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Genetic variants, such as single-nucleotide polymorphisms SNPs , and polymorphic regions of the DA system genes may in part explain interindividual differences in the acute responses to MDMA in humans. Plasma concentrations of MDMA were used as covariate in the analysis to control for individual pharmacokinetic metabolic and weight differences. None of the tested genetic polymorphisms within the DA system altered effects of MDMA when adjusting for multiple comparisons. Genetic variations in genes coding for players of the DA system are unlikely to explain interindividual variations in the acute effects of MDMA in humans. Additionally, recent investigations are looking into MDMA as a medication to assist psychotherapy in patients with posttraumatic stress disorder PTSD 1 — 3. In animals, however, the possibility was raised that the importance of interaction with the DA system would increase with the amount of drug taken 9. For example, the positive effects of MDMA were diminished after pharmacological inhibition of DA receptors with haloperidol Studies on the influence of genetic polymorphisms in the DA system could add adjuvant information to this matter and may also explore the role of the DA system in the interindividual differences in the response to MDMA. However, genetic variants of pharmacological targets of MDMA may also alter its pharmacodynamic effects. A few studies explored the role of genetic polymorphisms of the 5-HT, NE, and oxytocin systems and found only minimal influences on acute effects of MDMA 19 — Additionally, the transporter is involved in various psychiatric disorders and treatment approaches 25 — Two common variable-number tandem repeat VNTR polymorphisms were most extensively studied. The most common forms of this VNTR are 5 or 6 repeats A study in a Brazilian sample found a positive association of the 6-repeat allele and cocaine addiction Especially the inhibition of the D 2 with haloperidol showed a significant reduction in MDMA positive effects MDMA-unrelated pharmacogenetic studies showed a positive association of the minor allele of the DRD2 single-nucleotide polymorphisms SNPs rs and rs with heroin dependence 41 , rs and rs with nicotine dependence 42 , and rs with alcohol dependence in males The VNTR polymorphism within the gene coding for the subtype 4 of the DA receptors DRD4 is also frequently studied in relation to psychiatric disorders and personality traits 44 — The presence of a 7-repeat allele has been linked with personal traits like high novelty seeking, risky decision making, and broad sexual interest 44 , Moreover, children and adolescents suffering from ADHD and carrying the 7-repeat allele had to take higher doses of methylphenidate to reach sufficient efficacy This finding is in line with earlier results from an in vitro study showing a reduced sensitivity of the 7-repeat allele toward DA compared with the 2- and 4-repeat allele The present study is the first to explore the influence of variants within genes coding for the DA system on the acute effects of MDMA in humans. Given the partially inconclusive pharmacogenetic studies in addition to the unclear degree to which MDMA effects are driven by the interaction with the DA system, we hypothesized that genetic mutations of the DA system would not influence cardiostimulant effects and have only minimal influence on the mood effects of MDMA. This was a pooled analysis of nine double-blind, placebo-controlled, crossover studies that used similar methods and were conducted in healthy subjects and in the same laboratory 14 , 15 , 51 — The studies included a total of healthy subjects. Seven studies included 16 subjects each, for a total of subjects, who received mg MDMA twice, once alone and once after pretreatment with a medication 14 , 15 , 51 — Two additional studies included 24 and 28 subjects who received mg MDMA alone, placebo, or other treatments 55 ; Holze et al. In the present analysis, only data from the MDMA-alone and placebo sessions were used. In all of the studies, the washout periods between single-dose administrations of MDMA were at least 7 days to exclude possible carryover effects. The studies were all registered at ClinicalTrials. All of the studies were approved by the local ethics committee and, if necessary, Swiss Agency for Therapeutic Products Swissmedic. The studies were conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all of the participants. All of the subjects were paid for their participation. Detailed pharmacokinetic and safety data from these studies have been reported elsewhere 17 , 18 , Test sessions were conducted in a quiet hospital research ward with no more than two research subjects present per session. The participants were comfortably lying in hospital beds and were mostly listening to music and not engaging in physical activities. A small standardized lunch was served at — PM. One genotyping sample was missing, three participants did not give consent for genotyping, and 11 subjects participated twice only one participation that included all outcome measures was used , resulting in a final data set of subjects 76 women. The exclusion criteria included a history of psychiatric disorders, physical illness, a