During June 2003, two studies in Ecstasy users, two studies of Ecstasy user demographics, one case report, one review, seven in-vitro or non-human animal studies and one forensic/chemistry study (not summarized) were located.

Former Ecstasy users, but not current users, had higher plasma tryptophan levels after consuming an amino acid drink containing tryptophan (tryptophan augmentation) than gender-matched non-Ecstasy using controls (Curran et al. 2003) in a study in men. (No groups differed on baseline plasma tryptophan levels). Former Ecstasy users had lower prose recall scores after consuming a tryptophan-free drink (tryptophan depletion), and improved prose recall scores after tryptophan augmentation. However, former Ecstasy users had lower scores at baseline on tests of verbal recall and attention that were not altered in any group by altering tryptophan levels. Tryptophan manipulation failed to alter mood in any of the participants. This is the second of two studies finding reduced cognitive function in former, but not current, Ecstasy users (see also Thomasius et al. 2003), and the first to alter tryptophan levels as a means of indirectly altering brain serotonin. Possible explanations for study findings include long-term effects of regular Ecstasy use, short or long-term effects of other drugs, and pre-existing factors associated with abstention from Ecstasy and reduced verbal recall.

The second of two reports measuring signs of oxidative stress in a large group of Chinese Ecstasy users (Zhou et al. 2003B) found lower levels of erythrocyte acetylcholinesterase (enzyme that breaks down acetylcholine) in Ecstasy users, and lower acetylcholinesterase levels were associated with more lipid peroxidation, a sign of oxidative stress. Ecstasy users also had lower levels of antioxidant enzymes, and higher levels of peroxidation. However, as was true of the first report (Zhou et al. 2003A), key information on subject recruitment and drug use parameters is lacking, making it hard to tell whether signs of oxidative stress appear only immediately after Ecstasy use or whether they remain after a period of abstinence.

One study found that Ecstasy-using undergraduates were more likely to report using other substances than non-using students, were more likely to belong to a fraternity or sorority and were more likely to be White (Yacoubian et al. 2003). Another survey found that undergraduates who self-identified as gay, lesbian or bisexual were more likely to report using Ecstasy than heterosexual undergraduates (McCabe et al. 2003).

A case of hyponatremia with evidence of kidney injury was reported in an 18-year old woman after use of an unspecified amount of Ecstasy (Kwon et al. 2003). The patient fully recovered after three days’ hospitalization.

Meta-analytic procedures were performed on selected studies of long-term verbal memory, short term verbal memory, attention and attention performance in Ecstasy users and non-Ecstasy using controls (Verbaten et al. 2003). Analyses found that Ecstasy use explained reductions in long-term memory, but that cannabis use explained reductions in short-term memory. In examining drug use data, the author acknowledges that differences in use of other drugs, such as amphetamines, might also affect verbal recall. A systematic bias for publishing findings of impaired recall in Ecstasy users may invalidate or weaken these findings, since such a bias violates assumptions of meta-analyses.

A study assessing plasma levels of injected S-(+)-MDMA (and its metabolite S-(+)-MDA) in rhesus monkeys (Bowyer et al. 2003 ) after the first and next to last dose in a neurotoxic regimen of 10 mg/kg MDMA (twice daily for 4 days) reported that plasma MDMA levels assessed at first dose were ten times greater than levels in humans after typical doses used in laboratory and non-medical settings (40-125 mg). Monkeys with higher plasma MDMA were slower at learning tasks a week after S-(+)-MDMA regimen, though this difference disappeared a month after S-(+)-MDMA. Yet six months post-S—(+)-MDMA, all subjects showed similar reductions in brain serotonin. These findings suggest that doses of MDMA used in studies of neurotoxicity in non-human primates are not equivalent to those used by humans in typical laboratory or non-medical settings.

Researchers found differences in how MDMA and the serotonin uptake inhibitor (SSRI) paroxetine altered neurotransmitter uptake in rat brain tissue (Bogen et al. 2003); both substances inhibited synaptosomal uptake, but MDMA inhibited vesicular uptake of serotonin and dopamine at lower doses than paroxetine. Vesicular serotonin uptake was still reduced 18, 42 and 66 h post-MDMA. The authors believe that vesicular uptake inhibition may be a marker for neurotoxicity. They also found that 3 doses of 15 mg/kg MDMA given every 2 hours reduced dopamine uptake immediately afterwards. However, findings of lower dopamine in primates after MDMA have since been retracted (Ricaurte et al. 2003), and it is unclear whether these findings are relevant for humans. Another study in rats used flouro-jade B staining to assess neuronal damage, finding that 20 and 40 mg/kg MDMA, but not 10 mg/kg, increased staining, a sign of neuronal degeneration, in specific brain areas (Schmued et al. 2003). However, these effects were closely linked with hyperthermia, with increasing body temperature associated with increased staining. This is also not the first report of potential neuronal degeneration (see Fornai et al. 2002).

An extensive receptor profile of MDMA found activity at the newly discovered 5HT2B receptor (Setola et al. 2003). Like other 5HT2B agonists, MDMA stimulates growth in human heart valve cells, suggesting that chronic, very frequent use of MDMA could increase risk of valvular heart disease (VHD). However, VHD remains a relatively rare complication even after daily use of other 5HT2B agonists, such as d-fenfluramine, and no cases of VHD after Ecstasy use have been reported so far. This paper also contains the first comprehensive receptor profile since 1988 (Battaglia et al. 1988).

Researchers found that rats self-administered MDMA (Schenk et al. 2003), and that they made more responses when doses administered were smaller. This is not the first report of MDMA-self-administration in rats (see Ratzenboeck et al. 2001), but response rates in this study were higher than previously reported. Rats that first learned to self-administer cocaine were more proficient at learning to self-administer MDMA, either because of pharmacological effects of cocaine, prior experience with self-administration, or a combination of the two. Another study in rats found that damaging a specific brain area (dentate gyrus) made rats more active, and that it enhanced MDMA-fueled increases in activity (Won et al. 2003), a sign that the dentate gyrus usually dampens these effects. Comparing markers of gene expression after MDMA administration in rats with and without damaged dentate gyrus indicates that MDMA does not uniquely activate the nucleus accumbens core, though it increased gene expression in several brain areas. Study findings suggest that variation in response to MDMA could involve individual differences in brain function that are not themselves directly affected by MDMA.