MDMA, SSRI antidepressants and serotonin syndrome risk

Does combining MDMA with an SSRI lead to an increased risk of serotonin syndrome?

Originally posted in SR forum 6/7/13 . Reviewed 9/2/23

There have been many clinical trials in humans co-administrating different SSRIs (paroxetine, citalopram, sertraline…) to study pharmacological properties.

There is a theoretical risk but it is probably overestimated. According to a recent systematic review (one of the highest quality methods of scientific research)  this situation is exceptional.

Anyway, combination of MDMA and SSRI is not recommended.

First because, in general, it lowers MDMA effects.

Second because people under SSRI treatment usually suffer problems as depression or anxiety disorders and, MDMA is not recommended because of these problems.

In animal models combination of MDMA and some SSRI showed lower neurotoxicity.But doses and patterns of administration make that these results can´t be extrapolated to humans. It is not likely that SSRIs have a neuroprotective effect in humans at doses available.

In my opinion risk of neurotoxicity associated to MDMA is sometimes exagerated. There is no evidence that occasional moderate doses (lower than 120-150 mg) have any neurotoxic effects. In fact at least four investigation teams have been administrating MDMA to healthy human volunteers in clinical trials with the approval of sanitary authorities and ethical comitees of clinical trials. In this case neuroprotective drugs are unnecessary. People who take large doses during long time are probably more exposed to this risks, and in this case there are no neuroprotective measures that have shown efficacy.

Substances that inhibit monoamine oxidase (MAOI: phenelzine, moclobemide) are most likely to lead to serious increases in serotonin when used with ecstasy, and develop a serotonin syndrome. In people who use these drugs MDMA is absolutely not recommended.