Antidepressant-like effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy).

Abstract

3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a popular club drug that is abused worldwide. The main subjective effects of the drug include enhanced mood and self-esteem. Due to these effects, ecstasy may be used at higher rates by people with pre-existing mood disorders, or a predisposition to depression, in order to ‘self-medicate’ their state. This, in turn, may lead to more regular drug use, and, hence, a higher risk of side effects and negative impact on health. Moreover, some mechanisms of MDMA action in the brain are similar to those of clinically prescribed antidepressants, as the drug primarily affects the serotonin (5-HT) system. This suggests that the drug may have antidepressant‐like activity. The studies reported here, both preclinical and clinical, were designed to investigate possible antidepressant-like effects of MDMA in subjects with a predisposition to depression. In the animal study, the effects of MDMA following single and repeated administration were compared between Sprague-Dawley and the Flinders Sensitive Line rat strains, the latter being a putative model of depression. The drug’s effects on behaviour were assessed in the Forced Swimming Test, which is widely used to detect the depressivelike state in laboratory animals. Acute MDMA administration had a dose-dependent antidepressant-like effect that was more evident in the Flinders Sensitive Line animals. This effect was diminished following 3 weeks of repeated drug injection, possibly due to the development of tolerance. The chosen dosing regime didn’t affect the cortical levels of 5-HT and its metabolite. 40 current ecstasy users participated in the clinical study. Predisposition to depression was assessed using a questionnaire (Brief Symptom Inventory) that determines the rates of distress in various psychological spheres. Mood scores and depressive symptoms were assessed when participants were drug-free and when they attended a social gathering. Twenty participants, with and without a predisposition to depression, who voluntarily chose to take a pill at a social gathering, were assessed 1 hour after drug consumption, and the mood disturbance and depressive symptoms were compared with participants who abstained from pill consumption. Ecstasy users with a predisposition to depression reported higher mood disturbance and more prominent depressive symptoms when they were not under the influence of the drug. At the party, mood was improved in all participants irrespective of whether they chose to consume a pill, whereas subjects predisposed to depression reported a relative decrease in depressive symptoms only after pill consumption, which may be considered as an antidepressant‐like effect of the drug. Certain variants of the 5-HT transporter gene polymorphism were associated with higher depressive scores. Analysis of the effects of different previous ecstasy exposure revealed that subjects with a greater number of pills consumed in their lifetime report more prominent positive effects following ecstasy consumption, which may explain their more frequent use. In sum, an immediate antidepressant-like effect of MDMA was evident both in an animal model of depression and in users predisposed to depression. This may suggest the self-medicating potential of MDMA in subjects with a predisposition to depression.