Introduction
MDMA has been administered to over 240 people in Phase 1 clinical trials conducted throughout the world (see Baggott et al. 2001; Jerome and Baggott 2002; Jerome 2004 for detailed reviews). Clinical trials examined the subjective, physiological, neuroendocrine and immunological effects of MDMA (for example Cami et al. 2000; Forsling et al. 2001; Grob et al. 1996; Harris et al. 2002; Lamers et al. 2003; Lester et al. 2000; Liechti et al. 2001; Mas et al. 1999; Pacifici et al. 2004; Tancer and Johanson 2003), and at least two teams of researchers have examined MDMA metabolism (see for example de la Torre et al. 2000; Farre et al. 2004; Samyn et al. 2002). As of January, 2005, seven research teams have performed clinical trials of MDMA in humans. This includes researchers in the Netherlands (e.g. Lamers et al. 2003), Spain (e.g. Farre et al. 2004; Pacifici et al. 2004), Switzerland (e.g. Gamma et al. 2000; Liechti et al. 2001), the United Kingdom (e.g. Forsling et al. 2001) and the United States (e.g. Grob et al. 1996; Harris et al. 2002; Tancer and Johanson 2003). MDMA was well-tolerated in all studies, with no occurrence of serious adverse events during these studies.

Five research participants have completed a randomized, double-blind, placebo- controlled trial of 125 mg MDMA administered in each of two drug-assisted psychotherapy sessions in people with posttraumatic stress disorder (PTSD), and a seventh participant has undergone the first of two experimental sessions (Mithoefer 2005, personal communication) without any occurrences of serious adverse events. Previous to the start of this study, a team of researchers in Spain began performing a dose-response study of MDMA in women with PTSD arising from sexual assault. The study was halted by a local drug law administration (the Madrid Anti-Drug Authority), apparently for political reasons.

A randomized, dose-response study of MDMA in people with anxiety arising from diagnosis with advanced stage cancer and a life expectancy of less than 12 months received approval from both relevant IRBs, and the FDA also granted permission for the study. Screening and enrollment of participants will begin once the principal investigator receives a Schedule 1 handling license from the DEA.

Clinical trials have been conducted with doses of MDMA ranging from 0.25 mg/kg, or about 17.5 mg (Grob et al. Unpublished) to 2.5 mg/kg, or about 175 mg (Grob et al. Unpublished), with the most frequently used doses ranging from 75 to 145 mg. More detailed discussion of study findings can be found in the IB and updates of the IB (Baggott et al. 2001; Jerome and Baggott 2003; Jerome 2004). As noted in the IB and in previous updates to the IB, these studies have produced a consistent physiological and psychological profile of MDMA. In controlled settings, MDMA elevates blood pressure and heart rate and produces a slight increase in body temperature. Participants in controlled studies of MDMA reported experiencing stimulant-like and hallucinogen-like effects, but their reports on other self-reported effects indicated that MDMA possesses a unique pharmacological profile distinct from that of the stimulants or hallucinogens (Liechti et al. 2001). Informal reports of subjective effects and responses to specific items on some measures (see Vollenweider et al. 1998; Tancer and Johanson 2003; Tancer and Johanson 2001) have detected the increases in sociability, closeness to others and empathy referred to in anecdotal reports, retrospective studies and uncontrolled trials (see discussion in Baggott et al. 2001). However, an attempt at formal measurement of these effects failed to detect them (Harris et al. 2002). As discussed in the IB and previous updates to the IB, MDMA elevated stress hormones and increased levels of the anti- diuretic hormone arginine vasopressin (Baggott et al. 2001; Jerome and Baggott 2003; Jerome 2004). Researchers in Spain have found that MDMA produces transient immunological changes. These changes include decreased numbers of CD4 cells, increased numbers of NK cells, increased levels of immunosuppressant and anti- inflammatory cytokines, and decreased levels of immunostimulating and pro- inflammatory cytokines (see Pacifici et al. 2004; Pacifici et al. 2002).

As of January 2005, there have been two published clinical trials of MDMA (Gamma et al. 2004; Pizarro et al. 2004), and one conference presentation of data from a clinical trial (Tancer and Johanson 2004). One paper compared positron emission imaging data with electroencephalographic data simultaneously recorded in a largely drug-naïve sample that received 1.7 mg/kg MDMA (Gamma et al. 2004), and the other examined MDMA pharmacokinetics in a sample of men who had reported previous experience with ecstasy (Pizarro et al. 2004). The conference presentation examined the effects of daily fluoxetine (Prozac) administration on the subjective effects of MDMA (Tancer and Johanson 2004).

