In an open‑label study of 14 participants with alcohol use disorder, clinically administered MDMA produced no post‑acute mood declines ('Blue Mondays'); participants maintained positive mood in the week after dosing, reported improved sleep at 3‑ and 6‑month follow‑ups, and none sought illicit MDMA. These results support the safety and tolerability of therapeutic MDMA and suggest previously reported come‑downs are likely due to illicit sourcing and recreational settings rather than clinical use.
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Background
Incorporating 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct to psychotherapy has shown promise in recent years for treating various mental health conditions, particularly those involving trauma. However, concerns about declines in mood and cognition during the days following dosing, also known as ‘Blue Mondays’, have been raised as limitations to its clinical use. Although these changes have been well-documented among recreational users, there are critical confounds to these reports that limit generalizability to clinically administered MDMA.
Aims
Here, we aimed to evaluate the evidence basis for the negative side effects associated with MDMA as well as inform our understanding of the drug’s post-acute effects in a clinical context with an open-label study.
Methods
The current open-label study examined MDMA therapy for alcohol use disorder (AUD; N = 14) and measured mood, sleep quality, illicit MDMA consumption and anecdotal reports after the acute drug effects had worn off.
Results
Participants maintained a positive mood during the week following drug administration in a clinical context. Relative to baseline, self-reported sleep quality improved at the 3- and 6-month follow-ups. Finally, no participants reported using or desiring to use illicit MDMA, and the anecdotal reports indicated that they perceived the treatment favourably.
Conclusion
The results support the overall safety and tolerability of clinically administered MDMA and, importantly, suggest that the ‘come downs’ previously associated with the substance may be explained by confounds in research relating to the illicit sourcing of the drug and specific environmental setting for recreational consumption.
MDMA (3,4-methylenedioxymethamphetamine) is being investigated as an adjunct to psychotherapy for conditions such as post-traumatic stress disorder and alcohol use disorder. However, public and scientific concerns about harms—including alleged neurotoxicity, potential for misuse and post-acute cognitive or affective impairments commonly referred to as 'come downs' or 'Blue Mondays'—have impeded clinical research. The authors argue that many of these adverse-effect narratives derive from studies of recreational use, where illicit drug adulteration, polydrug use and adverse environmental conditions (dehydration, overheating, sleep loss) confound causal attribution to MDMA itself. Sessa and colleagues set out to examine post-acute effects of clinically administered MDMA in a controlled therapeutic context. Specifically, the study evaluated mood during the week after dosing, longer-term sleep quality, subsequent illicit MDMA use or cravings, and participants' anecdotal experiences in an open-label within-subject trial of MDMA-assisted therapy for people with alcohol use disorder (AUD). The intent was to test whether the negative post-acute effects reported in recreational settings would be observed when MDMA purity, dose and context were controlled.
This was an open-label, within-subject safety and tolerability study of MDMA-assisted therapy for AUD conducted at Imperial College London with ethical and regulatory approvals from the relevant UK bodies. The investigational product was GMP-grade MDMA supplied as 62.5 mg capsules and formulated locally. Recruitment came from a regional substance-misuse service; 36 individuals were screened and 14 participants were enrolled (8 male, 6 female; mean age 48 years; all white British). The trial comprised an 8-week therapy course with 10 psychotherapy sessions. Dosing occurred during sessions 3 and 7. On each dosing day participants received an initial oral dose of 125 mg MDMA followed by a 62.5 mg booster 2 hours later; dosing sessions lasted 6–8 hours and patients stayed overnight with monitoring by a non-therapeutic night sitter. Non-dosing sessions comprised approximately 1 hour of therapy using motivational interviewing and recovery-based approaches. The primary outcomes reported elsewhere related to acute safety and alcohol consumption; this paper focuses on post-acute mood, sleep quality, illicit MDMA use/craving and qualitative anecdotes. Mood was measured with the Profile of Mood States (POMS), a 65-item inventory yielding a total score where lower values indicate more positive mood. Participants completed the POMS once daily for 7 days after each of the two dosing sessions; the two 7-day series were averaged per participant and analysed with a one-way ANOVA across Days 1–7. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) at baseline, 3 months and 6 months; lower PSQI scores denote better sleep. Binary self-report questions (yes/no) assessed illicit MDMA use and desire at session 10 and at 3-, 6- and 9-month follow-ups. Open-ended responses were collected on non-dosing days about expectations and experiences. Analyses were performed in SPSS v26; POMS totals underwent a one-way ANOVA with seven Day levels, and PSQI totals a one-way ANOVA with three Time levels. The extracted text does not provide full inclusion/exclusion criteria within this document nor any biomarker verification procedures for substance abstinence; those details are referred to elsewhere.
