Safety pharmacology of acute psilocybin administration in healthy participants

Classic psychedelic psilocybin is under investigation for multiple clinical indications including depression, anxiety, addiction and certain headache disorders. Earlier controlled trials have generally reported tolerable and transient adverse effects, but uncertainties remain about the detailed safety pharmacology profile—particularly the incidence of challenging psychological reactions ("bad trips"), acute anxiety, flashbacks or hallucinogen persisting perception disorder (HPPD), and cardiovascular and thermoregulatory effects. The authors note that many patient studies lack frequent, standardised vital-sign monitoring, creating a need for more granular safety data collected under highly controlled conditions. Straumann and colleagues therefore performed a pooled analysis of three Phase I, randomised crossover trials conducted in the same laboratory to describe the acute subjective, autonomic and adverse-effect profile, and to examine kidney and liver function before and after study participation. The pooled dataset spans a representative clinical dose range (15–30 mg single oral doses of psilocybin dihydrate) in psychiatrically and physically screened healthy adults with no or minimal prior psychedelic use, with the goal of informing safety considerations for single-dose, infrequent psilocybin administration in a clinical research setting.

The analysis pooled data from three double-blind, placebo-controlled, random-order crossover studies carried out at the University Hospital Basel, comprising 85 healthy participants and 113 single psilocybin administrations. Washout periods between sessions were at least 10 days. Study 1 contributed 25 mg administrations (with placebo pretreatment sessions included in this analysis), Study 2 included 15 mg and 30 mg psilocybin doses among other arms, and Study 3 included a 20 mg psilocybin arm; only psilocybin-alone and placebo conditions were used here. Participants were psychiatrically and physically screened; exclusion criteria (reported elsewhere) included a history of psychiatric disorder, significant physical illness and limits on lifetime illicit drug use. The sample was 43 men and 42 women, aged 25–55 years, with 64% reporting some prior drug use and 48% indicating prior psychedelic exposure (mostly 1–10 uses). Psilocybin (analytically characterised, administered in opaque capsules containing nominal 5 mg psilocybin dihydrate; measured content 4.61 ± 0.09 mg per capsule) and matched placebo were produced under GMP conditions. Study 1 participants were aware they would receive psilocybin; Studies 2 and 3 were double-blind and included other psychoactive comparators. Sessions took place in a calm hospital room with one participant and one or two investigators; participants were monitored continuously for 7–12 h and had investigator access for up to 24 h. Primary pharmacodynamic measures included repeated Visual Analogue Scales (VAS; 0–100 mm) for "any drug effect", "good drug effect", "bad drug effect", "anxiety" and "ego dissolution" at baseline and multiple post-dose time points (including 0, 0.25, 0.5, 0.75, 1, 1.5–? and 24 h, with some variations between studies). The 5 Dimensions of Altered States of Consciousness (5D-ASC) instrument was administered to capture Oceanic Boundlessness (OB) and Anxious Ego-Dissolution (AED). Vital signs (systolic/diastolic blood pressure, heart rate) were measured in duplicate after ≥10 min rest and tympanic temperature was recorded. Predefined thresholds were used to classify hypertension, tachycardia and hyperthermia. Acute and subacute adverse effects were assessed with a 66-item List of Complaints administered before, ~12 h (7 h in Study 1) and 24 h after dosing; subacute effects were not recorded in Study 1. QTc intervals were measured in Study 1 at −1 h and +2.5 h around 25 mg dosing. Blood chemistry and cell counts were measured at screening and at an end-of-study visit (screening to end-of-study interval 161 ± 85 days; end-of-study blood sampling occurred at a median 28 ± 18 days after the last administration). Estimated glomerular filtration rate was calculated using Cockcroft–Gault. Participants were asked at the end-of-study visit about flashbacks, perceived overall valence of the experience and willingness to use psilocybin again. Statistical analyses used ANOVAs with dose as factor and Tukey post hoc tests, Fisher's exact tests for proportions, paired t-tests for before–after laboratory measures, and order (psilocybin-first vs psilocybin-second) was examined; significance was set at p < 0.05.

