Comparison of acute effects of 3,4-methylenedioxymethamphetamine (MDMA) with and without a supplemental booster dose in healthy participants: a double-blind, randomized, placebo-controlled, crossover study

MDMA produces acute emotional and physiological effects through serotonergic, noradrenergic and oxytocin-related mechanisms, and MDMA-assisted psychotherapy is being investigated for several psychiatric disorders, especially post-traumatic stress disorder. In Phase 2 and Phase 3 trials, MDMA has commonly been given as a split dose, with a second “booster” dose 1.5-2.5 h later, but the actual benefits and risks of this practice had not been systematically tested. Earlier work also suggested that MDMA shows acute pharmacological tolerance, meaning that subjective and autonomic effects can decline before plasma concentrations fall, making it uncertain whether a booster dose truly extends the acute experience. Humbert-Droz and colleagues therefore set out to directly compare a standard split-dose regimen with a single MDMA dose in healthy volunteers. Their main aim was to test whether a 60 mg booster given 2 h after 120 mg MDMA would prolong the duration of subjective drug effects, with further outcomes including tolerability, autonomic responses, endocrine markers and pharmacokinetics. The study was designed to inform whether the split-dose approach used in MDMA-assisted therapy meaningfully changes the acute drug response.

This was a Phase 1, double-blind, placebo-controlled, crossover study conducted at the University Hospital Basel. Participants completed three 10 h dosing sessions in a quiet hospital room: 120 mg MDMA followed by 60 mg placebo after 2 h, 120 mg MDMA followed by a 60 mg MDMA booster after 2 h, and placebo followed by placebo. The extracted text states that full eligibility criteria are in the Supplementary Methods and Materials, but does not clearly list them in the main text. Twenty-five healthy volunteers were enrolled and 23 completed all dosing sessions; the final sample included 12 men and 11 women, with a mean age of 35 years. The study drug was racemic MDMA in oral capsules containing 20 mg MDMA hydrochloride, with matching placebo capsules containing mannitol. Randomisation, packaging, labelling and quality control were carried out under Good Manufacturing Practice. Participants attended screening, three dosing visits and an end-of-study visit. The dosing sessions started at 8 am, baseline safety measures were taken on arrival, the first dose was given around 9 am, and the second dose exactly 2 h later. Participants remained under continuous supervision, and outcomes were assessed repeatedly over 9 h; additional questionnaires were completed at 3 and 7 days after dosing. The primary outcome was the duration of the VAS item “any drug effect”, defined as the cumulative time this rating stayed above 10%. Subjective effects were measured with repeated visual analogue scales, including items for drug liking, good and bad drug effects, stimulation, anxiety, and social/emotional effects, and mood was assessed with the Adjective Mood Rating Scale. Adverse effects were measured with the revised List of Complaints, which was also used at 3 and 7 days, and mental well-being and sleep were assessed with the GHQ-12, WEMWBS and ISI. Blood pressure, heart rate and temperature were recorded serially; plasma MDMA, MDA and HMMA were measured throughout the session; and oxytocin and neurophysin I were measured before dosing and at 2, 4 and 6 h. Pharmacokinetic parameters were estimated using non-compartmental analysis in Phoenix WinNonlin. The sample size calculation indicated that 20 participants would provide 80% power to detect a within-subject difference of moderate effect size. Repeated-measures ANOVA with condition as the within-subject factor was used, followed by Tukey post hoc tests. The analyses were performed in jamovi and KNIME, with two-sided significance testing at p < 0.05. Exploratory analyses stratified adverse effects by sex, body weight and age.