lifetime history of illicit drug use more than 10 times with the exception of past cannabis use , illicit drug use within the past 2 months, and illicit drug use during the study, as determined by urine tests that were conducted before the test sessions, as reported in detail elsewhere 52 — Fifty-five subjects had prior illicit drug experiences 1—8 times , of which 27 subjects had previously used MDMA 1—5 times , 14 subjects had previously used amphetamine or methamphetamine 1—2 times , 11 subjects had previously used cocaine 1—4 times , eight subjects had previously used lysergic acid diethylamide 1—2 times , and 11 subjects had previously used psilocybin 1—4 times. Similar amounts of MDMA are found in ecstasy pills 57 and have been used in clinical trials in patients 1 , 2. The doses were not adjusted for body weight or sex. Blood pressure, heart rate, and body temperature were assessed repeatedly before and 0, 0. The measurements were performed in duplicate at an interval of 1 min and after a resting time of at least 10 min. The averages were calculated for the analysis. Not all VAS components were presented in all studies. Exact numbers of subjects per genotype group are reported in Tables 1 — 3. The VASs were applied before and 0, 0. The AMRS contains subscales for activity, well-being, and anxiety—depression. Genotypes were determined by polymerase chain reaction PCR using 2. The sizes of the resulting PCR products were assessed by 3. Four and 7-repeat amplicons were the most common forms. Complete genotype and allele distributions are depicted in Supplementary Table S1. Individuals possessing other repeats were excluded from the analysis. The Nyholt correction method was used to account for multiple comparisons and displayed separately in all tables To account for differences in plasma concentrations of MDMA that were caused by differences in body weight, dosing, or metabolizing enzymes 17 , 18 , the area under the MDMA plasma concentration—time curve from 0 to 6 h AUC was included as a covariate in the ANOVAs, and we report the corrected statistics. E max values were obtained directly from the observed data. The primary analysis was performed using an additive genotype model approach for SNPs. Recessive or dominant model analysis was also performed, the results of which are reported only when the additive model was initially significant. Subjects did not significantly differ in MDMA plasma concentration or previous drug experience across genotype groups, with the exception of DAT1 rs Nyholt correction for multiple comparisons yielded statistics indicating that the genetic polymorphisms had no significant effect on the subjective and autonomic parameters. Sex did not significantly modulate the results. The current study expands previous research on whether the acute effects of MDMA are modulated by common genetic polymorphisms in pharmacological targets of MDMA. Action on the DA system is thought to be crucial for the effects of most psychostimulant substances 6 , 24 , 61 , and pharmacogenetic studies demonstrated that different phenotypes are affected by various DA genotypes. As for MDMA, however, none of the herein investigated genetic polymorphisms significantly altered the acute effects after consideration of Type I error correction. Although MDMA is an amphetamine, it acts mainly on the 5-HT system and therefore leads to its classification as an entactogen 7 , The present study has limitations. Although this analysis was done using the largest sample of healthy human subjects who received MDMA in placebo-controlled studies, the sample size is still relatively small when considering the partially small rare allele groups and mostly weak effect sizes for the influence of genetic variants on the MDMA response. This is especially influencing spurious, uncorrected effects i. Larger cohorts might show a more balanced sample distribution, which might lead to different results. Additionally, the study was conducted in healthy volunteers with a single dose of mg MDMA. Therefore, the findings may not be applied to other populations and situations, such as psychiatric patients and the use of higher doses of MDMA. However, we corrected for the modulatory effects of known genetic variants that influence the metabolism of MDMA 17 , 18 by taking interindividual differences in plasma MDMA concentrations into account. We also might have missed some relevant genetic polymorphisms. We have also not tested for rare haplotypes because a haplotype approach may lead to very small groups and more potential statistical artifacts. However, a haplotype suggested by Brewer et al. The same haplotype showed no effect in the present study. This incoherency may be attributable to the different substances used cocaine vs. Finally, previous drug experiences were not equally distributed among DAT1 rs genotype groups, and effects might slightly depend on previous substance use experiences. Because of the involvement of DA in addiction, subjects carrying a TT genotype may be more prone to illicit substance use Apart from this finding, given that our cohort included mostly drug-naive subjects with limited drug use experience, some alleles associated with increased drug use might even be underrepresented. However, the