Subjective effects: All doses (15, 20, 25 and 30 mg) produced increases in general drug effects, "good drug effect" (VAS) and OB (5D-ASC) versus placebo. The 20–30 mg doses produced larger increases in "any drug effect" and "good drug effect" than the 15 mg dose. Proportions reporting "good drug effect" >50% were 79%, 91%, 88% and 96% at 15, 20, 25 and 30 mg respectively. Mean OB ratings were 24%, 31%, 41% and 37% across the dose range, and OB >50% occurred in 14%, 27%, 42% and 25% of participants at the respective doses. Negative experiences ("bad drug effect" and AED) increased at all doses versus placebo; "bad drug effect" >50% was reported by 14%, 18%, 42% and 32% at 15, 20, 25 and 30 mg, respectively. Anxiety (VAS) increased significantly only at 25 and 30 mg, with anxiety >50% reported in 7%, 6%, 17% and 11% for 15–30 mg. "Ego dissolution" increased dose-dependently; VAS >50% occurred in 46%, 67%, 75% and 89% at 15, 20, 25 and 30 mg. Mean onset, time to peak and duration of "any drug effect" across doses were 0.6 ± 0.4 h, 2.1 ± 0.8 h and 5.5 ± 2.1 h, respectively. No relevant order effects were detected. Cardiovascular and thermoregulatory effects: Psilocybin produced transient increases in blood pressure, heart rate and body temperature without clear dose dependence for blood pressure. Among all 113 psilocybin administrations, systolic blood pressure exceeded 140 mmHg in 50% of administrations and exceeded 160 mmHg in 6%; no instances above 180 mmHg were observed. Maximal recorded systolic and diastolic pressures were 180 mmHg and 115 mmHg, respectively. Tachycardia (>100 beats/min) occurred in 7% of administrations overall (by dose: 7% at 15 mg, 3% at 20 mg, 4% at 25 mg, 11% at 30 mg); the highest recorded heart rate was 140 beats/min. Tympanic temperature >38°C occurred in 16% of administrations overall (7%, 9%, 17% and 32% for 15, 20, 25 and 30 mg); the highest recorded temperature was 39.0°C and no hyperpyrexia (>40°C) occurred. QTc interval did not increase at peak response in Study 1; the longest single QTc observed was 481 ms at 2.5 h post-dose. Adverse events and follow-up laboratory tests: The List of Complaints showed significantly greater acute and subacute adverse-effect scores after psilocybin than after placebo, with similar overall counts across the four doses. Common acute complaints included fatigue, poor concentration, headache, lethargy, vertigo, weakness, decreased appetite and nausea; common subacute complaints at 24 h included tiredness, headache, lack of energy and neck pain. Acute anxiety on the List was reported by 7%, 6%, 38% and 21% at 15, 20, 25 and 30 mg respectively. Five participants (6%) reported transient flashbacks; four experienced a single episode approximately 10–72 h post-dose (mean 30 ± 29 h) and one reported recurring, non-disruptive visual flashbacks over several months. No cases meeting criteria for HPPD were identified and no serious adverse reactions occurred. Spontaneously reported events within 48 h included headache (10% after psilocybin, 7% after placebo), depressive mood (4% vs 0%), nausea (3% vs 0%) and several other low-frequency events. Laboratory measures: Creatinine, estimated glomerular filtration rate, alanine aminotransferase and γ-glutamyl transpeptidase were unchanged at the end-of-study visit (mean 28 ± 18 days after last administration) compared with screening. Haemoglobin decreased consistent with cumulative blood loss during study sampling; red and white cell counts were unchanged. Peak plasma psilocin concentrations and AUCs are reported in tables but the detailed pharmacokinetics are described elsewhere. Participant experience and willingness to repeat: At study end, 87% of participants rated the overall psilocybin experience as positive, 11% neutral and 2% negative. Eighty-two percent stated they would consider taking psilocybin again, 15% said they might, and 2% would probably not take it again. Preferences about setting varied (clinical study, recreational with friends, in nature), and about half reported prior psychedelic experience influenced their study session.

Straumann and colleagues interpret the pooled findings as indicating that single oral doses of psilocybin up to 30 mg produce predominantly positive acute subjective effects in healthy, screened adults, with transient and generally manageable physiological activation. The 20–30 mg doses produced stronger positive subjective effects than 15 mg, while appreciable anxiety occurred primarily at 25 and 30 mg. "Ego dissolution" increased with dose and correlated more with positive than negative valence. Pharmacodynamically, onset and total duration corroborated previous reports (onset ~20–40 min; duration <6 h) though time-to-peak was longer in this pooled dataset (~2 h) than some prior accounts. Cardiovascular activation was mild compared with stimulants such as MDMA and comparable to LSD at psychoactive doses; no instances of extreme hypertension or hyperpyrexia occurred and QTc prolongation was not observed in Study 1. The authors emphasise that acute adverse effects—fatigue, headache, nausea and transient anxiety—were common but typically transient and did not require benzodiazepine rescue in these sessions. Flashbacks occurred in a small minority (6%), were mostly single and transient, and no cases of HPPD were detected within the follow-up period. Liver and kidney function tests showed no clinically relevant changes at an average of about one month after dosing. Key limitations acknowledged include pooling studies with different participants and protocols (Study 1 lacked placebo control and assessed fewer late time points), the inclusion of sessions with other psychoactive compounds in the original trials (though order effects were not detected), a predominantly young and physically healthy sample, limited prior psychedelic exposure in participants, modest overall sample size (85 participants, 113 administrations) that is insufficient to detect rare adverse events (incidence 0.1–1% or <0.1%), lack of long-term follow-up, and absence of analyses of individual pharmacokinetic variability or detailed risk-factor modelling. The investigators note that risks might differ in more heterogeneous or clinical populations and recommend further research to characterise safety in patients and to identify predictors of adverse responses (previous work suggests pre-session emotional excitability may predict unpleasant reactions). Concluding, the pooled data support that single-dose, infrequent psilocybin administration in a controlled clinical setting appears to be safe with respect to acute psychological and physical harm in healthy participants, but the authors caution that additional study is required to define risks and benefits in patient populations and to detect rare adverse events.

Single-dose administrations of psilocybin up to 30 mg were judged by the study team to be safe regarding acute psychological and physical harm in psychiatrically and physically healthy participants when delivered in a controlled clinical research setting. Psilocybin induced mostly positive subjective effects, mild cardiovascular stimulation and transient adverse effects including fatigue, headache and occasional anxiety; flashbacks were infrequent and typically transient. The authors state that these safety data do not raise concerns for single, infrequent doses in controlled conditions but emphasise that further research is needed to evaluate risks and benefits in clinical populations and to identify rare or longer-term adverse outcomes.