Gay Men's Health Crisis: Treatment Issues, Volume 7 no. 9 - October, 1993
Derek Link

Although MDMA is certainly not an AIDS treatment, many physicians who treat people with HIV report that large numbers of their patients use the drug recreationally. Yet most physicians also report they have no knowledge about MDMA. This article reviews information from the medical literature and credible unpublished reports on the drug, including its clinical effects, toxicities, incidence, and use patterns.

History and Overview

MDMA was unsuccessfully developed as a weight loss pill by a German drug company in 1912. The drug remained obscure and forgotten until its psychedelic properties were rediscovered in the 1960s. MDMA emerged fully into public view in the late 1970s and early 1980s when a group of psychotherapists openly advocated for its use as an adjunct to therapy and underground chemists began producing it for recreational users.

MDMA is often called a designer drug, but for reasons different than most people realize. In pharmaceutical drug development, designer drugs refer to compounds synthesized using sophisticated, computerized modeling techniques. In the case of recreational drugs, designer drugs are chemically altered forms of illicit drugs which retain similar effects but have not yet been legally proscribed. MDMA is neither difficult to make nor was it designed to produce its pleasurable effects.

MDMA possession, distribution, and manufacture were criminalized in 1985 by the Drug Enforcement Agency (DEA), the Federal government's lead agency in the "War Against Drugs." Ecstasy is a Schedule I drug, which means the DEA has determined it has no medical use and a high potential for abuse. Penalties for manufacture and distribution of a Schedule I drug are fifteen years in prison and fines up to $125,000. The DEA reports that in fiscal year 1992 it made no arrests for MDMA distribution and seized 11,753 dosage units of the drug.

Incidence of MDMA Use

Data on the extent of recreational MDMA use are limited and incomplete, frustrating attempts to understand the drug. Yet some small studies and anecdotal information confirm that MDMA is widespread among some populations and that its use grew in the 1980s. The DEA estimates that MDMA production has increased dramatically since the 1970s. One Texas manufacturer reportedly made 10,000 doses in all of 1978, but increased production to 30,000 per month in 1985. One operation claimed to have manufactured and distributed 2 million doses in one month alone in 1985.[1]

The National Institute of Drug Abuse (NIDA) collects data on drug use patterns in young adults aged 19 to 28.[2] Since 1989, NIDA has collected data on MDMA use. Based on a sample of 2600 people, 3.9 percent in 1992 reported using MDMA at some point in the past, 1 percent reported using MDMA within the last twelve months, and 0.3 percent reported using it within the last 30 days. According to the NIDA data, MDMA use has remained at a constant level in this population since 1989. MDMA was perceived as one of the least harmful illegal drugs when taken intermittently by the young people in this survey. For unknown reasons, though, NIDA did not ask how respondents perceived MDMAs harmfulness when taken frequently. Most respondents perceived the harm of other drugs, including other amphetamines, to increase with chronic use.

Peroutka published an informal study of the incidence of MDMA use on the Stanford University campus in 1987.[3] He found that 39 percent of randomly selected Stanford undergraduates reported using MDMA recreationally. Most respondents reported using MDMA an average of five times.

Most observers agree that MDMA is most commonly used by urban populations. MDMA seems to be particularly popular with "college students, gays, yuppies, and New Age seekers of psychological and spiritual growth."[4]

Data from several other countries extend these observations. British health authorities estimate that a half million young people may have used MDMA in that country.[5] An Australian study examined MDMA use patterns among Sydney residents. Based on a sample of 100 MDMA users, the Australian study concludes that a typical MDMA user in Sydney is a 27-year- old, employed, college-educated person who lives in the inner city area.[6] Seventy-two percent reported using MDMA at social events and dance parties.

