Prediction of MDMA response in healthy humans: a pooled analysis of placebo-controlled studies

This pooled-data analysis (n=194) of healthy participants of RCTs with MDMA (75mg-125mg) found that MDMA plasma concentration was the strongest predictor of outcomes. The more active the CYP2D6 enzyme, the lower the plasma concentration. And the higher the score on Openness, the more closeness and two subscales of an altered states of consciousness questionnaire (5D-ASC).


“Background: 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) is used both recreationally and therapeutically. Little is known about the factors influencing inter- and intra-individual differences in the acute response to MDMA. Effects of other psychoactive substances have been shown to be critically influenced by personality traits and mood state before intake.

Methods: We pooled data from 10 randomized, double-blind, placebo-controlled, cross-over studies performed in the same laboratory in 194 healthy subjects receiving doses of 75 or 125mg of MDMA. We investigated the influence of drug dose, body weight, sex, age, drug pre-experience, genetics, personality and mental state before drug intake on the acute physiological and psychological response to MDMA.

Results: In univariable analyses, the MDMA plasma concentration was the strongest predictor for most outcome variables. When adjusting for dose per body weight, we found that (a) a higher activity of the enzyme CYP2D6 predicted lower MDMA plasma concentration, (b) a higher score in the personality trait “openness to experience” predicted more perceived “closeness”, a stronger decrease in “general inactivation”, and higher scores in the 5D-ASC (5 Dimensions of Altered States of Consciousness Questionnaire) scales “oceanic boundlessness” and “visionary restructuralization”, and (c) subjects with high “neuroticism” or trait anxiety were more likely to have unpleasant and/or anxious reactions.

Conclusions: Although MDMA plasma concentration was the strongest predictor, several personality traits and mood state variables additionally explained variance in the response to MDMA. The results confirm that both pharmacological and non-pharmacological variables influence the response to MDMA. These findings may be relevant for the therapeutic use of MDMA.

Authors: Erich Studerus, Patrick Vizeli, Samuel Harder, Laura Ley & Matthias E. Liechti


This study brought together data from 10 earlier studies that were conducted at the University Hospital Basel.

Not adjusting for weight or other factors, the concentration of MDMA in blood plasma (how much is going around the body) was the strongest predictor of both physiological and psychological outcomes.

When corrected for body weight and drug dose, the sex of the participants was no (longer) a predictor of MDMA plasma concentrations. Or in other words, someone with the same dose and weight between both sexes had the same level of MDMA in their blood plasma.

The higher activity of the CYP2D6 enzyme predicted lower MDMA plasma concentrations. Those with an (over) active expression of this gene (which encodes/asks your body to make enzymes) had lower MDMA plasma concentrations.

The psychological effects found were the following:

“… subjects with a high score in “openness to experience” responded with more “closeness”, a stronger decrease in “general inactivation” and higher scores in the 5D-ASC scales “oceanic boundlessness” and “visionary restructuralization” in response to MDMA, whereas subjects with high “neuroticism” or trait anxiety experienced more “anxious ego dissolution” and “impaired control and cognition”. Furthermore, being more anxious-depressive or introverted immediately before MDMA intake was associated with more anxiety in response to MDMA.”

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