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).

Abstract

“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

Notes

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.”

Summary

Introduction

MDMA is a psychoactive drug and can be used for treatment of post-traumatic stress disorder and other anxiety disorders. The effects of MDMA are dose dependent and are influenced by non-pharmacological variables such as the personality, current mood state, preparation, expectation and intention of the person having the experience.

In addition to the drug dose, personality traits and the mental state before drug intake influence the response to psychedelic drugs.

MDMA and psychedelics, such as psilocybin, are serotonergic substances interacting with the serotonin 5-HT2A receptor and serotonin transporter. The relative contribution of pharmacological and non-pharmacological variables to the effects of MDMA has not been systematically investigated.

Little is known about how personality traits and mood state influence the acute response to MDMA.

We pooled data from 10 studies on 194 healthy subjects receiving doses of 75 or 125mg of MDMA and found that the MDMA plasma concentration was the strongest predictor for most outcome variables, but several personality traits and mood state variables additionally explained variance in the response to MDMA.

In view of methodological limitations and the current interest in MDMA research, it is important to investigate predictor variables that may moderate MDMA effects. This study investigated the effects of a large number of predictor variables on the acute physiological and psychological response to MDMA.

Study design

This is a pooled analysis of 10 double-blind, placebo-controlled, crossover studies in healthy human subjects, of which 112 received 125 mg MDMA twice within four experimental sessions and 3 received MDMA once within three or four experimental sessions.

The use of MDMA in the studies was approved by the local ethics committee and the Swiss Federal Office for Public Health. Written informed consent was obtained from all participants.

MDMA was administered to two research subjects in a quiet hospital research ward. They were listening to music and not engaging in physical activities.

Subjects

A total of 194 healthy subjects aged 18-45 years were recruited from the University of Basel campus and participated in the study. Of these, 75 had prior illicit substance experiences, of which 41 had previously used MDMA, 18 had previously used amphetamine or methamphetamine, 15 had previously used cocaine, and 15 had previously used psilocybin.

MDMA was administered orally at a single dose of 75 or 125 mg prepared as gelatin capsules. Male and female subjects received the same doses irrespective of their body weight.

Predictor variables

MDMA effects are dose- and body-weight-dependent, with females requiring a higher mg/kg dose compared to males.

Sex and age were included as predictors because of the reported sex differences in the MDMA experience and the known association between younger age and more unpleasant acute effects of psilocybin.

Individual metabolic differences in the enzymes metabolizing MDMA influence the exposure to MDMA and thereby its acute effects. The CYP2D6 genetic activity score was included as an additional predictor variable.

Although all subjects had no or only very limited previous experiences with psychoactive substances, more experienced users experienced smaller drug effects than inexperienced persons.

Mood states prior to the administration of a psychoactive substance influence its response. The Adjective Mood Rating Scale (AMRS) was used to assess mood states prior to the administration of MDMA.

The NEO-FFI and STAI-T were used to assess personality traits, and anxiety as a stable personality trait was assessed using the STAI-T.

Response variables

Blood samples were collected at 0, 0.33, 0.67, 1, 1.5, 2, 3, 4 and 6 h after administration of MDMA or placebo and stored at – 20°C until analysis.

Blood pressure, heart rate, and body temperature were measured repeatedly before and 0, 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 5 and 6 h after MDMA or placebo administration. The highest values were used as outcome variables for the analysis.

Subjective response to MDMA was assessed using psychometric scales. The response on each VAS and AMRS subscale was included into the analysis as area under the effect-time-curve (AUEC) value, reflecting the overall response throughout the study day.

The 5D-ASC questionnaire measures three etiology-independent and two etiology-dependent dimensions of altered states of consciousness. The anxiety and impaired control and cognition subscales were additionally administered 6 h after drug administration.

Statistical analyses

We performed multiple imputation using the Multivariate Imputation via Chained Equations (MICE) package in R to fill in missing data and maximize statistical power by using all available information. The analyses of interest were conducted in each completed data set and parameter estimates were pooled according to Rubin’s rules.