tested variants were consistent with the Hardy—Weinberg equilibrium and comparable with frequencies found in European genome databases. We conclude that the present findings align with previous studies in that variations in genes coding for players of the monoaminergic systems are unlikely to explain interindividual variations in the acute effects of MDMA in humans. The datasets for this manuscript are not publicly available because the individual genotyping consent did not include storing in public repository. Requests to access the datasets should be directed to Matthias Liechti, Matthias. PV analyzed the data and wrote the manuscript. ML conceived the study, obtained funding, and wrote the manuscript. This study was supported by the Swiss National Science Foundation grant no. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors acknowledge the assistance of C. Hysek, A. Rickli, Y. Schmid, P. Dolder, and F. Holze in conducting the clinical studies, H. Meyer zu Schwabedissen, K. Prestin, and Janine J. Hussner for assistance with genotyping, and M. Arends for text editing. J Psychopharmacol — J Psychopharmacol 27 1 — Lancet Psychiatry 5 6 — Pharmacologic profile of MDMA 3,4-methylenedioxymethamphetamine at various brain recognition sites. Eur J Pharmacol 1—2 — MDMA ecstasy and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment. Psychopharmacology 4 — Luethi D, Liechti ME. Monoamine transporter and receptor interaction Profiles in vitro predict reported human doses of novel psychoactive stimulants and psychedelics. Int J Neuropsychopharmacol 21 10 — Pharmacology of MDMA- and amphetamine-like new psychoactive substances. Handb Exp Pharmacol. Behav Pharmacol 28 4 — Eur Neuropsychopharmacol a 10 4 — Neuropsychopharmacology 31 11 — Neuropsychopharmacology 22 5 — Tancer M, Johanson CE. The effects of fluoxetine on the subjective and physiological effects of 3,4-methylenedioxymethamphetamine MDMA in humans. Pharmacokinetic and pharmacodynamic effects of methylphenidate and MDMA administered alone and in combination. Int J Neuropsychopharmacol b — Interactions between bupropion and 3,4-methylenedioxymethamphetamine in healthy subjects. J Pharmacol Exp Ther 1 — Front Genet Pharmacogenet Genom — Eur Neuropsychopharmacol —8. Oxytocin receptor gene variation predicts subjective responses to MDMA. Soc Neurosci 11 6 —9. Depressive mood ratings are reduced by MDMA in female polydrug ecstasy users homozygous for the l-allele of the serotonin transporter. Sci Rep 8 1 Vizeli P, Liechti ME. Oxytocin receptor gene variations and socio-emotional effects of MDMA: a pooled analysis of controlled studies in healthy subjects. No major role of norepinephrine transporter gene variations in the cardiostimulant effects of MDMA. Eur J Clin Pharmacol a 74 3 — Role of serotonin transporter and receptor gene variations in the acute effects of MDMA in healthy subjects. ACS Chem Neurosci. Effect fingerprinting of new psychoactive substances NPS : what can we learn from in vitro data? Pharmacol Ther — Monoamine transporter gene structure and polymorphisms in relation to psychiatric and other complex disorders. Pharmacogenomics J 2 4 — The dopamine transporter: relevance to attention deficit hyperactivity disorder ADHD. Behav Brain Res 1—2 — Molecular genetics of monoamine transporters: relevance to brain disorders. Neurochem Res 33 4 — Biol Psychiatry 49 4 —9. Nine- or fewer repeat alleles in VNTR polymorphism of the dopamine transporter gene is a strong risk factor for prolonged methamphetamine psychosis. Pharmacogenomics J 3 4 —7. A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample. Confirmation that a specific haplotype of the dopamine transporter gene is associated with combined-type ADHD. Am J Psychiatry 4 —7. Association and linkage of allelic variants of the dopamine transporter gene in ADHD. Mol Psychiatry 12 10 — Psychiatr Genet 20 6 — Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder. Neuropsychopharmacology 36 8 — Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene-gene-environment interaction. Transl Psychiatry 3:e Pharmacogenomics J 17 1 — Human dopamine transporter gene DAT1 maps to chromosome 5p Genomics 14 4 —6. Neuropsychopharmacology 35 3 — Dopamine transporter gene associated with diminished subjective response to amphetamine. Neuropsychopharmacology 30 3 —9. Genetic variation of the dopamine transporter DAT1 influences the acute subjective responses to cocaine in volunteers with cocaine use disorders. Pharmacogenet Genomics 25 6 — Multivariate analysis of dopaminergic gene variants as risk factors of heroin dependence. Psychiatry Res 2—3 —9. Alcohol Alcohol 47 4 — Cognitive and emotional processing in high novelty seeking associated with the L-DRD4 genotype. Neuropsychologia 47 7 —9. Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders. Med Sci Monit 17 9 :RA— Neurosci Lett 1 :9— Arch Sex Behav 45 8 — The world-wide distribution of allele frequencies at the human dopamine D4 receptor locus. Hum Genet 98 1 — Dopamine receptor 4 DRD4 7-repeat allele predicts methylphenidate dose response in children with attention deficit hyperactivity disorder: a pharmacogenetic study. J Child Adolesc Psychopharmacol 14 4 — Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Neurochem 65 3 — Clin Pharmacol Ther 90 2 — J Pharmacol Exp Ther a — Carvedilol inhibits the cardiostimulant and thermogenic effects of MDMA in humans. Br J Pharmacol b — Effects of MDMA alone and after pretreatement with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin on pupillary light reflex. Psychopharmacology Berl — Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects. Psychopharmacology Berl 2 — Safety pharmacology of acute MDMA administration in healthy subjects. J Psychopharmacol 31 5 — Linking the pharmacological content of ecstasy tablets to the subjective experiences of drug users. Psychopharmacology Berl 4 — MDMA enhances emotional empathy and prosocial behavior. Soc Cogn Affect Neurosci a — Janke W, Debus G. Google Scholar. Nyholt DR. A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74 4 —9. Wise RA. Dopamine and reward: the anhedonia hypothesis 30 years on. Neurotox Res 14 2—3 — Nichols DE. Identification of a new therapeutic class: entactogens. J Psychoactive Drugs 18 4 — Differential effects of psychoactive substances on human wildtype and polymorphic TM dopamine transporters DAT. Toxicology — Neuropharmacology 87C— Dopamine and addiction: what have we learned from 40 years of research. J Neural Transm Vienna 4 — Psychiatry The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Liechti, matthias. Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Top bar navigation. About us About us. Sections Sections. About journal About journal. Article types Author guidelines Editor guidelines Publishing fees Submission checklist Contact editorial office. Psychiatry , 24 October View all 11 articles. Patrick Vizeli Matthias E. Introduction 3,4-Methylenedioxymethamphetamine MDMA; ecstasy is widely used recreationally for its euphoric effects. Methods Study Design This was a pooled analysis of nine double-blind, placebo-controlled, crossover studies that used similar methods and were conducted in healthy subjects and in the same laboratory 14 , 15 , 51 — Physiological Effects Blood pressure, heart rate, and body temperature were assessed repeatedly before and 0, 0. Edited by: Matthew W.

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

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Official websites use. Share sensitive information only on official, secure websites. Email: erich. 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. We pooled data from 10 randomized, double-blind, placebo-controlled, cross-over studies performed in the same laboratory in healthy subjects receiving doses of 75 or mg 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. In univariable analyses, the MDMA plasma concentration was the strongest predictor for most outcome variables. 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. The acute effects of MDMA typically include enhanced mood, openness, trust and enhanced empathy Hysek et al. Most of the MDMA effects were found to be dose dependent Bedi and de Wit, ; Vizeli and Liechti, and overall comparable across different laboratories Kirkpatrick et al. However, like any psychoactive drug, the response to MDMA is also influenced by non-pharmacological variables — also often referred to as set and setting Hartogsohn, ; Kirkpatrick and de Wit, Set includes the personality, current mood state, preparation, expectation and intention of the person having the experience, whereas setting refers to the physical, social and cultural environment in which the experience takes place Hartogsohn, ; Leary et al. The influence of set and setting has been traditionally studied in the context of psychedelic drugs as responses to these drugs are thought to be particularly dependent on them Carhart-Harris et al. Thus, several studies have demonstrated that — in addition to drug dose — personality traits, such as absorption and neuroticism, as well the mental state before drug intake shape the response to psychedelics Carhart-Harris et al. Both drugs are serotonergic substances interacting with the serotonin 5-HT2A receptor and serotonin transporter Hysek et al. It is therefore conceivable that responses to these substances are also at least in part similarly shaped by set and setting. However, this has not been systematically investigated. So far, few studies have investigated the relative contribution of pharmacological and non-pharmacological variables to the effects of MDMA. Among the studied predictors were sex e. However, these studies each assessed only a small number of potential predictors, did not adjust for potentially confounding variables, and did not assess the importance of different variables. Additionally, the sample sizes were mostly rather small for such analyses. In view of these methodological limitations and the current interest in MDMA research, including phase 3 trials Mithoefer et al. Expanding the knowledge on such influencing variables could potentially not only increase the safety of the use of MDMA in research and psychotherapy, it could also inform treatment planning in MDMA-assisted psychotherapy. For example, it could help to set the environment and to prepare and select the patients in such a way that therapeutic effects are increased and the risk of adverse effects is minimized. Thus, the present study investigated the relative