Acute effects of psilocybin on glutamate concentration levels, functional connectivity and subjective state

Psilocybin is a classic serotonergic psychedelic under investigation for treatment of depression and anxiety. Previous clinical and experimental work has linked acute positive experiences induced by psilocybin—such as mystical-type experiences and Oceanic Boundlessness—to longer-term improvements in mood disorders, and preclinical and some human data suggest psychedelics may elicit neuroplastic changes and increase markers such as brain-derived neurotrophic factor (BDNF). At the same time, psilocybin can produce negative acute effects including anxiety, nausea and autonomic activation, and there is uncertainty about how concomitant use of serotonergic antidepressants might alter either therapeutic or adverse responses to psychedelics. Becker and colleagues set out to test whether short-term pretreatment with the selective serotonin reuptake inhibitor escitalopram alters the acute subjective, physiological, pharmacokinetic and biomarker responses to a fixed clinical dose of psilocybin (25 mg) in healthy volunteers. The primary endpoint was alteration of consciousness measured by the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale, and secondary outcomes included detailed subjective measures over time, autonomic and adverse effects, plasma BDNF, QTc interval, gene expression of HTR2A and SLC6A4, and psilocin pharmacokinetics.

The study used a double-blind, placebo-controlled, within-subject crossover design with two 14-day pretreatment conditions: escitalopram (10 mg daily for 7 days followed by 20 mg daily for 7 days) and placebo. Twenty-seven participants were recruited; after dropouts 23 healthy adults (12 men, 11 women; mean age 34 ± 10 years) completed both test sessions. Key exclusion criteria included major psychiatric history, recent or heavy illicit drug use, pregnancy and medications likely to interact with study drugs. The last dose of escitalopram or placebo was given 2 hours before administration of a single 25 mg oral psilocybin dose; treatment order was randomised and counterbalanced and sessions were separated by at least 16 days. Test sessions lasted 10 hours in a controlled hospital room with repeated measurements. Primary subjective outcome was the 5D-ASC assessed 7 hours after psilocybin; other psychometric instruments included the 3D-OAV subscales, the Mystical Effects Questionnaires (MEQ43 and MEQ30), repeated visual analogue scales (VAS) and the Adjective Mood Rating Scale (AMRS). Autonomic measures (blood pressure, heart rate, tympanic temperature), adverse events (List of Complaints), and ECG-derived QTc intervals were collected. Plasma BDNF was sampled at baseline and 4 and 7 hours post-psilocybin. Gene expression of HTR2A and SCL6A4 was assayed from PAXgene blood samples taken before psilocybin administration after the pretreatment period. Pharmacokinetic sampling quantified unconjugated (free) psilocin, psilocin glucuronide (by deglucuronidation), and 4-hydroxyindole-3-acetic acid (4-HIAA) up to 7 hours post-dose; escitalopram concentrations were also measured. Noncompartmental methods were used to estimate pharmacokinetic parameters. Repeated measures data were summarised by peak changes (Emax/Emin or ΔEmax) and analysed with paired two-sided t-tests; significance threshold was P < 0.05 and no correction for multiple comparisons was applied. Order effects were tested by comparing first and second sequence.

