Lysergic acid diethylamide (LSD), a classic serotonergic psychedelic, shows promise in treating psychiatric conditions like anxiety and depression. While LSD primarily induces positive acute experiences, negative effects, such as anxiety, can occur. Positive acute experiences are linked to better long-term therapeutic outcomes in psychedelic-assisted therapy. 3,4-Methylenedioxymethamphetamine (MDMA) produces largely positive subjective effects and is recreationally combined with LSD ("candyflipping"). This study hypothesized that MDMA co-administration would enhance LSD's positive mood effects and reduce anxiety. The primary hypothesis was that MDMA and LSD co-administration would increase "good drug effects," well-being, openness, and trust, while decreasing "bad drug effects" and anxiety compared to LSD alone. The lack of prior controlled studies investigating this combination prompted this research.

Existing literature highlights LSD's potential in psychiatric treatment, noting the association between positive acute experiences and successful long-term outcomes. Studies have shown that positive psychedelic-induced experiences are associated with more positive long-term therapeutic improvements in patients in psychedelic-assisted therapy [1, 10–13]. Conversely, MDMA research indicates its ability to induce positive subjective effects, including increased well-being, empathy, and trust [3, 17–19]. Anecdotal reports suggest synergistic positive mood effects from the combined use of MDMA and LSD ("candyflipping") [20–24], but controlled research was lacking before this study.

A double-blind, randomized, placebo-controlled, crossover design was employed with 24 healthy participants (12 men, 12 women; mean age 30 ± 7 years). Participants underwent four 13-hour test sessions, separated by at least 10 days, receiving: (i) placebo, (ii) 100 mg MDMA, (iii) 100 µg LSD, and (iv) 100 µg LSD + 100 mg MDMA. Block randomization with counterbalanced treatment order was used. Subjective effects were assessed using visual analog scales (VAS), the Adjective Mood Rating Scale (AMRS), the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale, and the States of Consciousness Questionnaire (SOCQ). Autonomic effects (blood pressure, heart rate, body temperature, pupil size) and adverse effects (List of Complaints) were also monitored. Plasma levels of oxytocin and BDNF were measured. Plasma concentrations of LSD and MDMA and their metabolites were determined using ultra-high-performance liquid chromatography tandem mass spectrometry and high-performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were estimated using non-compartmental methods. Peak or peak change from baseline values were analyzed using repeated-measures analysis of variance (ANOVA) with Tukey post hoc tests.

The LSD + MDMA combination did not significantly differ from LSD alone in subjective effects measured by VAS, 5D-ASC, MEQ, or AMRS. However, the LSD + MDMA combination prolonged subjective effects by an average of 1.5 hours compared to LSD alone. This longer duration correlated with significantly higher LSD plasma concentrations (Cmax and AUC) and a longer elimination half-life when co-administered with MDMA. The combination also resulted in greater increases in blood pressure, heart rate, and pupil size than LSD alone. Both MDMA alone and the LSD + MDMA combination significantly increased oxytocin levels compared to LSD alone, suggesting an additive effect. There were no significant differences in adverse effects between LSD and the combination, although both resulted in more adverse effects than MDMA alone. MDMA appeared to inhibit the metabolism of LSD, leading to prolonged effects, while there was no substantial alteration of the subjective profile.

The study's primary finding, that MDMA co-administration did not significantly alter LSD's qualitative subjective effects, contradicts anecdotal reports of synergistic effects. The observed prolongation of LSD's effects, however, is attributable to pharmacokinetic interactions, specifically MDMA's inhibition of CYP2D6, an enzyme involved in LSD metabolism. This inhibition likely led to increased LSD plasma concentrations and longer half-life. The additive effect on oxytocin release is interesting and requires further research regarding its contribution to the overall subjective experience. The lack of significant differences in adverse effects between LSD and the combination is reassuring, though the higher cardiovascular effects should be noted. The limitations of this study include testing only single doses of both substances and simultaneous administration. Future research should explore different dose combinations and alternative administration time points.

This study demonstrates that MDMA co-administration does not qualitatively alter the acute subjective effects of LSD but does prolong them by inhibiting LSD's metabolism. The combination produces greater autonomic stimulation than LSD alone. These findings suggest that combining MDMA and LSD in psychedelic-assisted therapy offers limited benefits compared to LSD alone. Future research should investigate the effects of different doses and administration timings, as well as the potential impact of CYP2D6 inhibition by other commonly used drugs.

The study's limitations include the use of a single dose of both LSD and MDMA, and the simultaneous administration of both drugs, which might not reflect recreational "candyflipping" practices. Further research should consider the use of varying doses and different administration timings to investigate potential differences. A larger sample size might have detected small but potentially clinically relevant differences in subjective effects. The relatively homogeneous participant group may limit the generalizability of these findings.