Pharmacokinetics and pharmacodynamics of oral psilocybin administration in healthy participants

Psilocybin is a classic psychedelic that acts as a serotonin 5-HT2A receptor agonist and is under investigation for several psychiatric and neurological indications, including major depression, anxiety, cluster headache, and migraine. After oral administration psilocybin is rapidly dephosphorylated to psilocin, which reaches maximal plasma concentrations roughly 1.6–2 h after dosing and is subsequently metabolised to inactive products such as psilocin glucuronide and 4-hydroxyindole-3-acetic acid (4-HIAA). Earlier clinical pharmacokinetic (PK) studies were small and mostly used body weight–adjusted dosing; by contrast, contemporary therapeutic trials typically administer single fixed doses (commonly 15, 25, or 30 mg). As a result, detailed PK data and pharmacokinetic–pharmacodynamic (PK–PD) characterisation for these fixed doses have been lacking. Anna and colleagues set out to characterise the PK of unconjugated (free) psilocin and its main metabolites, to quantify urinary recovery, and to define the PK–PD relationship between psilocin plasma concentrations and subjective effects after clinically relevant fixed oral doses of 15, 25, and 30 mg. To do so they combined and analysed data from two Phase I, double-blind, placebo-controlled, cross-over studies in healthy volunteers, applying validated bioanalytical assays and established compartmental PK and PK–PD modelling techniques. The aim was to provide a reference dataset for future clinical trials using fixed-dose psilocybin regimens.

The analysis pooled data from two separately conducted Phase I, double-blind, placebo-controlled, crossover studies. One study involved 23 healthy participants (12 men, 11 women; mean age 34 ± 10 years; mean body weight 70 ± 14 kg; mean BMI 24 ± 3.5; mean GFR 110 ± 13 ml/min/1.73 m2). Details for the second study’s participant numbers and full demographics are not clearly reported in the extracted text. Both studies used identical psilocybin capsules manufactured under GMP; each capsule nominally contained 5 mg psilocybin dihydrate with an analytically confirmed content of 4.61 ± 0.09 mg per capsule. Psilocybin was administered orally in single fixed doses of 15, 25, or 30 mg during controlled test sessions. Test sessions typically began in the morning, with dosing at 10:00 AM in at least one study; outcome assessments were performed repeatedly for up to 7 h in the first study and up to 24 h in the second study. Participants were monitored continuously during the acute effect phase and precautions (never alone during early hours, overnight stay in one study) were taken for safety. Blood sampling schedules were dense and differed between studies: the first study collected plasma up to 7 h at multiple early time points (from pre-dose to 7 h), while the second study included additional later time points up to 24 h. Urine was collected in the second study over 0–8, 8–16, and 16–24 h intervals. Plasma and urine concentrations of unconjugated psilocin, psilocin glucuronide (determined by difference after β-glucuronidase deconjugation), and 4-HIAA were measured using a validated ultra-high-performance liquid chromatography–tandem mass spectrometry method. Pharmacokinetic modelling used Phoenix WinNonlin 8.3. A one-compartment model with first-order input, first-order elimination and a lag time was selected based on model fit criteria and visual inspection; non-compartmental analyses were used to derive initial parameter estimates. For PK–PD linkage the predicted plasma concentrations were input to a pharmacodynamic model using a first-order equilibrium rate constant (ke0) to account for delay between plasma and effect-site concentrations; a sigmoid Emax model (parameters EC50, Emax, γ) described concentration–effect relationships. EC50 denotes the concentration producing half-maximal effect; ke0 represents the rate constant governing equilibration of plasma and effect-site concentrations. Renal clearance was calculated as urinary recovery divided by AUC24. Onset, Tmax, offset and effect duration were derived from model-predicted "any drug effect" visual analogue scale (VAS) time curves using a 10% of individual maximum threshold. Pearson correlations assessed associations between body weight, BMI, GFR, age and plasma concentrations.

