Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine.

Abstract

The neurochemical effects of the unique psychedelic agent, methylenedioxymethamphetamine (MDMA), indicate it may be a serotonergic neurotoxin related to agents such as p-chloroamphetamine. MDMA had a biphasic effect on cortical serotonin concentrations beginning with an acute depletion of the transmitter which reached a maximum between 3 and 6 hr after drug administration. This early phase of depletion was reversible because cortical serotonin concentrations had recovered to control levels by 24 hr. However, transmitter concentrations were reduced significantly 1 week later, indicating a second phase of depletion. The latter phase of depletion was associated with a decrease in synaptosomal [3H]serotonin uptake due to a loss in the number of uptake sites with no change in the affinity of the carrier for serotonin. This neurotoxic effect of MDMA was found to be a property of the (+)-stereoisomer of the drug as only this enantiomer produced the depletion of cortical serotonin and the decrease in synaptosomal serotonin uptake at 1 week. In contrast to this, both stereoisomers of the drug could produce the acute depletion of cortical serotonin measured 3 hr after drug administration. Coadministration of the selective serotonin uptake inhibitor, fluoxetine, completely blocked the reduction in cortical serotonin concentrations 1 week after MDMA. Administration of fluoxetine at various times after MDMA revealed that the long-term effects of the drug developed independently of the acute depletion of serotonin and could be partially blocked by the uptake inhibitor as long as 6 hr after drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)

In the evidence

This study is part of the evidence base for 2 syntheses in the library. Here is how each one recorded it.

• State of the evidence: MDMA ↓Opposes

  MDMA caused a reversible acute serotonin depletion followed by a longer-lasting depletion with reduced serotonin uptake sites, specific to the (+)-stereoisomer and blocked by fluoxetine.

  Synthesized October 19, 2026

• State of the evidence: Serotonin ↓Opposes

  MDMA caused a reversible acute depletion of cortical serotonin followed by a longer-term neurotoxic depletion specific to the (+)-stereoisomer, which fluoxetine blocked.

  Synthesized October 19, 2026

Comparable studies

Other preclinical and animal studies on MDMA, most cited first.