Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects

This double-blind, placebo-controlled, randomized, cross-over study (n=16) investigated the subjective effects of LSD (from 0-200µg). It found higher anxiety and ego dissolution at the highest dosage and that ketanserin fully blocked the effects of LSD. The study could mainly help by providing dose-response information for future work.

Abstract

“Growing interest has been seen in using lysergic acid diethylamide (LSD) in psychiatric research and therapy. However, no modern studies have evaluated subjective and autonomic effects of different and pharmaceutically well-defined doses of LSD. We used a double-blind, randomized, placebo-controlled, crossover design in 16 healthy subjects (eight women, eight men) who underwent six 25 h sessions and received placebo, LSD (25, 50, 100, and 200 µg), and 200 µg LSD 1 h after administration of the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 24 h. The pharmacokinetic-subjective response relationship was evaluated. LSD showed dose-proportional pharmacokinetics and first-order elimination and dose-dependently induced subjective responses starting at the 25 µg dose. A ceiling effect was observed for good drug effects at 100 µg. The 200 µg dose of LSD induced greater ego dissolution than the 100 µg dose and induced significant anxiety. The average duration of subjective effects increased from 6.7 to 11 h with increasing doses of 25–200 µg. LSD moderately increased blood pressure and heart rate. Ketanserin effectively prevented the response to 200 µg LSD. The LSD dose–response curve showed a ceiling effect for subjective good effects, and ego dissolution and anxiety increased further at a dose above 100 µg. These results may assist with dose finding for future LSD research. The full psychedelic effects of LSD are primarily mediated by serotonin 5-HT2A receptor activation.”

Authors: Friederike Holze, Patrick Vizeli, Laura Ley, Felix Müller, Patrick Dolder, Melanie Stocker, Urs Duthaler, Nimmy Varghese, Anne Eckert, Stefan Borgwardt & Matthias E. Liechti

Notes

This study was sponsored (in part) by MindMed.

For a good analysis, see Psychedelic Science Review‘s article on this paper.

Summary

INTRODUCTION

In a study of healthy subjects, lysergic acid diethylamide (LSD) was administered at different doses to induce different subjective and autonomic effects. The pharmacokinetics of LSD was determined and the role of 5-HT2A receptors in the acute effects of LSD was evaluated.

We administered 200 g LSD to healthy subjects and compared their acute response to 200 g LSD alone. We hypothesized that LSD effects would be dose-dependent and blocked by ketanserin.

METHODS AND MATERIALS Study design

A double-blind, placebo-controlled, crossover study was conducted to investigate the responses to ketanserin, placebo, 25g LSD, 50g LSD, 100g LSD, 200g LSD, and 200g LSD 1 h after ketanserin administration.

Sixteen healthy subjects were recruited by word of mouth or an advertisement on the web market platform of the University of Basel. They received 1.3-fold higher doses/body weight of LSD than women. The study excluded participants who were 25 years or older, pregnant, had a history of major psychiatric disorders, used medications that may interfere with the study medications, smoked tobacco, had a history of illicit drug use, or had used illicit drugs during the study.

LSD base was administered as an oral solution, ketanserin was administered as a marketed drug, and a double-dummy method was used to ensure blinding. The subjects were asked to retrospectively guess their treatment assignment at the end of each session and at the end of the study.

A screening visit, six 25 h test sessions, and an end-of-study visit were conducted in a calm hospital room. Ketanserin and LSD were administered at 8:00 a.m. and 9:00 a.m., respectively, and the outcome measures were repeatedly assessed for 24 h.

Subjective drug effects were assessed repeatedly using visual analog scales (VASs), the Adjective Mood Rating Scale (AMRS), and the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale. Mystical experiences were assessed 24 h after drug administration using the States of Consciousness Questionnaire.

Blood was collected from volunteers and analyzed for LSD and O-H-LSD concentrations by ultra-high-performance liquid chromatography tandem mass spectrometry.

Pharmacokinetic parameters were estimated using a one-compartment model, and the predicted concentrations of LSD were used as an input to a pharmacodynamic model. The predicted effect duration was assessed using a VAS effect-time plot.

