Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double-blind, placebo-controlled, cross-over study in healthy subjects

Becker and colleagues place this study in the context of growing interest in psilocybin-assisted psychotherapy for depression and anxiety and ongoing uncertainty about how concomitant antidepressant treatment might interact with psychedelics. Earlier research shows that acute subjective experiences induced by serotonergic psychedelics—particularly positive mood, mystical-type experiences, and lower anxiety—are associated with longer-term clinical benefits. At the same time, psychedelics can cause negative acute effects such as anxiety, nausea, and autonomic activation, and case reports have suggested that chronic selective serotonin reuptake inhibitor (SSRI) use may attenuate responses to classic psychedelics. Because many patients receiving psilocybin in clinical settings will already be taking antidepressants, clarifying whether an SSRI modifies psilocybin's acute subjective, physiological, or pharmacokinetic effects is clinically important. The investigators therefore tested whether short-term pretreatment with escitalopram alters the acute effects of a standard clinical dose of psilocybin (25 mg) in healthy volunteers. The primary endpoint was the intensity of altered states of consciousness measured by the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale (3D-OAV total scores). Secondary outcomes included specific subjective measures (anxiety, mystical experiences), autonomic and adverse effects, QTc intervals, plasma brain-derived neurotrophic factor (BDNF), HTR2A and SLC6A4 gene expression, and detailed pharmacokinetics of unconjugated (psychoactive) psilocin. The principal hypothesis was that escitalopram pretreatment would reduce 5D-ASC scores compared with placebo pretreatment.

This was a randomized, double-blind, placebo-controlled, within-subject crossover study with two 14-day pretreatment periods and two 10-hour experimental test sessions. Participants received oral escitalopram (10 mg daily for 7 days followed by 20 mg daily for 7 days) in one treatment period and matched placebo for 14 days in the other period; the order was randomised and counterbalanced. A single 25 mg dose of psilocybin was given at the end of each pretreatment period, with the last daily dose of escitalopram or placebo administered 2 hours before psilocybin. A washout of at least 2 days separated the two treatment periods. The trial adhered to Good Clinical Practice and was approved by relevant ethics and regulatory bodies. Healthy volunteers were recruited and screened; 27 were enrolled, with 23 (12 men, 11 women; mean age 34 ± 10 years, range 25–55) completing the study. Key exclusions included current or lifetime major psychiatric disorder, family history of psychosis, use of medications that interfere with study drugs, recent illicit drug use, and significant medical conditions. Drug administration timing did not account for menstrual cycle; six female participants used hormonal contraception. Compliance with pretreatment was supported by electronic reminders, blister checks, and supervised final-dose administration with plasma escitalopram measurement. Outcome measures encompassed psychometrics and physiological and biological assays. The primary subjective measure was the 5D-ASC (3D-OAV main dimensions: Oceanic Boundlessness, Anxious Ego-Dissolution, Visionary Restructuralization), assessed 7 hours after psilocybin to capture peak effects. Additional instruments included the States of Consciousness Questionnaire (MEQ43/MEQ30), repeated visual analogue scales (VAS) and the Adjective Mood Rating Scale (AMRS). Autonomic measures (blood pressure, heart rate, body temperature), adverse events (List of Complaints), and ECG-derived QTc times were recorded. Plasma BDNF was measured at baseline and 4 and 7 hours after psilocybin. Gene expression of HTR2A and SLC6A4 (and reference genes) was assessed on blood collected before psilocybin. Pharmacokinetics of unconjugated psilocin, psilocin glucuronide and 4-HIAA were quantified by validated LC–MS/MS methods; samples were analysed with and without β-glucuronidase to distinguish conjugated from unconjugated analytes. Escitalopram concentrations were also measured. Statistical analyses used paired two-sided t-tests on peak or peak-change values derived from repeated measures; the significance threshold was P < 0.05 and no correction for multiple testing was applied. Order effects were checked by comparing first and second treatment sequences. Pharmacokinetic parameters were estimated noncompartmentally.

