Acute effects of MDMA and LSD co-administration in a double-blind placebo-controlled study in healthy participants

Straumann and colleagues frame the study within renewed clinical interest in LSD as a serotonergic psychedelic with generally positive acute subjective effects but a risk of negative experiences such as acute anxiety. The authors note that positive acute psychedelic experiences are associated with better long-term therapeutic outcomes in psychedelic-assisted therapy, and that reducing acute anxiety or increasing positive mood during the acute drug experience might therefore be desirable. MDMA, an empathogen that produces marked positive subjective effects (well-being, trust, closeness), is often co-used with LSD recreationally (“candyflipping”), and anecdotal reports suggest synergistic mood-enhancing effects. The present study tested whether co-administration of MDMA could optimise the acute subjective effect profile of LSD in a controlled laboratory setting. The primary hypothesis was that giving MDMA together with LSD (both at defined doses) would increase measures of “good drug effects,” well-being, openness and trust while reducing “bad drug effects” and anxiety compared with LSD alone. This is the first controlled trial, according to the authors, to evaluate the combined administration of MDMA and LSD with analytically confirmed doses and comprehensive psychometric, autonomic, endocrine, and pharmacokinetic outcomes.

The investigators used a randomized, double-blind, placebo-controlled, within-subject crossover design with four experimental sessions per participant: placebo, 100 mg MDMA, 100 µg LSD, and 100 µg LSD + 100 mg MDMA. Treatments were block-randomized and counterbalanced, with washout intervals of at least 10 days. The study was approved by the relevant ethics committee, complied with Good Clinical Practice, and was registered at ClinicalTrials.gov (NCT04516902). Twenty-four healthy volunteers (12 men, 12 women; mean age 30 ± 7 years, range 25–54) completed the study. Key exclusion criteria included pregnancy, a personal or first-degree family history of major psychiatric disorders, interfering medications, significant physical illness, heavy tobacco use (>10 cigarettes/day), lifetime hallucinogen or MDMA use >20 times, recent illicit drug use (within 2 months, except THC), and illicit drug use during the study. Participants were asked to limit alcohol intake prior to sessions. Prior recreational drug experience varied across the sample; a minority were drug-naïve. Study drugs were analytically characterised: LSD base solution targeted 100 µg (mean measured content 92.5 ± 1.89 µg) administered as 1 ml oral solution, and MDMA hydrochloride was given in four opaque capsules of 25 mg each (analytically confirmed 25.40 ± 0.48 mg per capsule), producing a 100 mg MDMA dose. A double-dummy approach was used so that each session involved one solution and four capsules; participants guessed treatment assignment after sessions to assess blinding. Sessions lasted 13 hours with standardised meals and a calm hospital setting; one subject and one investigator were present. Subjective effects were assessed repeatedly using visual analogue scales (VASs), the Adjective Mood Rating Scale (AMRS), and the 5 Dimensions of Altered States of Consciousness (5D-ASC) with the 5D-ASC administered 12 hours post-dose as the primary outcome measure. Mystical-type experiences were measured with the States of Consciousness Questionnaire (MEQ variants) at 12 hours. Autonomic measures (blood pressure, heart rate, tympanic temperature) and pupil size were recorded at frequent intervals. Plasma oxytocin and serum BDNF were sampled at specified time points, and plasma concentrations of LSD, MDMA and metabolites were measured up to 24 hours. Pharmacokinetic parameters were estimated non-compartmentally. Repeated-measures ANOVA with Tukey post hoc tests was used for statistical comparisons, with significance at p < 0.05.

