**********************************03319********************************** PAGE 1 DATE: JANUARY 13, 1993 CLIENT: . LIBRARY: MEDEX FILE: DRUGDX YOUR SEARCH REQUEST IS: MDMA OR ECSTASY OR ECSTACY NUMBER OF DOCUMENTS FOUND WITH YOUR REQUEST THROUGH: LEVEL 1... 3 PAGE 2 2ND DOCUMENT of Level 1 printed in FULL format. Copyright (c) 1974 - 1992 Micromedex, Inc. DRUGDEX (R) Drug Consults, Edition 75 MICROMEDEX data is provided for reference only. Health professionals are responsible for therapy decisions. Entire documents should be reviewed. MDMA - FDA REPORT, 1985 RESPONSE: The Food and Drug Administration has received inquiries about the drug MDMA (3,4-METHYLENEDIOXYMETHAMPHETAMINE) referred to in news media stories as an unregulated "DESIGNER DRUG." The following may be used to answer inquiries. MDMA is a psychotropic drug, street named "ADAM" and " ECSTASY, " popular among a small number of therapists and psychiatrists, although it has never been approved by FDA. The therapists claim that MDMA increases perceptions of self-insight and empathy. Recreational users claim that the drug relaxes inhibitions and enhances communications and sex. However, no INDs have been filed with FDA. Chemically, MDMA is related to both the amphetamines and mescaline and especially to a potent stimulant known as MDA. Although it was developed in the 1970's, there was no enforcement activity involving MDMA manufacture or possession prior to last July. At that time, after a strong upsurge of MDMA street use, the Drug Enforcement Administration (DEA) proposed listing it as a "Schedule 1 Controlled Substance" -- the category for drugs with no medical use and a high abuse potential. In the Schedule 1 category (which includes heroin, LSD and MDA), clandestine production or sale of MDMA would be punishable by up to 15 years in prison and a $125,000 fine. The DEA proposal was protested by some nurses, physicians and professors of pharmacology who wrote letters demanding a hearing. They challenged the proposed scheduling on the grounds that the drug has only a low or moderate abuse potential and has great therapeutic usefulness. DEA announced May 31, 1985 it will not wait for hearings before acting because recent data indicate that the drug is being abused in 28 states. DEA is using a 1984 change in the Controlled Substances Act which allows emergency scheduling of drugs for one year. DEA's emergency ban will become effective July 1. The emergency action is an interim measure to curb MDMA abuse until the longer administrative process can be completed. DEA has scheduled hearings June 10 and 11 in Los Angeles and July 10 and 11 in Kansas City. A third hearing will be scheduled later in Washington, DC. FDA will participate in the hearings to PAGE 3 (c) 1974 - 1992 Micromedex, Inc., Eval, 74 Ed. testify on the pharmacological aspects of the drug. PAGE 4 3RD DOCUMENT of Level 1 printed in FULL format. Copyright (c) 1974 - 1992 Micromedex, Inc. DRUGDEX (R) Drug Consults, Edition 75 MICROMEDEX data is provided for reference only. Health professionals are responsible for therapy decisions. Entire documents should be reviewed. MPTP-CONTAMINATED DESIGNER DRUGS - TREATMENT PATIENT DATA: Please review the presentation and treatment of patients who have used MPTP-contaminated designer drugs. RESPONSE: DESIGNER DRUGS are analogs of known pharmacological agents, synthesized by underground chemists, for sale on the street. The concept of designer drugs is to manipulate the chemical structure of a narcotic, for example, and create a totally new compound. The "underground" chemist has two goals. First, is the belief that the nature and duration of the "high" experienced can be changed through chemical manipulations. Although the science of medicinal chemistry involves predictions of structure-activity relationships regarding psychodynamic effects, associated toxicities are frequently unexpected. Second, since there are no laws against newly formulated compounds, legal ramifications are bypassed. Fortunately, emergency laws have been implemented against such agents and new regulations are being processed (Baum, 1985). This consult includes a brief overview of designer drugs and a discussion of DESIGNER MEPERIDINE, proposed mechanisms of its toxicities and some treatment possibilities. There are at least three popular types of designer drugs: MDMA (3,4-METHYLENEDIOXYMETHAMPHETAMINE), FENTANYL ANALOGS, and MEPERIDINE ANALOGS. MDMA is not a true designer drug, as this agent is a schedule I agent that was once used in psychiatry. Street names for MDMA include: MDA, ADAM, ECSTASY and XTC. MDMA interacts with serotonergic neurons. MDMA produces effects that are similar to those of LSD without hallucinatory properties. These include increased self-awareness and decreased communication barriers. Side effects consist of increased heart rate and blood pressure, irregular heart beat, panic attacks, anxiety, sleep disorders, drug craving, paranoia, and rebound depression. Fentanyl analogs include the following: alpha-methyl-p-fluoro-3-methyl and alpha-methyl-acetylfentanyl. In 1979 the alpha-methyl analog was found in users of "CHINA WHITE". The effects of these compounds are similar to heroin in terms of the nature of the "high" and its duration of action. PAGE 5 (c) 1974 - 1992 Micromedex, Inc., Eval, 74 Ed. However, these analogs can be up to 40 times more potent than heroin. This potency makes overdose a serious risk. The drug-induced respiratory depression can be fatal (Baum, 1985). Adverse Drug Reactions of Designer Meperidine Designer meperidine is sold as SYNTHETIC HEROIN. The primary street analog of meperidine is MPPP (1-methyl-4-phenyl-4-propionpiperidine). Very specific chemical reaction conditions are required to produce MPPP. In the event of sloppy synthesis, where the pH is too low or the temperature is too high, a contaminant, MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine) is formed. MPTP is a known industrial toxin which affects the dopaminergic neurons of the substantia nigra. Cases of PARKINSON'S DISEASE caused by MPTP have been reported (Baum, 1985). The proposed biochemical mechanism of action of MPTP involves the rapid oxidation of MPTP to MPP+ after systemic administration. This conversion takes place in all tissues studied (brain and systemic), except for the eye, and is necessary for MPTP to exert its toxic effects (Irwin & Langston, 1985). Monoamine oxidase catalyzes this reaction. Highly reactive intermediates may also be formed in the conversion. MPP+ is then taken up by neurons in the substantia nigra where it destroys dopaminergic neurons in this area. Although the formation of MPP+ occurs in many parts of the brain, it remains unclear as to why it selectively accumulates in the substantia nigra and not in other dopaminergic areas of the brain such as the striatum (Langston, 1985). These biochemical mechanisms are undergoing further studies. MPTP exposure is suspected if the patient answers "yes" to the following questions on initial presentation: 1. Did the pure form of the drug resemble brown sugar? 2. Was there a burning sensation on intravenous injection at the injection site and up through the vein? 3. Was the "high" more "spacey and giddy" than that of heroin? These questions can help identify MPTP exposures (Latimer, 1985). Other symptoms of MPTP toxicity are discussed below. Three phases of MPTP toxicity have been identified (Langston, 1985a). The first is an acute phase which occurs on initial exposure to MPTP. Symptoms include disorientation, hallucinations, blurred vision, "nodding off" (a slow downward drifting of the head, and drooping and closure of the eyelids), difficulties in speech and swallowing, intermittent jerking of the limbs, slow movement, and tremor at rest. The second phase is a subacute event which occurs after exposure to the drug. Two to three days post-exposure there are reports of increased bradykinesia and rigidity of extremities, abrupt onset of "freezing up" and inability to move. Up to three weeks after exposure, awkward posture, progressive slowness of movement and "freezing up" have been reported. Finally, if there is no recovery from the above two phases, a chronic syndrome results. PAGE 6 (c) 1974 - 1992 Micromedex, Inc., Eval, 74 Ed. A permanent Parkinsonian syndrome evolves consisting of classical Parkinsonian symptoms such as bradykinesia, rigidity, resting tremor, fixed stare, and loss of postural reflexes. Recovery from the acute or subacute phase may occur, but it is unlikely once the chronic phase has been reached. Several mechanisms have been proposed to explain the manifestations of each of the three phases. Possible mechanisms regarding the acute phase include an opiate receptor interaction with MPTP, serotonergic effects of the substance, and a slight dopaminergic deficiency caused by MPTP. Because MPTP is a meperidine analog, an opiate receptor interaction is probably responsible for the "nodding off" which takes place. This phenomenon is typical of exposure to heroin and is due to the same type of opiate receptor interaction. An initial suppression of serotonin in the central nervous system by MPTP is the suggested cause for the hallucinations and retropulsions which occur (Ballard et al, 1985). Motor symptoms are attributed to MPTP's effect on the dopaminergic neurons in the substantia nigra, but the dopamine deficiency is not yet substantial. The subacute phase is thought to occur once MPTP accumulation reaches a critical threshold before killing cells in the substantia nigra. This theory thus offers an explanation for the delayed onset of symptoms and for the continuation of symptoms after exposure. Metabolic damage, such as impaired dopamine synthesis, is also suggested as a cause of dopamine depletion. Further study of this delayed phase is in progress. The likely cause of the chronic phase is actual nigral cell death. This, in turn, leads to a permanent hypodopaminergic state, and thus permanent Parkinsonism. Recovery from the acute and subacute phases has two possible explanations. A critical toxic threshold of MPTP may not be reached intracellularly in the substantia nigra, thus the cells can return to normal once exposure is stopped. Or, perhaps less than a critical number of dopaminergic neurons are lost and the remaining cells are able to compensate by overproduction of dopamine, therefore resolving the clinical symptoms. Typical Parkinsonian treatment modalities are employed in patients who present with MPTP toxicity. Anticholinergic agents only help to reduce the tremor, and thus are of little benefit. CARBIDOPA and LEVODOPA therapy, with or without dopamine agonists, such as BROMOCRIPTINE, are helpful, but complications typical of this therapy have resulted. These problems include dyskinesias, end of dose deterioration, and on-off swings between choreathetosis and Parkinson's symptoms. Studies with monoamine oxidase type B inhibitors, such as PARGYLINE and SELEGILINE, suggest a possible alternative treatment (Tetrud & Langston, 1989; Langston et al, 1984; Fuller & Hemrick-Lueck, 1985). If monoamine oxidase (MAO) is inhibited, the conversion of MPTP to MPP+ is prevented. Thus, MAO inhibitor drugs may provide a protecting effect if given PAGE 7 (c) 1974 - 1992 Micromedex, Inc., Eval, 74 Ed. prior to MPTP and may be effective in retarding the progression of symptoms if given after MPTP. Further research is underway concerning drug therapy for MPTP toxicities. CONCLUSION: Several significant points can be noted regarding MPTP contamination. First, the risks of designer drugs are great due to the lack of purification after synthesis, the lack of knowledge about what is actually being created, and the presence of possible adulterants. Secondly, MPTP is a very specific neurotoxin which can induce irreversible Parkinson's symptoms at any age. Finally, MPTP administration to laboratory animals, provides scientists an opportunity to study the function of dopamine on the nervous system, the effects of chronic dopamine deficiency, and the effects of chronic dopamine agonist therapy, and other areas of interest. It is hopeful that understanding the mechanisms of MPTP will provide further understanding of Parkinsonism and offer new insights to the understanding and management of this disease. REFERENCES: 1. Ballard PA, Tetrud JW & Langston JW: Permanent human Parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology 1985; 35:949-956. 2. Baum RM: New variety of street drugs poses growing problem. Chem Eng 1985; 9:7-16. 3. Fuller RW & Hemrick-Lueck SK: Influence of selective reversible inhibitors of monoamine oxidase on the prolonged depletion of striatal dopamine by 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine in mice. Life Sci 1985; 37:1089-1095. 4. Irwin I & Langston JW: Selective accumulation of MPP+ in the substantia nigra: a key to neurotoxicity? Life Sci 1985; 36:207-212. 5. Langston JW: MPTP and Parkinson's disease. Trends in Neurosciences 1985; 8:79-83. 6. Langston JW: MPTP neurotoxicity: an overview and characterization of phases of toxicity. Life Sci 1985a; 36:201-206. 7. Langston JW, Irwin I & Langston EB: Pargyline prevents MPTP induced Parkinsonism in primates. Science 1984; 225(4669):1480-1482. 8. Latimer D: MPTP "brain damage dope" floods west coast suburbs. High Times 1985; 122:19-27. 9. Tetrud JW & Langston JW: The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. Science 1989; 245:519-522. PAGE 8 DATE: JANUARY 13, 1993 CLIENT: . LIBRARY: GENMED FILE: PINK YOUR SEARCH REQUEST IS: MDMA OR ECSTASY OR ECSTACY NUMBER OF ARTICLES FOUND WITH YOUR REQUEST THROUGH: LEVEL 1... 