Twenty-five participants were included, two dropped out after the first session, and 23 completed all dosing conditions. The participants were 12 men and 11 women, with mean age 35 ± 13 years and mean body weight 67 ± 12 kg. Ten participants had prior MDMA experience. Blinding was not complete: all participants correctly identified placebo, and 76% of MDMA conditions were identified immediately after dosing, rising to 87% by study end. The primary endpoint showed that the booster dose prolonged subjective effects. The duration of “any drug effect” was 5.6 ± 1.8 h after MDMA plus booster versus 4.6 ± 1.2 h after MDMA plus placebo, a significant difference (p = 0.001). Peak subjective intensity did not differ between the two MDMA conditions. Several other subjective effects had higher areas under the effect-time curve with the booster, and AMRS “well-being” scores were higher at 4 and 6 h after the booster condition. The authors also describe acute pharmacological tolerance in both MDMA conditions. Acute adverse effects were more common with both MDMA conditions than with placebo. The most frequent were tiredness, loss of appetite, bruxism and headache. Emesis occurred in 13% during the booster condition and 9% during the single-dose condition. Somatic complaints generally lessened by days 3 and 7, but psychological complaints such as rumination, fatigue, inner tension and restlessness persisted to days 3 and 7. In exploratory analyses, List of Complaints scores appeared higher in women and in participants weighing under 65 kg, particularly after the booster dose. GHQ-12 and WEMWBS did not differ between conditions, while ISI scores suggested slightly better sleep 4-7 days after the booster. One serious adverse event occurred: acute angle-closure glaucoma during the single-dose MDMA session, with full recovery after treatment. Two women withdrew after receiving the booster condition in their first-ever MDMA session; both had intense acute symptoms followed by weeks of psychological instability and received psychological support. Two men reported brief flashback-like experiences after MDMA. In endocrine analyses, both MDMA conditions increased oxytocin and neurophysin I versus placebo, and the booster produced higher concentrations at 4 and 6 h than single-dose MDMA; the two markers were strongly correlated (r = 0.86, p < 0.0001). Autonomic measures increased under both MDMA conditions versus placebo, with a longer duration but not a higher peak after the booster. No systolic blood pressure above 180 mmHg or hyperpyrexia above 40°C was observed. Routine laboratory measures did not change. Pharmacokinetically, MDMA exposure increased dose-proportionally after the booster, and the elimination half-life was 7.2 h in both conditions.

The authors interpret the study as showing that the commonly used split-dose MDMA regimen does prolong the acute drug experience, but by a relatively modest amount. The booster extended subjective effects by about 1 h on average and also prolonged several social and affective effects, as well as oxytocin release and autonomic activation, without increasing peak subjective or physiological responses. In their view, this pattern is consistent with acute pharmacodynamic tolerance: plasma MDMA concentrations rose further after the booster, yet maximal effects did not increase, and acute effects still subsided while drug levels remained high. They compare these findings with earlier work showing that repeated MDMA dosing can produce similar effect-time profiles despite higher plasma concentrations, and they suggest that prolongation of effects may be enhanced by redosing intervals or dosing schedules. The authors note that the split-dose regimen used in the study matches the most common regimen in MDMA-assisted therapy trials, where an initial 120 mg dose plus 60 mg booster is often used after earlier lower-dose sessions. They argue that the prolonged pro-social and affective effects, together with increased oxytocin, could be advantageous in psychotherapy, but they explicitly state that added clinical benefit remains unproven. The paper also emphasises safety and tolerability considerations. Although no acute serious safety signal emerged from the booster itself, the total 180 mg dose may be too high for some subgroups, and exploratory patterns suggested more adverse effects in women and in participants under 65 kg. The authors raise the possibility that lower doses, omission of the booster, or body-weight-adjusted dosing may be safer in some people. They also note a serious case of acute angle-closure glaucoma after single-dose MDMA, which they consider potentially relevant because of known risk factors such as narrow angles. Overall, they regard the regimen as generally well tolerated in healthy volunteers, but say the findings need confirmation in patient populations. The main limitations they acknowledge are the healthy, relatively young sample, which limits generalisability to clinical populations; the possibility of recall bias because adverse effects were not assessed daily; and the inability to disentangle sex from body weight because these characteristics were strongly correlated. Strengths included the randomised placebo-controlled within-subject design, the relatively large sample for this type of study, long washout periods, and comprehensive assessment of subjective, physiological, endocrine and pharmacokinetic outcomes.