Seven studies in humans and four studies conducted in vitro or in non-human animals were found in this time period. Studies in humans include one clinical trial, one study of ecstasy users, one study of ecstasy user demographics, one review, and three analyses of adverse events and deaths after ecstasy. In vitro and non-human found in this time period include one behavioral pharmacology study and three studies of MDMA neurotoxicity.

Subjective and Neuroendocrine Effects

The subjective, neuroendocrine and physiological effects of two different doses of MDMA were investigated in volunteers who reported experience with ecstasy (Harris et al. 2002). 1.5 mg/kg MDMA increased all scores on a measure previously used to distinguish the subjective effects of amphetamine from those of LSD, including effects that would seem to oppose each other, such as "Tension" and "Relaxation." 0.5 mg/kg MDMA produced far fewer alterations in mood or consciousness, but did elevate positive mood, tension and relaxation. Both 0.5 and 1.5 mg/kg MDMA were associated with cortisol release, though cortisol release was greater after 1.5 mg/kg MDMA, and 1.5 mg/kg MDMA was associated with release of dehydroxiepiandrosterone (DHEA) and prolactin. Cortisol and DHEA levels were associated with increased euphoria, whereas prolactin was associated with lower levels of giddy excitement. These findings suggest that MDMA is a member of a novel drug class different from stimulants or hallucinogens, and that neuroendocrine response to MDMA may play a role in producing or modulating the subjective effects of MDMA.

Plasma Monoamines

A study comparing plasma monoamine levels across three groups of ecstasy users (light, medium and heavy), abstinent users and polydrug users who reported no ecstasy use found that values for norepinephrine (NE), epinephrine, and dopamine were higher in "heavy" ecstasy users, considered an indicator of increased sympathetic tone (Stuerenberg et al. 2002). Only plasma epinephrine values were still higher in abstinent ecstasy users than in polydrug users, and values of serotonin (5-HT) and its metabolite 5-HIAA were not significantly different across groups. These findings suggest that regular ecstasy use increased sympathetic tone, a finding consonant with a cardiovascular study performed by Brody and colleagues (Brody et al. 1998), but the results fail to support decreased serotonergic activity after regular ecstasy use.

Demographics

The demographics of ecstasy use reported in young men entering required military service in northern Spain found approximately 10% had used ecstasy, and that most ecstasy users were polydrug users (Bobes et al. 2002).

Hyponatremia

Two reports addressing the issue of hyponatremia (low blood sodium, water intoxication) associated with ecstasy use. One paper approaches the issue through an examination of a case series (Hartung 2002), finding that hyponatremia followed a common course of symptoms, including strange behavior and seizures, and that most people covered afterwards. Another paper presented a hypothetical model of hyponatremia after ecstasy use through the device of a fictitious consultation with a physician known to have conducted research on water and salt retention in the 1930s (Cheney et al. 2002). Ecstasy0induced changes in the GI tract and sequestering of salt in intestinal tissues play a role in this model.

Ecstasy Deaths

An analysis of MDMA-related fatalities in New York City between 1997 and 2000 found that while ecstasy-related deaths had increased over time, they are still rare (Gill et al. 2002). Deaths frequently involved the combination of MDMA with other drugs, such as opiates or ethanol. Acute intoxication was the most commonly listed cause of death, followed by mechanical injury (accidents, reckless behavior, homicide).

Self Administration in Monkeys

A study found that rhesus monkeys trained to self-administer cocaine also self-administered both R-(-)-MDMA and S-(+)-MDMA, as well as racemic MDMA (contains both forms) when these were substituted for cocaine (Fantegrossi et al. 2002). 5-HT2A receptors may be partially involved in the rewarding properties of MDMA, since administering 5-HT2A antagonists either increased the dosage of MDMA needed to maintain self-administration (for S-(+)-MDMA) or eliminated responding for drug (for R-(-)-MDMA).

Neurotoxicity in Rats and Mice

A study in rats found that animals given a demonstrably neurotoxic dose of MDMA exhibited increased anxiety afterwards on a number of measures, including elevated plus maze and social interaction with an unfamiliar rat (Gurtman et al. 2002). While these findings are in agreement with other studies conducted by the same team (e.g. Morley 2002), other studies have found decreased anxiety after MDMA (Mechan et al. 2002.) However, the relationship between ecstasy use and anxiety in humans is complex, with increased anxiety in ecstasy users better explained through polydrug use than by ecstasy use. A study in rats (O'Shea et al. 2002) failed to find any evidence of increased neurotoxicity from conjugates of glutathione (antioxidant produced by the body) and MDMA or its metabolites. Instead, glutathione depletion tended to exacerbate neurotoxicity, and the apparent neuroprotection offered by one glutathione-depleting drug was instead linked to its capacity to reduce hyperthermia. The role played by dopamine release and uptake in MDMA neurotoxicity in mice was investigated via a series of studies using the dopamine uptake inhibitor GBR 12909 (Camerero et al. 2002). Research findings suggest that MDMA does not compete for the dopamine transporter, and that neuroprotective effects of the dopamine uptake inhibitor may be related to its moderate antioxidant properties. Hence while neurotoxic doses of MDMA effect rats and mice differently, oxidative stress may play a significant role in both cases.