Repeated measures analysis of variance was used to determine peak and change from baseline values, and the Tukey post hoc test was used to determine significance.

RESULTS

Subjective drug effects are shown in Figs. 1 and S2. Alterations of mind and mystical-type effects are shown in S2.

LSD produced dose-dependent subjective effects starting at the 25 g dose, which were significantly greater than placebo (p 0.05) and decreased with increasing dose. Ketanserin significantly reduced the subjective effects of LSD, but only with a temporal delay compared with LSD alone.

LSD moderately but significantly increased blood pressure and heart rate and had no effect on body temperature. Ketanserin significantly prevented the LSD-induced heart rate response and transiently reduced the LSD-induced blood pressure response.

LSD and its main metabolite 2-oxo-3-hydroxy LSD (O – H – LSD) were quantified in all of the subjects, at all doses, and at all time-points. The predicted VAS any drug effects and good drug effects increased proportionally with increasing doses of LSD.

Participants’ retrospective identification of the LSD dose condition is shown in Supplementary Table S7. The 100 and 200 g doses were identified as high doses, but could not be distinguished from placebo.

DISCUSSION

The present study investigated acute effects of LSD using a range of well-defined doses in healthy subjects. The results were consistent with previous studies using single-dose levels and found no sex differences in LSD concentrations or effects.

LSD dose-dependently increased subjective effects that were similar to previous studies that used single-dose levels. However, a ceiling effect was reached at higher doses of LSD (>100 g) with regard to its positive subjective effects, and the 200 g dose of LSD produced significantly greater ego dissolution and anxious ego dissolution than the 100 g dose.

In a previous study, the 200 g dose of LSD produced higher ratings of good drug effects, bad drug effects, fear, open, and trust on the VAS compared with 100 g. In the present study, we observed a ceiling effect on the dose – response curve.

A dose of 100 g of LSD base produced mainly high acute positive effects, and a dose of 50 g produced a moderately intense and predominantly positive psychedelic experience, and may be a good starting dose for patients with no previous experience with psychedelics or in subjects who are considered to be more sensitive to the effects of psychedelics.

LSD produced moderate elevations of arterial blood pressure and heart rate starting at the 50 g dose that were largely similar to the effects of 100 and 200 g LSD.

The 5-HT2A receptor antagonist ketanserin markedly reduced the subjective response to the 200 g LSD dose, and was identified correctly by the participants or mistaken as a low dose of LSD, but never mistaken for a high dose of LSD.

In the present study, 200 g LSD significantly increased BDNF plasma concentration compared with placebo, and higher BDNF levels were associated with lower depression ratings after administration of ayahuasca.

The present study provided dose-response data on full psychedelic doses of LSD, and further characterized the effects of small doses of LSD. Very low doses of LSD were postulated to have beneficial prolonged effects on mood while producing no or only minimal acute adverse subjective effects.

LSD did not have any adverse effects at doses up to 20 g, and had comparable dose-proportional peak concentrations. In a previous study, younger healthy subjects were given 6.5, 13, and 26 g of LSD tartrate. The 26 g dose produced significant effects on the 5D-ASC scale compared with placebo, and nominally greater ratings on the 5D-ASC subscales than the 25 g dose. The data from these controlled studies indicate that a 25 g dose of LSD is clearly acutely psychoactive in the majority of subjects, and that smaller doses may elicit small dose-dependent subjective effects.

Overall, the present dose – response study characterized a range of LSD doses, with good effects likely predominating at doses of 30 – 100 g (good-effect dose)

The present study has numerous strengths, including using four different doses of LSD within subjects and comparing them with placebo under double-blind conditions in a controlled laboratory setting. However, the study also has limitations, including using only healthy subjects and using standardized outcome measures.

CONCLUSION

LSD produces subjective responses that are dose dependent and peak at 100 g. The 200 g dose induces more ego dissolution but also more anxiety than the 100 g dose.

FUNDING AND DISCLOSURE

This work was supported by the Swiss National Science Foundation and was licensed to Mind Medicine, Inc. Mind Medicine, Inc. had no role in financing, planning, or conducting the present study.