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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. Author contributions: ES and PV contributed equally to this work. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.

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