Introduction

The pharmacology and effects of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") continue to be a topic of interest for medical and neuroscience researchers. Approximately 130 original research studies and one quantitative (meta-analytic) review of the nature and effects of MDMA have been published since the completion MAPS' second yearly review of the literature (Jerome and Baggott 2003). Published reports include trials of MDMA in humans, studies of Ecstasy users, studies in non-human animals (mostly rodents and non-human primates) and in vitro studies. The current review covers nearly all English-language original research papers appearing between January 2003 and late February to early March, 2004. As was the case with the earlier update, this review is chiefly concerned with studies relevant to estimating risks to human participants in trials of MDMA. This review does not cover studies of Ecstasy user demographics and studies in non-human animals relating to drug discrimination or pharmacology when it does not directly inform risk estimation in humans. Other recent reviews have tackled the pharmacological and neuropharmacological literature in non- human animals, either specifically (Cole and Sumnall 2003B) or in the context of a general review (Green et al 2003B), and those wishing to read more about pharmacology, acute behavioral effects of MDMA in rodents, or drug-discrimination studies may turn to these reviews. While most papers covered in this review were published between 2003 and 2004, I reviewed some papers that fell outside this time period. Exceptions to the March, 2004 cut-off date were made for clinical trials (Farre et al. 2004) and a few studies in Ecstasy users (Halpern et al. 2004; McCardle et al. 2004). In a very small percentage of papers, nearly all of them case reports, only the abstract could be located at the time of writing the review. Many of the research reports reviewed appeared in a single issue of Psychopharmacology specifically devoted to MDMA. While the issue appeared in print in 2004, a large number of papers were electronically published before then.

Nearly all studies were located through the use of the PubMed database maintained by the National Institute of Health. This is a searchable database containing citations and abstracts of papers appearing in a large number of scientific journals. In some cases, researchers sent their work upon request, and in other cases, researchers informed me of the existence of specific papers.

The first comprehensive literature review commissioned by MAPS was completed in August, 2001, (Baggott et al. 2001), and focused on research that might inform human trials with MDMA. This literature review, also referred to as the "Investigator's Brochure," or IB, covered all clinical trials of MDMA, a summary of early use by psychotherapists, retrospective studies of the effects of Ecstasy (material purported to contain MDMA), research investigating MDMA neurotoxicity in non-human animals and in humans, and an examination of case reports of adverse events in Ecstasy users. This review did not cover behavioral research on the acute effects of MDMA in non-human animals. An examination of all information available at the time of completion led us to conclude that human participants faced minimal risk in clinical trials of MDMA given at doses in the range of 125 mg. No serious adverse events had been reported during any of the trials conducted, and both drug-naïve and experienced participants tolerated MDMA at doses ranging from 16.6 mg (0.25 mg/kg in Grob et al., Unpublished) to 204 mg (2.5 mg/kg, Grob et al. Unpublished).

The second review of the literature covered the period after August 2001 to early 2003, and was completed in January, 2003 (Jerome and Baggott 2003). Unlike the initial review, the second yearly review only covered clinical trials, studies in Ecstasy users, and studies of neurotoxicity and toxicity in vitro and in non-human animals. It did not review studies of Ecstasy user demographics or case reports of adverse events. Clinical trials published in this period included investigations using doses that ranged from approximately 35 mg (0.5 mg/kg, Harris et al. 2002) to 171 mg (2 mg/kg, on average approximately 145 mg, Tancer et al. 2003, in press at the time of completion). Conclusions concerning the safety of clinical trials with MDMA remained the same, with two exceptions. When the second review was completed, it was apparent that the association between Ecstasy use and impaired psychological well-being, (such as increased dysphoria, psychological complaints, aggressiveness), while still present, might be due at least in part to factors other than Ecstasy use. Possible causes of the association included pre-existing conditions (Lieb et al. 2002) and polysubstance abuse itself (Daumann et al. 2001). Second of all, a study reporting dopamine toxicity in non-human primates raised concerns that MDMA might possess dopamine toxicity (Ricaurte et al. 2002). The 2002 update to the IB concluded that the methodological flaws in the study finding dopamine toxicity, along with the absence of any detectable dopamine toxicity in Ecstasy users (see Mithoefer et al. 2003), led us to conclude that the risk of dopamine toxicity from MDMA in humans was minimal. Human trials of MDMA published in this period continued to be free of serious adverse events, and MDMA was well-tolerated by volunteers in these studies. After examining research appearing in 2002, we concluded that MDMA still possessed some risks to human participants in clinical trials, but that these risks were minimal.