effects of a large number of predictor variables, including age, sex, drug dose, body weight, previous drug experience, genetics, personality and mood before intake on the acute physiological and psychological response to MDMA. The present analysis is based on data of 10 controlled experimental studies with a total sample size of healthy subjects tested in the same laboratory. This study is the first to evaluate potential predictors of the MDMA response covering a wide range of variables. This is a pooled analysis of the raw data from 10 double-blind, placebo-controlled, crossover studies in healthy human subjects, of all of which have previously been described Dolder et al. The studies were conducted at the University Hospital Basel from to and include a total of healthy subjects. In the present analysis, only data from the MDMA-alone and placebo sessions were used. The studies were all registered at ClinicalTrials. All of the studies were approved by the local ethics committee and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all of the participants. All of the subjects were paid for their participation. Detailed pharmacokinetic and safety data from these studies have been published elsewhere Schmid et al. Test sessions were conducted in a quiet hospital research ward with no more than two research subjects present per session. The participants were comfortably lying in hospital beds and were mostly listening to music and not engaging in physical activities. One genotyping sample was missing, and three participants did not give consent for genotyping. Drug screens were conducted before the test sessions as reported in detail elsewhere Hysek and Liechti, ; Hysek et al. Seventy-five subjects had prior illicit substance experiences 1—8 times , of which 41 subjects had previously used MDMA 1—5 times , 18 subjects had previously used amphetamine or methamphetamine 1—2 times , 15 subjects had previously used cocaine 1—4 times , 10 subjects had previously used lysergic acid diethylamide 1—2 times , and 15 subjects had previously used psilocybin 1—4 times. Male and female subjects received the same doses of MDMA irrespective of their body weight as it is done in therapeutic studies Mithoefer et al. Therefore, dose divided by body weight was included as covariate in the analysis. From the socio-demographic predictor variable domain, we included sex and age as predictors. Sex was included because sex differences in the MDMA experience were reported in several controlled studies even after adjusting for differences in dosing Bedi and de Wit, ; Liechti et al. Age was included since younger age was associated with more unpleasant acute effects of psilocybin Studerus et al. Specifically, the activity of cytochrome P enzymes has been shown to alter MDMA concentrations and concomitant subjective and cardiovascular responses de la Torre et al. We did not include measures of other CYP enzyme activity as these have been shown to have no or only very small effects on the response to MDMA Vizeli et al. Likewise, other potential pharmacogenetic predictors were not included, because they also showed no or only minimal effects on the acute response to MDMA Bershad et al. Although all subjects had no or only very limited previous experiences with psychoactive substances 0—5 times , the number of MDMA consumptions prior to participation was included as a continuous predictor variable in the analysis, since MDMA effects have been reported to change with long-term use Parrott, and more experienced users experienced smaller drug effects than inexperienced persons Kirkpatrick et al. Mood states prior to the administration of a psychoactive substance influence its response as previously shown for psilocybin in a similar study Studerus et al. Subjects completed the questionnaire as part of the screening procedure at the start of the study. This self-assessment questionnaire contains 20 statements describing anxiety as a stable personality trait. Blood samples for the pharmacokinetic response were collected in lithium heparin tubes 0, 0. Blood pressure, heart rate, and body temperature were assessed repeatedly before and 0, 0. The averages were calculated for analysis. For the different autonomic response measures, we used the highest values E max as outcome variable for the analysis because high cardiovascular stimulation or body temperature are the clinically relevant potentially adverse outcomes associated with MDMA use Liechti, ; Liechti et al. The subjective response to MDMA was assessed using psychometric scales. Additionally, the AMRS was administered 1. The 5D-ASC consists of 94 visual analog scale items and measures three etiology-independent and two etiology-dependent dimensions of altered states of consciousness. To reduce multiple testing, we only included the etiology-independent dimensions i. Furthermore, since these three dimensions are heterogenous constructs Studerus et al. All data were analyzed using the R language and environment for statistical computing R Core Team, The assumption of MAR was plausible in this study because the missing data mostly resulted from different study designs among the pooled studies. We generated 20 imputations of the missing values such that 20 completed datasets were