In an open‑label feasibility study of 14 recently detoxified participants, Bayesian analysis estimated a 55–63% probability that MDMA‑assisted psychotherapy produced a two‑level reduction in WHO drinking‑risk at 3‑month follow‑up, with preliminary reductions in alcohol craving and improvements in sleep and psychosocial functioning. The paper frames a harm‑reduction endpoint for AUD and provides early evidence that MDMA‑assisted psychotherapy may improve quality of life alongside reduced drinking.
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Aims
Safety and tolerability data from the first open-label feasibility study of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for alcohol use disorder was recently published. This paper presents a Bayesian analysis of the impact of MDMA-assisted psychotherapy on treatment success, defined as 2-level reduction in the World Health Organization (WHO) drinking risk at the 3 months follow-up. We also examined the impact on drinking behavior and psychosocial measures at 3 months compared to baseline.
Methods
Fourteen participants with a diagnosis of alcohol use disorder who had recently undergone detoxification completed an eight-week course of ten psychotherapy sessions, including two sessions with MDMA. Measures assessing drinking behavior, quality of life, sleep, self-compassion, and empathy were collected. Bayesian analysis using flat and skeptical priors was performed to determine treatment success defined as a 2-level reduction in WHO drinking risk.
Results
Bayesian analysis suggested that the probability of a 2-level reduction in WHO drinking risk from baseline to 3 months post-treatment is 55%–63%, based upon either a flat or skeptical prior respectively. We present preliminary findings suggesting reductions in alcohol craving (measured by the Penn Alcohol Craving Scale and Obsessive Compulsive Drinking Scale) and improvements in sleep and aspects of psychosocial functioning at 3 months follow-up compared to baseline.
Conclusions
The Bayesian analysis provides a useful harm reduction endpoint interpretation of drinking in terms of a 2-level reduction in WHO drinking risk. Further findings provide preliminary insights into the potential impact of MDMA-assisted psychotherapy on quality of life and well-being in addition to reductions in drinking. ClinicalTrials.gov ID: NCT04158778.
Thurgur and colleagues situate this work within the recent resurgence of clinical research on MDMA-assisted psychotherapy, noting robust Phase III evidence for PTSD and interest in applying the approach to other disorders linked with trauma, including alcohol use disorder (AUD). Earlier open-label work by the study team established safety and tolerability for MDMA-assisted psychotherapy in AUD and reported reductions in drinking and improvements in mood up to 9 months, but questions remain about clinically meaningful drinking endpoints, broader psychosocial outcomes, and potential mediators such as craving. This paper re-analyses data from that initial feasibility trial to address two aims. First, the investigators apply a Bayesian framework to estimate the probability that participants achieved a clinically relevant harm-reduction endpoint—defined as a 2-level reduction in World Health Organization (WHO) drinking risk—at 3 months post-treatment. Second, the study reports exploratory analyses of drinking behaviour, craving, quality of life (QOL), sleep, self-compassion and empathy at 3 months versus baseline to provide preliminary evidence on broader wellbeing outcomes beyond alcohol consumption metrics.
This was an open-label feasibility study previously reported in detail; the extracted text presents the secondary-analysis methods. Fourteen adults with AUD who had recently undergone detoxification enrolled and completed an eight-week recovery-based psychotherapy course comprising ten sessions, of which two (sessions 3 and 7) were MDMA-assisted dosing sessions. The MDMA regimen for each drug-assisted session was an oral 125 mg initial dose followed by a 62.5 mg booster. Primary safety and tolerability outcomes (treatment completion, acceptance of second MDMA dose, adverse events) were described in the earlier publication; this paper focuses on secondary outcomes. Alcohol consumption was measured using the Timeline Followback (TLFB) to derive WHO drinking risk categories; treatment success for the Bayesian analysis was defined as a 2-level reduction in WHO risk from baseline to 3 months. Additional patient-reported outcome measures (PROMs) included the Penn Alcohol Craving Scale (PACS) and Obsessive Compulsive Drinking Scale (OCDS) for craving and compulsive/obsessive drinking, the SF-36 for QOL, four items derived from the Pittsburgh Sleep Quality Index (PSQI) for sleep disturbance, the Self-Compassion Scale (SCS), and the Interpersonal Reactivity Index (IRI) for empathy subscales. For the binary WHO-risk endpoint a binomial test was performed and followed by Bayesian inference using two beta priors: a flat prior (a = 1, b = 1; mean 50%) and a skeptical prior (a = 1, b = 3; mean 25%), the latter reflecting a conservative assumption about placebo-level response rates in mental health trials. Continuous PROMs were analysed with Wilcoxon matched-pairs signed rank tests given the small sample; Bonferroni correction was applied for PROMs with multiple subscales. Analyses were conducted in Jamovi and figures produced in GraphPad Prism. Effect sizes (rank biserial correlations) are reported in the appendix per the extracted text.
