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

LSD is a classic serotonergic psychedelic under renewed clinical investigation for conditions such as anxiety and depression. While it typically induces positive alterations of consciousness, acute negative effects (e.g., anxiety) can occur and are considered major risks. Positive acute psychedelic experiences have been linked to better long-term therapeutic outcomes, and lower acute anxiety predicts better clinical response. MDMA, investigated in MDMA-assisted therapy, reliably increases positive mood, empathy, trust, and closeness. Recreational co-use of LSD and MDMA (“candyflipping”) is reported to enhance positive mood. The present study asked whether co-administering MDMA with LSD would improve the acute subjective effects profile of LSD—specifically, increase positive mood (good drug effects, well-being, openness, trust) and reduce negative effects (bad drug effects, anxiety) compared with LSD alone. The primary hypothesis was that LSD + MDMA would yield higher positive and lower negative acute subjective ratings than LSD alone.

Prior human studies show LSD produces strong positive psychedelic experiences but can also increase anxiety; positive acute experiences relate to better clinical outcomes. MDMA produces robust positive, prosocial effects and is being evaluated for PTSD. Recreational reports suggest synergistic positive mood from LSD + MDMA, but no controlled human study had evaluated this combination. Animal work indicated synergistic discriminative effects of LSD and MDMA, and prior human studies compared LSD and MDMA effects separately. LSD acts primarily via 5-HT2A receptor agonism, whereas MDMA releases serotonin, norepinephrine, and oxytocin. Pharmacogenetic work implicates CYP2D6 in MDMA kinetics and, separately, in LSD metabolism, suggesting potential pharmacokinetic interactions when co-administered.

Design: Double-blind, randomized, placebo-controlled, within-subjects crossover with four sessions: (i) placebo, (ii) MDMA 100 mg, (iii) LSD 100 µg, (iv) LSD 100 µg + MDMA 100 mg. Order counterbalanced in blocks; washout ≥10 days. Conducted per GCP and Declaration of Helsinki; approved by Ethics Committee Northwest Switzerland (EKNZ) and Swiss Federal Office of Public Health; registered at ClinicalTrials.gov (NCT04516902). Participants: 24 healthy adults (12 women, 12 men; mean age 30±7 years; range 25–54). Key exclusions: major psychiatric disorders (self or first-degree family), interfering medications (e.g., antidepressants, antipsychotics, sedatives), significant medical illness, tobacco >10 cig/day, lifetime use >20 of hallucinogens or MDMA, recent illicit drug use (2 months) or during study (urine screens). Some participants had limited prior experience with psychedelics/MDMA/stimulants; 4 had only cannabis use. Drugs and dosing: LSD base oral solution, nominal 100 µg (analytical mean 92.5±1.89 µg) in 1 mL 96% ethanol; MDMA HCl in opaque capsules, 4×25 mg (analytical mean per capsule 25.40±0.48 mg). Double-dummy: in each session, four capsules plus one solution according to condition. Administration at 09:00. Procedures: Sessions ran 13 hours (08:00–21:15) with standardized meals; participants continuously monitored and not left alone during acute effects; follow-up at 24 h and end-of-study visit ~31 days post last session. Blinding assessed during/after each session and end of study by treatment guess. Outcome measures: Subjective effects—Visual Analog Scales (VAS) repeatedly from pre-dose to 24 h; Adjective Mood Rating Scale (AMRS) at 3,6,9,12,24 h; 5 Dimensions of Altered States of Consciousness (5D-ASC) at 12 h for peak retrospective ratings; States of Consciousness Questionnaire (SOCQ) including MEQ43/MEQ30 and subscales at 12 h. Effect timing metrics (onset, tmax, offset, duration) from VAS “any drug effect” using 10% threshold. Autonomic/adverse effects: Blood pressure, heart rate, tympanic temperature repeatedly baseline to 24 h; pupil size at specified timepoints; adverse effects via List of Complaints at 12 h and 24 h. Endocrine/biomarkers: Plasma oxytocin at baseline, 1.5, 3, 6 h; serum BDNF at baseline, 3, 6, 9, 12, 24 h. Pharmacokinetics: Plasma concentrations of LSD and O-H-LSD; MDMA, MDA, HMMA (after deglucuronidation) at frequent intervals through 24 h; stored at −80°C; quantified by (U)HPLC-MS/MS (LSD LLOQ 10 pg/mL). Non-compartmental PK analyses in Phoenix WinNonlin 8.3. Statistics: For repeated measures, Emax/Emin or ΔEmax from baseline computed; repeated-measures ANOVA with drug as within-subject factor; Tukey post hocs. Significance p<0.05. Software: R 4.2.1 and Statistica 12.