1 PAGE 9 1ST ARTICLE of Level 1 printed in FULL format. Copyright (c) 1992 F-D-C Reports Inc. The Pink Sheet 1992; 54(29): T&G-11-T&G-12 July 20, 1992 SECTION: TRADE & GOVT. MEMOS LENGTH: 483 words TEXT: HALLUCINOGENS POSE NO GREATER RISK THAN OTHER INVESTIGATIONAL DRUGS, FDA's Drug Abuse Advisory Committee agreed at its July 15 meeting. Summarizing the committee's discussion, FDA Pilot Drug Staff Medical Officer Curtis Wright, MD, said: "I have not heard . . . any discussion of risks involving these compounds that we do not routinely face with every new drug we put through the IND process." The committee was asked to assess problems that might be associated with allowing research to be conducted with hallucinogenic drugs. Wright said FDA, in the last few years, automatically has put IND applications for hallucinogenic drugs on hold, taking from months to years to respond to investigators regarding their protocols. Wright told the group: "We are coming to the committee because we are going to have to deal with the issue of hallucinogens . . . because drugs of this class are likely to be explored as potential therapies or modifiers of the effects of a variety of agents, including cocaine." FDA's reluctance to approve IND requests for hallucinogens stems from several concerns, Wright explained, including the potential for diversion of controlled substances by researchers and patients, and animal data indicating that selective serotonin agonists, such as substituted amphetamines, can permanently alter the serotonin pathways. While committee members and consultants agreed that the potential long-lasting neurologic changes caused by these drugs are of concern, they concurred with Wright's comments that the harm caused by these agents "is outweighed in most cases by the knowledge to be obtained or by the therapeutic benefit to the patient." Wright said that all neurologic or psychological risks "need to be addressed in evaluation of the protocol." Synthesizing the comments of the committee and consultants, Wright said: "I have heard great concerns by almost every speaker that the usual standards of research must be followed: that there must be meticulous attention to questions of patient selection, informed consent, [and] monitoring." He remarked: "I haven't heard anything that leads me to believe that this is a qualitatively different kind of research than the rest of the research we do with other agents." In closed session, the committee considered an IND protocol submitted by University of California at Irvine researcher Charles Grog, MD, for the selective serotonin agonist methylenedeoxymethamphetamine ( MDMA, commonly known as " Ecstasy" ) for use in psychotherapy and pain relief of terminally-ill pancreatic cancer patients. PAGE 10 (c) 1992 F-D-C Reports, Inc., The Pink Sheet, July 20, 1992 Patients in the proposed protocol would receive 1.5-2 mg/kg MDMA every two to four weeks. MDMA, synthesized and purified at Purdue University, is one of the hallucinogenic drugs that has been found to be associated with neurotoxicity (alteration of the serotonin-producing neurons) in rodents and primates. PAGE 11 DATE: JANUARY 13, 1993 CLIENT: . LIBRARY: GENMED FILE: JNLS YOUR SEARCH REQUEST IS: MDMA OR ECSTASY OR ECSTACY NUMBER OF ARTICLES FOUND WITH YOUR REQUEST THROUGH: LEVEL 1... 39 PAGE 12 2ND ARTICLE of Level 1 printed in FULL format. Copyright (c) 1992 American Medical Association JAMA(R) 1992; 268: 1505-1506 September 23, 1992 / September 30, 1992 SECTION: MEDICAL NEWS & PERSPECTIVES LENGTH: 1565 words TITLE: Ecstasy -Fueled 'Rave' Parties Become Dances of Death for English Youths AUTHOR: Teri Randall TEXT: THE ILLEGAL designer drug ecstasy -- promoted by some as a safe, nontoxic means to "warm, loving relaxation" -- has killed at least 15 young people in England in the last 2 years and caused severe toxicity in numerous patients, experts report from that country's National Poisons Unit. In almost every case, a recreational dose of the drug had been taken at a dance club or party where crowds danced vigorously in popular, all-night dance sessions called "raves." In most of the serious cases reported, the users had collapsed unconscious or started to convulse while dancing. By the time they were noticed and taken to emergency departments, their body temperatures had soared as high as 110 degrees F (43.3 degrees C), their pulses were racing, and their blood pressures were plummeting. These patients with severe toxicity usually developed disseminated intravascular coagulation, rhabdomyolysis, and acute renal failure. Despite treatment, death sometimes ensued from 2 to 60 hours after admission, usually due to severe hyperthermia accompanied by disseminated intravascular coagulation. Severe or fatal reactions of this type are virtually undocumented in the US drug abuse literature concerning ecstasy (also known as MDMA for its chemical name, 3,4-methylenedioxymethamphetamine). But this pattern of illness has recently become all too familiar in British medical journals (J R Soc Med. 1991; 84:371; J R Soc Med. 1992;85:61; BMJ. 1992;305:5,6,29; BMJ. 1992;305:309-310; and Lancet. 1992;339:677-678). The most recent report, published 6 weeks ago, describes seven fatalities, all associated with rave dances (Lancet. 1992;340:384-387). The report also describes seven cases of unexplained hepatotoxicity (including one death) attributed to a history of ecstasy use. According to the authors, the pattern of illness and the amounts of MDMA ingested rule out the possibility of an overdose. In most cases the user had taken only a few tablets or capsules. By comparison, one analytically documented MDMA overdose -- allegedly 42 tablets taken at home -- was accompanied by no symptoms other than a "hangover" with tachycardia and hypertension. The patient's plasma MDMA level was 7.72 mg/L, which is six to 70 times greater than the plasma levels measured in the fatal cases. John Henry, MD, consulting physician for the National Poisons Unit at Guy's Hospital, London, England, and lead author of the most recent Lancet report, says that prolonged, vigorous dancing (which may itself be an effect of PAGE 13 Copyright 1992 Amer. Medical Assn., JAMA, September 23, 1992 MDMA) may compound the pharmacologic effects of the drug. The amphetamine-derived MDMA has been shown to increase body temperature in rats, presumably by interfering with serotonin metabolism in the brain. Higher ambient temperatures seem to intensify this effect, and the hot, poorly ventilated environments of some nightclubs, together with inadequate fluid replacement, may be sufficient to elevate body temperature to lethal levels in susceptible individuals, Henry suggests. The finding has relevance for the international medical community because the rave culture is now being exported to the United States and other countries (see accompanying article). Henry urges physicians to be aware of the drug's pharmacologic effects when it is combined with this type of dancing. Cases of severe hyperthermia or unexplained jaundice or hepatomegaly should suggest possible MDMA toxicity, he says. For the patient who is taken acutely ill, medical treatment is urgent and includes control of convulsions, measurement of core temperature, rapid rehydration, active cooling measures, and possibly use of the antispasmodic drug dantrolene (Anaesthesia. 1991; 47:686-687). A 'Cultural Reformulation' Of great interest to Henry is how the drug has been adopted by, and has perhaps even catalyzed, the new rave culture in England -- similar, he says, to the Acid Test parties of the 1960s and the use of LSD (lysergic acid diethylamide) and amphetamines. The drug's association with the rave scene has led to its enormous popularity in England. An estimated half-million people in that country have taken MDMA, he says, most of them young people. MDMA use had been widespread in both the United States and England throughout the 1980s, but in a much different context, and with different outcomes. Users usually took it while they were alone or with a small group of people. Ninety percent of users in one US study said the drug made them feel euphoric, more verbal, and closer to other individuals. Some called it the "love drug." In a study done at Stanford (Calif) University School of Medicine in 1987 -- at the peak of the drug's popularity in the United States -- 39% of the undergraduates reported they had used MDMA at least once (N Engl J Med. 1987;317:1542-1543). In the late 1980s, the drug was "'reformulated,'" Henry says, "not in the pharmacologic sense, but in the cultural sense." The rave scene in England provided a "new 'formula,' a new package, a new culture." And it is this new cultural context that has, unfortunately, provided a real-life showcase for ecstasy's previously unknown lethal potential. Before this "reformulation," the handful of reported fatalities were mostly cardiac arrhythmias in individuals with underlying natural disease (JAMA. 1987; 257:1615-1617). Many users did experience adverse effects, however. In a 1986 study, 29 volunteers were given 75 mg to 150 mg (a "recreational dose") of pure MDMA by psychotherapists (J Psychoactive Drugs. 1986;18:319-327). All 29 experienced PAGE 14 Copyright 1992 Amer. Medical Assn., JAMA, September 23, 1992 undesirable physical symptoms: 28 lost their appetite, 22 had trismus or bruxism, nine had nausea, eight had muscle aches or stiffness, and three had ataxia. Sweating was common, and tachycardia and hypertension were recorded. Afterward, 23 people noted fatigue for hours or days, and 11 had insomnia. The mechanism by which MDMA elevates body temperature is still a matter of speculation, although experts suspect it involves the drug's interference with serotonin metabolism in the brain. In experimental animals, MDMA stimulates the release of this neurotransmitter from serotonergic neurons, particularly from those in the dorsal raphe. Under normal conditions, released serotonin is taken up into the terminal endings of the cells that released it. But in the presence of MDMA, this reuptake process is altered, leaving the nerve cells depleted of serotonin. The waters are muddied, however, when one looks at clinical experience. Some experts have argued that there is no clinical evidence that people who use MDMA develop such typical symptoms of serotonin depletion as disorders of sleep, mood, and sexual function (Arch Gen Psychiatry. 1990;47:288-289). Lewis Seiden, PhD, professor of pharmacology at the University of Chicago, Ill, conducted extensive research on the neurotoxicity of MDMA in the mid-1980s. When he heard of the recent reports of fatalities associated with the use of the drug in English nightclubs, he was reminded, he says, of a well-established phenomenon in amphetamine research called "aggregation toxicology": One solitary rat or mouse given an injection of amphetamine will survive. But several animals, confined in a small cage and given the identical dose of amphetamine, will die. Over the years, one of several proposed explanations for this phenomenon has been amphetamine-induced hyperthermia, Seiden says. On the other hand, one "can't make the assumption the MDMA is just a fancy form of amphetamine," points out Steven Karch, MD, research director of the Trauma Center at the University Medical Center of Southern Nevada, Las Vegas. "The molecules are very close structurally [figure]. But then again, all stimulants look roughly the same." Seiden also speculates that because MDMA is such a potent serotonin-releasing agent in the brain, it might also effect serotonin-releasing cells elsewhere in the body. Ninety percent of the serotonin in the body is located outside the brain, much of it in the gut and mast cells, he says. The Long Road to Rave MDMA has a long, controversial history that spans nearly a century, says Karch, who is also editor of the Forensic Drug Abuse Advisor. The patent for MDMA was initially granted in 1914 to E. Merck in Darmstadt, Germany, as an appetite suppressant. The compound's toxicology wasn't systematically studied until the early 1950s, under a US Army contract with a group at the University of Michigan, Ann Arbor. The results of these studies were eventually declassified and published in 1973, when it was revealed that MDMA is somewhat less toxic than MDA (another amphetamine derivative), but more toxic than the hallucinogen mescaline (Toxicol Appl Pharmacol. 1973;25:299-309). PAGE 15 Copyright 1992 Amer. Medical Assn., JAMA, September 23, 1992 No pharmaceutical company has ever made MDMA, nor has the Food and Drug Administration approved it. A small number of psychiatrists have advocated its use in therapy, based on the belief that it lowers patients' defenses and promotes trust and confidence. In 1985, after several studies showed neurotoxicity in animals, the Drug Enforcement Agency classified MDMA as a Schedule I compound. Schedule I compounds, such as heroin and LSD, are believed by the agency to have a high potential for abuse and no currently accepted medical use. GRAPHIC: Figure, Structural formulas of amphetamine, methamphetamine, and MDMA ("Ecstasy" ). PAGE 16 3RD ARTICLE of Level 1 printed in FULL format. Copyright (c) 1992 American Medical Association JAMA(R) 1992; 268: 1506 September 23, 1992 / September 30, 1992 SECTION: MEDICAL NEWS & PERSPECTIVES LENGTH: 493 words TITLE: 'Rave' Scene, Ecstasy Use, Leap Atlantic AUTHOR: Teri Randall TEXT: THE BRITISH rave counterculture, and its liberal use of ecstasy (MDMA) , has become a hot export to the United States, wrapped in a high-tech music and video package and supported by low-tech laboratories that illicitly produce the drug stateside. An August 19, 1992, article by United Press International says that a clamp-down on rave parties by British authorities has inspired several English rave promoters to move their business to the United States. Staged in empty warehouses or open fields outside San Francisco or Los Angeles, their parties are drawing thousands of young Californians on designated weekend nights. Partygoers -- attired in Cat in the Hat-hats and psychedelic jumpsuits -- pay $ 20 at the door to dance all night to heavily mixed, electronically generated sound, surrounded by computer-generated video and laser light shows. They pay another $ 3 to $ 5 for "smart drinks" -- amino acid-laced beverages that reputedly enhance energy and alertness. And for another $ 20, those so inclined can purchase an ecstasy tablet (see accompanying article). Many observers can't help but draw comparisons to the LSD-laced "human be-ins" of a quarter-century ago. The scene has come full circle, they add, noting that several Los Angeles raves have been hosted by Timothy Leary's son. The elder Leary, a former Harvard professor who advocated the use of LSD (lysergic acid diethylamide) three decades ago, has made several appearances at his son's raves, calling them "high-tech Acid Tests." Large raves also have been staged in New York, NY, and other urban centers in the United States. Their popularity is increasing in parts of India, Indonesia, Belgium, and New Zealand, and a promoter is working to popularize the scene in Sweden, United Press International reports. So far, there appear to be no published reports of death or severe toxicity caused by MDMA use. Most of the MDMA available in England is supplied by clandestine laboratories in the Netherlands. In the United States, the drug is made predominantly on the West Coast by small-scale operators, says Joseph Bono, supervisory chemist, special testing, Drug Enforcement Agency. The synthesis of MDMA requires minimal knowledge of chemistry. Illicit laboratories are often set up in kitchens, mobile trailers, or garages with PAGE 17 Copyright 1992 Amer. Medical Assn., JAMA, September 23, 1992 little concern for cleanliness. Reactions may be set up in cookie jars. Solid products may be removed with coffee filters; and the coffee filter may be thrown back into the reaction vessel for a second synthesis step (J Forensic Sci. 1988;33:576-587). Bono detects a lot of contaminants and by-products in the samples that reach his laboratory for analysis. "We're not dealing with Smith, Kline, and French here. We're dealing with people who are just interested in turning out a product," Bono says. "If