Gamma et al. 2004
Gamma and colleagues compared data from [H2 15 0]-PET imaging with simultaneously recorded data from low resolution brain electromagnetic tomography (LORETA), with recordings made after placebo and after 1.7 mg/kg (approximately 119 mg) MDMA in a sample of six women and ten men (Gamma et al. 2004). This research report is based on data that has already appeared in previous reports (Frei et al. 2001; Gamma et al. 2000), where the researchers presented information on subjective and physiological effects of MDMA in this sample. MDMA was tolerated by this largely drug-naïve sample, and no serious adverse events occurred.

In this study, the researchers measured brain activity while participants performed the Continuous Performance Task, which required them to respond upon the appearance of a specific pair of letters, and during a control task, which required viewing non-target characters only. Simultaneous measurements occurred during two one-minute PET scans, with epochs of EEG lasting from about 30 seconds to one minute. Correlations between raw PET and EEG made during the control task detected positive correlations between beta band activity and increased cerebral blood flow (CBF) in temporal and frontal cortices after placebo, and positive correlations between Beta2 band activity and CBF in the occipital and parietal cortices after MDMA. When MDMA and placebo PET scans were compared across control task and Continuous Performance Task, Gamma and colleagues found that MDMA was associated with global decreases in CBF during both tasks. However, cross-drug comparisons of EEG data found more limited decreases (for instance, decreased alpha and theta bands). The researchers found no significant correlations between raw PET and EEG taken during cognitive task performance, whether performed after placebo or MDMA. More generally, the researchers failed to find significant relationships between changes CBF seen in the PET scans and changes in EEG activity, even when length of EEG unit recordings were increased to make them more similar to PET imaging. This report might help neuroscientists to arrive at an understanding of the relationship between EEG and imaging data, and the limitations of such comparisons. As expected, the researchers detected positive correlations between beta activity and CBF, assumed to be an indirect measure of excitatory activity. In contrast, the researchers were surprised when they detected a positive relationship between delta activity and increased CBF, since delta activity is assumed to be an indicator of inhibitory activity. Gamma and colleagues offer several explanations for this finding. They note that previous investigations of EEG and PET occurred in patient populations, whereas this study examined a non-patient sample. They also consider the possibility that inhibitory activity might be associated with increased CBF.

Pizarro et al. 2004
Pizarro and colleagues gave 100 mg MDMA to seven men reporting past experience with ecstasy. In this report, the researchers described findings on MDMA pharmacokinetics in blood and urine, and did not provide information on subjective, physiological or neuroendocrine effects of MDMA. Pizarro and colleagues successfully detected both R-(-) and S-(+) enantiomers of MDMA and the MDMA metabolites HMMA and HHMA (DHMA) in blood and urine over a two-day period. No serious adverse events occurred during this study. The researchers reported novel findings concerning enantioselective metabolism of MDMA, but none of these findings alter the current estimated risks or benefits in participating in a human trial of MDMA.

In agreement with earlier reports by the same team (e.g. de la Torre et al. 2000; Lanz et al. 1997; Pizarro et al. 2002), Pizarro and colleagues reported that in humans, HMMA was a major MDMA metabolite, and MDA a minor metabolite. Pizarro and colleagues reported the half-life of MDMA to be 11 hours, a somewhat higher figure than the 7 to 9 hour half-life reported in earlier studies (de la Torre et al. 2000; Mas et al. 1999). The R- (-) enantiomer of HMMA had a half-life of 42 hours. It is unclear what significance these pharmacokinetic findings have in terms of understanding the subjective, physiological or neuroendocrine effects of MDMA, especially given the small sample size and gender restrictions of this sample.

Study findings are similar to previous reports of enantioselective metabolism (preferential metabolism of one enantiomer) of MDMA, with S-(+)-MDMA metabolized more rapidly than R-(-)-MDMA. This study also reported that HMMA was not enantioselectively metabolized, a finding that is also in agreement with earlier reports by the same research team (Pizarro et al. 2003). Metabolism of the metabolite HHMA, described here for the first time, was enantioselective, with R-(-)-HHMA metabolized more rapidly than S-(+)- HHMA, but the ratio is less enantioselective than predicted. The authors hypothesize that this difference in degree of enantioselective metabolism is an indicator that MDMA inhibits function of the enzyme CYP2D6. These results support conclusions voiced in a recent commentary and review by one member of the same research team that genetic variation in human CYP2D6 function has little relevance in explaining variance in response to MDMA (de la Torre and Farre 2004). De la Torre and Farre note that larger doses of MDMA inhibit CYP2D6 in people with intact enzyme, rendering them similar to those with reduced CYP2D6 activity levels.