The third review of the MDMA literature is identical to the review written in 2002 in its inclusion of clinical trials of MDMA, studies in Ecstasy users, and toxicity studies in non-human animals. New avenues of research and novel findings include a study of the subjective, physiological and neuroendocrine effects of an initial dose of MDMA followed a day later by a second dose of MDMA, studies that found former Ecstasy users had lower scores on some measures of memory than current Ecstasy users, polysubstance using or cannabis-using controls, the retraction of the study claiming to have found dopamine toxicity in non-human primates, and a report on the effects of 18 months of MDMA self-administration in rhesus monkeys. Studies published in 2003 and 2004 cast further doubt on the link between Ecstasy use and decline in psychological well-being, with a number of studies either failing to find the association or finding an equally strong or stronger association between decline in psychological well-being and other factors, such as polydrug or cannabis use. Researchers continue to find that Ecstasy users have subtle but detectable impairments in memory and cognitive function, with recent studies finding effects on visual working memory as well as verbal memory. However, recent studies also raise issues about the nature of this link between Ecstasy use and deficits in cognitive function. There is no longer any evidence for dopamine toxicity after MDMA in any species outside the mouse. The original research and a quantitative review published in 2003 have not caused us to re-evaluate our original assessment of risk to human participants in clinical trials of MDMA. There are still some potential risks involved in clinical trials of MDMA, and they are still minimal. As noted in previous documents, reliance on studies in people who repeatedly used Ecstasy has produced a cautious assessment of risk, given that Ecstasy users represent people who have taken MDMA (and other drugs) frequently and repeatedly in sub-optimal conditions, such as warm, crowded dance clubs.

During the past year and a quarter, researchers in the Netherlands, Spain and the US reported findings from clinical trials of MDMA in humans, and a team of researchers in Switzerland presented findings of their investigations into the long-term effects of 1.5 to 1.7 mg MDMA in MDMA-naïve humans. Researchers assessed the effects of doses ranging from 1 mg/kg (52.3 mg in one subject in Tancer and Johanson 2003) to 2 mg/kg (171 mg in another subject in Tancer and Johanson 2003), with most studies administering doses ranging from 100 to approximately 120 mg. New findings include assessments of the subjective, physiological and pharmacological effects of two repeated doses of MDMA (Farre et al. 2004), at a cumulative dose of 200 mg (or 100 mg per day), evidence for serotonin release in the immunological effects of MDMA (Pacifici et al. 2004), and evidence that skills involved in driving motor vehicles are impaired acutely after MDMA (Lamers et al. 2003). No serious adverse events were reported during these clinical trials, and MDMA was well tolerated in all studies. None of the research teams reported the occurrence of any serious adverse events. It also appears that a second, and equal, dose of MDMA given a day after an initial dose is well-tolerated by human participants and did not provoke any adverse events.

The long-term effects of administering more than one dose of MDMA per session have not yet been studied in humans. It is possible that some long-term effects require a threshold dose, and that risks increase by some degree with increasing dose. However, it should also be noted that even some Ecstasy users who reported taking doses similar to or greater than 187 mg did not exhibit detectable signs of reduced cognitive function when former Ecstasy users reporting similar dosing patterns did show some impairments (Curran et al. 2003; Thomasius et al. 2003).

Studies in Ecstasy users continued to investigate psychological well-being, cognitive function, brain structure and function, and other domains thought to be associated with the serotonin system or relating to previously detected differences in Ecstasy users. Researchers in Australia, Germany, Italy, the Netherlands, Spain, the UK and the US examined various samples of mostly young people reporting Ecstasy use, comparing them with one or more groups of controls who reported no Ecstasy use. Recent studies continued to find an association between repeated Ecstasy use and reduced psychological well-being. However, continuing the trend seen in 2002, a large number of studies also reported findings that suggest that polydrug use, cannabis use, or pre-existing conditions associated with drug use may explain at least part and perhaps most of the decline in psychological well-being in Ecstasy users. In contrast, researchers continued to find that Ecstasy users had impairments in memory, executive function (planning and decision making), and information processing. It appears that one or more parameters of Ecstasy use, such as lifetime consumption and average dose per use, may be related to some of these impairments. However, an examination of the findings also suggests that cognitive function in Ecstasy users may be influenced by factors other than those related to Ecstasy use. One new development in studies of cognitive function in Ecstasy users is a pair of reports that detected impaired cognitive function in former Ecstasy users, but not in current users (Curran et al. 2003; Thomasius et al. 2003). These findings are open to a number of interpretations, but do not support simple claims of permanent long-term effects appearing in all users, or of transient effects that dissipate with abstinence. Another new development is findings of impaired visual working memory in Ecstasy users, even without any decline in verbal working memory. As well, several studies have only detected impaired cognition in people reporting Ecstasy use above a specific level (usually lifetime consumption equal to or greater than 50 to 80 occasions or tablets). The only data presented on the long-term effects of MDMA after human clinical trials failed to detect any differences in markers of serotonin function or in cognitive function. One recent report (Buchert et al. 2003) may indicate that earlier studies of serotonin function in Ecstasy users (McCann et al. 1998) overestimated degree of reduced serotonin transporter sites, and that these reductions in serotonin transporter sites disappear with abstinence from MDMA. After considering recent study findings, it appears that human volunteers in clinical trials face very little risk of decline in psychological well-being afterwards, while the original estimates of minimal risk to serotonin or cognitive function remain much the same.

