Acute effects of R-MDMA, S-MDMA, and racemic MDMA in a randomized double-blind cross-over trial in healthy participants

Abstract

Racemic 3,4-methylenedioxymethamphetamine (MDMA) acutely increases mood, feelings of empathy, trust, and closeness to others and is investigated to assist psychotherapy. Preclinical research indicates that S-MDMA releases monoamines and oxytocin more potently than R-MDMA, whereas R-MDMA more potently stimulates serotonin 5-hydroxytryptamine-2A receptors. S-MDMA may have more stimulant properties, and R-MDMA may be more psychedelic-like. However, acute effects of S- and R-MDMA have not been examined in a controlled human study. We used a double-blind, randomized, placebo-controlled, crossover design to compare acute effects of MDMA (125 mg), S-MDMA (125 mg), R-MDMA (125 mg and 250 mg), and placebo in 24 healthy participants. Outcome measures included subjective, autonomic, and adverse effects, pharmacokinetics, and plasma oxytocin, prolactin, and cortisol concentrations. S-MDMA (125 mg) induced greater subjective effects ("stimulation," "drug high," "happy," "open") and higher increases in blood pressure than R-MDMA (both 125 and 250 mg) and MDMA (125 mg). Unexpectedly, R-MDMA did not produce more psychedelic-like effects than S-MDMA. S-MDMA increased plasma prolactin more than MDMA, and S-MDMA increased plasma cortisol and oxytocin more than MDMA and R-MDMA. The plasma elimination half-life of S-MDMA was 4.1 h after administration. The half-life of R-MDMA was 12 and 14 h after the administration of 125 and 250 mg, respectively. Half-lives for S-MDMA and R-MDMA were 5.1 h and 11 h, respectively, after racemic MDMA administration. Concentrations of the CYP2D6-formed MDMA-metabolite 4-hydroxy-3-methoxymethamphetamine were lower after R-MDMA administration compared with S-MDMA administration. The pharmacokinetic findings are consistent with the R-MDMA-mediated inhibition of CYP2D6. Stronger stimulant-like effects of S-MDMA in the present study may reflect the higher potency of S-MDMA rather than qualitative differences between S-MDMA and R-MDMA. Equivalent acute effects of S-MDMA, MDMA, and R-MDMA can be expected at doses of 100, 125, and 300 mg, respectively, and need to be investigated.Trial registration: ClinicalTrials.gov identifier: NCT05277636.

Fig. 1. Acute subjective effects of 125 mg MDMA, 125 mg S-MDMA, 125 mg R-MDMA, and 250 mg R-MDMA on the Visual Analog Scale (VAS).

S-MDMA produced overall stronger subjective responses than MDMA, with significant differences in “bad drug effects,” “alteration of vision,” and “audio-visual synesthesia.” R-MDMA at both doses produced overall lower subjective effects than MDMA, with significant differences in “drug high,” “happy,” “content,” “talkative,” “open,” “trust,” and “I feel close to others.” The substances were administered at t = 0 h. The data are expressed as the mean ± SEM percentage of maximally possible scores in 24 participants. The corresponding maximal responses and statistics are shown in Table 1.

Fig. 2. Acute mystical-type experiences on the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale.

MDMA, S-MDMA, and 250 mg R-MDMA induced comparable alterations of mind. The data are expressed as the mean ± SEM percentage of maximally possible scale scores in 24 participants. Statistics are shown in Supplementary Table S5.

Fig. 3. Acute autonomic effects.

S-MDMA induced greater increases in blood pressure compared with MDMA and both R-MDMA doses. MDMA, S-MDMA, and 250 mg R-MDMA increased heart rate and body temperature comparably. The substances were administered at t = 0 h. The data are expressed mean ± SEM in 24 participants. The corresponding maximal responses and statistics are shown in Table 1.