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

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

Neuropsychopharmacology, 2022, 1-8.

Doi : 10.1038/s41386-022-01297-2

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

INTRODUCTION

Lysergic acid diethylamide (LSD) and psilocybin are both classic serotonergic psychedelics that are used recreationally [1] and have recently become promising candidates for the treatment of various psychiatric disorders (e.g., anxiety disorders and major depressive disorder) and neurologic disorders (e.g., cluster headache and migraine) [2–6]. Both substances induce complex alterations of mind via stimulation of the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor [7–9]. LSD exerts additional activity at dopamine D1-3 receptors, whereas psilocin, the active metabolite of psilocybin, inhibits the serotonin transporter[10]. Whether these differences in receptor binding profiles produce differential subjective effects in humans has not yet been studied. Recent research has investigated either psilocybin
or LSD alone [7, 11–15]. Differences between the two substances with regard to their acute effects, similarities, and doseequivalence remain unclear.

Therefore, 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. The acute subjective effects of LSD and psilocybin were determined using validated psychometric instruments that are used internationally in healthy subjects as well as in therapeutic studies in patients [3, 16–18]. In addition, we determined plasma LSD and psilocin concentrations over time and over 24 h to provide valid pharmacokinetic parameters for all substances and doses used. Previous research has shown that plasma concentrations of LSD and psilocybin are strongly linked to
subjective effects [7, 19, 20]. Pharmacokinetic data are thus important and needed for the potential development of these substances into medications. Both LSD and psilocybin have previously been shown to induce dose-dependent cardiovascular stimulation and influence endocrine functions [11, 15, 21–23].
However, potential differences between these two substances are unexplored. Therefore, we assessed blood pressure, heart rate, body temperature, and endocrine effects, including plasma levels of cortisol, prolactin (PRL), and oxytocin. In addition, we assessed plasma levels of brain-derived neurotrophic factor (BDNF), which is considered a possible marker of neurogenesis [24] and has been shown to increase following psychedelic administration [7, 25–27].

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