In: Substance abuse: A Comprehensive Textbook, Third Edition, Lowlinson JH, Ruiz P,
Millman RB, Langrod JG (Eds), Williams & Wilkins, Baltimore, 1997. pp. 269-275.
MDMA
HISTORICAL BACKGROUND
MDMA was first synthesized in 1912 by chemists working for Merck Pharmaceuticals in Germany searching for a new class of appetite suppressant drugs, and patented in 1914. With the outbreak of World War 1. however, industrial scientists were forced to turn their at-inn elsewhere, and further explorations of the properties and potential applications of MDMA were halted (108, 110). In the early 1950s, as part of systematic U.S. Army Intelligence research on potential psychotropic drug applications to espionagc and counter-espionage endeavors. MDMA once again came to the attention of research pharmacologists. Allocated to the Edgewood Arsenal's Cherrucal Warfare Service, and provided the code name EA-1475, MDMA was administered to a variety of animals for standard LD5() screening. Plans to initiate human trials with MDMA were abandoned. however. following the tragic and untimely death in 1953 of a subject enrolled in a U.S. Army contract study at the New York State Psychiatric Institute who had received "forced injections" of EA-1298. or MDA (3.4-methylonedioxyamphetamine), an analogue and an active metabolite of MDMA (62). As a testimony to the capricious and often unethical "research" conducted under the auspices of U.S. Intelligence services during this period. one of the lead investigators of the fatal MDA study would later state. "We didn't know whether it was dog piss or what it was we were giving him" (67).
As with many of the powerful consciousness-altering compounds examined by the CIA and U.S. Army Intelligence, the 1960s witnessed a proliferation of information and interest in the phenethylamine psychedelics within the growing counter-culture movement. MDA in particular enjoyed a brief period of popularity in the late 1960s and early 1970s, when it was cuphentistically attributed the exotic name of the "love drug." MDMA, though, remained largely unknown to psychedelic enthusiasts and would not be examined until the mid 1970s when University of California Berkeley biochemist and toxicologist, Alexander Shulgin, acting on the suggestion of a student who claimed to have successfully alleviated a severe stutter with the drug, synthesized and self-administered 120 mg of the compound (110). He would later describe MDMA as evoking "an easily controlled altered state of consciousness with emotional and sensual overtones. and with little hallucinatory effect" (109).
Highly impressed with the drug's apparent capacity to induce heightened states of empathic rapport. a critical component of successful psychotherapy, Shulgin introduced several psychiatrist and psychologist acquaintances to MDMA's unusual profile of action. Their responses, both to their own subjective experience. as well as to those of patients to whom they had administered the drug. were an unequivocal endorsement of MDMA's apparent capacitv to facilitate the process of psychotherapy. For the remainder of the 1970s. a quiet underground of psychotherapists. particularly on the West coast of the United States. conducted thousands of MDMA-augmented treatments with what at that time was still a legal and uncontrolled substance. Although unfortunately no methodological research was conducted to substantiate MDMA's alleged efficacy in alleviating psychological distress and modifying maladaptive personality structures, testimonials to its therapeutic range of action abounded. Unbridled enthusiasm for this novel and as yet unsubstantiated treatment was best summed up by a psychiatrist colleague of Shulgin's who told him. -MDMA is penicillin for the soul. and you don't give up penicillin, once you've seen what it can do" (110).Sensitive to the late suffered in the 1960s by proponents of psychiatric research and treatment with psychedelics once word of their highly unusual effects had been disseminated to the culture at large (49), knowledge of .VIDMA remained a tiehily guarded secret among practitioners of its use and their patients for several years. By the early 1980s. however. word of NIDMA had filtered out. abetted by media accounts of a new psychotherapeutic 'miracle medicine" and the spread of an alECmative recreational drug on some college campuses (particularly in California and Texas). where for a period of time MDMA replaced cocaine as a new drug of choice. First popularIv called Adam during its early phase of use among psychotherapists. to signify "the condition of primal innocence and unity with all life" (1), it soon acquired the alternative appellation of "Ecstasy," the name by which it is popularly known to this day. Indeed, the transformation of MDM.A as "Adam' into MDMA as "Ecstasy" appears to have been a marketing decision reached by an enterprising distributor searching for art alternative code name. who concluded that it would not be profitable to take advantage of the druv s most salient features. "Ecstasy was chosen for obvious reasons," this individual later reported. "because it would sell better than callinglik 'Empathy.' 'Empathy' would be more appropriate, but how many people know what it means?- (34).
