Epidemiological Evidence for MDMA/Ecstasy Dependence

Epidemiological Evidence for MDMA/Ecstasy Dependence

Linda B. Cottler, Ph.DDepartment of Psychiatry

Director, Epidemiology & Prevention Research Group

Washington University School of Medicine

St. Louis

23 January, 2007

Acknowledgements

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

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

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

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

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

Whether there is epidemiological evidence for MDMA/Ecstasy dependence

Whether the evidence might suggest a separate category in the DSM

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--

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--

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

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

0

2

4

6

8

10

12

95 96 97 98 99 '00 '02 '05

8th10th12th

//

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

0

10

20

30

40

50

60

70

80

'00 '01 '02 '03 '04 '05

% whothinkMDMA isharmful

“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 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)

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)

March 2006, printed

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%)

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)

Miami collaborators

Jim Inciardi, PhD Hilary Surratt, PhD Steve Kurtz, PhD

Jan Copeland, PhD, Maree Teesson, PhD

National Drug and Alcohol Research Center, NSW

Sydney collaborators

Design:

(SCAN) Clinical Interview (N=295)

(N=305)(N=305)

Random assignment

(1:2)

Time I(N = 637)

Subjects receive: RBA, SAM, CES-D

Subjects receive: RBA SAM


Time II

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

Characteristics of Tri-City Study of Ecstasy Dependence

Miami(n=186)

St. Louis(n=297)

Sydney(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

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(n=297)

Sydney(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

Abuse Only

Dependence

(+/- Abuse)

21%

16%

63%

32%

16%

52%

24%

10%

66%

X2=11.26 (4 df) p=.02

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

Test/Re-test

Abuse criteria: kappas between 0.58 and 0.77

Dependence criteria: kappas between 0.51 and 0.75.

St. Louis Design:

Sub-study Group B (St. Louis):Do not meet withdrawal criteria from SAM (time 1) interview, N=75

(SCAN) Clinical Interview (N=150)

(N=150)(N=150)

Random assignment

(1:2)

Time I(N = 300)

Sub-study A (St. Louis):Meet withdrawal criteria from SAM (time 1) interview, N=75

Random assignment

(1:3)

Random assignment

(1:3)

Ethnographic Sub-study (N=50)

(N=25)(N=25)




Time II

Eligibility: 18 to 35 years of age; recruited via flyers, newspaper, chain referral methods

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?”

Patterns of Lifetime Ecstasy Use

Lifetime # of pills*

Miami(n=186)

St. Louis(n=297)

Sydney(n=154)

Mean(SD)

1-99 (n=387; 4-99)

100-499 (n=178; 100-482)

500+ (n=72; 500-5200)

57%

32%

11%

68%

23%

9%

51%

32%

17%

30.5

(22.1)

214.5

(103.0)

1341.1

(1118.4)

*X2=15.9 (4 df) p=.03

Mean # pills (SD)

255.34(608.49)

181.14

(525.62)

271.94

(495.01)

224.8(543.9)

“Adopted” DSM-IV Abuse Criteria by Pill Use

0

20

40

60

80

100

Neglected obligations Hazardous Use Legal problems Use despite social problems

1-99 pills (n=387) 100-499 pills (n=178) 500+ pills (n=69)

p<.0001

p<.0001

p<.0001

p<.0001

“Adopted” DSM-IV Dependence Criteria by Pill Use

0

20

40

60

80

100

Tolerance Withdrawal Takes substance inlarger amounts or

over longer period

Can't cut down or control use

Much time spentusing/recovering

from use

Important activities given up for substance

Substance useddespite knowing itcaused physical or psychological harm

1-99 pills (n=387) 100-499 pills (n=178) 500+ pills (n=69)

p<.0001

p<.0001 p<.0001

p<.0001

p<.0001

p=.0014p<.0001

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

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)

Table 3. Mean number of Physical Conditions in Young, Low-Income 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

Total Physical condition

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

Specificity of Ecstasy Dependence

Miami(n=183)

St. Louis(n=279)

Sydney(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 AbuseDA 14854

Figure 2. Latent class conditional probabilities for THREE cluster model.

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

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:

(MRI) Clinical Interview (N=75 +)

(N=75)(N=75)

Random assignment

(1:2)

Time I(N = 150)

Subjects receive:

RBA, SAM and CES-D

Subjects receive: no clinical interview

(all given opportunity to receive clinical SAM)

Subjects receive: Clinical SAM at Tri-Service General Hospital

Time II

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

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.

Epidemiological Evidence for MDMA/Ecstasy Dependence

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