obtained to avoid a potential power falloff from an insufficient number of imputations Graham et al. To account for the clustering in our data arising from pooling across studies, we used linear mixed effects models in which the intercepts were allowed to vary randomly across studies. For each combination of predictor and response variable, an adjusted and unadjusted model was fitted using the R package nlme Pinheiro et al. Predictor and response variables were z-transformed before inclusion in the models, such that the estimated regression coefficients were fully standardized and comparable across predictors and responses. In each model, the amount of variance explained by each fixed effects predictor was determined by calculating the semi-partial R 2 using r2beta function in r2glmm package with the Kenward—Roger approach Jaeger et al. To account for multiple testing, p -values were corrected across all significance tests using the Benjamini—Hochberg procedure Benjamini and Hochberg, To identify the best subset of predictors for each response variable and to determine relative importance of these predictors, we applied the least absolute shrinkage and selection operator LASSO using the R package penalized Goeman, LASSO conducts both variable selection and regularization i. It has been shown that variable selection with the LASSO is often more accurate than with traditional methods, such as stepwise methods Tibshirani, First, the optimal shrinkage parameter of each model was determined by performing grid search. For each lambda in the grid, bootstrapping with 50 iterations was performed and the average predictive performance i. Second, the lambda value producing the highest out-of-bag predictive performance was chosen as the optimal lambda value and used for the final LASSO model fitted on the whole sample. Since it is currently unclear how to combine LASSO models across multiply imputed datasets and since the amount of missing data in our data set was relatively small, only single imputation was used for the LASSO models. Furthermore, for simplicity, we did not account for a potential clustering in our data in these analyses. The size of the fully standardized regression coefficients and statistical significance of each predictor variable for each outcome variable in the unadjusted and adjusted analyses are shown in Supplementary Figure 1 and Figure 1 , respectively. Standardized regression coefficients and statistical significance of each predictor variable in the linear mixed effects models adjusting for drug dose per body weight. Smaller asterisks show the uncorrected statistical significance. In the unadjusted i. It was significantly associated with 16 of 24 outcome variables when not correcting for multiple testing and with eight variables after the correction. However, despite its superior predictive power, we did not use this variable as a covariate in the adjusted analysis because we wanted to predict the response to MDMA already at the time of drug intake, when MDMA plasma concentration is not yet known. Instead, we used the drug dose per kg body as a covariate, as drug dose and body weight were both strong determinants of the MDMA plasma concentration see Supplementary Figure 1. After adjusting for drug dose per body weight and correcting for multiple testing, sex was no longer predictive for the MDMA plasma concentration. On average, 8. Dose per body weight was the most frequently selected predictor variable i. For 12 response variables, it also had the largest absolute standardized regression coefficient and thus was the most important predictor. Size of the penalized regression coefficients and rank of importance of the predictor variables in the LASSO models. As one Lasso model was developed for each response variable, each column in the tile plot reports the results of one Lasso model. The rank of importance of each predictor for each outcome was determined by ranking the predictor variables according to their absolute size of the regression coefficients in each Lasso model. This study investigated the influence of 20 predictor variables on the physiological and psychological response to MDMA in healthy humans. We found that physiological as well as most psychological effects were most strongly dependent on MDMA plasma levels, which in turn was most strongly dependent on drug dose and body weight. When adjusted for drug dose per body weight and corrected for multiple testing, only age and the genetically determined activity of the enzyme CYP2D6 had an influence on the physiological response to MDMA. However, as can be seen in Supplementary Figure 1 , there were also several outcome variables that were not or only weakly predicted by MDMA plasma concentration. This supports the study of Kolbrich et al. We also found that the MDMA plasma concentration was positively associated with mean arterial blood pressure and heart rate, but not with body temperature, which is again in line with the study of Kolbrich et al. To investigate the effects of all other predictors adjusted for the amount of drug, we used drug dose per body weight rather than MDMA plasma concentration as a covariate since the latter is not known in advance and unlikely to be determined in the clinical setting. Drug