it assays at 50% as opposed to 100% or 95%, they don't really care. And what is that other 50%? Who knows?" PAGE 18 9TH ARTICLE of Level 1 printed in FULL format. Copyright (c) 1990 American Medical Association Arch Gen Psychiatry 1990; 47: 288-289 March, 1990 SECTION: LETTERS TO THE EDITOR LENGTH: 1278 words TITLE: Second Thoughts on 3,4-Methylenedioxymethamphetamine ( MDMA) Neurotoxicity AUTHOR: CHARLES GROB, MD, GARY BRAVO, MD, ROGER WALSH, MD, PHD, University of California, Irvine Medical Center, Department of Psychiatry and Human Behavior, 101 City Dr S Rte 88, Orange, CA 92668 TEXT: To the Editor. -- Recent attention has been drawn to the purported neurotoxic dangers associated with 3,4-methylenedioxymethamphetamine ( MDMA) . Price et al [n1] have attempted to assess possible serotonergic neurotransmitter damage by contrasting serum prolactin response to the challenge with intravenous L-tryptophan in subjects with a history of MDMA use vs control subjects. Their primary finding was a blunted rise in the expected serum prolactin level in MDMA users, but not to a statistically significant degree. The importance of this finding appears to be questionable and perhaps misleading. Even if the data had yielded a statistically significant result, would such a correlation necessarily imply causation? A methodological limitation to the study would appear to be that subjects were not adequately screened on selection to exclude those who were using other psychotropic drugs. There is no mention that toxicology screens were ever performed. In fact, three subjects (33%) admitted to marijuana use during the 3-week supposed drug-free interval prior to the testing. As marijuana is known to affect dopaminergic function (and, consequently, prolactin secretion), [n2] the implications for MDMA effect on serotonergic function are further questioned. One additional point regarding this study is that even if one could demonstrate that MDMA users had diminished serotonergic function compared with control subjects, what does this imply? Without data as to baseline serotonergic functioning prior to the first ingestion of MDMA, such findings are of limited significance. Numerous animal studies have been performed over the past several years that were designed to evaluate the neurotoxic potential of MDMA. Until recently, most have examined short-term degeneration of serotonin neurons in animal brain following repeated systemic administration of MDMA. Battaglia et al [n3] have examined the brains of rats treated with massive subcutaneous dosages of MDMA (cumulatively up to 100 times the usual human oral dose) over time, and have noted complete regeneration 1 year after administration of the drug. This, together with the fact that there have yet to be documented clinical cases of MDMA -induced serotonergic neurotoxicity (ie, there have been no reports of sleep, mood, appetite, aggressive, or sexual dysregulation), may indicate that concerns over long-term neuropsychiatric damage have been overstated. PAGE 19 Copyright 1990 Amer. Medical Assn., Arch Gen Psychiatry, March, 1990 The related controversy over fenfluramine hydrochloride has some relevance here. During the last 25 years, approximately 50 million people have been clinically treated with fenfluramine. [n4] Fenfluramine has been utilized primarily as a weight-reducing agent and has also been used in clinical trials for the treatment of infantile autism and childhood attention-deficit disorder with hyperactivity. However, animal studies have demonstrated that fenfluramine has a serotonergic neurotoxic capability three times that of MDMA. [n5] Yet despite such findings, fenfluramine has accepted clinical indications, has a history of widespread use, and is without the known induction of neurological side effects. Claims have been made that MDMA enhances the processes of psychotherapy by facilitating empathy, heightening introspection, and lowering defensive anxiety. [n6] Because of concerns of possible neurotoxicity, however, rigorous clinical trials designed to validate these claims have not been performed. The data reviewed suggest that fears of MDMA neurotoxicity may have been exaggerated and it may well be significantly less toxic than a very widely used medication, fenfluramine. In view of its purported unique psychoactive properties, it may be appropriate to pursue clinical trials of MDMA. Alternatively, the search for a nontoxic analogue should be encouraged. REFERENCES: [n1.] Price LH, Ricaurte GA, Krystal JH, Henninger GR. Neuroendocrine and mood responses to intravenous L-tryptophan in 3,4-methylenedioxymethamphetamine ( MDMA) users. Arch Gen Psychiatry. 1989;46:20-22. [n2.] Markianos M, Stefonis C. Effects of acute cannabis use and short-term deprivation on plasma prolactin and dopamine-beta-hydroxylase in long-term users. Drug Alcohol Depend. 1982;9:251-255. [n3.] Battaglia G, Yeh SY, DeSouza EB. MDMA -induced neurotoxicity: parameters of degeneration and recovery of brain serotonin neurons. Pharmacol Biochem Behav. 1987;29:269-274. [n4.] Derome-Tremblay M, Nathan C. Fenfluramine studies. Science. 1989;243:991. [n5.] Barnes DM. Neurotoxicity creates regulatory dilemma. Science. 1989;243:29-30. [n6.] Grinspoon L, Bakalar JB. Can drugs be used to enhance the psychotherapeutic process? Am J Psychother. 1986;40:393-404. In Reply. -- Grob et al raise some valid points regarding the methodological limitations of our findings, which we ourselves had attempted to acknowledge, both in the "Comment" section and in our characterization of our results as "preliminary observations." There are, however, several other issues raised by Grob et al on which we offer the following comments: 1. Urine toxicology by enzyme immunoassay (EMIT) was obtained on all subjects on the morning of the intravenous L-tryptophan test, immediately prior to beginning the test. Although inadvertently omitted from the final draft of the article, these screens revealed no evidence of recent use of psychoactive drugs. However, most of our subjects did have a past history of use of illicit psychoactive drugs; as Grob et al imply, we cannot state with certainty that use of these other drugs did not account for or contribute to the altered PAGE 20 Copyright 1990 Amer. Medical Assn., Arch Gen Psychiatry, March, 1990 responses to L-tryptophan. The fact is, however, that extensive preclinical evidence demonstrates considerable effects of MDMA on serotonergic function, and our subjects were primarily heavy users of MDMA. We disagree with the assertion that the demonstration of altered serotonergic function in MDMA users would be of limited significance "Without data as to baseline serotonergic functioning prior to the first ingestion of MDMA. " Altered serotonergic function in MDMA users would suggest, but not confirm, effects of MDMA on serotonergic functioning in such individuals. Even though inconclusive, we believe such a suggestion would be of very real significance. As Grob et al well know, the classification of MDMA as a schedule I drug currently makes it virtually impossible to conduct the kind of study that we and they agree would be "conclusive." 2. As Grob et al note, the clinical implications of serotonergic neurotoxicity are controversial and currently undefined. Their reference to the current debate surrounding fenfluramine is entirely appropriate. However, their citation of the Barnes [n1] report is somewhat disingenuous. In that article, it is noted that "Fenfluramine has demonstrated clinical usefulness, whereas MDMA does not. MDMA is also classified as a substance that people abuse, but fenfluramine is not." We would further point out that the general tone of the Barnes article is not exculpatory, but cautionary; although fenfluramine has not been known frequently to cause clinically significant neurotoxic effects, the possibility that it may do so is now under intensive scrutiny. 3. Claims that MDMA may be a useful pharmacological adjunct to psychotherapy are of great theoretical and practical interest. Of course, such claims have been made for numerous other compounds over the years, and none have borne fruit. We agree that rigorous clinical trials are necessary to validate such claims, but we do not feel that "concerns of possible neurotoxicity" are irrelevant to the initiation or conduct of such trials. It may be that Grob et al are correct in suggesting that fears of MDMA neurotoxicity have been exaggerated; we trust that further research can and will clarify this point. Until such clarification is made, we believe it would be premature to pursue clinical trials of MDMA in conditions that are not life-threatening. LAWRENCE H. PRICE, MD JOHN H. KRYSTAL, MD GEORGE R. HENINGER, MD Department of Psychiatry Yale University School of Medicine and the Connecticut Mental Health Center Clinical Neuroscience Research Unit Ribicoff Research Facilities 34 Park St New Haven, CT 06508 GEORGE A. RICAURTE, MD, PHD Department of Neurology The Johns Hopkins University School of Medicine 4940 Eastern Ave Baltimore, MD 21224 [n1.] Barnes DM. Neurotoxicity creates regulatory dilemma. Science. 1989;243:29-30. PAGE 21 13TH ARTICLE of Level 1 printed in FULL format. Copyright (c) 1989 American Medical Association Arch Gen Psychiatry 1989; 46: 191 February, 1989 SECTION: LETTERS TO THE EDITOR LENGTH: 623 words TITLE: ' Ecstasy' : A Human Neurotoxin? AUTHOR: STEPHEN J. PEROUTKA, MD, PHD, Department of Neurology, C-338, Stanford University Medical Center, Stanford, CA 94305 TEXT: To the Editor. -- 3,4-Methylenedioxymethamphetamine ( MDMA; "ecstasy" ) is a ring-substituted amphetamine derivative that is chemically related to both hallucinogens and stimulants. The drug appears to have unique psychoactive properties and has been advocated by certain therapists as an adjunct to psychotherapy. [n1] However, due to findings in laboratory animals [n2] of neurotoxicity caused by MDMA and related compounds, the drug was placed on Schedule I by the Food and Drug Administration in July 1985. Significant controversy exists concerning the legal status of MDMA, its potential clinical efficacy, and, most importantly, the possibility that it may cause irreversible neurotoxicity in human users. [n3] In addition, undocumented reports have suggested that the recreational use of MDMA has been increasing at university campuses in the United States during the past few years. Although no formal epidemiological studies have been performed, a recent informal survey found that a significant number of students on an undergraduate campus reported taking at least one recreational dose of MDMA. [n4] The median amount of MDMA usage was four doses, while the mean number of doses taken was 5.4. The amount of drug taken in a single dose ranged from 60 to 250 mg (approximately 1 to 4 mg/kg). Similar dosage patterns have been reported to be neurotoxic in primates, [n3] and at least five deaths in humans have been attributed to recreational use of MDMA and related compounds. [n5] Presently, there are no data to indicate that recreational doses of MDMA permanently damage the human brain. However, it should also be stressed that no scientific studies have addressed this problem. Nonetheless, based on informal discussions with approximately 100 recreational users of MDMA, a number of personal observations suggest that MDMA is much different from other recreational drugs, as described below. 1. Recreational users of MDMA frequently state that they usually wait at least two to three weeks between doses of the drug. The reason given for this unusual pattern of recreational drug use is that the "good" effects of the drug appear to diminish while the "negative" side effects of the drug appear to increase if the drug is taken too frequently. For example, taking a double dose of MDMA does not double the supposed good effects of the drug but simply increases the negative effects of the drug. PAGE 22 Copyright 1989 Amer. Medical Assn., Arch Gen Psychiatry, February, 1989 2. The majority of people who have taken more than five individual doses of MDMA state that the good effects of the drug change with successive doses. As stated by one college student, "Freshmen love it; sophomores like it; juniors are ambivalent, and seniors are afraid of it." These observations are of concern, since no other drugs are known that, when taken at very infrequent intervals (ie, every month or so), cause different effects with successive doses. 3. MDMA is not "addictive." It is extremely rare to find individuals who have taken large quantities of this drug. Again, this is quite different from many recreational drugs, which tend to be either psychologically or physically addictive. To my knowledge, there are simply no reports of individuals who take frequent and large amounts of MDMA for an extended period. In summary, these completely informal anecdotal observations are consistent with the belief that there is a long-term, and potentially irreversible, effect of MDMA on the human brain. Obviously, a definitive assessment of the human neurotoxic potential of MDMA must await the completion of formal clinical [n6] and epidemiological studies. However, a reasonable and informed conclusion would be that recreational use of MDMA should be avoided. REFERENCES: [n1.] Greer G, Tolbert R: Subjective reports of the effects of MDMA in a clinical setting. J Psychoactive Drugs 1986;18:319-328. [n2.] Schmidt CJ: Neurotoxicity of the psychedelic amphetamine, MDMA. J Pharmacol Exp Ther 1987;240:1-7. [n3.] Barnes DM: New data intensify the agony over ecstasy. Science 1988;239:864-866. [n4.] Peroutka SJ: Incidence of recreational use of 3,4-methylenedioxymethamphetamine ( MDMA, 'Ecstasy' ) on an undergraduate campus. N Engl J Med 1987;317:1542-1543. [n5.] Dowling GP, McDonough ET, Bost RO: 'Eve' and ' ecstasy' : A report of five deaths associated with the use of MDEA and MDMA. JAMA 1987;257:1615-1617. [n6.] Price LH, Ricaurte GA, Krystal JH, Heninger GR: Neuroendocrine and mood responses to intravenous L-tryptophanin 3,4-methylenedioxymethamphetamine ( MDMA) users: Preliminary observations. Arch Gen Psychiatry 1989;46:20-22. PAGE 23 14TH ARTICLE of Level 1 printed in FULL format. Copyright (c) 1989 American Medical Association Arch Gen Psychiatry 1989; 46: 20-22 January, 1989 SECTION: ORIGINAL ARTICLE LENGTH: 2051 words TITLE: Neuroendocrine and Mood Responses to Intravenous L-Tryptophan in 3,4-Methylenedioxymethamphetamine ( MDMA) Users; Preliminary Observations AUTHOR: Lawrence H. Price, MD; George A. Ricaurte, MD, PhD; John H. Krystal, MD; George R. Heninger, MD ABSTRACT:3,4-Methylenedioxymethamphetamine ( MDMA; "ecstasy" ) is a selective serotonin (5-HT) neurotoxin in laboratory animals. To assess its effects on 5-HT function in humans, serum prolactin (PRL) and mood responses to intravenous L-tryptophan were measured in nine recreational users of MDMA and compared with findings from nine matched healthy controls. L-Tryptophan induced