In addition to the two clinical trials described above, a review written by one of the leading experts in human MDMA pharmacology and pharmacokinetics expressed skepticism and caution in relation to generalizing findings from neurotoxicity studies in non-human animals to humans (De la Torre and Farre 2004). In this review, de la Torre concluded that non-linear pharmacokinetics make it difficult to rely on interspecies scaling to arrive at human-equivalent doses on the basis of studies in non-human animals, and that many non-human animal studies use doses of MDMA that are far greater than commonly used doses in humans. In this and another review, De la Torre also presents evidence indicating that MDMA is a potent inhibitor of the metabolic enzyme CYP2D6 (De la Torre and Farre 2004; De la Torre et al. 2004). Previously, some researchers had argued that genetic variation in CYP2D6 function could pose a risk for people taking MDMA (See for example Schifano et al. 2003; Tucker et al. 1994). However, if most active doses of MDMA inhibit CYP2D6 function, then variations in enzyme function may be less significant than previously imagined. In vitro studies support this conclusion (Heydari et al. 2004; Wu et al. 1997), and researchers failed to detect a relationship between one or more dysfunctional CYP2D6 gene and fatality (O'Donohoe et al. 1998; Gilhooly and Daly 2002).

Tancer and Johanson 2004
Tancer and Johanson presented data on the effects of fluoxetine pretreatment on the subjective effects of MDMA in eight ecstasy-user volunteers at the 2004 College on Problems of Drug Dependence (CPDD) conference. The study employed a crossover design, wherein people received placebo for a week, followed by two weeks of fluoxetine. MDMA and two other test drugs were administered first during placebo administration and then during fluoxetine administration, with fluoxetine administered one hour prior to test drug administration. MDMA (1.5 mg/kg, or about 105 mg) was compared with the stimulant d-amphetamine (10 mg) and the serotonin releaser and 5HT2C antagonist m-chlorophenylpiperazine (mCPP) (0.5 mg/kg, or about 35 mg). Participants completed the Profile of Mood States (POMS), a measure of state mood, researcher-created visual analog scales, the Hallucinogen Rating Scale (HRS) and the Addiction Research Center Inventory (ARCI), another measure of alterations in consciousness, every hour after drug administration. Fluoxetine pre-treatment attenuated most of the scale scores elevated after MDMA (specifics not supplied in abstract), while having little effect on scales increased by amphetamine. Fluoxetine reduced some of the scale scores elevated by mCPP, such as Arousal, Elation and Vigor, but increased scores on other scales, such as Bad Drug Effects and HRS Cognition and Somasthesia (bodily sensations, physical effects). Data on the impact of fluoxetine pre-treatment on the physiological effects of MDMA were not reported in this poster. No information is presented on side effects or occurrence of serious adverse events during this study, but it seems likely that none occurred.

These findings are in agreement with earlier studies of interactions between MDMA and selective serotonin uptake inhibitors, or SSRIs (Liechti et al. 2000; Liechti and Vollenweider 2000; Pacifici et al. 2004). Previous reports employed citalopram (Celexa) (Liechti et al. 2000; Liechti and Vollenweider 2000) and paroxetine (Paxil) (Pacifici et al. 20004). Liechti and colleagues found that citalopram pre-treatment attenuated or eliminated most of the subjective effects of MDMA, including positive mood, anxiety over loss of control, perceptual alterations, elevated blood pressure, and heart rate. The only effect that citalopram did not attenuate or reduce was the slight elevation in body temperature seen after MDMA. Pacifici and colleagues found that paroxetine pretreatment attenuated or nearly eliminated the immunological effects of MDMA. Taken together, all three research studies suggest that serotonin release plays a significant role in producing the acute pharmacological effects of MDMA, including subjective effects. However, it is also possible that these drugs attenuate the effects of MDMA by interfering with drug metabolism rather than by preventing MDMA from releasing serotonin. These studies also suggest that SSRIs can be safely co-administered along with MDMA, but that doing so reduces most of MDMA's acute pharmacological effects.

Bateman et al. 2004 - Case Series
Human reproductive toxicity of MDMA and other drugs was assessed in a case-control study of 296 women in two cities in the North of England (Bateman et al. 2004). Some of these researchers had previously reported a possible link between ecstasy use and birth defects (McElhattan et al. 1999). In the current study, the researchers matched women who had given birth to children with ventricular septal defect, a specific heart defect, with women who gave birth to healthy infants. Bateman and colleagues reported that exposure to ecstasy was too low in these samples to establish risk, with only three people reporting ecstasy use, and all reported ecstasy use occurring before pregnancy. However, the authors detected a link between using cold or cough remedies containing sympathomimetic drugs or non-steroidal anti-inflammatory medications (NSAIDs) and increased risk of ventricular septal defect. Since MDMA is also sympathomimetic, it is possible that MDMA poses such a risk as well, but the authors also suggest that viral infections might pose a risk as well, since cold and cough remedies are usually taken in response to a viral infection. Exposure to ecstasy was lower in this sample than the authors had expected, possibly because the mean age in this sample was older than 25, and also possibly because women restricted their substance use after learning they were pregnant.