3,4-methylenedioxymethamphetamine (MDMA): pharmacology, toxicology, usage patterns, and neurological effects in humans

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) is a ring-substituted amphetamine with a potential for abuse. Although originally developed by Merck, MDMA is an illegal drug that is popular recreationally, and is more recently being touted as a therapeutic agent. Unlike some other drugs in the amphetamine class, the mechanism(s) by which MDMA produces its subjective effects are not well understood. MDMA is a selective serotonin (5-HT) neurotoxin. Exposure to MDMA can lead to lasting reductions in brain 5-HT and 5-HT axonal markers. Somewhat paradoxically, its acute pharmacological effects involve a dramatic acute increase in serotonin (and other monoamine) levels in the brain and the periphery. MDMA is also a direct agonist at several different monoaminergic receptors. Although these pharmacological properties of MDMA are known, they don't appear to fully explain the subjective of effects of MDMA, which include feelings of well-being and euphoria. One unfortunate notion held by many MDMA users is that the drug is safe, or at least safer than many other illegal drugs. This is a notion that is strengthened by MDMA's current and past use as a psychotherapeutic agent, although definitive safety/efficacy reports have yet to appear in the literature. In recent years, there has been a renewed push to acknowledge the potential utility of MDMA in the treatment of conditions such as post-traumatic stress disorder. MDMA has been reported to damage a number of organ systems in addition to its properties as a selective 5-HT neurotoxin in the brain. Furthermore, recreational MDMA users develop tolerance, which results in a need to increase the dose to achieve the same subjective effects, thereby also increasing the risk for dose-related adverse effects. A number of research laboratories have demonstrated that abstinent MDMA users develop both a loss of brain 5-HT markers, in addition to potential functional consequences of 5-HT neurotoxicity, including deficits in cognitive function, endocrine modulation, and sleep regulation. Although these effects have been well-described, the mechanism by which MDMA leads to neurotoxicity remains unclear, and multiple theories have been suggested. There are many unanswered questions when it comes to MDMA. Without knowing more about how MDMA acts in the body and how it produces toxicities, use of the drug constitutes a significant risk. Not only are the acute, systemic and potentially fatal effects of MDMA problematic, but longer term functional consequences secondary to serotonin depletion may pose significant problems for abstinent MDMA users as they age. In light of the drug's popularity, the need for answers and increased public awareness has never been more pressing. Although MDMA is classified by the Drug Enforcement Agency (DEA) as schedule I, popular musicians have begun to positively reference MDMA in their lyrics, which has likely contributed to the observed rise in MDMA-related hospital visits and fatalities. Communities, parents, and healthcare professionals must make a more concerted effort to raise public awareness of the potential dangers of MDMA use.