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Randomized Controlled Trial
. 2022 Apr;111(4):886-895.
doi: 10.1002/cpt.2487. Epub 2021 Nov 22.

Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Subjects

Anna M Becker  1   2   3 , Friederike Holze  1   2   3 , Tanja Grandinetti  1   2   3 , Aaron Klaiber  1   2   3 , Vanja E Toedtli  1   2   3 , Karolina E Kolaczynska  1   2   3 , Urs Duthaler  1   2   3 , Nimmy Varghese  4   5 , Anne Eckert  4   5 , Edna Grünblatt  6   7   8 , Matthias E Liechti  1   2   3
Affiliations
Randomized Controlled Trial

Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Subjects

Anna M Becker et al. Clin Pharmacol Ther. 2022 Apr.

Abstract

The psychedelic psilocybin is being investigated for the treatment of depression and anxiety. Unclear is whether antidepressant treatments interact with psilocybin. The present study used a double-blind, placebo-controlled, crossover design with two experimental test sessions to investigate the response to psilocybin (25 mg) in healthy subjects after pretreatment with escitalopram or placebo. The treatment order was random and counterbalanced. Pretreatment consisted of 10 mg escitalopram daily for 7 days, followed by 20 mg daily for 7 days, including the day of psilocybin administration, or 14 days of placebo pretreatment before psilocybin administration. Psilocybin treatments were separated by at least 16 days. The outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor (BDNF) levels, electrocardiogram QTc time, whole-blood HTR2A and SCL6A4 gene expression, and pharmacokinetics. Escitalopram pretreatment had no relevant effect on positive mood effects of psilocybin but significantly reduced bad drug effects, anxiety, adverse cardiovascular effects, and other adverse effects of psilocybin compared with placebo pretreatment. Escitalopram did not alter the pharmacokinetics of psilocin. The half-life of psychoactive free (unconjugated) psilocin was 1.8 hours (range 1.1-2.2 hours), consistent with the short duration of action of psilocybin. Escitalopram did not alter HTR2A or SCL6A4 gene expression before psilocybin administration, QTc intervals, or circulating BDNF levels before or after psilocybin administration. Further studies are needed with a longer antidepressant pretreatment time and patients with psychiatric disorders to further define interactions between antidepressants and psilocybin.

Trial registration: ClinicalTrials.gov NCT03912974.

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Conflict of interest statement

M.E.L. is a consultant for Mind Medicine, Inc. All other authors declare no competing interests for this work.

Figures

Figure 1
Figure 1
Acute alterations of mind on the 5 Dimensions of Altered States of Consciousness (5D‐ASC) Scale. Psilocybin produced similar overall alterations of mind after escitalopram pretreatment compared with placebo, indicated by similar 3D‐OAV and 5D‐ASC total scores. Psilocybin similarly increased “Oceanic Boundlessness” (OB), “Visionary Restructuralization” (VR), “Auditory Alterations” (AA), and “Vigilance Reductions” (VIR) after escitalopram compared with placebo. Escitalopram significantly reduced psilocybin‐induced increases in “Anxious Ego‐Dissolution” (AED; P = 0.03) and “Anxiety” (P = 0.03) compared with placebo. The data are expressed as the mean ± SEM percentage of maximally possible scale scores in 23 subjects. Statistics are shown in Table  S1 .
Figure 2
Figure 2
Acute subjective effects of psilocybin over time on the visual analog scale (VAS). Escitalopram slightly but significantly reduced psilocybin‐induced increases in “any drug effect” (P = 0.02), “bad drug effect” (P = 0.004), and “fear” (P = 0.004) but had no effect on “good drug effect,” “drug liking,” “drug high,” or “feeling stimulated.” Psilocybin was administered at t = 0 hour. The data are expressed as the mean ± SEM in 23 subjects. Additional subjective effects are shown in Figure  S1 . The corresponding maximal responses and statistics are shown in Table  S2 .
Figure 3
Figure 3
Pharmacokinetics of free psilocin (unconjugated), psilocin glucuronide, and 4‐hydroxyindole‐3‐acetic acid (4‐HIAA). Escitalopram had no effect on the pharmacokinetics of psilocin or its metabolites compared with placebo. The data are expressed as the mean ± SEM in 23 subjects. Psilocybin was administered at t = 0 hour. Pharmacokinetic parameters are listed in Table  2 .
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References

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