Abstract

There is renewed interest in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. While acute subjective effects of LSD are mostly positive, negative subjective effects, including anxiety, may occur. The induction of overall positive acute subjective effects is desired in psychedelic-assisted therapy because positive acute experiences are associated with greater therapeutic long-term benefits. 3,4-methylenedioxymethamphetamine (MDMA) produces marked positive subjective effects and is used recreationally with LSD as “candyflipping”. The present study investigated whether the co-administration of MDMA could be used to augment the acute subjective effects of LSD.

We used a double-blind, randomized, placebo-controlled, crossover design with 24 healthy subjects (12 women, 12 men) to compare the co-administration of MDMA (100 mg) and LSD (100 µg) with MDMA and LSD administration alone and placebo. Outcome measures included subjective effects, autonomic effects, adverse effects, pharmacokinetics, plasma levels of oxytocin, and serum levels of brain-derived neurotropic factor (BDNF).

MDMA co-administration with LSD did not change the quality of acute subjective effects compared with LSD alone. However, acute subjective effects lasted longer after LSD+MDMA co-administration compared with LSD and MDMA alone, consistent with higher plasma concentrations of LSD (Cmax and area under the curve) and a longer plasma elimination half-life of LSD when MDMA was co-administered. The LSD+MDMA combination increased blood pressure, heart rate, and pupil size more than LSD alone, while body temperature increased similarly for LSD and the LSD+MDMA combination but less with MDMA alone.

Common side effects, such as headache, lack of energy, loss of appetite, and dry mouth were similarly often reported with all three conditions. No severe adverse effects were observed. Both MDMA alone and the LSD+MDMA combination increased oxytocin levels more than LSD alone, but none of the substance conditions had a significant effect on serum BDNF concentrations.

Overall, co-use of MDMA (100 mg) did not improve the acute effects and safety profile of LSD (100 µg). Combined use of MDMA and LSD is unlikely to provide relevant benefits over LSD alone in psychedelic-assisted therapy.