The serotonin lesion induced by MDMA (Ecstasy) in non-human primate produces an acute anxiety disorder and a disturbance of fluoxetine therapeutic effects.
Year: 2023
Type: conference-paper
Abstract: 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy”), a recreational drug, is a potent serotonin (5-HT) releaser which acts like selective serotonin reuptake inhibitors (SSRI), drugs widely used in psychiatric disorders. MDMA has been proposed as treatment for some psychiatric disorders, like post-traumatic stress disorder, autism, and anxiety-related disorders, where SSRI resistance can exceed 60% of patients. However, in non-human primates (NHP), MDMA can cause irreversible lesions in 5-HT terminal fibres, where therapeutic effects of SSRIs (ex: fluoxetine), can be exerted. This emphasises the risk of using MDMA therapeutically without a preclinical safety study to determine its effects. This study conducted on NHP had two aims: 1) To determine the severity of MDMA-induced serotonergic lesion and its effects on behaviour and 2) To study interactions between a prior possible protective fluoxetine treatment and the impact of MDMA lesion on post-MDMA fluoxetine treatments. After receiving MDMA, all monkeys (n=7) exhibited increased anxious-like behaviours for two weeks, before returning to pre-MDMA rates for most animals. This acute anxiety-related effect was characterized in the aversive context of an approach-avoidance behavioural task, where monkeys had significantly lower completion rates and higher escape rates. Three weeks after MDMA administration, [11C]DASB-PET imaging specific to the 5-HT transporter (SERT) revealed reductions in SERT density, confirming previous findings on MDMA-induced toxicity in 5-HT axon terminals. The ventral striatum, anterior caudate and insula were most affected while the pallidum and raphe nucleus preserved their SERT density, with increases in some animals. Before MDMA administration, fluoxetine treatments induced beneficial effects on behavioural markers of anxiety by increasing completion rates and lowering escape rates in aversive context in 5/6 monkeys. After MDMA administration, beneficial effects of fluoxetine were lost in 5/6 animals. These findings show that the severity of anxious-like behaviours and the efficacy of fluoxetine in NHP depends on the integrity of 5-HT projections. In conclusion, the administration of MDMA as a therapeutic strategy in SSRI-resistant psychiatric disorders appears risky and should be used with caution, based on these NHP results showing major adverse effects of MDMA via production of an acute anxiety disorder, and loss of fluoxetine therapeutic effects in most of our animals.
Source: HAL
Author: Tremblay, Léon
Institution: Institut des Sciences Cognitives Marc Jeannerod
Language: English
Subfield: Clinical Psychology
Field: Psychology
Domain: Social Sciences
Open Access status: green
OpenAlex ID: W7207473640