills*
1-99
Miami
(n=186)
St. Louis Sydney
(n=297) (n=154)
Mean
(SD)
57%
68%
51%
30.5
(22.1)
100-499 (n=178; 100-482)
32%
23%
32%
214.5
(103.0)
500+
11%
9%
17%
1341.1
(1118.4)
(n=387; 4-99)
(n=72; 500-5200)
*X2=15.9 (4 df) p=.03
Mean # pills
(SD)
255.34
(608.49)
181.14
271.94
(525.62) (495.01)
224.8
(543.9)
“Adopted” DSM-IV Abuse Criteria by Pill Use
1-99 pills (n=387)
100-499 pills (n=178)
500+ pills (n=69)
100
80
p<.0001
60
p<.0001
p<.0001
p<.0001
40
20
0
Neglected obligations
Hazardous Use
Legal problems
Use despite social problems
“Adopted” DSM-IV Dependence Criteria by Pill Use
1-99 pills (n=387)
100-499 pills (n=178)
500+ pills (n=69)
100
p<.0001
p=.0014
p<.0001
80
p<.0001
p<.0001
60
p<.0001
40
p<.0001
20
0
Tolerance
Withdrawal
Takes substance in
larger amounts or
over longer period
Can't cut down
or control use
Much time spent
using/recovering
from use
Important
activities given
up for substance
Substance used
despite knowing it
caused physical or
psychological harm
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

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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
• 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, LowIncome Women (n = 696)
Wu et al, CPDD Poster Presentation. 2006
Ecstasy
(n = 106)
Other illicit drugs
(n = 64)
Marijuana
only
(n = 173)
None
(n = 343)
Diabetes
4.04
0.00
0.61
2.45
Hypertension
1.00
3.45
3.68
3.67
Heart disease
2.02
0.00
0.00
0.91
Kidney disease
4.95
0.00
1.85
0.92
Gall bladder
7.07
7.02
1.23
3.38
Breast disease
5.26
1.89
3.77
3.24
0
67.96
81.03
79.88
79.76
1
22.33
13.79
17.07
18.82
2+
9.71
5.17
3.05
2.42
Total Physical
condition
Specificity of Ecstasy Dependence
Miami
(n=183)
St. Louis Sydney
(n=279) (n=143)
p value
Ecstasy Dependence
Alcohol Dependence
Cannabis Dependence
63%
62%
59%
52%
60%
56%
66%
61%
50%
.02
N/S
N/S
Stimulant Dependence
28%
35%
47%
.008
Cocaine Dependence
57%
58%
15%
.0001
Hallucinogen Dependence
35%
30%
18%
.004
GHB Dependence
Ketamine Dependence
Rohypnol Dependence
ALL AMONG USERS OF
THAT SPECIFIC
SUBSTANCE ONLY
14%
0%
9%
13%
0%
7%
10%
0%
0%
.04
N/S
N/S
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
Figure 2. Latent class conditional probabilities for THREE cluster model.
Additional Findings
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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?



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:
Time I
(N = 150)
Subjects receive:
Eligibility: 18 to 35 years
of age; recruited via
flyers, newspaper,
respondent driven
methods
RBA, SAM and CES-D
Time II
(N=75)
Subjects receive:
no clinical interview
(all given opportunity to receive clinical SAM)
Random
assignment
(1:2)
(N=75)
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?


Data indicate this to be the case.
But, we have just scratched the surface.