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

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.Trial registration: ClinicalTrials.gov identifier: NCT03604744

Lysergic Acid Diethylamide–Assisted Therapy in Patients With Anxiety With and Without a Life-Threatening Illness: A Randomized, Double-Blind, Placebo-Controlled Phase II Study

“…LSD may produce acute anxiety in some people, particularly at high doses (4,20). Specifically, effects of LSD at the dose and formulation that were used in the present study have been characterized very well in healthy subjects, and the dose could be considered high and have a greater risk of acute anxiety (4,6). Transient anxiety and confrontation with a fear of death were also reported in the pilot study.…”

“…Additionally, acute LSD effects last longer compared to those of psilocybin. However, a recent study documented otherwise comparable acute subjective effects and tolerability of LSD and psilocybin in healthy subjects (6). In the 1950s to 1970s, LSD was used in patients with endstage cancer to improve mood and reduce anxiety (7)(8)(9).…”

Towards an understanding of psychedelic-induced neuroplasticity

“…Though ayahuasca increased BDNF levels in both healthy and depressed people in one study, another found no change [46,47]. Several studies have measured the effects of LSD on BDNF, with some finding an increase [48,49] and others no change [50,51]. In two studies in healthy subjects, comparable doses of psilocybin did not elevate plasma BDNF in one [50], but did so in the other [52].…”

“…Sub-hallucinogenic doses of between 5 and 20 µg LSD produced significant short-term enhancements in plasma BDNF [48]. However, a similar study using doses of between 25 µg and 200 µg LSD only found significant effects on BDNF at 200 µg [49], and another failed to find significant changes even at this dose [50]. Perhaps using different methods, future research should seek to clarify the minimum and optimal doses for stimulating neuroplasticity with different psychedelics.…”

“…Several studies have measured the effects of LSD on BDNF, with some finding an increase [48,49] and others no change [50,51]. In two studies in healthy subjects, comparable doses of psilocybin did not elevate plasma BDNF in one [50], but did so in the other [52]. This variability may be partially due to the limitations of peripheral BDNF as a biomarker in pharmacological studies.…”