For the binary outcome measure, i.e. a 2-level reduction in WHO drinking risk levels, we used binomial test, which we followed up by a Bayesian analysis. Bayesian analysis is an alternative statistical method to the commonly used frequentist approaches, often providing a more clinically informative analysis of treatment impacts. This view is supported by a systematic review of Bayesian reanalyses involving 82 studies from high-impact critical care journals revealed that instances of disagreement between frequentist and Bayesian outcomes are infrequent. Furthermore, there are exemplars within cannabis and psychedelic research that reveal benefits of employing Bayesian analysis. We used two priors for the Bayesian analysis, both from the beta distribution family. We used a flat prior (a = 1, b = 1; i.e. mean success rate is 50%) and skeptical (a = 1, b = 3; i.e. mean success rate is 25%) priors. This choice of the skeptical prior was driven by that in mental health treatments the response rates in placebo conditions are typically in the 25-40% range. We took the lower end of this range to define the mean of the skeptical prior. In other words, if it is assumed that a treatment has no specific effect, which represent a skeptical attitude, even then at least 25% success rate is expected. All PROMs data were continuous outcomes and these were analysed with Jamovi (Version 2.3) and graphs were created using GraphPad Prism 9 (GraphPad Software Inc.). Data on graphs are presented as mean ± standard error of mean (SEM). Due to the small population, Wilcoxon matchedpairs signed rank tests were performed for non-parametric data. We provide 95% confidence intervals (CI) around the mean differences. Bonferroni corrected p values were used for PROMs with multiple subscales. We calculated effect sizes and present the rank biserial correlation in the appendix.
We present a Bayesian reanalysis of data from a previously published feasibility study of MDMA-assisted psychotherapy in AUD. Treatment success was defined as 2-level reduction in WHO drinking risk. Our analysis estimates that there is a probability of treatment success of 55%-63%, dependent upon a flat or skeptical prior respectively. Additionally, we present preliminary findings indicating reductions in alcohol craving, improvements in sleep, and self-compassion, as well as a trend toward significant improvements in several aspects of QOL. The European Medicines Agency (EMA) recommends abstinence as a primary endpoint, but also accepts intermediate harm reduction endpoints, including reductions in total alcohol consumption, reduction in heavy drinking days, or reduction in WHO drinking risk levels (European Medicines Agency 2010). The inclusion of harm reduction endpoints other than abstinence is important because most individuals who receive treatment for AUD have difficulty sustaining abstinence and many prefer drinking reduction goals. Reductions in WHO risk levels for alcohol consumption appear to be achievable, associated with better functioning, and maintained over time in both the United States and the United Kingdom. Beyond meaningful improvements in functioning, physical health, and QOL, a reduction of at least two levels in WHO risk drinking categories is also linked to lower healthcare costs over 1 and 3 years. The WHO Risk Drinking Levels of Alcohol Consumption has been accepted within the process of the FDA COA Qualification Program, but it yet to be accepted as a Full Qualification Package (FQP) (FDA 2020). Our analysis estimates treatment success of 55-63% for a 2-level reduction in WHO drinking risk at 3 months post-MDMA assisted therapy, which is consistent with success reported in other AUD trials. Specifically, secondary data analysis of patients with AUD enrolled in the two large multi-center trials, COMBINE Study and Project MATCH, report two-level WHO drinking risk reductions achieved by 68% of patients at the end of treatment, with 77.7% of those individuals maintaining that reduction at a 3-year follow-up. Although the findings reported in this paper are preliminary and of a small sample size, the treatment success of MDMAassisted psychotherapy (55%-63%) is comparable with those reported for current behavioral interventions and/or nonpsychedelic drugs for AUD as demonstrated by the secondary analysis from the COMIBINE study and Project MATCH (68%). Importantly, these results suggest that MDMAassisted psychotherapy may produce clinically meaningful reductions in alcohol consumption in a manner comparable with established treatments, warranting further investigation in larger trials. Understanding the relationship between craving and alcohol use after treatments can be useful for treatment planning and modulating intervention approaches). The OCDS is considered a robust predictor of alcohol use in the following week after assessmentbut not in longer term periods. Secondary analysis from the COMBINE trial demonstrated that craving for alcohol, assessed by a 3-item self-report Craving Scale, is strongly associated with alcohol use in the following week). We show a reduction in craving assessed using the PACS and OCDS. Future studies should determine whether craving mediates or predicts outcome response in the context of MDMA-assisted psychotherapy. There is growing recognition of the value and importance of QOL, as well as broader well-being, in healthcare and research, including in the context of AUD. QOL and well-being measures provide insights into the impact of a treatment beyond specific symptom relief, reflecting daily functioning and the perceived ability to lead a fulfilling life. Furthermore, sleep contributes to QOL and general well-being. Therefore, the assessment of QOL and sleep in AUD studies provides a more comprehensive understanding on the impact of treatment beyond just drinking behavior. We show a trend toward significant improvements in several aspects of health, specifically energy/fatigue, emotional well-being, social functioning, pain, general health, change in reported health. The improvements in social functioning are of relevance as AUD can lead to substantial problems in interpersonal relationships. Acutely MDMA produces subjective prosocial feelings, as well as enhances empathy and sociability, which are thought to contribute to its role in psychotherapy. These acute effects appear to persist as we found improvements in self-compassion and personal distress on the IRI scale. This is in-line with improvements in emotional empathy and self-compassion have been reported in recreational MDMA use. Further studies should establish the role of self-compassion and empathy in MDMA-assisted psychotherapy for AUD.