Twenty-three participants completed both treatment arms. Becker and colleagues report that escitalopram pretreatment did not reduce the primary outcome: overall 5D-ASC and 3D-OAV total scores were similar after escitalopram and after placebo, indicating no overall attenuation of psilocybin-induced alterations of consciousness. Despite the null primary result, escitalopram selectively reduced several adverse and anxiety-related subjective effects induced by psilocybin. Compared with placebo pretreatment, escitalopram significantly reduced Anxious Ego-Dissolution (P = 0.03) and anxiety ratings on the 5D-ASC and AMRS (P = 0.03 and P = 0.007, respectively). On repeated VAS measures escitalopram attenuated peak increases in "any drug effect" (P = 0.02), "bad drug effects" (P = 0.004), and "fear" (P = 0.004), and reduced items such as "talkative" (P = 0.03) and "open" (P = 0.03). Escitalopram also attenuated reductions in "happy" (P = 0.04) and "concentration" (P = 0.01). Measures of positive acute experience were largely preserved: escitalopram did not significantly alter "Oceanic Boundlessness," "Visionary Restructuralization," global MEQ30 total score, or ratings of "good drug effects" and drug liking. On MEQ subscales escitalopram lowered "nadir effects" (P = 0.001) and "ineffability" (P = 0.02) but did not affect positive mood subscales. Autonomic data showed that escitalopram reduced some psilocybin-induced physiological responses; peak increases in blood pressure and pupil size were attenuated and overall acute adverse effects measured by the List of Complaints were reduced (P = 0.03). QTc intervals did not differ overall between conditions, and psilocybin did not significantly change QTc at 2.5 hours versus baseline; nevertheless the longest individual QTc values observed reached 509 ms after combined escitalopram and psilocybin in one participant. Common adverse events after psilocybin (headache, occasional nausea, one vasovagal syncope) were similar in type and frequency across pretreatment conditions. During the escitalopram pretreatment period itself, participants reported more treatment-related complaints (nausea, headache, tiredness, decreased libido and others) than during placebo, though the List of Complaints scores did not differ significantly. One severe nontreatment-related adverse event (symptomatic vertebral disc hernia requiring surgery) led to withdrawal before psilocybin administration. Plasma BDNF levels rose after psilocybin in both pretreatment conditions (t22 = 5.4, P < 0.001 with escitalopram; t22 = 3.6, P = 0.002 with placebo), and escitalopram did not significantly alter this increase. Gene expression assays showed no significant changes in HTR2A or SLC6A4 expression after 2 weeks of escitalopram compared with placebo. Mean peak plasma escitalopram concentrations at the time of psilocybin dosing were 41 ng/mL (range 35–53 ng/mL), consistent with therapeutic levels. Pharmacokinetics: unconjugated (psychoactive) psilocin reached mean maximal plasma concentrations of approximately 20 ng/mL at about 2 hours post-dose and had an elimination half-life of roughly 1.8–2.0 hours (range reported 1.1–2.2 hours). A large fraction of psilocin underwent glucuronidation; psilocin glucuronide peaked later (mean 3.7–3.8 hours) and had a longer half-life (approx. 4.5–5.2 hours). 4-HIAA concentrations rose rapidly and were not substantially conjugated. Escitalopram pretreatment did not significantly alter psilocin, psilocin glucuronide or 4-HIAA pharmacokinetics.

Becker and colleagues interpret their findings as not supporting the primary hypothesis that serotonin reuptake inhibition would blunt the overall mind‑altering effects of a full clinical psilocybin dose. Two weeks of daily escitalopram did not reduce positive acute experiences such as Oceanic Boundlessness or overall mystical-type scores, but it did attenuate anxiety-related and negative subjective effects, as well as some autonomic responses and reported acute adverse events. No pharmacokinetic interaction between escitalopram and psilocybin was observed, and there was no clear signal of increased serotonergic toxicity; QTc intervals were similar across conditions though isolated long QTc values in individual participants were noted. The authors situate these results amid prior, largely retrospective reports suggesting that some antidepressants reduce responses to LSD and other psychedelics, but they note pharmacological differences between compounds that might produce different interactions. They caution that their findings apply only to escitalopram after 14 days of pretreatment in healthy volunteers and may not generalise to other antidepressant classes, longer or chronic antidepressant exposure, or clinical populations. Relevant limitations highlighted include the short pretreatment duration that might not produce chronic receptor adaptations, absence of measures for some receptor or gene targets (for example HTR1A), lack of measurement of escitalopram metabolites, and the healthy volunteer setting rather than a therapeutic context. Strengths of the study cited by the investigators include the within-subject, double-blind crossover design, balanced sex distribution, use of validated psychometric measures, and detailed pharmacokinetic characterisation including unconjugated psilocin. The authors conclude that, in this experimental setting, escitalopram did not compromise the positive acute subjective effects of psilocybin and in fact reduced several adverse effects, suggesting that stopping escitalopram prior to psilocybin administration may not be necessary; nevertheless they call for further studies with longer antidepressant pretreatment and in patient populations to determine effects on therapeutic outcomes and to guide clinical practice.

Escitalopram pretreatment for 2 weeks did not meaningfully affect the acute positive mood and mind‑altering effects of a 25 mg psilocybin dose in healthy volunteers, but it significantly reduced several negative subjective, autonomic and adverse effects compared with placebo. No pharmacokinetic interaction or change in HTR2A/SLC6A4 expression was observed. The investigators state that escitalopram and psilocybin can be administered together without evident acute safety concerns in this setting, while emphasising the need for further research with longer antidepressant exposure and in patient populations to clarify implications for therapeutic use.