A large number of in vitro and non-human animal studies published in 2003 further investigated MDMA neurotoxicity, its mechanisms, and ways to reduce it. This included the one report in rats of damage to serotonin neurons (Schmued et al. 2003), with the damage associated with a combination of hyperthermia and high dose (20 or 40 mg/kg). In contrast, a study in mice did not detect cell death in substantia nigra or striatum (mice are subject to dopamine toxicity after MDMA), though it did find signs of oxidative stress (Fornai et al. 2004). Other studies examined various treatments that attenuated or eliminated brain serotonin reduction in rats or dopamine reduction in mice; these included lower ambient temperature, stress, and THC, the active ingredient in cannabis.

A number of new developments in this research area also appeared during this period. Several papers raise questions about the relevance and generalizability of neurotoxicity studies in nonhuman animals. Research finding that blood S-(+)-MDMA in monkeys given 10 mg/kg of this enantiomer (form) of the drug was ten times higher than MDMA levels in humans given typical active doses (Bowyer et al. 2003) casts doubt on the accuracy of interspecies scaling as a means of calculating dose equivalents across species. A study of self-administered MDMA in monkeys found no signs of damage to axons, non-significant reductions in serotonin, and no reductions in dopamine after 18 months of self-administration, though monkeys seemed to lose interest in self- administering MDMA over time. However, most significant among new developments was the retraction of the report finding dopamine toxicity after repeated MDMA administration in non-human primates. The findings were retracted after the authors discovered that all but one animal in this study had received methamphetamine, not MDMA, and that subsequent attempts to replicate this study failed to find dopamine toxicity. Dopamine toxicity was not detected even after giving monkeys up to cumulative doses of 25.8 mg/kg intragastric and 12 mg/kg injected in a six hour period (Ricaurte 2004). In vitro and non-human animal studies in 2003 are likely to keep alive controversies over MDMA neurotoxicity. None of the findings alter original estimations of risk in humans given fully active doses of MDMA in "room temperature" (normothermic) settings.

Other areas of MDMA toxicity in non-human animals included studies of effects on liver and heart valve cells and a number of investigations of the mechanisms and effects of MDMA-induced hyperthermia. Among these findings is the publication of data previously only supplied to institutional review boards indicating that MDMA, like fenfluramine, is an agonist at the newly discovered 5HT2B cell and triggers growth in heart valve cells (Setola et al. 2003). However, its actions at 5HT2B receptors and on heart valve cells are far weaker than those of fenfluramine or fenfluramine metabolites, and these effects are unlikely to be significant when MDMA is administered intermittently rather than on a chronic basis. To date, there are still no reported cases of heart valve disease in Ecstasy users. Research into the mechanisms of MDMA- associated hyperthermia suggest that non-shivering heat, associated in part with action of uncoupling proteins, may be involved in raising body temperature after MDMA (Sprague et al. 2003; Mills et al. 2003). Since high doses were used in these studies (40 to 50 mg/kg), it is unclear whether non-shivering heat is involved at lower doses or has relevance either for hyperthermia in Ecstasy users or in slight increases in body temperature sometimes seen in clinical trials of MDMA.