By 1984. with growing use on college campuses and increased media attention and embellishment. political pressure was placed on federal regulators to establish tight controls on what was still a legal drug. Consequently, in 19X5 the U.S. Drue Enforcement Agency (DEA) convened hearings to determine the fate of MDMA. These highly publicized hearings achieved the iminterided effect of further raising public awareness of MDMA as well as interest in experimentation. Media accounts further polarized opinion, pitting. enthusiastic claims of MDMA by proponents on the one hand. versus dire warnings of unknown dangers to the nation's youth on the other. Covera2e of the MDMA scheduling controversy included a national daytime television talk show (the Phil Donahue program) highlighting the surprising disclosure by a prominent University of Chicago neuroscientist that recent (but as vet unpublished) research had detected "brain damage" in rats injected with large quantities of MDA, an analogue and metabolite of MDMA. Public debate was further confounded by the frequent confusion of MDMA with MPTP, a doparninergic neurotoxin that had recently been revealed to have induced severe Parkinson's-like disorders in users seeking synthetic heroin substitute highs. With growing concern over the dangers of new "de~igner drues." public discussion took an increasingly discordant tone (11). In the spring of 1986. following a series of scheduling hearings on MDMA conducted by the DEA in several U.S. cities. the DEA administrauve law judge presiding over the case determined on the weight of the evidence presented that there was sufficient indication for safe utilization under medical supervision and recommended Schedule III status (124). Not obliged to follow the recommendation of his administrative law judge, however, and expressing grave concerns that MDMA's growing abuse liability posed a serious threat to public health and safety, the DEA director overruled the advisement and ruled that MDMA be placed in the most restrictive category, Schedule 1 (61). Since then. with the exception of a three-month period in early 1988 when it was briefly unscheduled due to a court challenge. MDMA has re-classified as a Schedule I substance.
In the decade following the MDMA scheduling controversy, pattems d use have undergone a marked shift. With the failure to establish official~ lion for MDMA treatment. most psychotherapists who had used the drug aid. junctively in their work ceased to do so, unwilling to violate the law and jeopardize their livelihoods through the use of a now illegal drug. In the wake of the highly publicized scheduling hearings, however. use ai young people escalated. By the late 1980s, interest in MDMA had s~ from the United States across the Atlantic to Europe, where it became dx drug of choice at marathon dance parties called---raves.---Beginning on dx Spanish island of Ibizia, spreading across the Continent. and then back to dz United States. MDMA-catalyzed "raves" have drawn large numben of young people, often attracting greater than 10.000 individuals at a si gk event (100). Although use in the United States has tended to be cyclicaL waxing and waning depending upon an often erratic supply, popularity in Europe has remained high (20, 99). With multiple illicit laboratories. in. cluding pharmaceutical manufacturers in former "Iron Curtain" countnea, the European youth market appears to have become saturated with the drug in recent years (117).
EPIDEMIOLOGY
Although various estimates have been given on the extent of current fllicit MDMA use in the United States and western Europe, the exact prtya. lence remains unknown. Saunders (98) has stated that "millions" of young people in the United Kingdom have taken MDMA. A Harris Opinion Poll (55) for the BBC in Great Britain presented data that 3 1 % of people betwem the ages of 16 and 25 admitted to taking MDMA. most often at "da= clubs," and that 67% reported that their friends had tried the drug. In a sur. vey of school children across the whole of England. 4.25% of 14-year-olds and. in another survey, 6.0% of those ages 14 and 15, were reported to have Laken MDMA (100). The popular British press have recently reported that an estimated 500,000-1,000,000 young people in Great Britain take MDMA every weekend (107, 117). The "rave scene" in particular appears to be responsible for the explosive growth of MDMA in the United Kingdom (74), and has been described as developing into what many believe to be the "largest youth movement in British history" (10).
