One study addressing ecstasy-related adverse events, one study of metabolic enzymes in ecstasy fatalities, seven in vitro and non-human animal studies, and one forensic study (not summarized, text not found) were located during this time period.

Ecstasy-Related Adverse Events

A health surveillance system enacted during the 2000 Olympic Games in Sydney, Australia detected a cluster of 3 grand-mal seizures occurring after ecstasy use at a dance event (Jorm et al. 2003). Though drug identification in blood or urine was either not performed or not collected, the authors hypothesize that the seizures resulted from ingesting fake or adulterated pills. Another study assessed P40 CYP2D6 genotype in tissue from 14 British ecstasy-related fatalities (cases with detectable levels of MDMA, MDA and/or MDE in tissues) did not find any poor metabolizers among the fatalities (Gilhooly et al. 2003). The study also failed to find a greater percentage of ecstasy-related fatalities with a single copy of a non-functional CYP2D6 gene than the percentage observed in a larger sample of British volunteers.

Case Report

A subarachnoid hemorrhage is reported in an 18-year old man who ingested one ecstasy tablet (Auer et al. 2003). The hemorrhage was treated surgically and the patient recovered, experiencing transient left-sided paralysis that lasted for four days.

R-(-)-MDMA and S-(+)-MDMA: Different Drugs

A study in mice compared the effects of R-(-)-MDMA, S-(+)-MDMA, and racemic MDMA (an equal combination of both) on lethality, hyperthermia and locomotion, with lethality examined in singly housed and group-housed mice (Fantegrossi et al. 2003). (Ecstasy tablets are assumed to contain the racemate, and to date, the racemate has been employed in all human trials with MDMA). Aggregate housing (6 or 12 mice per cage) increased lethality of all forms of MDMA, but R-(-)-MDMA was only half as lethal as S-(+)-MDMA or the racemate. Furthermore, response to various attempts to reduce hyperthermia and lethality, including administration of a selective serotonin uptake inhibitor (SSRI), serotonin 5HT2A receptor antagonists, or placement in a cold room, did not produce identical effects in R-(-)-MDMA, S-(+)-MDMA and racemate-treated mice. R-(-)-MDMA did not produce hyperthermia, even at lethal doses, and it produced only one tenth the locomotion seen after racemic or S-(+)-MDMA. The research also found that 5HT2A antagonists that reduced locomotion after racemic MDMA increased locomotion after S-(+)-MDMA. Taken together, these findings suggest that effects produced by the racemate arise out of synergistic actions of the two enantiomers, and do not reflect additive effects. Study findings also suggest that research employing only one enantiomer cannot be used to generalize findings to racemic MDMA, the form found in street ecstasy.

MDMA, Monoamines and Behavior in Rats

Research investigating the effects of MDMA on the noradrenergic (norepinephrine, NE) system in rats suggest that MDMA-induced norepinephrine and serotonin release act together to desensitize alpha2 adrenergic receptors (Arrue et al. 2003). In this study, NE neurons in the locus coeruleus (LC) fired at a lower rate 8 days after repeated, but not single, doses of 20 mg/kg MDMA. Rats given repeated doses of MDMA were also less responsive to the alpha2 agonist clonidine 18 h, but not 8 days, after MDMA. These findings suggest that changes in noradrenergic receptors might explain at least some sub-acute effects of MDMA reported one to 3 days post-drug in humans (e.g. Harris et al. 2002; Vollenweider et al. 1998). Another study in two different rat strains (Fischer 344 and Lewis rats) found that 10 mg/kg MDMA made Fischer rats more active than Lewis rats, even though the two rat strains did not release different amounts of dopamine in the nucleus accumbens (Fernandez et al. 2003). These findings suggest that, at least in rats, increased locomotion after MDMA is not strongly related to actions on the dopamine system. Such findings are consonant with research that has found a role for the 5-HT2A and 5HT2C receptors in MDMA-induced hyperactivity (Fletcher et al. 2002).

MDMA Neurotoxicity in Mice: Protection from the Norepinephrine System?

A study in mice found that MDMA produced greater reductions in striatal dopamine and more signs of ultrastructural whorls in striatal dopamine neurons in mice pre-treated with the noradrenergic neurotoxin DSP-4 than in controls (Ferrucci et al. 2003). Hence it is possible that the health or function of one neurotransmitter system may influence the impact of MDMA on another neurotransmitter system. However, not only does MDMA neurotoxicity affect mice differently than rats, but mechanisms of neurotoxicity in the two species of rodent may also differ (Colado et al 2001). Given these interspecies differences, and given that the effects of neurotoxic doses of MDMA in non-human primates are more similar to effects in rats than mice, the relevance of these findings to humans are uncertain.