This document will review and discuss research on or about methylenedioxymethamphetamine (MDMA) published between March 2004 and January 2005, and is a yearly update to the review first conducted in 2001 (Baggott et al. 2001). Two clinical trials (Pacifici et al. 2004; Farre et al. 2004) and a few studies in Ecstasy users (Halpern et al. 2004; McCardle et al. 2004) appearing subsequent to March 2004 appear in the previous update to the literature review (Jerome 2004). Except for these studies in humans, most research published after March 2004 but before or during January 2005 is addressed in this review.

The review is intended to reach an understanding of the current knowledge concerning the risks and benefits of MDMA. This means that the focus of the review is on human research, with a secondary focus on specific studies in non-human animals. This review considers all clinical trials of MDMA in humans, all studies of ecstasy users, with "ecstasy" referring to material represented as MDMA, and in vitro and non-human animal studies with findings that may be relevant to the risks and benefits of MDMA. This review will not cover studies examining the demographics of ecstasy users in a given region, drug discrimination studies in non-human animals, or other behavioral pharmacology studies. However, some of these studies may be referred to when their findings increase understanding of studies included within the review.

I located research reports through periodic searches of the PubMed database and through contacts with researchers. The review was performed with a cut-off date of January 2004, with exceptions made only for any clinical trial of MDMA or any study in ecstasy users reporting significant results. Research reports appearing after the cut-off date will be addressed in later reviews. Abstracts and full text reports of nearly all of the papers cited within this review can be found in MAPS' Psychedelic Bibliography.

To date, no studies in humans have altered our original assessment of the risks and benefits for participants in human trials of MDMA. Nearly all study findings reported in recent publications either replicate previously reported findings or are similar in nature to previously reported findings. Hence recent MDMA research does not raise any new questions or concerns about the safety of human trials with MDMA. If they continue to be replicated, some recent in vitro and non-human animal study findings may lead to revised interpretations of earlier research into MDMA neurotoxicity, but making such revisions now would be premature. Specifically, a number of research studies question the validity of markers of brain chemistry treated as indicative of neurotoxicity, and a few studies suggest that high doses of MDMA combined with hyperthermia may produce more extensive MDMA neurotoxicity. However, as noted, both of these recent developments occurred in studies in non-human animals, and do not necessarily affect interpretations of studies in humans.

Only two clinical trials of MDMA were published after March 2004, and one of these trials was a re-examination of data from earlier studies. However, no serious adverse events occurred during either study. An ongoing study of MDMA-assisted psychotherapy in people with posttraumatic stress disorder (PTSD) has also been underway since April, 2004, and MDMA has not produced any serious adverse events. Research investigating potential links between specific drugs and a specific birth defect failed to find a specific link between ecstasy and this heart defect. Though study findings detected a risk associated with sympathomimetic drugs, the researchers could not detect risks associated with specific drugs, including ecstasy. Hence this report does not increase or decrease estimated risk of reproductive toxicity from exposure to MDMA. However, women who are pregnant or lactating are excluded from all clinical trials of MDMA to date.

Studies in ecstasy users continue to examine the effects of repeated use on mood, psychological well-being, cognitive function, and brain function. Thirteen research studies in ecstasy users have been published since March 2004, and researchers made one research presentation. Study findings concerning long-term effects on mood and psychological well-being continue to find a relationship between use of many drugs and decline in psychological well-being, and a few studies also found that intensity of ecstasy use is associated with using other drugs with more intensity. Studies of cognitive function in ecstasy users also continued to find relationships between repeated use of ecstasy and impairments in memory and executive function, with findings similar in nature to previously reported findings. Lastly, a series of studies examining brain chemistry and function have found some changes in patterns of brain function, but did not find significant indications of brain injury. As has been the case with previously reported findings from imaging studies, findings from recently published studies in this area reported mixed results. Imaging study findings continue to question strong support for a link between MDMA and changes in psychological function while still supporting a link between MDMA and impaired cognitive function. None of the studies presented findings that would lead to increases or decreases in estimated risk to participants in clinical trials of MDMA, though it appears that links between regular ecstasy use and negative mood or psychological problems are complex and less strong than previously believed.

Recent studies conducted in vitro or in non-human animals explored the presence, nature and potential causes of MDMA neurotoxicity, the effects of environment and individual differences on MDMA neurotoxicity, the effects of MDMA on thermoregulation, potential developmental toxicity and effects on the liver and immune system. Researchers comparing MDMA with drugs known to reduce brain serotonin or damage serotonin neurons found that MDMA did not produce the same effects as these drugs. For instance, it appears that reduced brain serotonin was not always correlated with signs of neuronal injury. If researchers replicate these findings, they may be cause for reconsidering all previous studies employing these measures as indices of neurotoxicity. Other researchers tested hypotheses about the source or sources of MDMA neurotoxicity at the cellular level, or examined the combined effects of a behavior, such as strenuous exercise or exposure to loud noise, in combination with MDMA. A number of researchers investigated mechanisms of MDMA-induced hyperthermia in rodents, examining the roles played stimulation of the sympathetic nervous system, specific neurotransmitter systems, and cellular metabolism in producing MDMA-associated hyperthermia.

Researchers administered MDMA to neonatal and young rats to detect developmental toxicity, producing inconsistent study findings, but offering enough evidence for continuing to exclude pregnant or lactating women from clinical trials of MDMA. Researchers continued to investigate the effects of MDMA on liver cells and the immune system, and how MDMA affects the function of the metabolic enzyme CYP2D6. Study results were similar to previously reported findings in these areas, and include detection of signs of oxidative stress in liver cells and changes in immune response after MDMA. Very few of the in vitro and non-human animal studies published during this period describe new phenomena or report new findings, and the few studies that do so, such as those finding differences in effects of MDMA and another known neurotoxin, do not at present change the estimated risks of clinical trials with MDMA.