Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects

This RCT (n=28) compared the effects of LSD (100 & 200µg) and psilocybin (15 & 30mg) to placebo. Findings include that the doses of 100 & 200 µg LSD and 30 mg psilocybin produced comparable subjective effects. LSD at both doses had longer effect durations than psilocybin. Psilocybin increased blood pressure more than LSD, whereas LSD increased heart rate more than psilocybin. Ultimately, any differences between LSD and psilocybin are dose-dependent rather than substance-dependent.

Abstract

“Growing interest has been seen in using lysergic acid diethylamide (LSD) and psilocybin in psychiatric research and therapy. However, no modern studies have evaluated differences in subjective and autonomic effects of LSD and psilocybin or their similarities and dose equivalence. We used a double-blind, randomized, placebo-controlled, crossover design in 28 healthy subjects (14 women, 14 men) who underwent five 25 h sessions and received placebo, LSD (100 and 200 µg), and psilocybin (15 and 30 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales for subjective effects, autonomic effects, adverse effects, effect durations, plasma levels of brain-derived neurotrophic factor (BDNF), prolactin, cortisol, and oxytocin, and pharmacokinetics. The doses of 100 and 200 µg LSD and 30 mg psilocybin produced comparable subjective effects. The 15 mg psilocybin dose produced clearly weaker subjective effects compared with both doses of LSD and 30 mg psilocybin. The 200 µg dose of LSD induced higher ratings of ego-dissolution, impairments in control and cognition, and anxiety than the 100 µg dose. The 200 µg dose of LSD increased only ratings of ineffability significantly more than 30 mg psilocybin. LSD at both doses had clearly longer effect durations than psilocybin. Psilocybin increased blood pressure more than LSD, whereas LSD increased heart rate more than psilocybin. However, both LSD and psilocybin showed comparable cardiostimulant properties, assessed by the rate-pressure product. Both LSD and psilocybin had dose-proportional pharmacokinetics and first-order elimination. Both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration. Any differences between LSD and psilocybin are dose-dependent rather than substance-dependent. However, LSD and psilocybin differentially increased heart rate and blood pressure. These results may assist with dose-finding for future psychedelic research.“

Authors: Friederike Holze, Laura Ley, Felix Müller, Anna M. Becker, Isabelle Straumann, Patrick Vizeli, Sebastian S. Kuehne, Marc A. Roder, Urs Duthaler, Karolina E. Kolaczynska, Nimmy Varghese, Anne Eckert & Matthias E. Liechti

Notes

The city of Basel in Switzerland has a long history with psychedelic substances ever since the discovery of LSD by Albert Hofmann in 1938. Today, research with these substances is continuing at the University of Basel by the team at the Liechti Lab. The team here has conducted clinical trials with substances including MDMA, psilocybin and perhaps most notably, LSD, making significant contributions to advancing psychedelics as medicine for the past number of years. At present, their clinical research with LSD is unparalleled in the field of psychedelics. Their latest endeavour is an interesting one.

The present study sought to evaluate and directly compare the acute subjective, autonomic, and endocrine effects of LSD and psilocybin using two doses of each substance and placebo within the same subject. This is the first study to make such comparisons within the same study and using the within-subject design. A total of 28 healthy participants took part in the study. The study consisted of five 25hr experimental sessions where participants were received a placebo, LSD (100 and 200 µg) and psilocybin (15 and 30 mg) in a randomized order (these doses are similar to those used in therapeutic studies). Experimental sessions were separated by 10 days. Outcome measures included self-rating scales for subjective effects, autonomic effects, adverse effects, effect durations, plasma levels of brain-derived neurotrophic factor (BDNF), prolactin, cortisol, and oxytocin, and pharmacokinetics.

Comparing the results:

• LSD at doses of 100 and 200 µg and the psilocybin dose of 30 mg produced comparable subjective effects. Specifically, 200 µg LSD produced comparable positive drug effects to 100 µg LSD, but the higher dose produced greater ego-dissolution and a trend toward an increase in anxiety.
• The 200 µg dose of LSD increased only ratings of ineffability significantly more than 30 mg psilocybin.
• LSD increased blood pressure and body temperature only moderately, whereas 30 mg psilocybin produced significantly greater increases in blood pressure and body temperature compared with LSD and 15 mg psilocybin.
• Both LSD and psilocybin significantly increased plasma cortisol, PRL, and oxytocin levels. Neither LSD nor psilocybin significantly elevated plasma BDNF levels.
• LSD at both doses had clearly longer effect durations than psilocybin.

Overall, both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration. In an equal number of male and female participants, this study used two well-characterized doses within-subjects to compare the effects of LSD and psilocybin under double-blind conditions in a laboratory setting. However, the highly controlled setting in which the study took place and the involvement of healthy participants only is also the study’s weaknesses.

In terms of blinding, no participant could distinguish between doses of psilocybin/LSD but the placebo was easily identified by participants. When asked to identify the doses, 15 mg psilocybin was mostly mistaken for 30 mg psilocybin, 30 mg psilocybin was mostly mistaken for 100 µg LSD, 100 µg LSD was mostly mistaken for 15 mg psilocybin, and 200 µg LSD was mostly mistaken for 100 µg LSD. Nonetheless, this study indicates that any differences between LSD and psilocybin are dose-dependent rather than substance-dependent and is another significant contribution to psychedelic medicine by the team at the University of Basel.