Primary sample characteristics: 24 subjects completed all four conditions. No severe adverse events occurred. Subjective effects: The LSD + MDMA combination produced subjective responses that were overall comparable in quality to LSD alone on the VAS, 5D-ASC, MEQ and AMRS; the primary outcome (5D-ASC) showed no significant differences between LSD and LSD + MDMA. Both LSD and LSD + MDMA induced substantially greater psychedelic effects than MDMA alone, increasing dimensions such as “any drug effects,” “good drug effects,” ego dissolution, alteration of vision, and audio–visual synesthesia. Ratings of “drug high” were similar across MDMA, LSD and the combination. The anxiety subscale of the 5D-ASC showed only a trend-level increase with LSD (p = 0.073). On the AMRS, LSD and the combination produced more emotional excitation, introversion, anxiety and depression than MDMA. The only timing difference of note was that subjective “any drug effects” lasted longer after the LSD + MDMA condition (mean 9.9 h) than after LSD alone (mean 8.4 h; p < 0.05). Autonomic and adverse effects: MDMA and the LSD + MDMA combination produced greater increases in blood pressure, heart rate and pupil size than LSD alone; body temperature rose similarly after LSD and LSD + MDMA and less after MDMA alone. Total acute and subacute adverse effect scores were similar for LSD and LSD + MDMA and exceeded those for MDMA alone. Frequently reported complaints (headache, lack of energy, loss of appetite, dry mouth) occurred at similar rates across active conditions; acute nausea was more common with MDMA than with LSD. No instances of serotonin toxicity were reported. Endocrine and neurotrophic markers: MDMA alone and LSD + MDMA produced robust increases in plasma oxytocin, with greater peak increases than LSD alone; effects appeared additive when combined. None of the active conditions produced significant changes in serum BDNF. Pharmacokinetics: Co-administration of MDMA altered LSD pharmacokinetics. Measured LSD Cmax was higher with LSD + MDMA (2.1 ng/mL) than with LSD alone (1.9 ng/mL; T = 2.09; p < 0.05). The elimination half-life of LSD increased from 3.9 h (LSD alone) to 5.2 h with the combination (T = 5.00; p < 0.001). The AUC∞ rose from 14 ng·h/mL to 19 ng·h/mL with MDMA co-administration (T = 3.53; p < 0.01). These pharmacokinetic changes are consistent with the longer subjective effect duration observed with the combination. Blinding: Retrospective guesses indicated imperfect blinding: during LSD + MDMA, about 50% of participants thought they had received LSD alone; during LSD alone, a minority thought they had received the combination. At study end, 25% of participants confused LSD and LSD + MDMA.

Straumann and colleagues interpret the principal finding as that MDMA co-administration did not meaningfully change the qualitative acute psychedelic effects of LSD but did prolong the duration of LSD’s subjective effects and increased autonomic stimulation. The prolonged psychedelic response corresponded to higher LSD plasma exposure (Cmax and AUC) and a longer elimination half-life when MDMA was co-administered. The authors therefore conclude the interaction is primarily pharmacokinetic rather than pharmacodynamic. They suggest that MDMA’s inhibition of the cytochrome P450 enzyme CYP2D6 may underlie the increased LSD exposure, noting that MDMA is a strong CYP2D6 inhibitor and that CYP2D6 poor metabolizers have higher LSD plasma concentrations and longer half-lives. From this, the authors raise the clinical concern that concomitant use of LSD with medications that inhibit CYP2D6 (for example certain antidepressants) could similarly increase LSD exposure and warrants further study. Relative to earlier work, the study adds the first controlled human data on MDMA + LSD co-administration. Although recreational reports suggest synergistic mood effects, the controlled data did not show clear improvements in measures of positive mood or reductions in anxiety when MDMA was added to a moderately high LSD dose (100 µg). The authors note some nonsignificant early trends toward greater happiness, openness and trust with the combination, and they acknowledge that different dose levels or timing (for example administering MDMA later, using extended-release MDMA, or combining MDMA with a psychedelic of similar duration such as psilocybin) might produce different interactions. Limitations acknowledged by the authors include the testing of only a single dose level of each drug, administration at the same time point, a highly controlled hospital setting, and recruitment of healthy volunteers rather than clinical populations. They also note that the psychometric instruments used may not capture all subtle experiential differences. Finally, the authors report no signal of increased serotonin toxicity with the combination and attribute greater cardiovascular effects to MDMA’s noradrenergic action.

The authors conclude that adding MDMA (100 mg) to LSD (100 µg) does not meaningfully change the acute subjective psychedelic profile of LSD but does prolong LSD’s effects by increasing plasma exposure and elimination half-life, and it increases autonomic stimulation. Given these findings, they state there is likely little benefit to combining MDMA and LSD in psychedelic-assisted therapy and caution that CYP2D6 inhibition (by MDMA or certain medications) can increase LSD exposure and should be considered in clinical contexts.