In the United States, according to a 1993 NaLional Institute on Drug Abuse survey, 2.0% of all United States college students had admitted to taking MDMA in the previous 12 months (83a). An interview study of Stanford University undergraduate students reported that 39% had taken MDMA at least once in their lives (85), while a Tulane University survey revealed dult '4.3% of over 1,200 students questioned had experimented with the drug (26). MDMA has been described as having the "greatest growth potential among all illicit drugs" in the United States. with tens of thousands of new users being introduced to the drug every month. particularly within the context of the "rave scene" (82).
POTENTIAL TREATMENT APPUCATIONS
Psychopharmaccilogical modification of psychotherapy is a treatment modality with prehistoric roots in the sharrianic healing application of psychedelic plants within a societally sanctioned and ritualized context (17). Evidence has accumulated that the controlled utilization of psychedelics for therapeutic and initiatory purposes has played a vital role in aboriginal and preindustrial societies from before recorded history to the present (28, 29, 52). Indeed, over the last four decades the advent of psychopharmacological treatments has transformed the theory and practice of psychiatry; neverdieless, their impact upon psychotherapeutic technique and efficacy has been marginal (48). From 1950 to the mid 1960s, over 1,000 professional papers were published in the clinical psychiatric literature in Europe and the United Stat describing the treatment of an estimate4 40,000 patients with psychedelic substances (47), yet this era in the history of psychiatry has been virtually forgotten.
Beginning in the late 1970s, proponents of this form of drug-enhanced psychotherapy began to investigate the therapeutic potential of the still-legal MDMA. Compared to LSD, the prototype psychedelic of the twentieth cenfury, MDMA was judged to possess distinct advantages as a therapeutic adjunct. MDMA was described as being a relatively mild, short-acting drug capable of facilitating heightened states of introspection and intimacy along with temporary freedom from anxiety and depression. yet without distracting alterations in perception, body image, and sense of self. Patients were reported as losing defensive anxiety, feeling more emotionally open and accessing feelings and thoughts not ordinarily available to them. Lasting improvement was often reported in patients' self esteem. ability to communicate with significant others, capacity for achieving empathic rapport. interest in and capacity for insight. strengthened capacity for trust and intimacy, and enhanced therapeutic alliance (48).
A variety of treatment applications were explored prior to MDMA's scheduling in the mid 1980s, including the physical pain and emotional distress associated with severe medical illness. posttraumatic stress disorders, depression, phobias, addictions, psychosomatic disorders. and relationship (marital) problems (2, 32. 45, 62). In reviewing their work with 80 patients treated with MDMA-augmented psychotherapy, Greer and Tolbert (46) have noted long lasting benefits in symptom reduction, particularly in diminishing the pathological effects of prior traumatic experience, as well as sustained improvement in effective and empathic communication skills with famuly members. More recently, Riedlinger and Riedlinger (9 1) have examined the putative rationale for tre-n-ing suicidal depression with MDMA.
Unfortunately, before MDMA's value as a treatment modality could be subjected to rigorous. methodological research evaluation in the United States, the drug was placed in the most restrictive Schedule I status. All applications since the mid 1980s to conduct clinical trials with MDMA have consequently been rejected, although an approved Phase I investigation of physiological and psychological effects in normal volunteers with prior MDMA experience was recently concluded by the authors at Harbor-UCLA Medical Center (53). Because clinical patient populations iZave never been subjected to formal examination with MDMA. only anecdotal case reports have been available for examination. In addition to accounts of treatment outcome, the experiences of long-term users of MDMA have also been systematicaRy examined. One study (65). which subjected 20 psychiatrists with past personal histories of MDMA use to extensive semi-structured interviews, reported that 85% had increased ability to interact with or be open with others. 80% had decreased defensiveness. 65% had decreased fear, 60% had decreased sense of separation or alienation from others, 50% had increased awareness of emotions, and 50% had decreased aggression. Onehalf of these psychiatrists with MDMA use experience also reported longterm improvement in social and interpersonal functioning.