Finally, a study conducted at the Kobler Center, an outpatient HIV clinic in London, confirms the observation that HIV-infected people, at least in Britain, are using MDMA in large numbers. Mansfield and colleagues studied 196 patients at their clinic. Recreational drug use was common overall; forty percent reported MDMA use within the last year.[7]

MDMA and Unsafe Sex

Recreational drug use, and MDMA in particular, may be related to unsafe sexual practices and HIV infection among gay men, according to two reports. Coates and associates report that MDMA was significantly correlated with HIV seropositivity among men who have sex with men.[8] Although other recreational drugs were associated with HIV infection, once frequency of receptive anal sex was statistically controlled, only MDMA remained significantly correlated with HIV infection in this group. Interestingly, neither injection drugs nor needle sharing were correlated with increased HIV infection in this group.

The Kobler center study examined the sexual practices of gay men attending an HIV clinic in London. Users of Ecstasy, LSD, amphetamines, and cocaine were more likely to engage in unprotected sex and had more sexual partners.

MDMA Clinical Effect

MDMA is most commonly sold in doses of 100 to 150mg. Most MDMA users ingest the drug orally, although some report snorting or injecting. Twenty minutes to one hour after ingestion, MDMA produces an initial burst of energy and euphoria. These effects continue for approximately two to three hours. A slow "coming down" period is the followed by a characteristic MDMA hangover which usually lasts about one day. The hangover typically involves depression, irritability, and fatigue.

MDMA increases the release of 5-HT (also called serotonin), a brain chemical which is believed to play a significant role in mood, sleep, and sexual function, from reserve storage in tissues. This burst of 5-HT causes more neurons (brain cells) to respond in a rapid period, producing the effect of "ecstasy." However, once released from reserve storage, 5-HT levels are greatly diminished, producing the hang over effect. 5-HT reserves are slowly replenished over the next 24 hours. Interestingly, studies in rats suggest that MDMA 5-HT depletion may be biphasic -- that is, once reserves have been restored 24 hours after MDMA use, another transient decline occurs approximately seven days later.[9]

Several informal clinical studies have been conducted with the drug. For the most part, these studies rely on volunteer self-assessment questionnaires and a limited amount of physical data to make their conclusions. The studies were conducted primarily in healthy, adult men, although a few women were also enrolled. No study described the racial or ethnic background of its participants.

It should be noted that this research was conducted primarily by renegade psychiatrists, usually from California, who are also advocates for the use of MDMA in psychotherapy. This research was conducted prior to MDMA's classification as a Schedule I drug. Unfortunately, rigorous clinical studies of MDMA are now impossible since MDMA's Schedule I status prohibits further clinical research. However, MDMA research continues in other countries, most notably Switzerland, so more clinical data may become available in the future. Downing conducted an informal study of MDMA with twenty-one volunteers given the drug at a dose of their own choosing.[10] Volunteers were recruited in San Francisco in October 1984. Doses ranged from 0.8 to 1.9mg/LB with a mean dose of 1.14mg/LB. Eight women volunteered for the study. The study volunteers were better educated and earned higher incomes than the general population and all reported previous MDMA use.

Liester and colleagues conducted an observational MDMA study in Southern California with twenty psychiatrists who had previously used MDMA.[11] Two psychiatrists were women. The psychiatrists reported their previous MDMA experiences on questionnaires.

Greer and Tolbert administered MDMA to volunteers in San Francisco and Santa Fe between 1980 to 1983.[12] Twenty nine volunteers were administered 75 to 150mg of MDMA in their own homes. When the drug's effect began to diminish, usually after about two hours, volunteers were offered a second dose of 50mg to "prolong the session and to provide a more gradual return to their usual state of consciousness."

These studies all point to the same conclusion: when used in a controlled environment, MDMA can be relatively safe, with no life-threatening toxicities. The side effects typically seen with the drug in these studies include dilated pupils, clenched jaw, grinding teeth, elevated blood pressure, nausea, vomiting, dizziness, headache, decreased appetite, eyelid twitches, muscle aches, insomnia, and other general stimulant effects.