a rise in the PRL concentration in controls, but not in MDMA users. Peak change and the area under the curve of the PRL response appeared to be blunted in MDMA users, but the difference from controls did not reach statistical significance. This study provides suggestive evidence of altered 5-HT function in MDMA users, but more definitive studies clearly are needed. TEXT: Aring-substituted amphetamine derivative, 3,4-methylenedioxymethamphetamine ( MDMA; "ecstasy" ) has serotonin ic effects in the vrains of (5-HT)-selective neurotoxic effects in the brains of rats [n1-n5] and nonhman primates. [n6,n7] Although classified on Schedule I by the Drug Enforcement Agency since July 1985, MDMA has become popular in some settings as a recreational drug. In an informal survey, up to 40% of undergraduates at a major university reported having used it at least once. [n8] Some clinicans have claimed therapeutic utility for MDMA as an adjunct to psychotherapy, stating that it facilitates interpersonal communication, enhances insight, and increases selfesteem. [n9] We are aware of only one published report on the effects of MDMA on 5-HT function in humans. Peroutka et al [n10] measured cerebrospinal fluid levels of the 5-HT metabolite 5-hydroxyindoleacetic acid in five recreational MDMA users. They found no significant difference from mean levels in historical control subjects. It is possible, of course, that this sample was too small to detect a difference, or that lumbar cerebrospinal fluid does not sensitively reflect MDMA -induced changes in central 5-HT function in humans. The neuroendocrine challenge strategy offers a more dynamic means of assessing central 5-HT function. Intravenous infusion of the 5-HT precursor L-tryptophan increases the serum prolactin (PRL) concentration, probably via enhanced synthesis and release of 5-HT from hypothalamic 5-HT neurons. [n11] The PRL response to L-tryptophan is blunted in depressed patients compared with healthy controls, [n12] consistent with other evidence of abnormal 5-HT function in depression. [n13] May antidepressant drugs, particularly those with demonstrable effects on 5-HT function, enhance the PRL response. [n14] PAGE 24 Copyright 1989 Amer. Medical Assn., Arch Gen Psychiatry, January, 1989 Depletion of dietary L-tryptophan also enhances the PRL response, perhaps by a mechanism analogous to denervation supersensitivity. [n15] In a pilot study, we compared neuroendocrine and behavioral responses to L-tryptophan in nine heavy users of MDMA with those of matched healthy controls. SUBJECTS AND METHODS Nine subjects (seven male, two female; mean [+/- SD] age, 34 +/- 7 years; age range, 22 to 47 years) with a current or recent history of substantial MDMA use volunteered to participate. They had been using what they believed to be MDMA for a mean of 5.1 +/- 2.3 years (range, two to seven years) at a rate of 1.9 +/- 1.7 times per month (range, 0.33 to 5.0 times per month). The average "usual" dose used was 135 +/- 44 mg (range, 50 to 200 mg), corresponding to a mean dose of 1.8 +/- 0.4 mg/kg (range, 1.1 to 2.3 mg/kg). Many subjects reported the occasional use of much higher doses (up to 500 mg, or 6 mg/kg). The mean cumulative total dose of MDMA was estimated at 13.3 +/- 13.4g (range, 2.5 to 44.2g). Nine healthy controls (seven male, two female; mean age, 33 +/8 years; age range, 22 to 48 years), matched to the MDMA -using subjects for sex and age, were selected from a larger sample of normal volunteers who had undergone testing. Controls were screened for mental disorder and substance abuse by a research psychiatrist using a structured review. All subjects gave voluntary informed consent and were found to be free of serious medical illness after physical, neurologic, and laboratory evaluations. Among MDMA -using subjects, the last reported use of MDMA was a mean of 66+/-50 days before testing (range, 20 to 180 days). Both control and MDMA -using subjects were instructed to remain free of psychoactive drugs for at least three weeks before testing, although three MDMA -using subjects admitted to infrequent marijuana use during that time. Testing was conducted on an outpatient basis at the Clinical Neuroscience Research Unit, New Haven, Conn. Control subjects were recruited locally, but MDMA -using subjects flew to New Haven from their previous residences the day before testing. Subjects fasted overnight and throughout the three-hour L-tryptophan test, which began at 9 AM. The test dose consisted of 7 g of L-trypophan diluted in 500 mL of 0.45% saline solution that was infused through an antecubital vein catheter over 20 minutes. Subjects were awake and supine with the head elevated during the test. Blood for PRL measurement was obtained through the indwelling catheter, which was kept patent by the slow infusion of saline solution. Starting at least 60 minutes after catheter insertion, samples were obtained at 15 and 0.5 minutes before, and at 30, 40, 50, 60, 70, and 90 minutes after the start of the L-tryptophan infusion. Visual analog scales (0 indicates "not at all"; 100 indicates "most ever") and 11 different mood states (happy, sad, drowsy, nervous, calm, depressed, anxious, energetic, fearful, mellow, high) were scored by subjects at these times. The L-tryptophan infusions were prepared by dissolving 8.4 g of L-tryptophan in 600 mL of a 0.45% saline solution, with 50% sodium hydroxide added to bring the solution to a pH of 7.4. Each 600-mL aliquot was sterilized by passage through a 0.22-mm filter and tested for pyrogenicity and sterility before use. Serum was assayed for PRL in control subjects using a radioimmunoassay (RIA) kit (Serono Diagnostics Inc, Randolph, Mass) with intra-assay and interassay coefficients of variation of 3% and 7%, respectively. Because manufacture of this kit was discontinued, all serum from MDMA -using subjects was assayed for PRL with a radioimmunoassay kit (Clinical Assays, Cambridge, Mass), with PAGE 25 Copyright 1989 Amer. Medical Assn., Arch Gen Psychiatry, January, 1989 intra-assay and interassay coefficients of variation of 6% and 11%, respectively. Values obtained with the Serono assay were converted to values comparable with those obtained with the Clinical Assay kit using a formula (y=1.99x+14.343; r= .93) that we derived from the testing of 59 specimens with both kits. Data from the -15-minute and -0.5-minute time points were averaged to obtain a single baseline value for each variable. The peak change in the PRL level was determined by subtracting the baseline from the highest PRL value after L-tryptophan infusion. The area under the curve (AUC) was calculated for PRL responses using the trapezoidal rule. Because of nonnormal distributions, comparisons of PRL data within and between subjects used the Wilcoxon signed-rank and Wilcoxon rank-sum tests, respectively. Mood ratings were subjected to analysis of variance (ANOVA) with repeated measures. Correlations were determined using Spearman's p. All tests were two-tailed, with significance set at P< .05. RESULTS The mean (+/-SD) baseline PRL concentration did not differ between MDMA -using subjects (9.8+/-5.4 mu g/L) and controls (10.8+/-4.8 mu g/L). After L-tryptophan infusion the peak increase in the PRL level over baseline was robustly significant in the controls (11.0+/-13.1 mu g/L; P< .008), but failed to reach statistical significance in the MDMA users (5.9+/-8.5 mu g/L; P< .07). However, the difference in peak change in the PRL concentration between the two groups was not statistically significant. There was no correlation between the baseline PRL concentration and peak change in the PRL concentration in the MDMA group (p=-0.12; not significant), whereas these variables were significantly correlated in the controls (p=0.72; P< .03). The AUC PRL response was also significantly greater than baseline in the controls (568.8+/-762.5 mu g-min/L; P< .02), without reaching statistical significance in the MDMA users (224.8+/-491.9 mu g-min/L; P< .09) (Figure). Again, the difference between groups was not significant. Within the MDMA group, baseline PRL and peak PRL concentrations and the AUC PRL did not correlate with total duration of MDMA use, frequency of monthly use, "usual" dose, or estimated cumulative dose. As in previous studies, L-tryptophan caused significant decreases in ratings of energy (F=4.7; df=5,80; P< .001) and happiness (F=3.2; df=5,80; P< .02), and increases in ratings of drowsiness (F=5.2; df=5,80; P< .0005). However, there were no significant differences between diagnostic groups nor were there differences in group responses to L-tryptophan. COMMENT Results of this exploratory study have suggested some intriguing differences between MDMA users and healthy controls. The peak change in the PRL concentration after L-tryptophan administration was 46% lower and the AUC in the PRL response was 60% lower in MDMA -using subjects than in controls. Although neither of these differences between groups was statistically significant, PRL response measures within the control group were significantly greater than baseline, while those within the MDMA group were not. Most subjects in both groups had relatively modest increases in their PRL concentration after administration of L-tryptophan, as would be expected in samples composed primarily of men. [n12] However, the MDMA users seemed less likely to manifest the very marked PRL responses demonstrated by some healthy subjects, PAGE 26 Copyright 1989 Amer. Medical Assn., Arch Gen Psychiatry, January, 1989 suggesting a degree of blunting in the responsivity of those subjects ordinarily most sensitive to the effects of L-tryptophan. This evidence suggesting altered 5-HT function in MDMA users is consistent with preclinical studies in laboratory animals that have found MDMA to have highly toxic effects on 5-HT neurons. Such studies have reported MDMA to cause decreased brain levels of 5-HT and 5-hydroxyindoleacetic acid, [n1-n7] decreased tryptophan hydroxylase activity, [n1] loss of 5-HT uptake sites, [n2,n5] and degeneration of 5-HT axons and cell bodies. [n3,n6] While large doses of MDMA (10 to 20 mg/kg) have been required to demonstrate these effects in rodents, neurotoxicity in monkeys has been observed at doses comparable with those used by our subjects (2.5 to 5.0 mg/kg). [n6,n7] The present findings obviously must be interpreted cautiously. The suggested attenuation in the PRL response to L-tryptophan in MDMA users must be considered in light of the multiple factors known to affect PRL secretion. [n16] It is also possible that our findings could reflect the nonspecific stress experienced by MDMA subjects in flying to New Haven on the day before testing, although our extensive experience with PRL in neuropsychiatric assessment does not support this hypothesis. Our failure to demonstrate more statistically significant effects of MDMA probably reflects the small sample size of this study. Even assuming a large effect of MDMA (standardized difference between group means=0.8), ruling out a type II error (alpha=0.05; 1-beta=0.80) would require 26 subjects in each group. In addition to larger samples and more rigorous methodology, other approaches to assessing 5-HT function in humans might prove more sensitive to MDMA effects. Such approaches include modification of the standard L-tryptophan test (eg, use of lower or higher doses of L-tryptophan to determine if the "threshold" for an increase in PRL is altered), use of tryptophan depletion techniques, and use of direct 5-HT agonists (eg, m-chlorophenylpiperazine). At present, the nature of MDMA's effects on 5-HT function in humans is unknown and the alteration in function suggested by the results of this study cannot be considered established. The potential for 5-HT neurotoxicity in humans is a pressing concern, however, and the development of sensitive and reliable tests for assessing this remains a challenge. SUPPLEMENTARY INFORMATION: Accepted for publication Oct 19, 1988. From the Department of Psychiatry, Yale University School of Medicine, and the Connecticut Mental Health Center, Clinical Neuroscience Research Unit, Ribicoff Research Facilities, New Haven, Conn (Drs Price, Krystal, and Heninger); and the Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore (Dr Ricaurte). Reprint requests to Department of Psychiatry, Yale University School of Medicine, and the Connecticut Mental Health Center, Clinical Neuroscience Research Unit, Ribicoff Research Facilities, 34 Park St, New Haven, CN 06508 (Dr Price). This study was supported in part by grants MH-00579, MH-36229, MH25642, and DA-04060 from the US Public Health Service, Washington, DC; by the Multidisciplinary Association for Psychedelic Studies, Sarasota, Fla; and by the state of Connecticut. PAGE 27 Copyright 1989 Amer. Medical Assn., Arch Gen Psychiatry, January, 1989 Daniel X. Freedman, MD, was instrumental in facilitating the collaboration. The laboratory, clinical, and research staffs of the Abraham Ribicoff Research Facilities, New Haven, Conn, provided assistance. Huan Gao, MA, assisted in the data analysis and Evelyn Testa typed the manuscript. REFERENCES: [n1.] Stone DM, Stahl DC, Hanson GR, Gibb JW: The effects of 3,4-methylenedioxymethamphetamine ( MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain. Eur J Pharmacol 1986;128:41-48. [n2.] Battaglia G, Yeh SY, O'Hearn, Molliver ME, Kuhar MJ, DeSouza EB: 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: Quantification of neurodegeneration by measurement of [<3>H] paroxetine-labeled serotonin uptake sites. J Pharmacol Exp Ther 1987;242:911-916. [n3.] Commins DL, Vosmer G, Virus RM, Woolverton WL, Schuster CR, Seiden LS: Biochemical and histological evidence that methylenedioxymethylamphetamine ( MDMA) is toxic to neurons in the rat brain. J Pharmacol Exp Ther 1987;241:338-345. [n4.] Mokler DJ, Robinson SE, Rosecrans JA: (+/-) 3,4-Methylenedioxymethamphetamine ( MDMA) produces long-term reductions in brain 5-hydroxytryptamine in rats. Eur J Pharmacol 1987;138:265-268. [n5.] Schmidt CJ: Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. J Pharmacol Exp Ther 1987;240:1-7. [n6.] Ricaurte GA, Forno LS, Wilson MA, DeLanney LE, Irwin I, Molliver ME, Langston JW: (+/-) 3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates. JAMA 1988;260:51-55 [n7.] Ricaurte GA, DeLanney LE, Irwin I, Langston JW: Toxic effects of MDMA on central serotonergic neurons in the primate: Importance of route and frequency of drug administration. Brain Res 1988;446:165-168. [n8.] Peroutka SJ: Incidence of recreational use of 3,4-methylenedioxymethamphetamine ( MDMA, 'ecstasy' ) on an undergraduate campus. N Engl J Med 1987;317:1542-1543. [n9.] Greer G, Tolbert R: Subjective reports on the effects of MDMA in a clinical setting. J Psychoactive Drugs 1986;18:319-327. [n10.] Peroutka SJ, Pascoe N, Faull KF: Monoamine metabolites in the cerebrospinal fluid of recreational users of 3,4-methylenedioxymethamphetamine ( MDMA; 