In Europe. opportunities for more systematic study of MDMA treatment have been possible. Between 1988 and 1993. permission was granted by public health officials in Switzerland to several psychiatric clinicians. under the auspices of the Swiss Medical Society for Psycholytic Therapy, to treat patients with MDMA. Although authorities neglected to insist upon the implementation of prospective research designs, a retrospective analysis of treatment outcomes was recently conducted (41, 42). One hundred and twenty-one former patients consented to examination. on average two years following termination of treatment. Patients (predominantly diagnosed with affective disorders. adjustment disorders, and personality disorders) had been engaged in long-term psychotherapy augmented with an average of 6.8 MDMA sessions over three years. Overall. 90.9% of patients reported to have experienced improved clinical status as a result of their prior treatment with MDMA. while 2.5% claimed to have clinically "deteriorated." Significant decreases were noted in self-administration of nicotine, alcohol, and cannabis in the years following MDMA treatment. and significant improvements were noted in seif-acceptance. autonomy, and overall quality of life.
ADVERSE CUNICAL EFFECTS
When examining adverse effects of MDMA. it is important to distinguish between relatively benign, timmient effects experienced by healthy, occasional users ingesting relatively moderate dosagc3 versus mom dangerous sequeiae reported to occur in a small minority of individuals taking MDMA, often in the context of significant premorbid pathology, adverse settings. polysubstance use, and excessive dosing. Liester et al. (65) have reported in their evaluation of psychiatrists with past. personal use that common shortterm side effects of MDMA were similar to effects induced by amphetamines, including trismus, bruxism. restlessness. anxiety, and decreased appetite. Other investigators have reported tachycardia, palpitations. dry mouth, and insomnia (45. 87).
With substantial alterations in patterns of use over the past decade. from occasional use for therapeutic and spiritual purposes (119) to frequent, repeated ingestion at large rave dances, the reported risks have increased significantly (90). Although earlier investigations had concluded that MDMA was a drug with a relatively low potential for abuse (9, 59, 111, 114) and where persistent use patterns were described as "extremely rare" (88), the likelihood of individuals frequently ingesting higher dosages of MDMA. often in association with other drugs or alcohol. appears to be increasing (99). Most reports of severe adverse effects over the past several years have in fact occurred in Europe, particularly Great Britain. where the phenomenon ot widespread. frequent use among youth is far more prevalent than in the United States. It is also critical to note that given the clandestine (and often amateur) context within which MDMA is manufactured for the escalatine mass market. the available black market drug is often not necessarily what
it is advertised as being (15. 122), nor is it necessarily free of contaminants and adulterants (19. 125). As was the case with psychedelics in the 1960s, following the transition over time from limited and legal use by relatively welleducated aficionados to mass market consumption for illicit and "recreational" purposes by youth. the purity and quality of MDMA has progressively declined while the associated risks to the user have climbed.Given the extent to which MDMA has been subject to widespread use and abuse in the past decade, it is somewhat surprising that more reports ot serious adverse effects have not been reported. Particularly within a context of grave concerns raised over potential risks. fueled by media publicity and hyperbole. only a relatively small number of fatal reactions to the drug have made their way into the medical literature. Nevertheless. serious attention needs to be accorded the potential for catastrophic medical reactions. as they have occurred and are likely to continue, particularly to individuals with preexisting vulnerabilities (both medical and psychological) who take the drue under circumstances that accentuate the risks.
