Acute Effects of Psilocybin After Escitalopram or Placebo Pretreatment in a Randomized, Double‐Blind, Placebo‐Controlled, Crossover Study in Healthy Subjects
Open accessAbstract
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.
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Some studies showed inconsistent application of correction for multiple testing, no consideration of confounding factors, lack of randomization, and relatively short-term follow-up periods generally between one and 6 months after one or two single active psilocybin treatments.
“In terms of methodology, some studies showed inconsistent application of correction for multiple testing, 26,74 no consideration of confounding factors, 57,78 lack of randomization, 72 and relatively short-term follow-up periods were often observed, 25,26,31-33,39,57,72-81 generally between one and 6 months after one or two single active psilocybin treatments.”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [74]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThere are clear limitations such as small sample sizes with lack of diversity among participants and potential selection biases.
“Concerning the recruitment phase, there are clear limitations such as small sample sizes 25,31-33,39,57,60,72-74,77-81 with lack of diversity among participants 32,33,39,57,60,72,75-79 and potential selection biases. 26,31,39,72-74,76”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [74]
The Participants section (page unavailable) reports that only 23 healthy subjects completed the study and that recruitment was by word of mouth or a university web advertisement, supporting the small-sample concern and a potential for selection bias. The Discussion notes that patients with psychiatric disorders may respond differently, but the paper does not establish the claimed lack of participant diversity. (LLM, conf=0.84)
Experimental — accuracy not yet measuredResearch on MDD, anxiety and depressive symptoms associated with life-threatening cancer, and TRD showed the most robust evidence, supported by a non-randomized study and several RCTs.
“Research on MDD, anxiety and depressive symptoms associated with life-threatening cancer, and TRD showed the most robust evidence, supported by a non-randomized study 72 and several RCTs. 26,31-33,60,73-77”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [74]
The References (page unavailable) list an open-label study of treatment-resistant depression and randomized trials concerning major depressive disorder and depression or anxiety in patients with life-threatening cancer. But this paper’s Discussion (page unavailable) says its own study involved healthy subjects without a therapeutic setting; it does not establish that these conditions have the ‘most robust evidence.’ (LLM, conf=0.83)
Experimental — accuracy not yet measuredBlinding procedures were not consistently robust, and comparison with placebo or standard treatments was lacking in many studies.
“Blinding procedures were not consistently robust, 26,32,60,72-76 and comparison with placebo or standard treatments was lacking in many studies. 25,26,31-33,39,57,60,72,73,75-81”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [74]
The Study design section describes a placebo comparison for escitalopram pretreatment, but both conditions received psilocybin; there was no psilocybin-versus-placebo comparison. The Discussion says participants could not correctly identify their pretreatment assignment, indicating adequate blinding. Thus, the source supports the narrower point about the missing psilocybin placebo comparison, but not a claim that this study’s blinding was inadequate. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThere is some evidence that SSRIs blunt unpleasant drug effects from psychedelics, though they do not appear to reduce the overall effect.
“There is some evidence that SSRIs blunt unpleasant drug effects from psychedelics, though they do not appear to reduce the overall effect (Becker et al., 2022).”
From Naturalistic psychedelic therapy: The role of relaxation and subjective drug effects in antidepressant response (2024) · cites this paper as Becker et al., 2022
Escitalopram and psilocybin co-administration were well tolerated.
“Consistently, escitalopram and psilocybin co-administration were well tolerated (Becker et al., 2022).”
From Naturalistic psychedelic therapy: The role of relaxation and subjective drug effects in antidepressant response (2024) · cites this paper as Becker et al., 2022
One study only recruited healthy subjects.
“One study only recruited healthy subjects. 74”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [74]
In some instances, control groups consisted of waiting lists rather than active comparators, and therapeutic settings were sometimes not consistently provided.
“In some instances, control groups consisted of waiting lists rather than active comparators, 60,73 and therapeutic settings were sometimes not consistently provided. 74,76”
From The revival of psilocybin between scientific excitement, evidence of efficacy, and real-world challenges (2024) · cites this paper as [74]
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References 50 · Cited by 184
- Authors
- Becker, A. M., Holze, F., Grandinetti, T., Klaiber, A., Toedtli, V. E., Kolaczynska, K. E., Duthaler, U., Varghese, N., Eckert, A., Grünblatt, E., & Liechti, M. E.
- Affiliations
- University of Basel (CH)
- University of Zurich (CH)
- Corresponding author
- Liechti, Matthias E.
- ORCID
- Venue
- Clinical Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2021-11-22
- Volume
- 111
- Issue
- 4
- Pages
- 886-895
- ISSN
- 0009-9236 (ISSN-L)
- 1532-6535
- PMC
- PMC9299061
- OpenAlex
- W3213378850
- Cited by
- 184
- References
- 50
- Citations by year
- 2026: 33 · 2025: 38 · 2024: 63 · 2023: 34 · 2022: 14 · 2021: 2
- FWCI
- 19.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Clinical Pharmacology & Therapeutics (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- edoc (University of Basel) (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc)
- ETH Zürich Research Collection
- Zurich Open Repository and Archive (University of Zurich)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- psilocybin, escitalopram, drug-drug interactions, adverse effects, anxiety, mood improvement, brain-derived neurotrophic factor, QTc interval, healthy volunteers
- MeSH terms
- Escitalopram, Antidepressive Agents, Double-Blind Method, Humans, Psilocybin, Citalopram, Cross-Over Studies, Brain-Derived Neurotrophic Factor, Healthy Volunteers
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