'ecstasy' ). Res Commun Drug Abuse 1987;8:125-138. [n11.] Charney DS, Heninger GR, Reinhard JF Jr, Sternberg DE, Hafstead KM: The effect of IV L-tryptophan on prolactin, growth hormone, and mood in healthy subjects. Psychopharmacology 1982;78:38-43. [n12.] Heninger GR, Charney DS, Sternberg DE: Serotonergic function in depression: Prolactin response to intravenous tryptophan in depressed patients and healthy subjects. Arch Gen Psychiatry 1984;41:398-402. PAGE 28 Copyright 1989 Amer. Medical Assn., Arch Gen Psychiatry, January, 1989 [n13.] Meltzer HY, Lowy MT: The serotonin hypothesis of depression, in Meltzer HY (ed): Psychopharmacology: The Third Generation of Progress. New York, Raven Press, 1987, pp 513-526. [n14.] Price LH, Charney DS, Delgado PL, Heninger GR: Lithium treatment and serotonergic function: Neuroendocrine and behavioral responses to intravenous L-tryptophan in affective disorder patients. Arch Gen Psychiatry 1989;46:13-19. [n15.] Gelgado PL, Charney DS, Price LH, Anderson G, Landis H, Heninger GR: Dietary tryptophan restriction produces an upregulation of the neuroendocrine response to infused tryptophan in healthy subjects. Soc Neurosci Abstr 1987;13:227. [n16.] McCann SM: Lumpkin MD, Mizunuma H, Khorram O, Ottlecz A, Samson WK: Peptidergic and dopaminergic control of prolactin release. Trends Neurosci 1984;5:127-131. GRAPHIC: Figure, Mean (+/-SEM) prolactin response over time to intravenous L-tryptophan in nine 3,4-methylenedioxymethamphetamine users and nine healthy controls. PAGE 29 17TH ARTICLE of Level 1 printed in FULL format. Copyright (c) 1988 American Medical Association JAMA(R) 1988; 260: 1791 September 23, 1988 / September 30, 1988 SECTION: BOOKS LENGTH: 500 words TITLE: Designer Drugs, By M. M. Kirsch, 176 pp. $ 7.95, Minneapolis, CompCare Publications, 1986. AUTHOR: Peter L. Putnam, MD, MPH, Washington, DC ED/SECT: Edited by Harriet S. Meyer, MD, Contributing Editor; adviser for software, Robert Hogan, MD, San Diego. TEXT: Designer drugs, like designer clothes, are produced to sell. They are created and marketed to a clientele of growing size that is looking for an ever more varied or specific experience in a recreational drug. The designer drug is usually a variation on a previously controlled substance. These drugs, which are manufactured by altering the chemical structure of narcotics, stimulants, or other recreational drugs, produce similar effects. Often, as in the case of " Ecstasy, " the effect is preferred to that of the original drug. Crack has been successfully marketed because its use replaces free-basing in convenient form. It is easily produced from cocaine with little equipment. Similarly, phencyclidine (PCP) can be produced in almost any home or garage laboratory by anyone who is willing and able to follow a simple cookbook. Synthetic narcotics many times as potent as natural narcotics can be produced by a chemist who has a little skill and ingenuity. This book, in fact, describes one such chemist who apparently grew tired of working for the salary he received from a large chemical company. It is clear that the drugs described, such as "Ectasy," "crack," "dust," "china white," and MPTP (methylphenyltetrahydropyridine), represent a serious health menace -- some because of the unknown potency and ease of overdose (such as the fentanyl derivatives), some because of the inherent quality of the drug itself (such as PCP), and others because of poor manufacturing techniques (such as the fenantyl derivatives) that produce toxic analogues. The book uses generous excerpts from a variety of sources, including the producers, distributors, users, and law enforcement officers. Even though there are vivid descriptions of the risks involved in the use of such drugs, it will come as no surprise to the reader that there is convincing evidence in this book that the manufacture, distribution, and sales of these drugs are a well-established business worth billions of dollars. This business has grown despite all attempts at federal and local interdiction. It is not surprising, therefore, that the authors have PAGE 30 Copyright 1988 Amer. Medical Assn., JAMA, September 23, 1988 concluded that the way to stop the drug trade is not by increased police and military action to halt manufacture and distribution but by means that will reduce the demand. The book goes so far as to suggest that the most important thing that prohibition has done has been to increase the price and profit in the drug trade. The focus of intervention would be on increasing a sense of individual responsibility and public awareness of the risks involved in drug use. This is not a clinical handbook and is of little value in the recognition and treatment of chemical dependence. It is of significance in that it might promote a rational debate about the issues. Certainly on these issues, as physicians, we should be part of an informed electorate. It is quite clear that the rhetoric of our representatives is often more emotional than rational. PAGE 31 18TH ARTICLE of Level 1 printed in FULL format. Copyright (c) 1988 American Medical Association JAMA(R) 1988; 260: 51-55 July 1, 1988 SECTION: CLINICAL INVESTIGATION LENGTH: 3242 words TITLE: (+/-) 3, 4-Methylenedioxymethamphetamine Selectively Damages Central Serotonergic Neurons in Nonhuman Primates AUTHOR: George A. Ricaurte, MD, PhD; Lysia S. Forno, MD; Mary A. Wilson; Louis E. DeLanney, PhD; Ian Irwin; Mark E. Molliver, MD; J. William Langston, MD ED/SECT: Thomas P. Stossel, MD, Section Editor ABSTRACT: (+/-) 3, 4-Methylenedioxymethamphetamine ( MDMA) is a popular recreational drug that has been proposed to be useful as an adjunct to psychotherapy. This study assessed the neurotoxic potential of MDMA in nonhuman primates. Monkeys were repeatedly administered doses (2.50, 3.75, and 5.00 mg/kg) of MDMA subcutaneously and analyzed for regional brain content of serotonin and 5-hydroxyindoleacetic acid two weeks later. In all regions of the monkey brain examined, MDMA produced a selective dose-related depletion of serotonin and 5-hydroxyindoleacetic acid. These neurochemical deficits were associated with evidence of structural damage to serotonergic nerve fibers. In addition, MDMA produced pathological changes in nerve cell bodies in the dorsal, but not median, raphe nucleus. These results indicate that MDMA is a selective serotonergic neurotoxin in nonhuman primates and that humans using this drug may be at risk for incurring central serotonergic neuronal damage. TEXT: RECREATIONAL abuse of controlled substance analogues ("designer drugs") potentially poses a major health problem. [n1-n3] (+/-) 3, 4-Methylenedioxymethamphetamine ( MDMA) , variously known on the street as " Ecstasy, " "Adam," or "XTC," [n4] is an analogue of the controlled substance (+/-) 3, 4-methylenedioxyamphetamine (MDA). Presently, MDMA is one of the more popular recreational drugs in the United States. [n5] It has been estimated that 30 000 capsules of the drug are sold each month (R. K. Siegel, PhD, unpublished data, 1985). It has also been proposed that MDMA may be useful as an adjunct to insight-oriented psychotherapy. [n6, n7] This suggestion is based largely on subjective reports that MDMA improves interpersonal communication and enhances emotional awareness. In 1985, the Drug Enforcement Agency placed MDMA on Schedule I of controlled substances, citing increasing recreational use of this drug and expressing concern that MDMA might cause neurological damage. [n8] This concern arose largely because of evidence that MDA (the N-desmethyl derivative of MDMA) destroys central serotonergic nerve terminals in rats. [n9] Recent studies indicate that MDMA, like MDA, is toxic to serotonergic nerve terminals in the rodent brain. [n10-n15] However, findings in rats appear to have done little to deter recreational use of MDMA. At least in part, this may be because studies in rodents do not always accurately predict drug toxicity in humans For example, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) is PAGE 32 Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988 relatively inactive in rats [n16, n17] but profoundly toxic in primates. [n18, n19] Conversely, 1, 2, 3, 6-tetrahydro-1-methyl-4-(methylpyrrol-2-yl)pyridine, an analogue of MPTP, is very toxic in rodents [n20] but inactive orally in primates. [n21] In addition, differences in the way rodents and primates metabolize amphetamines [n22] may alter the neurotoxic effects of these drugs. For these reasons, we thought it critical to assess the neurotoxic activity of MDMA in nonhuman primates. METHODS Subjects Seventeen monkeys were used in this study. Eleven female squirrel monkeys (Saimiri sciureus) 6 to 8 years of age and weighing 0.6 to 0.7 kg were used for neurochemical studies and for anatomic studies of the raphe nuclei. Three female rhesus monkeys (Macaca mulatta) 1.5 to 4.0 years of age and weighing 2.5 to 3.5 kg and two female and one male cynomolgus monkeys (Macaca fascicularis) weighing 2.0 to 4.5 kg were used for immunohistochemical studies. No differences in response to MDMA were noted among the three species. Drug Treatment The hydrochloride salt of MDMA was administered subcutaneously twice daily at 0800 and 1700 hours for four consecutive days. This dosing regimen was used to permit comparison of the present results with those previously obtained in rodents. [n12, n14] For neurochemical studies, eight of 11 squirrel monkeys were administered the following doses of MDMA according to the above-mentioned schedule of drug administration: 2.50 mg/kg (n = 2), 3.75 mg/kg (n = 3), and 5.00 mg/kg (n = 3). The three remaining squirrel monkeys served as untreated controls. For immunohistochemical studies, three of six macaque monkeys were given the high-dose (5.00 mg/kg) regimen of MDMA; the other three untreated monkeys served as controls. Neurochemistry Two weeks after drug treatment, the monkeys were killed under deep ether anesthesia. The brain was removed from the skull, and the brainstem was dissected away and placed in 10% formol saline for later anatomical study. The forebrain was dissected over ice, and the various brain regions were isolated for analysis of monoamine content. Concentrations of serotonin, 5-hydroxyindoleacetic acid, dopamine, and norepinephrine were measured by reverse-phase high-performance liquid chromatography coupled with electro-chemical detection, using the method of Kotake et al [n23] with minor modification. [n24] Histology For routine histological studies of the raphe nuclei, the brainstems of three monkeys that had received the 5-mg/kg regimen of MDMA two weeks previously were immersion-fixed in 10% formol saline for one week prior to paraffin embedding and staining. Sections were stained with hematoxylin-eosin, Luxol fast blue (LFB)-cresyl violet, LFB-periodic acid-Schiff (PAS), or LFB-Bielschowsky. For immunohistochemical studies of serotonergic nerve fibers in the forebrain, three monkeys that had received the 5-mg/kg regimen of MDMA two weeks previously and three controls were administered the monoamine PAGE 33 Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988 oxidase inhibitor trans-2-phenylcyclopropylamine (10 mg/kg intraperitoneally) one hour prior to being killed by intracardiac perfusion under deep sodium pentobarbital anesthesia. After the vascular tree was cleared with ice-cold phosphate-buffered saline, perfusion was continued with 4% paraformaldehyde, pH 6.5, followed by 4% paraformaldehyde and 0.12% glutaraldehyde (pH 9.5). Tissue blocks were placed in buffered 4% paraformaldehyde for seven hours and then in 10% dimethyl sulfoxide in phosphate-buffered saline overnight. Frozen sections (30 mum) were incubated in an antiserotonin antisera (R8) diluted 1:5000 (or in anti-tyrosine hydroxylase antisera diluted 1 U:48 mL) in phosphate-buffered saline with 0.2% octyl phenoxy polyethoxyethanol (Triton X-100) and 1% normal goat serum at 4 degrees C for three days. The antibody was visualized with a peroxidase-labeled avidin-biotin complex (Vector Laboratories Inc, Burlingame, Calif), and staining was enhanced with the osmiophilic reaction sequence of Gerfen. [n25] Statistics After a simple one-way analysis of variance showed an F value of P<.05, individual values were compared with the control using a two-tailed Student's t test. Thereafter, regression analysis was performed and the 3df between groups were partitioned into a regression component (1 df) and a deviation from regression component (2df). Materials Dopamine hydrochloride, norepinephrine hydrochloride, and serotonin creatinine sulfate were purchased from the Sigma Chemical Company, St Louis; MDMA hydrochloride was provided by David Nichols, PhD, Department of Medicinal Chemistry, Purdue University, Lafayette, Ind, and the National Institute of Drug Abuse. Tranylcypromine (tranyl-2-phenylcyclopropylamine) was purchased from Regis Chemical Company, Morton Grove, Ill. The rabbit antiserotonin was generated by H. Lidov against serotonin conjugated to bovine serum albumin with formaldehyde. Rabbit anti-tyrosine hydroxylase antisera was purchased from Eugene Tech International Inc, Allendale, NJ. RESULTS Chemistry Dose Response. -- Measurement of serotonin two weeks after drug treatment showed that multiple subcutaneous doses of MDMA 92.50, 3.75, and 5.00 mg/kg) produced a dose-related depletion of serotonin in the somatosensory cortex of the monkey, with the lowest dose (2.50 mg/kg) producing a 44% depletion and the highest dose (5.00 mg/kg) producing a 90% depletion (Table 1). Statistical analysis (simple analysis of variance followed linear regression with partitioning of the degrees of freedom into a regression component [1 df] and a deviation from regression component [2 df] revealed that linearity explained virtually all of the variability between doses (r = .97). The deviation from regression component was not statistically significant (F [2, 8] = 2.28; P>.05). Table 1. -- Dose-Related Decrease in Serotonin Concentration in the Somatosensory Cortex of the Monkey Two Weeks After Administration of MDMA [SEE ORIGINAL SOURCE] PAGE 34 Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988 Regional Effects. -- Multiple doses of MDMA also produced large depletions of serotonin in the caudate nucleus, putamen, hippocampus, hypothalamus, and thalamus of the monkey (Table 2). One of the most severely affected areas was the cerebral cortex (Table 2), where the lowest dose (2.5 mg/kg) of MDMA produced a 44% depletion of serotonin (Table 1). Table 2. -- Regional Concentrations of Serotonin in the Monkey Brain Two Weeks After Administration of MDMA (5 mg/kg) [SEE ORIGINAL SOURCE] Other Markers. -- Measurement of 5-hydroxyindoleacetic acid, another chemical marker for serotonergic nerve fibers, showed that multiple doses of MDMA also markedly reduced the concentration of this compound (Table 3). Concentrations of 5-hydroxyindoleacetic acid were reduced by 84% in the neocortex, 76% in