The first reports of fatalities associated with MDMA ingestion occurred in the United States in 1987. Dowling et al. (31) described five cases of individuals who had precipitously died~ they had detected at postmortem positive toxicological screens for MDMA or MDEA, an MDMA analogue. One of these cases was an individual who was electrocuted while under the influence of MDMA, whereas the other four were all associated with individuals who sustained fatal cardiovascular events. Three of these individuals apparently had pre-"isting severe cardiac or respiratory disease (atherosclerotic coronary artery disease. idiopathic hypertrophic cardioniyopathy. and bronchial asthma), which were felt to have played a primary role in their sudden death. Alcohol and drugs in addition to MDMA were also found to have been associated with the four cases of death induced by cardiovascular collapse. In two of these cases alcohol use occurred shortly before death, in one case alcohol along with a narcotic analgesic were found to be positive on post-mortem toxicological screen-, and in one case presence of a barbiturate was detected. Individuals who may be at heightened risk of life-threatening cardiac arrhythmias and associated cardiovascular collapse are those having underlying illnesses with heightened sensitivity to exogenousinduced adrenergic stimulation, such as ischemic heart disease. cardiac conduction defects, cardiornyopathy and mitral valve prolapse (19, 81), When MDMA is taken by such individuals with pre-existing medical vulnerabilities, and particularly in the presence of alcohol or other drugs. licit or illicit. the risks for life-threatening events are compounded.
Several cases have also been reported over the last few years in the medical literature of severe cerebrovascular accidents apparently induced by MDMA. Manchandit and Connolly (66) described a young man who expertenced a cerebral infarction after having consumed "several" MDMA tablets. Similarly, Rothwell and Grant (98) reported a young woman who had taken MDMA who subsequently sustained a cerebral venous sinus thrombosis after engaging in an extended period of prolonged dancing and associated dehydration . Pre-existing neurological vulnerabilities appear to accentuate the risks tor devastating cerebrovascular events. as was the case of a young woman who had an intracerebral bleed from an aneurysm of the left postenor communicating artery shortly after ingesting two and a half MDMA tablet, (41). Associated polysubstance and alcohol use also appear to potentiate t~ie dangers of MDNIA use, inducing injury to central nervous system structures ( 116). Damage to subcortical structures through a mechanism of vasoconstriction brought on by enhanced serotonin neurotransmission has also been suggested as the pathogenesis of some strokes associated with MDNIIA (54).
With increasing use of MDMA. often of indeterminate quality and excessive quantity, cases of apparent hepatoEoxicity have begun to emerge, pairticularly in Great Britain. Henry et al. (56) have reported six young men and one young woman who had used MDMA within the previous few weeks who presenEed with jaundice, elevated bilirubin, and abnormal liver chemi-stries. Each was without a known history of heavy alcohol use. intra~enoos drue use. or evidence of infectious hepatitis. Dykhuizen et al. (33) have
also reported on three cases of idiosyncratic toxic hepatitis. presumably secondary to MDMA. Whether the liver damage in these cases was caused by an idiosyncratic reaction to MDMA or to some contaminant ingested alone with it is not known (58). Although such case reports provoke the need to inquire about MDMA use histories in youne people presenting with unexplained jaundice and hepatomegaiy, they io appear to be extremely rare, even in the context of increasing usage of an often impure. illicit compound. Basic 28-day toxicological studies in does and rats have reported no evidence of liver damage (40). Thus. the mechanism underlying the reported liver oamage remains to be determined.Additional case reports have surfaced over the past several years of isolated instances of catastrophic hyperthermic reactions leading to disscminateci intravascular coagulation (DIC), rhabdomyolysis. acute renal failure. and. on occasion. death (56). Virtually all of such reported cascs~have occurred in the setting of prolonged vigorous dancing in poorly ventilated environments and were associated with inadequate fluid replacement. To date, all Known fatalities caused by malignant hyperthcrmia have occurred in Great Britain and have been in rave dance club settings. These environments are described as being very crowded with exceedingly high ambient temperatures (90). Indeed. in some British rave dance halls. including settings where deaths from hyperthermia had occurred. supplies of v, ater were often restricted by club manaeement in order to increase the sales of soft drinks. In one particularly unscrupulous establishment the water taps were repoirt.,,dlv turned off in the bathrooms while tap water was sold over the counter at the bar for the same price as beer (68).