To account for clustering in our data arising from pooling across studies, linear mixed effects models were fitted using the R package nlme. The amount of variance explained by each fixed effects predictor was determined by calculating the semi-partial R2 using the Kenward – Roger approach.

To identify the best predictors for each response variable, we applied the least absolute shrinkage and selection operator (LASSO) using the R package penalized.

For each response variable, a LASSO model was developed by performing grid search, bootstrapping with 50 iterations, and calculating the average predictive performance across all out-of-bag samples. The optimal lambda value was chosen as the final LASSO model fit on the whole sample.

Results

MDMA plasma concentration was the strongest predictor of the physiological and psychological response to MDMA, and was associated with 16 of 24 outcome variables when not correcting for multiple testing and with eight variables after the correction. The strongest predictor of the VAS scale “any drug effect” was MDMA plasma concentration, but we did not use this variable as a covariate in the adjusted analysis.

After adjusting for drug dose per body weight and multiple testing, sex was no longer predictive for MDMA plasma concentration. However, a genetically determined low CYP2D6 activity still predicted a larger MDMA plasma concentration. Subjects with higher scores on the NEO-FFI or STAI-T were more likely to experience “dread of ego dissolution” and “impaired control and cognition” as measured by the 5D-ASC.

The most important predictor for the VAS scales “any drug effects”, “good drug effects”, “high mood”, “stimulated” and “liking” as well as “oceanic boundlessness” in the 5D-ASC was dose per body weight, while older age was the most important predictor for the prediction of unpleasant or anxious reactions to MDMA.

Discussion

In this study, 20 predictor variables were investigated for the physiological and psychological response to MDMA in healthy humans. It was found that the physiological response was most strongly dependent on MDMA plasma levels, which were most strongly dependent on drug dose and body weight.

Our finding that MDMA plasma concentration was the most important predictor for the response to MDMA is in line with previous dose-response studies. However, there were also several outcome variables that were not or only weakly predicted by MDMA plasma concentration.

To predict MDMA plasma concentration, we used drug dose per body weight as a covariate. Drug dose per body weight was shown to be a good proxy for MDMA plasma concentration.

After adjusting for body weight, sex did not significantly influence the effects of MDMA. Women experienced more intense positive and negative subjective effects, but men showed a higher increase in blood pressure in response to MDMA.

Age was associated with a decrease in MDMA-induced heart rate elevation, a decrease in body temperature, less “liking”, less “good drug effects” and more “bad drug effects”. However, these relationships should be interpreted cautiously as the study was limited in terms of age variation.

In our study, previous MDMA experience had no effect on the response to MDMA, which was surprising since recreational MDMA users often report experiencing the strongest effects the first time they ever tried MDMA and developing tolerance to the positive subjective effects of MDMA over time.

Personality traits such as “openness to experience” and “absorption” are positively associated with the subjective effects of MDMA, including experiences of oneness with the self and the world, liberation from the restrictive aspects of space and time, and altered perception and meaning.

More “openness to experience” and less “neuroticism” intensified the pleasant and prosocial effects of MDMA, while more “anxiety-depressiveness” and more “introversion” increased the likelihood of anxious responses to MDMA. However, anxiety scores are rather small and only 7% of subjects reported anxiety as an acute adverse effect.

This study suggests that personality traits such as “openness to experience” and “neuroticism” influence the MDMA experience. This effect may potentially act as a therapeutic mechanism of change, as patients become more open to the experience over time.

Strengths and limitations

Besides the present work, there are no other studies investigating the predictors of the physiological and psychological response to MDMA in a controlled setting.

Limitations of the study include the young, mostly MDMA-naive, healthy study population, the fact that the study population mirrors the general population in illicit drug experience better than most previous studies with MDMA, and the fact that 85% of subjects received the higher dose of MDMA.

This study was conducted in a highly standardized research setting with little variation, leaving minimal scope for research on the influence of the physical and social environment on the response to MDMA.

Conclusions

We could demonstrate that both pharmacological and non-pharmacological variables play a role in the effects of MDMA, and that personality traits could inform the planning of MDMA-assisted psychotherapy.