the caudate nucleus, 75% in the hippocampus, and 40% in the hypothalamus. Table 3. -- Decreased Concentration of 5HIAA in the Monkey Brain Two Weeks After Administration of MDMA (5 mg/kg) [SEE ORIGINAL SOURCE] Selectivity. -- Measurement of dopamine and norepinephrine concentrations in monkeys receiving the highest dose (5 mg/kg) showed that MDMA produced no depletion of dopamine or norepinephrine (Table 4). Table 4. -- Unchanged Concentrations of Dopamine and Norepinephrine in the Monkey Brain Two Weeks After Administration of MDMA (5 mg/kg) [SEE ORIGINAL SOURCE] Morphology Nerve Fibers. -- Immunohistochemical studies performed to assess the structural integrity of serotonergic nerve fiber projections to the forebrain demonstrated a marked reduction in the number and density of serotoninimmunoreactive axons throughout the cerebral cortex of three of three monkeys receiving the 5-mg/kg dose of MDMA (Fig 1). In addition, at higher power, some serotonergic axons appeared swollen and misshapen. Staining with an antibody to tyrosine hydrosylase revealed no evidence of damage to catecholamine-containing nerve fibers in the cerebral cortex. Cell Bodies. -- Examination of nerve cell bodies in the raphe nuclei of the monkeys receiving the highest dose of MDMA (5 mg/kg) showed that while MDMA produced no obvious cell loss in either the dorsal or median raphe nuclei, the drug induced striking cytopathological changes in nerve cells of the dorsal raphe nucleus. In three of three of these animals, hematoxylineosin-stained paraffin sections of the dorsal raphe nucleus showed numerous, somewhat shrunken nerve cells that contained brownish-red spherical cytoplasmic inclusions that displaced the nucleus to the periphery of the cell (Fig 2, top left). In LFB-PAS-stained sections, the inclusions appeared granular and were vividly PAS positive (Fig 2, bottom right). This staining reaction suggests the presence of an increased amount of ceroid or lipofuscin, possibly due to lipid peroxidation of cell components and subsequent phagolysosomal activity. The presence of lipofuscin within the inclusions was confirmed by a number of staining PAGE 35 Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988 procedures. Specifically, the granules were autofluorescent in ultraviolet light, acid fast in Ziehl-Nielsen stain for lipofuscin, and positive with Schmorl's reaction and Sudan Black B stain. Glycogen did not account for the staining, as demonstrated in PAS stain with and without diastase. No abnormal inclusion-bearing cells were found in the median raphe nucleus, in other raphe nuclei, or in nonserotonergic nuclei such as the substantia nigra or locus ceruleus. No similar inclusions were found in ten control monkeys of varying ages (including three 15- to 20year-old monkeys), although some increased lipofuscin pigment was occasionally found in the older animals. (Seven of these ten animals were not formally part of the present study but had served as controls in other experiments. The brains of these seven animals were fixed by immersion in 10% formol saline.) COMMENT The major finding of this study is that central serotonergic neurons in nonhuman primates are highly vulnerable to toxic effects of MDMA. Compared with the rodent, [n10-n15] the primate has been found to be approximately four to eight times more sensitive. In the monkey, a dose of 2.5 mg/kg produces a 44% depletion of serotonin in the cerebral cortex (Table 1). By contrast, in the rat a 10- to 20-mg/kg dose is required to produce a comparable effect. [n14] Also of note is the fact that in the primate small increments in dose from 2.50 mg/kg to 3.75 and 5.00 mg/kg produced 78% and 90% depletions of serotonin, respectively (Table 1). This indicates that the dose-response curve of MDMA in the monkey is steep, suggesting that the margin of safety of MDMA in humans may be narrow. The striking loss of serotonin-immunoreactive nerve fibers in the cerebral cortex of the MDMA -treated primate (Fig 1) suggests that MDMA produces a long-term depletion of serotonin by actually damaging serotonergic nerve fibers. Axonal damage is further suggested by the swollen and distorted appearance of some of the remaining fibers. Morphological evidence of nerve fiber damage is important because it suggests that the prolonged depletion of serotonin induced by MDMA is not merely due to a pharmacologic action of the drug, but rather represents a neurotoxic effect. Anatomical studies in rats have led to a similar conclusion. [n12, n14] It is not yet known whether the effects of MDMA on serotonergic neurons in the primate are permanent or reversible. Under some circumstances, regeneration of serotonergic nerve fibers in the central nervous system can take place. [n26] However, for axon regrowth to occur, the cell body must be preserved. It remains to be determined if serotonin-containing cell bodies in the dorsal raphe nucleus of the MDMA -treated primate survive beyond two weeks. If they do, and if regeneration of nerve fibers takes place, it is still not certain that the new fibers would establish normal connections. For functional integrity to be maintained, normal connections would need to be reestablished. It will be important to determine if this occurs in MDMA -treated animals. This study provides the first direct evidence that serotonergic cell bodies, as well as nerve fibers, are affected by MDMA. As shown in Fig 2, the pathological change in cell bodies involves formation of intracytoplasmic inclusions. These inclusions resemble the more eosinophilic but usually PAS-negative inclusions recently described in monkeys given MPTP, [n27] a compound that destroys nigral cell bodies. [n18, n19] Whether the inclusions PAGE 36 Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988 in the MDMA -treated primate herald nerve cell death or reflect a metabolic response of the cell body to anoxal injury is not yet known but needs to be ascertained because, if cell-body death occurs, the possibility of axonal regeneration would be precluded. The fact that abnormal inclusions were found in nerve cells of the dorsal, but not median, raphe nucleus is noteworthy because it suggests that MDMA selectively damages a particular subset of serotonergic neurons in the brain (ie, the B7 group of Dahlstrom and Fuxe). That this is the case is also suggested by the recent finding in the rat that serotonergic nerve fibers arising from the dorsal, but not median, raphe nucleus are damaged by MDMA. [n12, n28] Taken together, these findings indicate that MDMA is likely to be a valuable new tool for further defining the functional anatomy of different serotonergic cell groups in the mammalian brain. The mechanism by which MDMA exerts its toxic effects on central serotonergic neurons is at present not well understood. Like a number of other ring-substituted amphetamines (eg, p-chloroamphetamine, fenfluramine hydrochloride, MDA), MDMA appears to release serotonin. [n29-n31] Commins and colleagues [n32] have proposed that MDMA and related compounds destroy serotonergic neurons by releasing large amounts of serotonin and inducing endogenous formation of 5, 6-dihydroxytryptamine, a well-known serotonergic neurotoxin. [n33] However, other investigators [n34] maintain that the degenerative effects of ring-substituted amphetamines may be mediated by a toxic metabolite. It remains to be determined which, if either, of these possibilities proves correct. The results of this study raise concern that humans presently using MDMA may be incurring serotonergic neuronal damage. The fact that monkeys are considerably more sensitive than rats to the toxic effects of MDMA suggests that humans may be even more sensitive. Before extrapolating the present results to humans, however, it should be noted that monkeys were given multiple rather than single doses of MDMA and that the drug was given subcutaneously rather than orally. Humans generally take MDMA via the oral route and use single 1.7- to 2.7-mg/kg doses of the drug, usually weeks apart, although some individuals have used higher and more frequent doses. [n4] It remains to be determined if administration of MDMA to monkeys in a pattern identical to that used by humans produces similar neurotoxicity. In this regard, however, it is important to bear in mind that the sensitivity of human and nonhuman primates to the toxic effects of MDMA may not be the same. In fact, humans are generally regarded as being more sensitive than monkeys to the toxic effects of drugs. For example, humans are fivefold to tenfold more sensitive than monkeys to the toxic effects of MPTP (compare references 19 and 35). In view of these considerations, it would seem prudent for humans to exercise caution in the use of MDMA. Caution may also be warranted in the use of fenfluramine, a ring-substituted amphetamine that is closely related to MDMA and is currently prescribed for obesity [n36] and autism. [n37] From an experimental standpoint, MDMA appears to hold promise as a systemically active toxin that can be used to study the functional consequences of altered serotonergic neurotransmission in higher animals. Clinically, it will be important to determine if humans who have taken MDMA show biochemical signs of serotonergic neurotoxicity (eg, decreased 5-hydroxyindoleacetic acid concentration in their cerebrospinal fluid). If they do, it will be critical to ascertain if these individuals have any functional impairment. In particular, PAGE 37 Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988 such individuals will need to be evaluated for possible disorders of sleep, mood, sexual function, appetite regulation, or pain perception, since central serotonergic neurons have been implicated in all of these functions. [n38, n39] These studies could offer the unique opportunity to better delineate the neurobiology of central serotonergic neurons in the human brain, something that until now has not been possible. SUPPLEMENTARY INFORMATION: From the Departments of Neurology and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore (Drs Ricaurte and Molliver and Ms Wilson); the Department of Pathology, Veterans Administration Medical Center, Palo Alto, Calif (Dr Forno); and the institute for Medical Research, San Jose, Calif (Drs Ricaurte, DeLanney, and Langston and Mr Irwin). Reprint requests to the Department of Neurology, Francis Scott Key Medical Center, The Johns Hopkins Health Center, 4940 Eastern Ave, Baltimore, MD 21224 (Dr Ricaurte). This work was supported in part by the Multidisciplinary Association for Psychedelic Studies, Sarasota, Fla; the Veterans Administration Medical Research Program; National Institutes of Health grant NS21011 (M.E.M.); and California Public Health Foundation Ltd subcontract 091A-701. One of the authors (M.A.W.) was supported by the L. P. Markey Fund. We thank Lorrene Davis-Ritchie, ZoAnn McBride, David Rosner, and Patrice Carr for expert technical assistance. REFERENCES: [n1.] Ziporyn T: A growing industry and menace: Makeshift laboratory's designer drugs. JAMA 1986;256:3061-3061. [n2.] Baum RM: New variety of street drugs poses growing problem. Chem Engineering News 1985;63:7-16. [n3.] Hagerty C: 'Designer Drug' Enforcement Act seeks to attack problem at source. Am Pharm 1985;NS25(10):10. [n4.] Seymour RB: MDMA. San Francisco, Haight Ashbury Publications, 1986. [n5.] Barnes DM: New data intensify the agony over ecstasy. Science 1988;239:864-866. [n6.] Greer G, Tolbert R: Subjective reports of the effects of MDMA in a clinical setting. J Psychoactive Drugs 1986;18:319-327. [n7.] Cotton R: In the matter of MDMA scheduling. Brief including proposed findings of fact and conclusions of law on behalf of Drs Greer and Grinspoon, and Professors Bakalar and Roberts. Dewey, Ballantine, Bushby, Palmer and Wood, 1775 Pennsylvania Ave NW, Washington, DC 20006, Jan 15, 1986. [n8.] Lawn JC: Schedules of controlled substances: Temporary placement of 3, 4-methylenedioxymethamphetamine ( MDMA) into Schedule I. Federal Register 1985;50(July 1):23118-23120. [n9.] Ricaurte GA, Bryan G, Strauss L, et al: Hallucinogenic amphetamine selectively destroys brain serotonin nerve terminals. Science PAGE 38 Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988 1985;222:986-988. [n10.] Schmidt CJ, Wu L, Lovenberg W: Methylenedioxymethamphetamine: A potentially neurotoxic amphetamine analogue. Eur J Pharmacol 1985;124:175-178. [n11.] Stone DM, Stahl DS, Hanson GL, et al: The effects of 3, 4-methylenedioxymethamphetamine ( MDMA) and 3, 4-methylenedioxyamphetamine on monoaminergic systems in the rat brain. Eur J Pharmacol 1986;128:41-48. [n12.] O'Hearn EG, Battaglia G, De Souza EB, et al: Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine ( MDMA) cause ablation of serotonergic axon terminals in forebrain: Immunocytochemical evidence. J Neurosci, in press. [n13.] Schmidt CJ: Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. J Pharmacol Exp Ther 1987;240:1-7. [n14.] Commins DL, Vosmer G, Virus R, et al: Biochemical and histological evidence that methylenedioxymethylamphetamine ( MDMA) is toxic to neurons in the rat brain. J Pharmacol Exp Ther 1987;241:338-345. [n15.] Battaglia G, Yeh SY, O'Hearn E, et al: 3, 4-Methylenedioxymethamphetamine and 3, 4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: Quantification of neurodegeneration by measurement of [3H] paroxetine-labeled serotonin uptake sites. J Pharmacol Exp Ther 1988;242:911-916. [n16.] Chiueh CC, Markey SP, Burns RS, et al: N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine, a parkinsonian syndrome-causing agent in man and monkey, produces different effects in the guinea pig and rat. Pharmacologist 1983;25:131-138. [n17.] Boyce S, Kelley E, Reavill C, et al: Repeated administration of N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine to rats is not toxic to striatal dopamine neurones. Biochem Pharmacol 1984;33:1747-1752. [n18.] Burns RS, Chieuh CC, Markey SP, et al: A primate model of parkinsonism: Selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. Proc Natl Acad Sci USA 1983;80:4546-4550. [n19.] Langston JW, Forno LS, Rebert CS, et al: Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyridine (MPTP) in the squirrel monkey. Brain Res 1984;292:390-394. [n20.] Finnegan KT, Irwin I, DeLanney LE, et al: 1, 2, 3, 6-Tetahydro-1-methyl-4- (methylpyrrol-2-yl) pyridine: Studies on the mechanism of action of MPTP. J Pharmacol Exp Ther 1988;242:1144-1151. [n21.] Wilkening D, Vernier VG, Arthaud LE, et al: A parkinson-like neurologic deficit in primates is caused by a novel 4-substituted piperidine. Brain Res 1986;368:239-246. [n22.] Caldwell J, Dring LG, Williams RT: Metabolism of [14C] methamphetamine in man, the guinea pig and the rat. Biochem J 1976;129:11-21. [n23.] Kotake C, Heffner T, Vosmer G, et al: Determination of dopamine, PAGE 39 Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988 norepinephrine, serotonin and their major metabolic products in rat