Given that the degree of MDMA use has climbed well into the millions, particularly in Europe, it is not surprising that cases of psychiatric disturbance have been reported. Such adverse psychiatric events reported have included panic disorder (70. 84, 121), paranoid psychoses 1,24, 75, 76) and depression (69). What is remarkable about many of these reports, apart from the surprisingly small numbers of presenting cases conumted to the exceedingly large potential pool of (mostly young) individuals who have used .MDMA, is the extremely high and frequent dosages of the drug that had been consumed by many of those individuals who had experienced adverse psychiatric sequelae (69, 75, 76, 101, 120). In the face of significant premorbid psychopathology, and often in combinaucin with other drugs or alcohol, frequent use of high-dose MDMA does appear to heighten risks for deterioration ot psychiatric status. 'ne evidence. however, for occasional. low-dose N4DNI A use. taken in controlled settings without additional drugs or alcohol by inuividuals with negative histories for psychiatric disorders, appears to be considerably lower.
NEUROTOXICITY
Since the mid 1980s, evidence has existed that MDMA and its analogues are capable of inflicting profound changes on brain serotonin systems in laboratory animals (92). Preclinical studies have consistently demonstrated that MDMA causes an acute. but reversible, depletion of serotorun (77). Unlike other ampheta
mine-like compounds, which exert comparable effects on both serotonergic and dopaminergic neurons (106), MDMA's predominant target is the serotonin system (although dopamine systems also can be affected) (1231Effects of serotonin systems in laboratory animals subjected to administration of large dosages of MDMA has been divided into short-term and long-term effects. Some of the acute effects of MDMA, including the rapid release of intracellular scrotonin, are presumed to mediate the behavioral and psychological profile observed in humans (53), whereas in animals the neurotoxic effects are not manifested until days later (7). It would appear that neurotoxicity is not inextricably linked to the acute effects of the drug. Administration of fluoxetine prior to. or up to six hours after, MDMA administration blocks or attenuates the development of neurotoxiciry (44). whereas some acute effects of MDMA (e.g., behavioral, neuroendocrine, and temperature) occur within minutes and peak within a few hours (18, 53, 80) (Poland and Grob, unpublished data). The majority of work on MDMA has revolved around its neurotoxic effects and the mechanisms by which these effects are produced. Rats administered multiple d oses of MDMA undergo serotonergic neurotoxic changes that can last for many months before neurochemical recovery occurs (7), although there can be considerable interanimal variability in the degree of neurotoxicity, as well as in the extent of recovery, from the same dosage regimen. In rats. neurotoxicity appears to be limited to axon terrrunals. with relative sparing of cell bodies (8). Regeneration and resprouting of brain serotonin axonal projections do occur. yet may take up to a year to develop in rodents. and perhaps longer in non-human primates (95). Ile question of whether these axonal connections observed during recovery are "normal" or not. however, remains to be elucidated. In squirrel monkeys administered MDMA (5.0 mg/kg. subcutaneous) twice daily for four consecutive days, profound reductions of brain serotonin, 5hydroxyindole acetic acid (5-HIAA), the primary metabolite of semtonin, and serotorun uptake sites, persist even at 18 months. Interestingly, the thalamus shows some recovery. while the hypothalamus shows an (apparent) overshoot in regeneration (3), suggesting that under some circumstances MDMA administration can lead to a lasting reorganization of ascending 5HT axon projections (36). A single oral dose of 5.0 mg/kg in primates, only 2-3 times higher than that usually taken by humans, produces thalarnic and hypothalamic effects observed only at two weeks after administration (93). A no-effect level in monkeys, however, has been reported between 2.5-5.0 mg/kg (Ricaurte GA. unpublished data). Despite the widespread damage to 5-HT neurons produced by high doses of the drug, few functional changes have been found (39, 63, 97). However, the authors (53) (Poland and Grob, unpublished data) have found that the neuroendocrine response to acute fenfluramme challenge is altered for up to one year in rats treated with high doses of MDMA (20 mg/kg. bid X 4 days). In contrast, we have not found such changes in humans with a history of MDMA use.