dose per body weight was shown to be a good proxy for MDMA plasma concentration, because, when adjusting for drug dose per body weight, only the genetically-determined enzyme CYP2D6 activity contributed to the prediction of MDMA plasma concentration. After adjusting for drug dose per body weight, sex did not significantly influence the effects of MDMA indicating that the stronger response in women as shown in the unadjusted analyses was due to lower body weight and correspondingly higher drug dose per body weight in women. Thus, this study could not confirm earlier studies reporting sex-differences in acute physiological and subjective responses to MDMA even after adjusting for body weight for review, see Allott and Redman, For example, Liechti et al. Other studies suggested that women may be particularly vulnerable to acute negative subjective and cardiovascular Bedi and de Wit, ; Pardo-Lozano et al. A more consistent effect was observed for age, which inversely correlated with the MDMA-induced heart rate elevation. This finding might be explained by an age-associated decrease of adrenergic receptor sensitivity and density in cardiac muscle Xiao and Lakatta, and supports the theory of an adrenergic receptor mediated cardiovascular effect of MDMA that can be inhibited by carvedilol Hysek et al. However, we do not think that this relationship is of high clinical relevance or use in practice. However, these associations should be interpreted cautiously as they did not withstand correction for multiple testing and result from a rather limited dataset in terms of age variation. Individuals over 45 were excluded from the study and could react differently, especially since comorbidities also increase with age. Accordingly, one laboratory based multicenter study has found modest evidence that greater prior use of MDMA is associated with lesser ratings of feeling any drug effect Kirkpatrick et al. However, this association was not consistently observed across all study centers and a further laboratory-based study could also not detect it Bedi and de Wit, Therefore, the influence of heavier past MDMA use could not be assessed in the present study. Notably, patients in clinical trials using MDMA will, similar to the present study population, likely have no to little experience in using MDMA, enhancing the relevance of the present data for the clinical situation. In contrast, the majority of other controlled studies using MDMA in healthy subjects has been conducted in persons with considerably greater MDMA use in the past. Thus, challenging experiences are considered less likely to occur after MDMA than after high dose of psychedelics. A similar persisting effect on personality traits was also observed after the ingestion of psilocybin or LSD Erritzoe et al. Besides the present work, we are not aware of any other study investigating the predictors of the physiological and psychological response to MDMA to a similar extent in a controlled setting. There are a few studies with a small number of potential predictors, but their results were not adjusted for potentially confounding variables and did not display the importance of different variables. Thus, the findings only partly translate to patients with psychiatric disorders showing clearly greater psychopathology and presumably a greater likelihood of adverse psychological responses to MDMA. Furthermore, even though this study population mirrors the general population in illicit drug experience better than most previous studies with MDMA, it still includes more illicit drug experiences than one would expect within the general population European Monitoring Centre for Drugs and Drug Addiction, Second, only one of two different doses of MDMA was administered i. It is therefore conceivable that with more varied drug doses the relative contribution of MDMA plasma levels to the response to MDMA would have been even higher. For example, effects of MDMA may be different in a therapeutic setting with high engagement of the therapist or in a large party setting etc. However, this study was conducted in a highly standardized research setting with little variation, leaving minimal scope for research on this potential predictor. Finally, while the present study is informative on the acute effects of MDMA, little can be extrapolated to address longer-term effects. Taken together, we could demonstrate that both pharmacological and non-pharmacological variables play a role in the effects of MDMA. These associations are strikingly similar to those previously observed in psychedelics Haijen et al. Supplemental material, sj-docxjop The other authors declare no conflicts of interests. Knowhow and data associated with this work and owned by the University Hospital Basel were licensed by Mind Medicine, Inc. Mind Medicine, Inc. Matthias E. Supplemental material: Supplemental material for this article is available online. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. J Psychopharmacol. Find articles by Erich Studerus. Find articles by Patrick Vizeli. Find articles by Samuel Harder. Find articles by Laura Ley. Find articles by Matthias E Liechti. Issue date May. Open in a new tab. Click here for additional data file. 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