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The study sample comprised 14 participants (8 males, 6 females; mean age 48 years), all reported as white British in the extracted text. The binomial test for the predefined 2-level WHO drinking risk reduction did not reject the null hypothesis against an expected 50% success rate (k = .64, P = .423); the 95% confidence interval for the observed success rate was 0.35–0.87. Bayesian re-analysis provided probabilistic estimates of treatment success. Using the flat prior (a = 1, b = 1), the posterior probability that participants achieved a 2-level reduction in WHO drinking risk at 3 months was 63% with a 95% credible interval of 40%–85%. Using the skeptical prior (a = 1, b = 3), the posterior probability was 55% with a 95% credible interval of 33%–77%. Measures of drinking-related behaviour and craving showed reductions at 3 months versus baseline. PACS total scores decreased (difference 5.50, 95% CI 0.5–13, P = .031, rank biserial r_b = .781). On the OCDS, the obsessive subscale decreased by 5.00 (95% CI 2.00–8.50, P = .006, r_b = .868) and the compulsive subscale decreased by 5.00 (95% CI 1.00–9.00, P = .021, r_b = .769). Broad wellbeing measures showed mixed results. Several SF-36 subscales (energy/fatigue, emotional well-being, social functioning, pain, general health, and change in reported health) showed increases at 3 months, but none remained statistically significant after Bonferroni correction. Sleep improved as indicated by a reduction in total PSQI-derived score (difference 2.00, 95% CI ~7.54e-6–3.00, P = .041, r_b = .648). Self-compassion increased substantially (SCS difference 12.1, 95% CI 9.09–14.4, P < .001, r_b = 1.00). For the IRI empathy subscales, only the personal distress subscale showed a significant reduction (difference 0.5, 95% CI 0.143–0.929, P = .009, r_b = .945), with positive mean differences reported as baseline minus 3-month scores indicating reductions over time. The extracted text notes that full statistical details and supplementary tables/figures are provided in the article's supplementary materials.
Thurgur and colleagues interpret their Bayesian re-analysis as indicating a 55%–63% probability that participants achieved a clinically meaningful 2-level reduction in WHO drinking risk at 3 months following MDMA-assisted psychotherapy. They argue this harm-reduction endpoint is relevant to regulatory and clinical contexts, noting that agencies such as the EMA accept intermediate endpoints in AUD trials and that WHO risk reductions have been associated with improved functioning and lower healthcare costs. The authors compare their estimated success probabilities with secondary analyses from large AUD trials (COMBINE and Project MATCH), which reported a 68% two-level reduction at end of treatment, and suggest the MDMA-assisted psychotherapy outcomes are broadly comparable, while emphasising the preliminary nature of the data. Beyond drinking metrics, the investigators highlight reductions in craving (PACS and OCDS), improvements in sleep and self-compassion, and a decrease in personal distress as indicators that MDMA-assisted psychotherapy may yield broader psychosocial benefits. They link these findings to the known acute prosocial and empathogenic effects of MDMA and propose self-compassion and empathy as possible transdiagnostic mediators deserving further study. The authors acknowledge several important limitations: the open-label design, small sample size, exploratory multiple secondary outcomes (risking Type I error), challenges with blinding in psychedelic research, lack of long-term follow-up in this analysis, restrictive exclusion criteria (notably excluding antidepressant users and certain comorbidities) which limit generalisability, and the sample's lack of ethnic diversity. They also note that SF-36 scores can be influenced by comorbid conditions and that the extracted text did not allow adjustment for such confounds due to limited comorbidity data. Practical and implementation barriers are discussed, including the need for manualised psychotherapeutic approaches, therapist training, resource-intensive 8-hour dosing sessions with two therapists, and overnight stays used for safety in this feasibility trial. The authors suggest that future trials should be larger, randomised, placebo-controlled, measure deblinding and expectancy, include more diverse and representative samples, assess mediation by craving, and evaluate whether more time- and cost-efficient models of MDMA delivery and therapy could be developed.
The paper extends previously reported safety and tolerability data by providing a Bayesian estimate of treatment success for MDMA-assisted psychotherapy in AUD, framing success as a 2-level reduction in WHO drinking risk and estimating a 55%–63% probability of achieving this at 3 months. Preliminary secondary findings suggest reductions in alcohol craving and improvements in sleep, self-compassion and some aspects of wellbeing, but the authors emphasise these are hypothesis-generating results from a small, open-label sample. They recommend larger, placebo-controlled trials using these measures to determine the efficacy and practical feasibility of MDMA-assisted psychotherapy for AUD.