The mechanisms underlying MDMA-induced serotonin neurotoxicity are thought to occur by the uptake of MDMA into serotonin nerve terminals. causing an initial reduction of serotonin levels. A second phase of serotonin reduction follows, possibly due to the formation of neurotoxic metabolites (5) or by generation of free radicals (8). which causes degeneration of serotonin terminals (and in some cases axons) for weeks to months. depending upon the species and dosage regimen employed. Additional data indicate that doparnme also plays a role in the mechanism underlying the neurotoxic effects of MDMA on serotonin neurons (105), as does glutamate, since various N-methyl-D-aspartate antagonists can inhibit or attenuate MDMA induced neurotoxicity (44). Other compounds that have been shown to modulate or prevent long-term scrotonergic neurotoxic changes in laboratory animals administered MDMA include the serotonin re-uptake inhibitors fluoxetme and citalopram (102. 103). the serotonin antagonist ritanserin (104), the dopantine antagonist haloperidoll (57), and the monoamine oxidase-B inhibitor LDeprenyl (115), as well as the N-methyl-D-asparmte antagonists dizocilpine (22. 57) and dextromethorphan (3j). Furthermore, in addition to pure neurochenucal modulators, temperature appears to be another variable in the mediation of MDMA neurotoxicity (18).
Whereas muitiple studies have established and reconfirmed that MDMA provokes profound changes in brain serotonin systems of laboratory animals, there has been virtually no demonstration that functional or behavioral abnormalities have been induced. Similarly, no data are available addressing the issue of whether normal function is restored following biochemical recovery. It has long been demonstrated that at least in some species serotonin and other monoaminergic neurons can undergo extensive regeneration following neurotoxin-incluced degenerative change (13). As determined by immunocytochemical and autoradiographic techniques, regeneration of scrotonin fibers have been observed in the hypothalamus following serotonin lesions induced by the experimental neurotoxin 5,7-dihydroxytryptimine (5. 7-DHT). This reinnervation appears to be structurally normal (38). Atthough it is not known to what extent regenerated (or sprouted~ fibers are able to re-establish original synaptic contacts (36), some recently published data suggest that the observed patterns of re-innervation are abnormal (36). Ile degree to which such biochemical alterations affect functional normality is a question still awaiting elucidation. Indeed, it appears that it is the specific "damage" to serotonin fibers, (primarily serotonergic axonal terminals originating from the dorsal raphe), induced by neurotoxins causing significant declines in serotonin levels. which ultimately reactivate latent developmental signals in the brain. Most likely, this occurs at the genomic level. thus encouraging resprouting and regeneration along with the stimulation of an astrocy(ic growth factor (6). Whether the degenerative axonal changes associated with the phenomenon of serotonergic neurotoxicity is simply a prelude to what may eventually be recognized as a healthy and adaptive neuroplasticity response. or whether it is the substrate for what will eventuate in neuropsychiatric pathology, is not yet known.
MDMA is not the only drug known to induce long standing effects on indices of scrotonergic neurotransmission (12, 16). However, the drug with the greatest relevance to MDMA in its effects on scrotonergic function is fenfluramine. Marketed as an anorectic drug for the treatment of obesity, fenfluramine has been administered to over 50 million patients during the past 25 years (27). Fenfluramine has also been explored in controlled trials as a putative treatment for a variety of psychopathological conditions, including infantile autism (96). attention deficit hyperactivity disi?rder (30), eating disorders ( 14). depression (118), and suicidal behavior (79). In spite of such a long history of clinical application without reports of adverse outcome. fenfluramine has come under increasing attack in recent years because preclinical investigations have identified that its effects on the briuns of laboratory animals induce what has been described as serotonergic neurotoxicity (72). In rats as well as non-human primates, fenfluramine has been shown to cause long-standing depletions of regional brain 5-HT and 5-HIAA, changes very similar to those induced by MDMA. Indeed, some fenfluramine-incluced neurotoxicity has been described as being the same as for MDMA-induced neurotoxicity (71). Recently. a vigorous debate occurred at the FDA over appmvai of the more 5-HT-active optical isomer of fenflurarnine, D-fenfluramine. Many of the same concerns over the long-term effects of serotonergic neurotoxicity as during the MDMA debates were raised: nevertheless, the decision of the FDA advisory panel was to recommend approval without restriction for the prescription drug D-fenflurarnine. Although without the high public profile and notoriety of MDMA, fenfluramine is not itself lacking in potential for abuse (64). Nevertheless. the government approval for the use of D-fenfluramine was no doubt influenced by the aggressive lobbying efforts of the pharmaceutical industry, a fact which underscores the intrusion of political and economic agendas into the realm of scientific policy.
