Methylenedioxymethamphetamine (MDMA, 'Ecstasy'): Neurodegeneration versus Neuromodulation
Elena Puerta, Norberto Aguirre
Pharmaceuticals July 5, 2011 Peer reviewed DOI: 10.3390/ph4070992
Summary
MDMA, commonly known as ecstasy, leads to lasting deficits in serotonin-related markers in the brain across various animal species. This includes reduced activity of tryptophan hydroxylase and lower levels of serotonin and its metabolite, 5-HIAA. Human users also show decreased levels of these markers, suggesting potential loss of serotonergic fibers. However, some studies challenge the neurotoxic potential of MDMA by not finding significant protein loss or reactive astrogliosis, indicating that while there may be down-regulation of serotonin transporters, it does not confirm neurodegeneration.
Study at a glance
| Population | animal species and human ecstasy users |
|---|---|
| Key finding | MDMA causes long-lasting deficits in serotonergic markers in both animal models and human users. |
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.