Twenty-three subjects completed both test sessions. Pretreatment produced expected escitalopram plasma levels (mean peak ≈ 41 ng/mL, range 35–53 ng/mL). Four participants dropped out (three before psilocybin, one after first administration); one dropout on escitalopram was due to an unrelated vertebral disc hernia requiring surgery. Primary outcome: Escitalopram pretreatment did not reduce overall alterations of mind induced by psilocybin. 3D-OAV total scores and 5D-ASC total scores were similar after escitalopram and placebo pretreatment, so the primary hypothesis was not confirmed. However, escitalopram selectively attenuated anxiety-related aspects of the experience: Anxious Ego-Dissolution and anxiety ratings were significantly lower after escitalopram (both P < 0.05). Subjective and mood measures over time showed that escitalopram modestly but significantly reduced several negative or aversive subjective effects induced by psilocybin. Compared with placebo pretreatment, escitalopram reduced VAS peak ratings of “any drug effect” (P = 0.02), “bad drug effects” (P = 0.004), “fear” (P = 0.004), and increases in ratings of being “talkative” (P = 0.03) and “open” (P = 0.03). It also attenuated psilocybin-induced decreases in “happy” (P = 0.04) and “concentration” (P = 0.01). There were no significant differences in positive drug experiences such as “good drug effects,” “drug liking,” or “drug high.” Overall mystical experience measured by MEQ30 total score was not significantly altered by escitalopram, although subscales for “nadir effects” (MEQ43; P = 0.001) and “ineffability” (MEQ30; P = 0.02) were reduced; positive mood subscales were unchanged. Autonomic and adverse effects: Escitalopram reduced some psilocybin-induced autonomic responses and acute adverse effects. The investigators report reduced peak increases in blood pressure and pupil size and an overall reduction in adverse autonomic effects with escitalopram compared with placebo. Psilocybin did not produce a statistically significant increase in QTc at 2.5 hours versus baseline, and escitalopram did not alter QTc before or after psilocybin; nevertheless the longest individual QTc values observed were 509 ms (escitalopram + psilocybin) and 481 ms (psilocybin alone). Common adverse events after psilocybin were similar across pretreatments (headache in six subjects in each condition; isolated reports of flashbacks, nausea, abdominal bloating, vasovagal syncope and lack of energy). Adverse events during escitalopram pretreatment included nausea (8 subjects), headache (6), tiredness (6), and decreased libido (5); these complaints were somewhat more frequent than during placebo pretreatment. BDNF and gene expression: Psilocybin significantly increased plasma BDNF peak levels compared with baseline in both escitalopram and placebo conditions (t22 = 5.4, P < 0.001 and t22 = 3.6, P = 0.002, respectively). Escitalopram pretreatment did not significantly alter the psilocybin-induced BDNF increase. No significant changes in peripheral expression of HTR2A or SLC6A4 were detected after the 2-week escitalopram pretreatment compared with placebo. Pharmacokinetics: Unconjugated (psychoactive) psilocin reached mean maximal plasma concentrations at approximately 2 hours postdose, with a mean elimination half-life of about 1.8–2.0 hours (range reported ~1.1–2.2 hours). A large fraction of psilocin underwent glucuronidation; psilocin glucuronide peak concentrations occurred later (mean tmax ≈ 3.7–3.8 hours) and had longer half-lives (≈4.5–5.2 hours). The inactive metabolite 4-HIAA rose more rapidly than glucuronide and was not conjugated. Escitalopram did not significantly alter the pharmacokinetic parameters of unconjugated psilocin, psilocin glucuronide, or 4-HIAA. The temporal profile of unconjugated psilocin closely paralleled the acute subjective effect time-course.

Becker and colleagues interpret the findings as not supporting their primary hypothesis: short-term escitalopram pretreatment did not blunt the overall mind‑altering or positive mood effects of a 25 mg psilocybin dose in healthy volunteers. Instead, escitalopram selectively reduced negative or aversive aspects of the acute experience, including anxious ego-dissolution, anxiety, ‘‘bad drug effects,’’ and several autonomic adverse effects, without evidence of increased serotonergic toxicity. No clinically relevant QTc prolongation attributable to the drug combination was observed overall, although isolated high QTc values occurred in some individuals. The investigators compare their null finding for overall intoxication to prior case reports and small studies suggesting that chronic SSRI use might reduce psychedelic responses and note pharmacological differences between psilocybin and other serotonergic drugs that may affect interactions. They also highlight that unconjugated psilocin appears to be the pharmacologically active analyte best aligned with the acute effect profile, and that psilocin glucuronide may be a longer-lived marker useful for toxicology. Several limitations are emphasised. Only escitalopram was tested and the 14-day pretreatment may have been too short to induce chronic neuroadaptations (for example, changes in receptor expression or transporter density) that could alter responses to 5-HT2A receptor stimulation. The study did not assess other potential molecular markers (e.g., HTR1A) and did not measure active escitalopram metabolites. Participants were healthy volunteers in a controlled laboratory setting rather than patients in a therapeutic context, which limits generalisability to clinical populations. The authors also note that adverse-event reporting suggested more complaints during escitalopram pretreatment, even though overall subjective complaints measured by the List of Complaints did not statistically differ. Strengths cited include the within-subject crossover design, double-blinding, balanced sex distribution, standardised psychometric instruments, and thorough pharmacokinetic characterisation including unconjugated psilocin. On balance, the investigators conclude that short-term escitalopram pretreatment did not meaningfully reduce positive acute psilocybin effects and in fact reduced certain negative and autonomic effects, providing no signal of harmful drug–drug interaction under the study conditions. They recommend further research with longer antidepressant pretreatment durations, other antidepressant classes, and studies in patient populations to determine whether antidepressant treatment should be maintained or stopped prior to psilocybin administration and to clarify effects on therapeutic outcomes.

Escitalopram given for 2 weeks did not diminish the acute positive mood or core mind‑altering effects of a 25 mg psilocybin dose in healthy subjects but did reduce several negative subjective and autonomic adverse effects compared with placebo pretreatment. No pharmacokinetic interaction with psilocin was detected, and peripheral measures (HTR2A/SLC6A4 expression, QTc intervals, BDNF) showed no clinically relevant detrimental changes attributable to combined treatment. The authors advise further studies with longer antidepressant pretreatment and in patient populations to define interactions relevant to therapeutic use and to determine whether antidepressant discontinuation is necessary before psilocybin administration.