Efforts to extend the neurotoxicity hypothesis to human populations have met with mixed results. Measurements of neurotransmitter metabolites in the cerebrospinal fluid of MDMA users were assessed in one early study as being within normal limits (86). A subsequent study (94), which reported to%% ci levels of CSF 5-HIAA in MDMA users. is difficult to interpret because thc control population employed was a group of patients with chronic back pain Such a choice for the control group is suspect because of evidence that serotonergic mechanisms are involved in pain control (25. 78) as well as thL known association of increased levels of CSF 5-HIAA in patients sufferitiv, from chronic non-malignant and malignant pain (21. 23). Additional studic~ which reported sercionereic abnormalities in MDMA subjects (60. 89). ,, reflected by abnormal neuroenclocrine response to 1-tryptophan and by milt, to moderate cognitive impairment. need to be interpreted cautiously due it methodological concerns surrounding subject recruitment and assessmen! (50. 51. Doblin. personal communication). The most methodological 1~ sound retrospective evaluation of human MDMA users. although finding lit' differences between prolactin secretion induced by the 1-tryptophan challenee test. did find significantly lower levels of cerebral spinal fluid 5-HIAA in MDMA users compared to controls (73). Surprisingly, however, and confounding expectations inferred by the neurotoxicity hypothesis. these same MDMA subjects with relatively low levels of cerebral spinal fluid 5-HIAA were also assessed as having significantly lower scores on personality measures of impulsivity and hostility: opposite results would have been expectcu (37, 112. 113). Finally. a decrease in stage 11 sleep and sleep time has beer reported in subjects with a history of MDMA (4). This is both an interestin, and perplexing observation. Given the prominent role that serotonin plays t: the regulation of both slow wave and REM sleep. one would have expeCtCL that these sleep EEG ineasures might have been most affected by MDM,\ In summary, most. if not all. of the observed changes reported thus far al, compatible with a general effect of MDMA on serotonin neurotransmissioi independent of neurotoxicity, although the latter effect cannot be ruled out
Unfortunately, the question of MDMA's potential neurotoxicity in hu rnans has been marked by unwelcome and excessive attention by the media This has led not only to often sensationalized and distorted media reportage but also to implicit and explicit pressures on scientific researchers to ali,-,i their findings with conventional expectations. Needless to say, MDMA's r0k as a recreational drug for millions of young people worldwide is worrisome particularly within the context of ill-prepared and vulnerable individuals con surning an illicitly manufactured and marketed drus! of dubious quality in un predictable and often dangerous settings. Nevertheless. for a true appreciatiot of MDMA's range of effects. it is imperative that objective investigation h, conducted in an impartial and fair scientific environment. As previously men tioned. the authors have recently been granted permission for the first FDA sanctioned administration of MDMA to human normal volunteers with prior experience with the drug, in order to accurately determine its range of physiological effects, safety parameters, and central nervous system mechanisms (53). In addition to standard Phase I investigational measures. brain imaging studies and neuropsychological testing will be administered in a prospcctive manner. to more clearly delineate MDMA's psychobiological effects and potential to cause injury to brain function. Hopetully. the future will provide additional controlled and methodologically sound investigations probing the full range of MDMA's effects, and begin to answer the questions surrounding the drug's capacity to cause harm versus its inuate potential under optimal conditions to facilitate beneficial outcomes.
Acknowledgments. This work was supported in part bv Nationul Institute.of Health grants MH00534. DA06863 and b , v General Clinical Research Cent
er. grant RR 00425. We thank Mrs. Debbie Hanava for experr adminisrrutive assitance.
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