brain by reverse-phase ion-pair high performance liquid chromatography with electrochemical detection. Pharmacol Biochem Behav 1985;22:85-90. [n24.] Ricaurte GA, Irwin I, Forno LS, et al: Aging and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydopyridine-induced degeneration of dopaminergic neurons in the substantia nigra. Brain Res 1987;403:43-51. [n25.] Gerfen C: The neostriatal mosaic: I. Compartmental organization of projections from the striatum to the substantia nigra in the rat. J Comp Neurol 1985;236:454-463. [n26.] Zhou FC, Azmitia EC: Induced homotypic collateral sprouting of serotonergic fibers in the hippocampus of rat. Brain Res 1984;308:53-62. [n27.] Forno LS, Langston JW, DeLanney LE, et al: Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys. Ann Neurol 1986;20:449-455. [n28.] Manmounas LA, Molliver ME: Dual serotonergic projections to forebrain have separate origins in the dorsal and median raphe nuclei: Retrograde transport after selective axonal ablation by p-chloroamphetamine (PCA). Soc Neurosci Abstr 1987;13:907. [n29.] Sanders-Bush E, Sulser F: P-chloroamphetamine: In vivo investigations on the mechanism of action of the selective depletion of cerebral serotonin. J Pharmacol Exp Ther 1970;175:419-426. [30.] Fuller RW, Perry KW, Molloy B: Reversible and irreversible phases of serotonin depletion by 4-chloroamphetamine. Eur J Pharmacol 1975;33:119-124. [n31.] Nichols DE, Lloyd DH, Hoffman AJ, et al: Effect of certain hallucinogenic amphetamine analogs on the release of [3H] serotonin from rat brain synaptosomes. J Med Chem 1986;25:530-536. [n32.] Commins D, Axt K, Vosmer G, et al: Endogenously produced 5, 6-dihydroxytryptamine may mediate the neurotoxic effects of para-chloroamphetamine. Brain Res 1987;403:7-14. [n33.] Baumgarten HG, Klemm HP, Lachenmayer L, et al: Mode and mechanism of action of neurotoxic indoleamines: A review and a progress report. Ann NY Acad Sci 1978;305:3-24. [n34.] Molliver ME, O'Hearn E, Battaglia G, et al: Direct intracerebral administration of MDA and MDMA does not produce serotonin neurotoxicity. Soc Neurosci Abstr 1986;12:1234. [n35.] Langston JW, Ballard PA, Tetrud JW, et al: Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983;219:979-980. [n36.] Craighead LW, Stunkard AJ, O'Brien R: Behavior therapy and pharmacotherapy for obesity. Arch Gen Psychiatry 1981;38:763-768. [n37.] Ritvo ER, Freeman DJ, Geller E, et al: Effects of fenfluramine on 14 outpatients with the syndrome of autism. J Am Acad Child Psychiatry 1983;22:549-556. PAGE 40 Copyright 1988 Amer. Medical Assn., JAMA, July 1, 1988 [n38.] Barchas J, Usdin E (eds): Serotonin and Behavior. New York, Academic Press Inc, 1973. [n39.] Messing RB, Pettibone DJ, Kaufman N, et al: Behavioral effects of serotonin neurotoxin: An overview. Ann NY Acad Sci 1978;305:480-496. GRAPHIC: Figure 1, Serotonin-immunoreactive fibers in somatosensory cortex (area 3) of cynomolgus monkey. Serotonergic axons form dense terminal plexus in control animal, in methylenedioxymethamphetamine ( MDMA) -treated animal (5 mg/kg), there is marked decrease in density of serotonergic axons after a two-week survival period. Changes in somatosensory cortex are representative of serotonergic denervation caused by MDMA throughout cerebral cortex. Scale bar, 100 mum; Figure 2, Nerve cells in dorsal raphe nucleus of methylenedioxymethamphetamine ( MDMA) -treated squirrel monkey. Several of slightly shrunken nerve cells contain intracytoplasmic inclusion (hematoxylin-eosin, x 550). Nerve cells in dorsal raphe nucleus from untreated 11-year-old squirrel monkey, (hematoxylin-eosin, x 550). Close-up view of one of abnormal inclusion-bearing cells in dorsal raphe nucleus of the MDMA -treated squirrel monkey (hematoxylin-eosin, oil immersion, x 1480). Close-up view of nerve cells in dorsal raphe nucleus to show vividly periodic acid-Schiff-positive granular inclusions in perikarya of several nerve cells (Luxol fast blue-periodic acid-Schiff stain, oil immersion, x 1480). PAGE 41 21ST ARTICLE of Level 1 printed in FULL format. Copyright (c) 1988 American Medical Association JAMA(R) 1988; 259: 1649-1650 March 18, 1988 SECTION: LETTERS LENGTH: 751 words TITLE: The Complications of ' Ecstasy' (MDMA) AUTHOR: Karl Verebey, PhD, New York State Division of Substance Abuse, Brooklyn; Jamyl Alrazi, Psychiatric Diagnostic Laboratories of America, South Plainfield, NJ; Jerome H. Jaffe, MD, National Institute on Drug Abuse, Baltimore ED/SECT: Edited by Drummond Rennie, MD, Senior Contributing Editor; Sharon Iverson, Assistant Editor. TEXT: To the Editor. -- Drs Brown and Osterloh, [n1] in a recent letter in THE JOURNAL, reported a nearly fatal toxic reaction to 3,4-methylenedioxymethamphetamine ( MDMA) . The estimated dose of MDMA administered was 100 to 150 mg and the blood levels, measured at one and two hours after hospital admission, were 6500 and 7000 ng/mL, respectively. Before MDMA became a Schedule 1 drug on July 1, 1985, [n2] it was used in doses of 100 to 150 mg by some psychiatrists who claimed that it was effective as a psychotropic catalyst and a sensory disinhibitor; at these doses, no toxic effects were reported. (The experiment was performed on March 12, 1985, before the scheduling in MDMA and was carried out by one of us [J.A.] in partial requirement for the degree of Doctor of Physiology.) At that time, we carried out a controlled study of MDMA metabolism and disposition in a single patient. On the basis of that study, we believe that the dose used in the study by Drs Brown and Osterloh would have had to have been much higher to produce the reported blood levels of MDMA of 6500 to 7000 ng/mL. Study. -- A healthy 40-year-old man weighing 74 kg ingested a single 50-mg dose of MDMA. [n3] Blood samples were collected one through 24 hours after administration of the dose. Fractional urine samples were collected from zero to 72 hours. The samples were analyzed for MDMA and 3,4-methylenedioxyamphetamine (MDA) by gas chromatography/mass spectrometry. 3,4-Methylenedioxyamphetamine, the N-demethylated biotransformation product of MDMA, also was identified in the plasma and urine samples. Plasma levels and urinary excretion of MDMA and MDA are presented in the Table. In plasma, the MDMA level peaked at 105.6 ng/mL two hours after administration of the dose and declined monoexponentially to 5.1 ng/mL by 24 hours. Plasma Levels and Urinary Excretion of MDMA and MDA in Man After Administration of a Single 50-mg Oral Dose of MDMA [SEE ORIGINAL SOURCE] Unchanged level of MDMA was the major urinary excretion product. In 72 hours, a total of 36 mg (72%) of the 50-mg dose was recovered from the urine. PAGE 42 Copyright 1988 Amer. Medical Assn., JAMA, March 18, 1988 The missing 28% of the dose may have been biotransformed into other metabolites. Comment. -- The plasma levels of MDMA of 6500 to 7000 ng/mL reported by Drs Brown and Osterloh were 60 to 70 times higher than the peak level seen in our study and indicate that their patient must have taken a much larger dose than 150 mg, a dose only three times more than that used in our study. It is more likely that the observed severe toxic effects in the report by Drs Brown and Osterloh represent an expected toxic reaction to an overdose rather than a hypersensitivity reaction to the then customary doses of MDMA. Since, to our knowledge, ours is the first report on blood levels of MDMA in man in which the dose is known, the blood level of MDMA found by Drs Brown and Osterloh cannot be compared with any previously reported MDMA blood level reference value. Recently, MDA was identified as a neurotoxic substance that selectively destroys serotonergic nerve terminals in rat brain. [n3,n4] The finding in our study that the biotransformation of MDMA in man results in the formation of MDA should be a warning for the future legal or illicit use of MDMA by man. REFERENCES: [n1.] Brown C, Osterloh J: Multiple severe complications from recreational ingestion of MDMA ('Ecstasy' ). JAMA 1987;258:780-781. [n2.] Seymore RB, Wesson DR, Smith DE (eds): MDMA: Proceedings of the conference. J Psychoactive Drugs 1986;18:278-378. [n3.] Ricaurte C, Bryan G, Strauss L, et al: Hallucinogenic amphetamine selectively destroys brain serotonin nerve terminals. Science 1985;229:986-988. [n4.] Battaglia G, Yeh SY, O'Hearn E, et al: 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetatmine destroy serotonin terminals in rat brain: Quantification of neurodegeneration by measurement of tritiated peroxylene labeled serotonin uptake sites. J Pharmacol Exp Ther 1987;242:911-916. In Reply. -- The data of Verebey et al are useful in interpreting the plasma concentrations of the MDMA measured in the patient we reported. The dose reported by the patient was certainly underestimated. The ratios of MDA/ MDMA concentrations were never more than 0.02. This also suggests an overdose when compared with the ratios in the data of Verebey et al. The major concern in our letter was to reinforce the warning of Dowling et al [n1] that severe consequences have resulted from the use of MDMA. This concern is heightened by (1) a recent report stating that 39% of students at one college campus had tried MDA [n2] and (2) the neurotoxic effect of the metabolite MDA cited by Verebey et al. John Osterloh, MD Christopher Brown, MD San Francisco General Hospital University of California, San Francisco [n1.] Dowling GP, McDonough ET, Bost RO: 'Eve' and ' Ecstasy' : A report of five deaths associated with the use of MDEA and MDMA. JAMA 1987;257:1615-1617. [n2.] Peroutka SJ: Incidence of recreational use of PAGE 43 Copyright 1988 Amer. Medical Assn., JAMA, March 18, 1988 3,4-methylenedimethoxymethamphetamine ( MDMA, 'Ecstasy' ) on an undergraduate campus. N Engl J Med 1987;317:1542-1543. PAGE 44 26TH ARTICLE of Level 1 printed in FULL format. Copyright (c) 1987 American Medical Association JAMA(R) 1987; 257: 1615-1617 March 27, 1987 SECTION: ORIGINAL CONTRIBUTIONS LENGTH: 2656 words TITLE: 'Eve' and ' Ecstasy' ; A Report of Five Deaths Associated With the Use of MDEA and MDMA AUTHOR: Graeme P. Dowling, MD; Edward T. McDonough III, MD; Robert O. Bost, PhD ABSTRACT: 3,4-Methylenedioxymethamphetamine ( MDMA, "Ecstasy" ), a synthetic analogue of 3,4-methylenedioxyamphetamine, has been the center of recent debate over its potential for abuse vs its use as a psychotherapeutic agent. Following its emergency classification in Schedule 1 by the Drug Enforcement Administration in 1985, 3,4-methylenedioxyethamphetamine (MDEA, "Eve") has appeared as MDMA's legal replacement. MDMA is thought to be safe by recreational users and by psychotherapists who support its use. The details of five deaths associated with the use of MDMA and MDEA are reported. In three patients, MDMA or MDEA may have contributed to death by the induction of arrhythmias in individuals with underlying natural disease. In another patient, use of MDMA preceded an episode of bizarre and risky behavior that resulted in accidental death. In another patient, MDMA was thought to be the immediate cause of death. Death as a consequence of the use of these drugs appears to be rare, but it does occur; this outcome may be more common in individuals with underlying cardiac disease. TEXT: MDMA (3,4-methylenedioxymethamphetamine, " Ecstasy" ), a synthetic analogue of 3,4-methylenedioxyamphetamine (MDA), was first developed as an appetite suppressant in 1914 but was never marketed. In the early 1970s, a small number of psychiatrists began using it as an adjunct to psychotherapy, noting that it appeared to facilitate therapeutic communication, increase patient self-esteem, and limit the use of other drugs (G. Greer, MD, unpublished data, 1983; Greer and Strassman [n1]; and Shafer [n2]). Since 1983, MDMA has become a popular recreational drug, especially among college students. It is also known as "XTC," "Adam," and "MDM" and is sold as gelatin capsules or loose powder for $10 to $40 per 100-mg dose (Newsweek, April 15, 1985, p 96). Users report that the drug is a pleasant way to get in touch with oneself and that it does not produce hallucinations (Newsweek, April 15, 1985, p 96; Life, August 1985, pp 88-94; and Baum [n3]). Until July 1, 1985, MDMA was not a controlled substance and was legally available for use. At that time, the Drug Enforcement Administration placed MDMA in Schedule 1 on an emergency basis, as a drug with high potential for abuse and without accepted medical use. It was claimed that the abuse potential of MDMA was proved by its widespread use. In addition, because of the structural similarity to MDA, which had been shown to selectively damage serotonin nerve terminals in rat brains, [n4] dangerous side effects were felt to be possible. PAGE 45 Copyright 1987 Amer. Medical Assn., JAMA, March 27, 1987 It was only later that Drug Enforcement Administration officials learned of the therapeutic use of MDMA in psychiatry. While MDMA is still available on the illicit drug market, a related drug, 3,4-methylenedioxyethamphetamine (MDEA, "Eve"), has appeared as a non-scheduled substitute for MDMA, with milder but similar effects. MDMA is reported to be safe by psychotherapists and users (Newsweek, April 15, 1985, p 96; Baum [n3]; and Gehlert et al [n5]), but the medical literature contains few articles on MDMA or MDEA, and no controlled trials to document and investigate their clinical effects have been completed. [n2] One death related to the use of MDMA has been reported in the popular media (Life, August 1985, pp 88-94). This article describes five patients, seen over a period of nine months (June 1985 to March 1986) in Dallas County, in which MDMA or MDEA were thought to have caused or contributed to death. METHODS All cases were examined by the Chief Medical Examiner's Office of Dallas County. Body fluid and tissue samples were screened for the presence of alkaline drugs, including MDMA and MDEA, by the method of Foerster et al. [n6] Gas chromatography was used with fused methylsilicone and fused 5% phenylmethylsilicone columns connected to flame ionization detectors. Identification was based on retention times on the two columns and confirmation was by gas chromatography-mass spectrometry. MDMA or MDEA levels were quantitated by gas chromatographic comparison with known standards of these drugs. Body fluids were also screened for the presence of acid and neutral drugs, narcotics, and alcohol. REPORT OF CASES CASE 1. -- The body of a 22-year-old man was found at the base of an electrical utility tower. He was reportedly last seen alive the previous evening when he ingested an unknown quantity of MDMA. Examination at the scene suggests that he drove his automobile to the utility tower and climbed it to a height of 13 m. At 1:23 AM, he came too close to one of the 138 000-V power lines, was electrocuted, and fell to the ground. At autopsy, widespread burning of the clothing and the skin of the face, thorax, abdomen, and both arms was noted, consistent