3,4‐Methylenedioxymethamphetamine (MDMA, “Ecstasy”): pharmacology and toxicology in animals and humans

Abstract

(+/-)3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"), a ring-substituted amphetamine derivative first synthesized in 1914, has emerged as a popular recreational drug of abuse over the last decade. Pharmacological studies indicate that MDMA produces a mixture of central stimulant and psychedelic effects, many of which appear to be mediated by brain monoamines, particularly serotonin and dopamine. In addition to its pharmacologic actions, MDMA has been found to possess toxic activity toward brain serotonin neurones. Serotonergic neurotoxicity after MDMA has been demonstrated in a variety of experimental animals (including non-human primates). In monkeys, the neurotoxic dose of MDMA closely approaches that used by humans. While the possibility that MDMA is also neurotoxic in humans is under investigation, other adverse effects of MDMA in humans have been documented, including various systemic complications and a number of untoward neuropsychiatric sequelae. Notably, many of the adverse neuropsychiatric consequences noted after MDMA involve behavioral domains putatively influenced by brain serotonin (e.g., mood, cognition and anxiety). Given the restricted status of MDMA use, retrospective clinical observations from suspecting clinicians will probably continue to be a primary source of information regarding MDMA's effects in humans. As such, this article is intended to familiarize the reader with the behavioral pharmacology and toxicology of MDMA, with the hope that improved recognition of MDMA-related syndromes will provide insight into the function of serotonin in the human brain, in health as well as disease.

Acute Effects of 3,4-Methylenedioxymethamphetamine (MDMA) on Behavioral Measures of Impulsivity: Alone and in Combination with Alcohol

“…The pharmacological mechanism underlying improvement in impulse control may be related to acute serotonergic or dopaminergic suppletion following a single dose of MDMA. MDMA is believed to increase 5HT levels during intoxication by stimulating the acute release of 5HT and by blocking the presynaptic reuptake of 5HT ( Steele et al, 1994Steele et al, , 1987. Improved impulse control during serotonergic suppletion seems in line with reports on impaired impulse control in heavy users of MDMA during periods of abstinence.…”

Recreational Use of “Ecstasy” (MDMA) Is Associated with Elevated Impulsivity

“…causes long-term decreases in brain 5-HT and 5-HIAA concentrations and suspected 5-HT axon terminal degeneration in a variety of animal species (for reviews, see McKenna and Peroutka 1990;Steele et al 1994;Green et al 1995;Frederick and Paule 1997). Recent evidence from studies with human participants is consistent with these findings.…”

Elevated Impulsivity and Impaired Decision-Making in Abstinent Ecstasy (MDMA) Users Compared to Polydrug and Drug-Naïve Controls

“…The popularity of this drug has given rise to concern, since preclinical research has demonstrated that repeated doses of MDMA can cause serotonergic neurodegeneration in animals (eg Ricaurte et al, 1992Ricaurte et al, , 2000Steele et al, 1994;Green et al, 1995), and there is some evidence that chronic consumption of ecstasy is associated with protracted dysregulation of 5-HT systems in humans. Drug-free ecstasy users have been found to have low levels of 5-HT, and its metabolite 5-HIAA Kish et al, 2000).…”