Reports of MDMA-Related Deaths

If these informal studies demonstrate that MDMA can be relatively safe when used in a controlled environment, wide- scale recreational use has shown its dangers. Several deaths linked to MDMA have been reported in the medical literature. However, in virtually every reported death, toxicology data (that is, testing body fluids to see if MDMA is actually present) were unavailable and other drugs were reportedly consumed along with MDMA. Furthermore, many deaths classed as MDMA-related resulted from impaired judgment while on the drug. One report describes a young man who climbed an electrical tower while on MDMA and fell to his death.

Despite the small number of cases and the difficulty collecting data on the drug, at least two deaths have been reported where MDMA appears to be the sole cause of death. In both cases, the users collapsed suddenly and died of cardiac arrhythmias. Interestingly, arrhythmias are a well-recognized mechanism of sudden death with amphetamine overdoses.[13] Although the numbers are far too small to draw firm conclusions, several points emerge from an examination of deaths where MDMA was the sole or contributing cause of death. Thus far, researchers have not determined if MDMA deaths result from a rare, idiosyncratic reaction to the drug or overdose reactions. Since MDMA's pharmacokinetics are unknown and overdose levels have not been determined, this question remains unresolved. However, in cases where MDMA was reported as the sole or significant cause of death (and where toxicology data are available), blood levels greater than 1mg/L of the drug have been found. In cases where MDMA was an incidental cause of death, blood levels of MDMA did not exceed 0.39mg/L.[14]

Furthermore, Greer recommends that individuals with "hypertension, heart disease, hypothyroidism, diabetes, hypoglycemia, seizure disorders, glaucoma, diminished liver function, or those who are pregnant" avoid the drug.[15]

MDMA-Associated toxicities

Several reports in the medical literature describe serious toxicities related to MDMA use. Hayner and McKinney summarize the immediate and residual toxicities experienced by recreational MDMA users in San Francisco.[16] This information is based on case reports from the medical literature as well as anecdotal reports from health care clinics and drug treatment programs.

Although serious toxicities have been reported in MDMA users, their causal mechanism and rate of occurrence are unknown. Most observers agree, however, that while serious toxicities are possible with MDMA, they are very rare. Furthermore, many MDMA users consume other drugs concomitantly, complicating a thorough toxicity analysis. Thus far, researchers do not know if MDMA toxicities are related to dose level, frequency of use, environmental factors, or idiosyncratic reactions to the drug.

Several observers note that hyperthermia reactions to MDMA may be related to strenuous physical activity and inadequate fluid consumption while on the drug. MDMA-related hyperthermia seems to occur most commonly in people who use the drug while dancing at clubs. Several physicians stress that MDMA users should rest frequently, avoid alcohol use, and drink plenty of water, soft drinks, or juices while on the drug.

One report describes a serious drug interaction between MDMA and a monoamine oxidase inhibitor (MAOI), a class of antidepressant drugs. Psychiatrists who prescribe MAOI consul their patients to avoid using other drugs, particularly those with central nervous system effects. Patients treated with MAOIs should not use MDMA.[17]

MDMA may exacerbate or provoke underlying psychiatric illness, according to the anecdotal, unpublished observations of some psychiatrists. Clinicians from the Haight-Ashbury Free Clinic in San Francisco describe a "delayed anxiety disorder" in MDMA users. A New York psychiatrist describes a "persistent perceptual disorder" in MDMA users. Thus far no published reports confirm these observations.

When asked to sum up the toxicity data, a clinical psychiatrist familiar with MDMA said: "If someone takes MDMA and they develop high temperatures and/or muscle rigidity, they should seek medical attention immediately at the nearest emergency room."

Possible Neurotoxic effects

No data prove that MDMA causes brain damage in humans. However, this question has not been addressed adequately due to prohibitions on MDMA research and the difficulty studying this problem in humans. Yet some researchers believe that MDMA does have neurotoxic effects, particularly when used chronically. These researchers cite animal data which suggest that chronic MDMA use permanently impairs the brain's 5-HT system.[18, 19, 20, 21, 22, 23, 24] They speculate that chronic MDMA use may permanently diminish the amount of 5-HT stored in tissues and impair the brain's complex system of 5-HT- sensitive neurons.