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Fourteen participants completed the protocol and provided data for the post-acute assessments. Demographically, four were employed, nine unemployed and one retired; the sample had a high prevalence of alcohol-related harms (e.g. 64% reported alcohol-related blackouts, 75% reported forensic/offending behaviour secondary to alcohol use). Acute physiological monitoring showed the expected mild rises in blood pressure, heart rate and temperature during MDMA sessions but no sustained physiological disturbances requiring medical intervention. One participant experienced an abnormal blood-pressure increase related to having missed an antihypertensive medication; otherwise measures remained within normal limits. Subjective Units of Distress ratings indicated the acute MDMA experience was overall positive and non-distressing. POMS total scores, averaged across the two dosing episodes, were analysed by one-way ANOVA across post-dose Days 1–7. The Day effect was non-significant, F(6, 7) = 0.143, p > 0.05, indicating no detectable decline in mood during the week after dosing. The authors describe participant mood as overall positive during that week—interpreted as an 'afterglow' rather than a 'come down'. PSQI total scores changed over time. The one-way ANOVA across Baseline, 3 months and 6 months was significant, F(2, 11) = 7.09, p < 0.01. Baseline mean PSQI was 9.57 (SD = 4.07), declining to 7.07 (SD = 4.53) at 3 months and 7.14 (SD = 4.72) at 6 months, consistent with improved sleep quality following MDMA therapy. Self-reported illicit MDMA use and desire to use were zero at session 10 and at 3-, 6- and 9-month follow-ups: no participant endorsed having used or wanting to use illicit MDMA. Open-ended anecdotal responses were predominantly positive; only isolated negative comments were recorded (one participant noted initial pre-dosing worry and one disliked a particular musical track). The extracted text does not present formal qualitative coding procedures or counts beyond reporting generally positive responses.
Sessa and colleagues interpret their findings as evidence that clinically administered, GMP-grade MDMA delivered in a controlled therapeutic context does not produce the post-acute affective declines commonly described in recreational settings. They attribute the discrepancy between clinical and recreational literature to several confounds in the latter: illicit product adulteration, concurrent drug use, uncertain dosing and environmental stressors such as dehydration, overheating and sleep loss. In line with this account, participants in the present clinical trial showed no significant mood drops during the week after dosing and in fact maintained positive mood. The authors note the observed improvements in sleep quality at 3 and 6 months, and relate these changes partly to reductions in alcohol consumption after treatment as well as concordance with prior studies of MDMA therapy for PTSD and life-threatening illness. They also point out that none of the participants reported seeking or desiring illicit MDMA following exposure in the trial, which they interpret as evidence that clinical administration does not promote drug-seeking in this sample; the authors acknowledge that Phase II and Phase III trials have reported similarly low rates of post-trial illicit use. Several limitations acknowledged by the study team temper these inferences. The open-label design and small sample size were mandated by regulators for this exploratory AUD trial, which limits generalisability and the ability to detect smaller effects. Abstinence from alcohol and illicit MDMA was measured by self-report rather than biochemical verification. The sample was limited to people with AUD and all were white British; consequently it is unclear whether the absence of post-acute mood drops and the sleep improvements would generalise to healthy participants or other clinical populations. The investigators also recognise that therapeutic support and reductions in alcohol use may themselves buffer mood and sleep outcomes, and thus disentangling direct pharmacological effects from indirect therapeutic effects requires further research. The authors conclude that when dose, purity and set-and-setting are controlled in clinical environments, many of the post-acute risks historically associated with MDMA appear mitigated. They recommend further studies—ideally with larger, controlled samples and objective substance-use verification—to determine the generalisability of these findings and to clarify mechanisms underlying the observed afterglow and sleep improvements.
The study concludes that clinically administered MDMA, given at controlled doses and purity within a therapeutic setting, was not associated with a measurable decline in mood during the week after dosing in this sample of people with alcohol use disorder. Improvements in sleep quality at 3 and 6 months were observed, and no participants reported using or desiring illicit MDMA during follow-up. The authors infer that many post-acute adverse effects reported in recreational contexts may reflect contextual confounds rather than intrinsic effects of MDMA when used clinically.