Neither the previous nor the current review of the literature includes an examination of adverse events in Ecstasy users. However, a survey of case reports published in 2002 and 2003 have only located two new conditions appearing in Ecstasy users, a case of gingivitis in an adolescent who stored an Ecstasy tablet between his upper lip and gum (Brazier et al. 2003), and serous chorioretinopathy, a transient eye condition associated with use of sympathomimetic drugs, including Ecstasy (Michael 2003), with the condition resolving after discontinuation of use. All other case reports described adverse events already known to be associated with Ecstasy use, and include hyperthermia (Ben- Abraham et al. 2003; Greene et al. 2003; Finsterer et al. 2003) cerebrovascular (Auer et al. 2002; Yin et al. 2003) and cardiac (Lai et al. 2003; Madhok et al. 2003) events, hyponatremia (Cabellero et al. 2002; Kwon et al. 2003, Sue et al. 2003; Traub et al. 2002) liver problems (Cabellero et al. 2002), and urinary retention (Delgado et al. 2004; Inman et al. 2003). There was one case of pneumomediastinum (a pulmonary condition that might also be associated with inhaled drugs, such as cannabis) (Badaoui et al. 2002), a case of kidney problems that may have been associated with hyponatremia (Kwon et al. 2003), a vehicular accident (Weinbroum et al. 2003), and catatonia (Masi et al. 2002). One report described a series of deaths after coadministration of Ecstasy with the MAOI inhibitor moclobemide in (Vuori et al. 2003). A case series of seven adverse events occurring at the same nightclub on the same evening found that severe adverse events (specifically hyperthermia) were dose dependent (Greene et al. 2003). Case reports cannot be used as a gauge of frequency of occurrence in the general population of Ecstasy users, since it is likely that unusual or serious events are more likely to be reported, but examining case reports can provide information on the possibility of events that might occur. Some of these events may be partially setting-dependent. For instance, the combination of sweating from strenuous exercise without replacing electrolytes and the injunction to drink plenty of water may increase the likelihood of hyponatremia in Ecstasy users. In addition, these events are relatively rare (Baggott 2002; Henry and Rella 2001; Gore 1999), probably affecting a fraction of 1% of the Ecstasy using population. To date, none of these serious adverse events have occurred in trials with MDMA. Carefully screening prospective participants for contraindicating conditions, providing electrolyte-containing beverages, and monitoring cardiovascular function and body temperature during MDMA administration should further reduce the likelihood of these events occurring within the context of a controlled trial.

Two cases of Parkinson's disease or parkinsonism were reported in former Ecstasy users (Kuniyoshi and Jankovic 2003; O'Suilleabhain and Giller 2003). However, an editorial commenting on these cases (Kish 2003) noted that there is no evidence of dopamine toxicity after Ecstasy use in humans or any other species besides mice. In one case, there was a family history of early-onset Parkinson's disease (Kuniyoshi and Jankovic 2003), and in another (O'Suilleabhain and Giller 2003), the case was insensitive to L-DOPA treatment. Given these criticisms, and the lack of dopamine toxicity detected in Ecstasy users and in a post-mortem study of the brain of an Ecstasy user (Kish et al. 2000; Reneman et al. 2002A; Semple et al. 1999), it seems very unlikely that a direct link exists between repeated Ecstasy use and movement disorders (Jerome et al. 2004; Kish et al. 2003; Sumnall et al. 2004).

Concluding Remarks

While there is still a great deal about MDMA and its effects that remain poorly understood, knowledge concerning the pharmacology and effects of MDMA has grown over the last five years and continues to grow. With a few exceptions, most findings reported in 2003 confirm or elaborate on previously reported research findings. It still seems that MDMA shares some effects with stimulants and other effects with hallucinogens acting on 5HT2A receptors in humans, but there continues to be evidence hinting at a unique profile of subjective effects that have led some to place it in a novel drug class, the "entactogens." An additional dose of 100 mg MDMA given 24 hours after an initial dose of 100 mg produced even greater changes in some subjective and physiological effects, yet the increase in strength was less than what was estimated on the basis of participants' plasma MDMA levels, suggesting some tolerance to specific MDMA effects. Acute immunological changes are associated with serotonin release. Ecstasy users continue to be impaired in specific areas of cognitive function, with lifetime Ecstasy consumption and abstinence from use, or effects related to these drug use parameters, may both influence effects on cognitive function. Specifically, heavy Ecstasy users (people reporting a lifetime consumption of 50 or more tablets, or on 50 or more occasions) were more likely to exhibit these impairments than moderate users (those with a lifetime consumption of fewer than 50 occasions or tablets), and former users were more likely to exhibit impairments than current users. Though one research team detected harm to serotonin neurons in rats, most studies continue to find lower levels of serotonin or signs of harm to axons only. Concerns about detrimental effects to dopamine cells turned out to be unfounded. Studies continue to suggest some developmental toxicity, though it must be noted that these studies employ high and repeated doses of MDMA. None of the studies reported so far suggest that clinical trials of MDMA present a high risk to human participants screened for contraindicating conditions and monitored for adverse events after drug administration.

Note

Abstracts of papers reviewed in this document can be located on PubMed or through MAPS' bibliography of the MDMA literature where copies of many papers may be viewed.