Two research teams have performed preliminary studies on people who use MDMA frequently and found little clinical or neurochemical evidence of brain damage. In fairness, though, these studies have been small, preliminary attempts to answer this question and did not possess sufficient statistical power to draw firm conclusions.

Kystal and colleagues examined the performance of nine chronic MDMA users on a standard battery of neuropsychologic tests.25 These chronic users consumed an average of 1.9 monthly doses of MDMA (+/- 1.7 doses) for an average of 5.1 years (+/- 2.3 years). No differences were seen in tests which measure affect (mood). Slight differences were observed in tests of attention and memory. These differences were too small to be observed clinically. However, given the small number of patients studied and the large number of tests performed, these differences could be the result of chance alone. The authors conclude: "These preliminary data raise the possibility that individuals with extensive MDMA use histories exhibit mild, subclinical impairments in cognitive function, but not affective disorder."

Price and associates performed a complex neurochemical study on the same group of chronic MDMA users. They measured serum prolactin response to intravenous L-tryptophan, an indirect surrogate marker of 5-HT function.[26] Although this test is imprecise, a decreased serum prolactin response to l-tryptophan has been linked to other diseases associated with abnormal 5-HT function, such as depression. Also, several antidepressant drugs which have known effects on 5-HT function increase the serum prolactin response.[27] The serum prolactin response was reduced in MDMA users, though not to statistically significant levels. The authors conclude, "MDMA users seemed less likely to manifest the very marked prolactin responses demonstrated by some healthy subjects, suggesting a degree of blunting in those subjects ordinarily most sensitive to l-tryptophan."

Is MDMA Addictive?

Researchers do not agree if MDMA is addictive. Most reports describe MDMA's abuse potential as low. However, scant data on the extent and frequency of MDMA use make it difficult to know for certain if MDMA addicts exist. In fact, two animal studies demonstrate that MDMA can be addictive in primates. Rhesus monkeys and baboons will self-administer MDMA.[28, 29] Tests of this sort -- determining if primates will self- administer a drug -- are a classic, well-known method of determining if a substance is addictive.

MDMA has been considered "nonaddictive" because most reports describe a pattern of use with the drug that is unusual for addictive substances. Most users report a disinclination to use MDMA frequently, waiting at least a week between doses. Furthermore, the pleasurable effects of the drug diminish while the negative effects increase with frequent use, according to several reports.[30]

Underground MDMA

MDMA is manufactured illegally by underground chemists. Thus no regulations govern its manufacture. As a result, there is no certainty that street MDMA is actually MDMA. There are numerous anecdotal reports of purported MDMA which turned out to be some other substance. In addition, some researchers question whether contaminants in MDMA could be responsible for some MDMA deaths and toxicities.

Renfroe describes an important and unique service called Analysis Anonymous sponsored by the not-for-profit group PharmChem Laboratories in California.31 During its period of operation from 1972 to 1984, recreational drug users could submit samples of their drugs for an analysis of purity. During this period, 101 MDMA samples were submitted for analysis. Most samples came from the San Francisco area, New York, and Los Angeles. Of the 101 samples analyzed, 59 contained MDMA only. Twenty-four samples contained MDMA with other substances, usually MDA, a closely related but more toxic compound, or chemical precursors from MDMA's manufacturing process, usually methylamine. Fifteen samples contained MDA alone or with its own chemical precursors. One sample "contained a nondescript amphetamine." Two samples contained no MDMA, MDA, or other known drugs; the constituents in these two samples could not be identified. Analysis Anonymous ceased operations before MDMA was criminalized. It is unknown what effect, if any, criminalization may have had on the purity of MDMA samples. Treatment Issues was unable to obtain information on the purity of MDMA now available on the street.