- Subjective effects: LSD + MDMA produced subjective effects comparable in quality and peak magnitude to LSD alone across VAS, 5D-ASC, MEQ, and AMRS; no significant differences in Emax. Both LSD and LSD + MDMA elicited significantly greater psychedelic effects than MDMA alone (e.g., higher “any drug effect,” “good drug effect,” “ego dissolution,” “alteration of vision,” “audio-visual synesthesia”). Ratings of “drug high” were similar across MDMA, LSD, and LSD + MDMA. - Duration: The LSD + MDMA combination prolonged subjective “any drug effect” duration by about 1.5 h vs LSD alone (mean 9.9 h vs 8.4 h; p<0.05). - 5D-ASC: LSD and LSD + MDMA increased all main dimensions and subscales except “anxiety” (trend with LSD, p=0.073). MDMA alone significantly increased only the lower-order “blissful state.” - Mood (AMRS): LSD and LSD + MDMA produced more emotional excitation, introversion, anxiety, and depression vs MDMA. Some early nonsignificant trends toward higher “happy/open/trust” with the combination versus LSD alone were noted. - Autonomic effects: MDMA alone and LSD + MDMA increased systolic/diastolic/mean arterial blood pressure, heart rate, and pupil size more than LSD alone. Body temperature increases were similar for LSD and LSD + MDMA, both greater than MDMA alone. - Adverse effects: Total acute and subacute List of Complaints scores were similar for LSD and LSD + MDMA and greater than MDMA alone. Common adverse events included headache, lack of energy, loss of appetite, dry mouth; acute nausea more frequent with MDMA than LSD. No severe adverse events occurred. - Endocrine/biomarkers: Oxytocin increased robustly with MDMA alone and LSD + MDMA, exceeding LSD alone; effects were additive when combined. No significant effects on serum BDNF for any condition. - Pharmacokinetics: Co-administration modestly increased LSD exposure: higher Cmax (approx. 2.1 vs 1.9 ng/mL; T=2.09; p<0.05), longer elimination half-life (approx. 5.2 vs 3.9 h; T=5.00; p<0.001), and higher AUC (approx. 19 vs 14 ng·h/mL; T=3.53; p<0.01) with LSD + MDMA vs LSD alone, consistent with prolonged subjective effects. Blinding: Participants often confused LSD and the combination (e.g., during/after LSD + MDMA, 50%/46% thought LSD alone).

The central finding is that adding 100 mg MDMA to 100 µg LSD does not meaningfully alter the qualitative profile or peak intensity of LSD’s acute subjective effects but does prolong the experience. The prolongation aligns with increased LSD plasma exposure (Cmax and AUC) and longer elimination half-life during co-administration, indicating a primarily pharmacokinetic interaction rather than pharmacodynamic synergy. Mechanistically, MDMA’s strong inhibition of CYP2D6 likely slows LSD metabolism; prior work has shown higher LSD exposure in CYP2D6 poor metabolizers. Clinically, co-administration heightened autonomic stimulation (blood pressure, heart rate, mydriasis) without evidence of enhanced thermogenesis or serotonin toxicity. The data suggest that, despite MDMA’s empathogenic properties and recreational reports of enhanced mood with “candyflipping,” the combination does not yield clinically meaningful improvements over LSD alone in terms of positive subjective effects or safety in this dosing/timing paradigm. The findings also imply that concomitant medications that inhibit CYP2D6 (e.g., some antidepressants) could increase LSD exposure in therapeutic settings and warrant careful consideration. Some early-phase trends toward higher positive mood constructs with the combination and timing mismatches between MDMA and LSD effects hint that different dosing regimens or staggered administration might produce different outcomes, but this remains to be tested.

Co-administering MDMA (100 mg) with LSD (100 µg) did not enhance the quality of acute psychedelic effects compared with LSD alone, but it prolonged the duration of effects and increased autonomic stimulation. The prolongation is consistent with a pharmacokinetic interaction whereby MDMA inhibits LSD metabolism (likely via CYP2D6), increasing LSD exposure. Given the lack of improved subjective benefit and the greater cardiovascular stimulation, the combined use is unlikely to offer advantages over LSD alone in psychedelic-assisted therapy. Future research could evaluate different dose levels, staggered timing (e.g., administering MDMA after LSD), or alternative combinations (e.g., MDMA with psilocybin) with matched time courses, and assess interactions with common CYP2D6-inhibiting medications used in psychiatric populations.

- Single fixed doses (LSD 100 µg; MDMA 100 mg) and simultaneous co-administration; results may differ at other dose levels or with staggered timing. - Healthy volunteer sample (N=24) limits generalizability to patient populations and larger clinical settings. - The LSD dose was moderately high with relatively low anxiety; MDMA might differentially affect responses at higher LSD doses. - The MDMA dose (100 mg) is slightly lower than the 120–125 mg often used in some research/patient settings; sex-related pharmacokinetics may modulate effects. - Study assessed acute effects up to 24 h; no long-term outcomes were measured. - Some subjective measures rely on retrospective ratings (e.g., 5D-ASC at 12 h), which may introduce recall bias.