with his having received a high-voltage electrical shock. Other injuries, presumably sustained in the fall, included a complete atlantooccipital dislocation, rib fractures, pulmonary contusions, and lacerations of the liver. Postmortem toxicology showed MDMA in the blood, but unfortunately, the amount could not be quantitated. No alcohol or other drugs were present. CASE 2. -- A 25-year-old man was seen by his family physician complaining of pleuritic chest pain on inspiration. Physical examination results and chest roentgenogram were unremarkable, and a follow-up appointment was arranged for the next day. While he was driving home, his truck jumped a curb and struck a telephone pole. His only apparent injury was a small laceration of the forehead, but he required cardiopulmonary resuscitation at the scene and en route to the hospital. He was pronounced dead one-half hour after the accident. PAGE 46 Copyright 1987 Amer. Medical Assn., JAMA, March 27, 1987 At autopsy, the only injury was a 4-cm laceration on the right side of the forehead. The proximal left anterior descending and left circumflex coronary arteries were narrowed to less than 75% of their original area by atherosclerotic plaques, and the lumen of the right coronary artery was narrowed to a pinpoint 5 cm from its origin. The heart was not enlarged (280 g), and there was no evidence of recent or old myocardial infarction. The other organs were unremarkable. Although the cause of death was listed as atherosclerotic cardiovascular disease, postmortem toxicology revealed 0.95 mg/L (4.6 mu mol/L) of MDEA and 0.8 mg/L (3.6 mu mol/L) of butalbital in the blood. No alcohol was detected. CASE 3. -- A 32-year-old man with a history of asthma was found dead beside his car. A 0.5% epinephrine inhaler was in his hand. He had been drinking alcohol with friends until two hours prior to the discovery of his body. Postmortem examination showed gross and histologic features of acute and chronic bronchial asthma, including hyperinflation of the lungs, mucus plugging, peribronchial muscular hyperplasia, submucosal eosinophilic infiltrates, and thickening of bronchial basement membranes. The remaining organs were congested but were otherwise unremarkable. The cause of death was attributed to asthma; however, postmortem toxicology showed 1.1 mg/L (5.7 mu mol/L) of MDMA in the blood. No alcohol or theophylline were detected. CASE 4. -- A healthy 18-year-old woman ingested 1 1/2 "hits" of Ecstasy (approximately 150 mg) and an unknown amount of alcohol within a 60- to 90-minute period. Shortly thereafter, she collapsed, and on arrival of the paramedics, she was found to be in ventricular fibrillation. She was pronounced dead after resuscitation attempts were unsuccessful. Autopsy findings included pulmonary congestion and edema, associated with congestion of other viscera. Postmortem toxicology revealed 1.0 mg/L (5.2 mu mol/L) of MDMA and 40 mg/dL (8.7 mmol/L) of ethanol in the blood. CASE 5. -- A 21-year-old man was found unconscious after ingesting three Ecstasy capsules (approximately 300 mg), one propoxyphene capsule (65 mg), and several drinks over a period of ten to 11 hours. Attempts at resuscitation were unsuccessful. Significant autopsy findings were confined to the heart, which was enlarged (420 g) due to concentric left ventricular hypertrophy and slight dilatation. The coronary arteries contained scattered, nonocclusive, atheromatous plaques, and the valves were unremarkable. Histologically, some myocytes showed enlarged, hyperchromatic nuclei, but there was no evidence of the bizarre cells found in hypertrophic cardiomyopathy. Given the absence of coronary atherosclerosis and valvular abnormalities and the lack of history of hypertension, the cause of death was attributed to idiopathic cardiomyopathy. Postmortem toxicology showed the following drug levels in the blood: MDEA, 2.0 mg/L (9.7 mu mol/L); propoxyphene, 0.26 mg/L (0.8 mu mol/L); and norpropoxyphene, 1.0 mg/L (3.1 mu mol/L). MDEA levels in other body fluids and tissues are shown in the Table. No MDMA (the drug the decedent thought he was taking) or alcohol was present. PAGE 47 Copyright 1987 Amer. Medical Assn., JAMA, March 27, 1987 Clinical, Autopsy, and Toxicology Findings in Five Deaths Associated With MDMA and MDEA Use [SEE ORIGINAL SOURCE] COMMENT MDMA and MDEA are structurally related to MDA, as shown in the Figure. All three drugs share structural similarities to methamphetamine, which has sympathomimetic properties, and to mescaline, a hallucinogen. MDA was a popular drug of abuse during the 1960s, and although several deaths related to MDA overdose were reported, [n7-n11] these appeared to be rare occurrences. MDMA and MDEA apparently cause euphoria and enhanced sociability as MDA does, [n7] but they are not thought to be hallucinogenic. [n3] Both have a rapid onset of action of approximately one-half hour. [n12] MDMA users describe three phases of action: an initial period of disorientation, followed by a rush during which the user experiences tingling and may exhibit spasmodic jerking motions, and finally a period of "happy sociability" (Life, August 1985, pp 88-94). Generally, MDMA's effects wear off in four to six hours [n1]; however, confusion, depression, and anxiety have been reported by some users for several weeks after a single dose. [n2] To date, there have been no reports of MDMA - or MDEA-related deaths in the medical literature, but one death has been described in the popular press (Life, August 1985, pp 88-94). The five cases reported herein and associated with MDMA and MDEA use were seen in Dallas and surrounding counties within a period of nine months (June 1985 to March 1986). In four patients, MDMA or MDEA appears to have played only a contributory role in causing death, while in the fifth, MDMA was the immediate cause of death. Although MDMA has not been described as causing bizarre behavior (Newsweek, April 15, 1985, p 96; Life, August 1985, pp 88-94; Shafer [n2]; and Baum [n3]), case 1 illustrates that such behavior is possible. Although it is not possible to rule out suicidal intent, information available from relatives and friends indicates that this individual's behavior was motivated solely by his use of MDMA. The role of MDMA and MDEA in patients 2 and 5 is more difficult to delineate, particulary in the presence of low concentrations of other drugs (butalbital in patient 2, propoxyphene in patient 5). Both individuals suffered from underlying cardiac diseases, which could have been responsible for death without MDMA or MDEA use. However, MDMA is known to have sympathomimetic actions, including mydriasis and hyperhidrosis (Life, August 1985, pp 88-94; Greer and Strassman [n1]; Shafer [n2]; and Riedlinger [n13]). Although their cardiovascular effects are unknown, MDMA and MDEA may well have actions similar to their parent amphetamines, including increased cardiac output, hypertension, and induction of arrhythmias. [n14] Arrhythmias are a recognized mechanism in amphetamine-related deaths, [n15] and are thought to be the mechanism of death in both patients 2 and 5. These two cases are not unlike an MDMA -related death, reported in the popular press (Life, August 1985, pp 88-94), wherein an individual with known cardiac disease died suddenly, shortly after taking a large dose of MDMA. PAGE 48 Copyright 1987 Amer. Medical Assn., JAMA, March 27, 1987 Therefore, it is possible that these drugs can induce or augment potentially fatal arrhythmias in those individuals with predisposing cardiac diseases. Clearly, this is an area that needs further study. In patient 3, MDEA use was associated with the sudden death of an individual who had asthma. The absence of theophylline in postmortem blood samples and his use of an over-the-counter epinephrine inhaler indicate that the individual was not likely receiving adequate medical therapy. Inadequate treatment is a major finding reported in those dying suddenly of asthma, [n16] so it is possible that this individual would have suffered his fatal attack even if he had not taken MDEA. Amphetamines, in general, relax bronchial smooth muscle, which would tend to argue against MDEA's playing a contributory role in initiating the acute attack. [n14] However, based on the previous discussion, one cannot rule out the possibility that MDEA potentiated a cardiac arrhythmia in this individual whose cardiopulmonary function was already impaired as a result of asphyxia induced by his asthma attack. Use of MDMA was thought to be the immediate cause of death in patient 4. This 18-year-old woman was healthy prior to her death. Autopsy revealed that she had no underlying natural disease that would predispose her to sudden death. If the witnesses to the event are reliable, she did not taken an extraordinarily large amount of MDMA (approximately 150 mg). The mechanism of death was clearly a cardiac arrhythmia, as she was determined to be in ventricular fibrillation on the arrival of paramedics. The low dose of MDMA ingested resulting in sudden death may be an example of an idiosyncratic reaction, or may suggest that the toxic-to-therapeutic ratio of MDMA is low. To our knowledge, levels of MDMA and MDEA in human blood and tissues have not previously been reported, so it is difficult to interpret the significance of the drug concentrations found. It is interesting to note that the blood MDMA level of 1.0 mg/L (5.2 mu mol/L) in patient 4, where the cause of death was attributed to MDMA intoxication, is slightly lower than that in patient 3 of 1.1 mg/L (5.7 mu mol/L), where an anatomic cause of death (ie, asthma) was found. At the present time, it is not known whether these represent unusually high or just "therapeutic" levels of MDMA. The tissue distribution of MDEA in patient 5 shows the highest concentrations of this drug in liver and lung. Amphetamines are metabolized in the liver and are also excreted in the urine in varying proportions, depending on urine pH. [n14] Metabolism of MDEA in the liver may account for the relatively high levels found in this organ; however, the significance of the high lung and lower kidney concentrations is unknown. Unfortunately, these five cases do little to resolve the present controversy as to the abuse potential and dangers of MDMA and MDEA vs the possible therapeutic usefulness of MDMA in psychotherapy. Deaths directly and indirectly related to the use of MDMA and MDEA do occur; however, they appear to be rare at this time. Their rarity is confirmed by the recently published statistics of the Drug Abuse Warning Network for 1985. Neither MDMA nor MDEA was included in the list of drugs found most frequently by 73 medical examiner facilities across the United States (drugs reported less than ten times were excluded from this list). [n17] It would appear that preexisting cardiac disease may be one factor that predisposes individuals to sudden death while using these drugs. It is hoped that the reporting of these cases will inaugurate a search for more objective information about MDMA and MDEA. PAGE 49 Copyright 1987 Amer. Medical Assn., JAMA, March 27, 1987 SUPPLEMENTARY INFORMATION: From the Department of Pathology, University of Texas Health Science Center, Dallas, and the Southwestern Institute of Forensic Sciences, Dallas. Dr Dowling is now with the Departments of Pathology at the Universities of Calgary and Alberta, and is the Assistant Deputy Chief Medical Examiner in Alberta. Dr McDonough is now the Associate Medical Examiner in Connecticut. Reprints not available. The authors are grateful to the Office of the Chief Medical Examiner of Dallas County for granting permission to publish these cases. We also wish to thank the toxicology technologists of the Institute of Forensic Sciences for their technical assistance, Elizabeth Todd, PhD, Thomas Kurt, MD, and Graham Jones, PhD, for their helpful suggestions, and Sylvia Plehwe for typing the manuscript. Standards for MDMA and MDEA levels were provided by the Drug Enforcement Administration South Central Regional Laboratory, Dallas. REFERENCES: [n1.] Greer G, Strassman RJ: Information on " Ecstasy. " Am J Psychiatry 1985;142:1391. [n2.] Shafer J: MDMA: Psychedelic drug faces regulation. Psychol Today 1985;19(5):68-69. [n3.] Baum RM: New variety of street drugs poses growing problem. Chem Eng News 1985;63(36):7-16. [n4.] Ricaurte G, Bryan G, Strauss L, et al: Hallucinogenic amphetamine selectively destroys brain serotonin nerve terminals. Science 1985;229:986-988. [n5.] Gehlert DR, Schmidt CJ, Wu L, et al: Evidence for specific methylenedioxymethamphetamine ( Ecstasy) binding sites in the rat brain. Eur J Pharmacol 1985;119:135-136. [n6.] Foerster EH, Hatchett D, Garriott JC: A rapid comprehensive screening procedure for basic drugs in blood or tissues by gas chromatography. J Anal Toxicol 1978;2:50-55. [n7.] Poklis A, Mackell MA, Drake WK: Fatal intoxication from 3,4-methylenedioxyamphetamine. J Forensic Sci 1979;24:70-75. [n8.] Reed D, Cravey RH, Sedgwick PR: A fatal case involving methylenedioxyamphetamine. Clin Toxicol 1972;5:3-6. [n9.] Cimbura G: 3,4-Methylenedioxyamphetamine (MDA): Analytical and forensic aspects of fatal poisoning. J Forensic Sci 1972;17:329-333. [n10.] Lukaszewski T: 3,4-Methylenedioxyamphetamine overdose. Clin Toxicol 1979;15:405-409. [n11.] Simpson DL, Rumack BH; Methylenedioxyamphetamine: Clinical description of overdose, death, and review of pharmacology. Arch Intern Med 1981;141:1507-1509. PAGE 50 Copyright 1987 Amer. Medical Assn., JAMA, March 27, 1987 [n12.] Shulgin AT: Psychotomimetic drugs: Structure-activity relationships, in Iversen LL, Eversen SD, Snyder SH (eds): Handbook of Psychopharmacology. New York, Plenum Publishing Corp, 1978, vol 11, pp 243-333. [n13.] Riedlinger JE: The scheduling of MDMA: A pharmacist's perspective. J Psychoactive Drugs 1985;17:167-171. [n14.] Weiner N: Norepinephrine, epinephrine, and the sympathomimetic amines, in Gilman AG, Goodman LS, Gilman A (eds): The Pharmacological Basis of Therapeutics. New York, MacMillan Publishing Co Inc, 1980, pp 138-175. [n15.] Benowitz NL, Rosenberg J, Becker CE: Cardiopulmonary catastrophes in drug-overdosed patients. Med Clin North Am 1979;63:267-296. [n16.] Benatar SR: Fatal asthma. N Engl J Med 1986;314:423-429. [n17.] Data From the Drug Abuse Warning Network. Series 1, No. 5. Rockville, Md, National Institute on Drug Abuse, 1985, p 53. GRAPHIC: Figure, Structural formulas of MDMA, MDEA, and related compounds.****------------------------------------------------------------------------**** * 50 PAGES 1,864 LINES * * 8:03 P.M. STARTED 8:13 P.M. ENDED * ****------------------------------------------------------------------------**** ****------------------------------------------------------------------------**** * EEEEE N N DDDD * * E N N D D * * E NN N D D * * EEE N N N D D * * E N NN D D * * E N N D D * * EEEEE N N DDDD * ****------------------------------------------------------------------------****