Methylenedioxymethamphetamine (MDMA, 'Ecstasy'): Neurodegeneration versus Neuromodulation

Abstract

The amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is widely abused as a recreational drug due to its unique psychological effects. Of interest, MDMA causes long-lasting deficits in neurochemical and histological markers of the serotonergic neurons in the brain of different animal species. Such deficits include the decline in the activity of tryptophan hydroxylase in parallel with the loss of 5-HT and its main metabolite 5-hydoxyindoleacetic acid (5-HIAA) along with a lower binding of specific ligands to the 5-HT transporters (SERT). Of concern, reduced 5-HIAA levels in the CSF and SERT density have also been reported in human ecstasy users, what has been interpreted to reflect the loss of serotonergic fibers and terminals. The neurotoxic potential of MDMA has been questioned in recent years based on studies that failed to show the loss of the SERT protein by western blot or the lack of reactive astrogliosis after MDMA exposure. In addition, MDMA produces a long-lasting down-regulation of SERT gene expression; which, on the whole, has been used to invoke neuromodulatory mechanisms as an explanation to MDMA-induced 5-HT deficits. While decreased protein levels do not necessarily reflect neurodegeneration, the opposite is also true, that is, neuroregulatory mechanisms do not preclude the existence of 5-HT terminal degeneration.

Psychoactive Drugs—From Chemical Structure to Oxidative Stress Related to Dopaminergic Neurotransmission. A Review

“…The cause of this similarity is the presence of a common pharmacophore in the molecule. Alkylation of the amino group (addition of an N-methyl group to amphetamine) alters the selectivity to transporters (increases to SERT vs DAT, does not change to NET)—also, the introduction of the methylenedioxy group (in the case of MDMA) leads to an increased selectivity for SERT (which explains the differences in psychotoxicity between amphetamine and MDMA) [ 75 ].…”

A proposed mechanism for the MDMA-mediated extinction of traumatic memories in PTSD patients treated with MDMA-assisted therapy

“…As noted above, the effects of MDMA consumption are unique, with stimulatory, hallucinogenic, and pro-social components that defy the easy categorization and inclusion of MDMA in other classes of drugs such as the “classical” psychedelics or other amphetamine-based, psycho-stimulant molecules ( 13 , 64 ). The pro-social effects of MDMA have resulted in its description as a novel drug termed an “Entactogen” or “empathogen” ( 14 , 64 , 70 ). The subjective effects of MDMA have been amply described in numerous studies, with sexual arousal, euphoria, relaxation, sensory enhancement, and mild visual hallucinations frequently described ( 10 , 71 , 72 ).…”