Conclusion

MDMA is a popular illicit drug widely used by some urban populations, including gay men and some HIV-infected people. Inadequate data describe the extent of MDMA use. MDMA is associated with increased risk of HIV infection in men who have sex with men. Although rare, MDMA use has been linked to serious toxicities and death. While no data support the belief that MDMA causes brain damage, scientific studies have not adequately addressed this question. MDMA addiction has not been described in humans, although it has been observed in two species of primates. MDMA is a street drug with unknown purity.

Possible MDMA-Related Toxicities

Tachycardia (rapid heartbeat) Hypertension progressing to Hypotension Hyperthermia (highly elevated body temperature) Hypertonicity (increased pressure of body fluids) Intravascular coagulation Kidney Failure Hallucinations Rhabdomyolysis (serious muscle degeneration) Possible Residual Effects of MDMA Flashbacks Anxiety Attacks Persistent Insomnia Psychotic Reactions Depression

1. Beck J. Public Health Consequences of MDMA. In: Ecstasy. Peroutka SJ (ed). 1990. Kluwer: Amsterdam.

2. Personal Communication. [Data on file at GMHC]

3. Peroutka SJ. New England Journal of Medicine. 317 (24) 1987: 1542-3 (letter).

4. Beck J. op cit.

5. Randall T. Journal of the American Medical Association. 268(12): 1992. 1505-6

6. Solowij J, et al. Survey of Ecstasy Users in Sydney. 1991. NSW Health Dept Research Grant Report DAD 91-69. [Data on file at GMHC.]

7. Mansfield S, et al. The Use of Ecstasy and Other Recreational Drugs in Patients Attending an HIV Clinic in London. 1993. [Data on file at GMHC]

8. Coates RE, et al. American Journal of Epidemiology. 128(4):1988. 729-39.

9. Schmidt CJ. Journal of Pharmacology and Experimental Therapeutics. 240:1987.1-7.

10. Downing J. Journal of Psychoactive Drugs. 18(4): 1986. 335-9.

11. Liester MB, et al. Journal of Nervous and Mental Disease. 180(6): 1992. 345-52.

12. Greer G, et al. Journal of Psychoactive Drugs. 18(4): 1986. 319-326.

13. Dowling G. Human Deaths Attributed to MDMA. In: Ecstasy. Peroutka SJ (ed). 1990. Kluwer: Amsterdam.

14. Ibid.

15. Greer G. op cit.

16. Hayner GN, et al. Journal of Psychoactive Drugs. 18(4): 1986. 341-7.

17. Smilkstein ML, et al. Clinical Toxicology. 25:1987. 149- 159.

18. Stone DM, et al. European Journal of Pharmacology. 128: 1986. 41-8.

19. Battaglia G, et al. Journal of Pharmacology and Experimental Therapy. 242:1987. 911-6.

20. Commins DL, et al. Journal of Pharmacology and Experimental Therapy. 241: 1987. 338-45.

21. Mokler DJ, et al. European Journal of Pharmacology. 138: 1987. 265-8.

22. Schmidt CJ. Journal of Pharmacology and Experimental Therapeutics. 240:1987.1-7.

23. Ricaurte GA, et al. JAMA. 260: 1988. 51-5

24. Ricaurte GA, et al. Brain Research. 446:1988. 165-8.

25. Krystal JH, et al. American Journal of Drug and Alcohol Abuse. 18(3):1992. 331-41.

26. Price LH, et al. Archives of General Psychiatry. 46:1989. 20-22.

27. Price LH, et al. Archives of General Psychiatry. 46:1989. 13-19

28. Beardsley PM, et al. Drug and Alcohol Dependency. 18:1986, 149-157.

29. Lamb RJ, et al. Psychopharmacology. 91:1987. 268-272.

30. Peroutka SJ. Archives of General Psychiatry. 46:1989. 191. (letter)

31. Renfroe CJ. Journal of Psychoactive Drugs. 18(4): 1986. 363-9.

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