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.

Summary

INTRODUCTION

LSD and psilocybin are serotonergic psychedelics that are used recreationally and have recently become promising candidates for the treatment of various psychiatric disorders and neurologic disorders. The present study evaluated and directly compared the acute subjective, autonomic, and endocrine effects of LSD and psilocybin using two doses of each substance and placebo within the same subjects. Both LSD and psilocybin induce dose-dependent cardiovascular stimulation and influence endocrine functions. We assessed blood pressure, heart rate, body temperature, and endocrine effects, including plasma levels of cortisol, prolactin, and oxytocin.

METHODS AND MATERIALS Study design

In a double-blind, placebo-controlled, crossover design, participants were given placebo, 100 g LSD, 200 g LSD, 15 mg psilocybin, and 30 mg psilocybin. The washout periods between sessions were at least 10 days.

Participants

Twenty-eight healthy participants were recruited from a pool of volunteers and provided written informed consent. They were also asked to consume no more than 10 standard alcoholic drinks/week and have no more than one drink on the day before the test sessions. Fourteen participants had used LSD, psilocybin, MDMA, 12 had used methylenedioxymethamphetamine, 13 had used a stimulant, and 10 had never used any illicit drugs with the exception of cannabis.

Study drugs

LSD base was administered as an oral solution, psilocybin was administered in opaque capsules, and a double-dummy method was used. The participants were asked to retrospectively guess their treatment assignment at the end of each session and at the end of the study.

Study procedures

A screening visit, five 25 h test sessions, and an end-of-study visit were conducted in a calm hospital room. LSD, psilocybin, or placebo was administered at 9:00 AM, and the outcome measures were repeatedly assessed for 24 h.

Subjective drug effects and effect durations

Subjective 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.

The time to onset, time to maximal effect, time to offset, and effect duration were assessed using the classic PK-PD link module.

Autonomic and adverse effects

Blood pressure, heart rate, tympanic body temperature, pupil size, and adverse effects were repeatedly measured at baseline and 1, 2.5, 4, 7, 11, and 24 h after drug administration.

Plasma LSD and psilocin concentrations

Blood samples were collected and stored at 80 ° C until analysis. LSD and psilocin concentrations were determined using ultra-high-performance liquid chromatography tandem mass spectrometry.

Data analysis

Peak values were determined for repeated measures and analyzed using repeated-measures analysis of variance (ANOVA), followed by Tukey post hoc tests.

Subjective drug effects

Subjective effects over time on the VAS and AMRS are shown in Fig. 1 and Supplementary Fig. S1, respectively.

LSD at 100 and 200 g and 30 mg psilocybin produced comparable subjective effects, with the 200 g LSD dose producing greater ego-dissolution and a trend toward an increase in anxiety. The 15 mg psilocybin dose produced significantly lower effects than the 200 g LSD dose.

On the AMRS, 100 and 200 g LSD had significantly longer effect durations and an earlier onset of effects compared with 15 and 30 mg psilocybin.

Autonomic and adverse effects

Autonomic effects of LSD and psilocybin include increased blood pressure, body temperature, and pupil size compared with placebo, as well as increased heart rate and blood pressure compared with both psilocybin doses and placebo.

LSD and psilocybin increased adverse effect scores on the LC compared with placebo, and increased adverse effect scores in the evening on the treatment day or within 48 h after treatment.

Psilocybin produced alterations of mind similar to LSD at 30 mg, but lower than LSD at 100 and 200 mg. Placebo scores were too low for visualization.

Adverse aftereffects included headaches, migraine attack, nosebleeds, low mood, nausea, nightmares, restlessness, vivid dreams, insomnia, involuntary movement of the lower extremities, and flashback episodes in five subjects. No severe adverse events were observed.

Plasma drug concentrations

LSD and psilocin showed linear pharmacokinetics with Cmax values of 1.9 ng/ml and 3.4 ng/ml, respectively, and Tmax values of 1.6 h and 1.6 h, respectively. The elimination half-lives were 4.3 h and 4.0 h, respectively.

Blinding

The participants could not clearly distinguish between LSD and psilocybin after the sessions, nor at the end of the study. The 15 mg dose of psilocybin was correctly identified in 64% of the sessions, and the 30 mg dose of psilocybin was mistaken for 15 mg LSD in 29% of the sessions.

DISCUSSION

The present study used well-defined doses of LSD and psilocybin in healthy participants and compared acute effects of both substances within the same study using a within-subjects design. Fixed doses of psilocybin were also used for the first time, and were found to have similar effects.

Subjective effects of LSD and the high 30 mg dose of psilocybin were largely comparable, whereas 15 mg psilocybin exerted clearly weaker effects. The dose-effect relationship of psilocybin was clearer than that of LSD, but ceiling effects were likely not reached for psilocybin compared with LSD. Psilocybin doses above 20 mg may have a ceiling effect, similar to LSD, on positive mood scale ratings. LSD is more effective than psilocybin on the ineffability scale, suggesting a dose effect rather than a substance-specific effect.

Both LSD and psilocybin had dose-dependent effect durations, but the effects of LSD were clearly longer than the effects of psilocybin. The differences in the duration of action can be fully explained by differences in the pharmacokinetics of LSD and psilocin.

LSD and psilocybin both produced significant autonomic stimulant effects, with psilocybin producing stronger elevations of arterial blood pressure and heart rate, whereas LSD produced stronger elevations of blood pressure and heart rate. Psilocybin also produced greater impairments in pupil contraction compared with LSD. We assessed acute and subacute adverse effects and spontaneously reported adverse events between test days. We found that higher doses produce longer-lasting and more unpleasant effects.

The true content of LSD in the present study was 11 – 14% lower than in previous studies, and the two doses of psilocybin used in this study were lower in terms of acute effect strength compared with the 100 and 200 g doses of LSD.

The present study was well blinded, and the subjects were not able to distinguish between the high dose of LSD (200 g) and the low dose of psilocybin (15 mg). This confirms that both classic psychedelics produce their effects via shared agonistic effects on 5-HT2A receptors.

In the present study, neither LSD nor psilocybin altered plasma BDNF concentrations compared with placebo. However, LSD and psilocybin increased PRL and cortisol levels, which are markers of serotonergic activity.

The present study has strengths, such as using well-characterized doses of LSD and psilocybin within-subjects and using internationally established psychometric outcome measures. It also has limitations, such as using a highly controlled setting and including only healthy subjects.

CONCLUSION

We characterized the effects of LSD and psilocybin at two different doses, and found no evidence of qualitative differences in altered states of consciousness.

AUTHOR CONTRIBUTIONS

FH, LL, FM, PV, MEL, AMB, IS, PV, SSK, MAR, UD, KEK, NV, and AE designed the research, and FH and MEL analyzed the data. FH and MEL wrote the paper.

COMPETING INTERESTS

MEL is a consultant for Mind Medicine, Inc., but had no role in financing, planning, or conducting the study.

ADDITIONAL INFORMATION

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