Plasma pharmacokinetics: Unconjugated psilocin, psilocin glucuronide and 4-HIAA were quantified in plasma at all sampled time points; all samples were reanalysed after deglucuronidation to enable determination of free and conjugated amounts. Psilocin displayed dose-proportional increases in plasma concentrations across the fixed 15, 25 and 30 mg doses. Mean maximal concentrations (Cmax) of unconjugated psilocin were approximately 11 ng/ml (15 mg), 17 ng/ml (25 mg) and 21 ng/ml (30 mg), with maximal concentrations reached at a mean of about 2.0, 1.9 and 2.2 h, respectively. Coefficients of variation for Cmax were moderate: 23%, 20% and 27% for the 15, 25 and 30 mg doses, indicating somewhat greater variability at the highest dose. Elimination and metabolites: Elimination followed first-order kinetics. Compartmental analysis yielded estimated elimination half-lives (t1/2) of about 1.8, 1.4 and 1.8 h for the 15, 25 and 30 mg doses, respectively; non-compartmental analyses produced longer terminal half-life estimates (2.4, 1.8 and 2.7 h for the same doses). Psilocin underwent extensive metabolism: roughly 20% of administered psilocybin dose was recovered in urine as psilocin glucuronide and 33% as 4-HIAA, while only about 1.5% was excreted as unchanged unconjugated psilocin within 24 h. Renal clearance of psilocin was reported as 42 ± 30 ml/min. Most unconjugated psilocin and 4-HIAA recovered in urine appeared within the first 8 h (averages reported as 75%, 61% and 81% across analytes for the first 8 h), whereas the largest portion of psilocin glucuronide was eliminated in the 8–16 h window. Overall, approximately 54% of the administered dose was recovered renally within 24 h as the measured analytes. Subjective effects and PK–PD relationships: Repeated VAS ratings for "any drug effect," "good drug effect," "bad drug effect," and "ego dissolution" were modelled against psilocin concentrations. Subjective effects were dose-dependent: mean durations of the subjective effect ("any drug effect") were 5.6 ± 2.2 h (15 mg), 5.5 ± 1.6 h (25 mg) and 6.4 ± 2.2 h (30 mg). Peak intensities for "any drug effect" increased with dose (mean maximal ratings ~58% ± 25% for 15 mg, 73% ± 27% for 25 mg, and 80% ± 18% for 30 mg). "Good drug effect" and "ego dissolution" increased with dose, whereas "bad drug effect" was generally low and did not show a clear dose–response across pooled data; EC50 estimates (psilocin concentration producing half-maximal effect) were in a similar range for the various subjective endpoints. The Emax (maximum predicted effect) for "bad drug effect" was 3–5 times lower than for the other subjective measures. PK–PD modelling indicated that subjective effects closely mirrored unconjugated psilocin concentrations within subjects, with no evidence of acute pharmacological tolerance during the monitored timeframe. Safety and tolerability: Adverse events were previously reported in detail; common acute complaints during the effect phase included fatigue, headache, reduced concentration and low energy, while subacute events included headache, migraine, low mood and nausea. No serious adverse events related to substance administration were reported in the extracted text.

Anna and colleagues interpret their findings as the first comprehensive description of the pharmacokinetics, urinary recovery and PK–PD relationships for commonly used fixed oral psilocybin doses (15–30 mg) in healthy volunteers. The data show dose-proportional plasma increases for free psilocin and its main metabolites and dose-proportional urinary recovery. The authors note that compartmental half-life estimates relevant to the acute phase (approximately 1.4–1.8 h) are shorter than many previously reported values; they argue that compartmental estimates better reflect the clinically relevant plasma half-life during the first 8 h when psychotropic effects occur, whereas non-compartmental estimates provide best estimates of the terminal elimination phase. The close temporal relationship between unconjugated psilocin concentrations and subjective effects supports a direct link between exposure and acute psychotropic response, and the PK–PD model showed no sign of acute tolerance within the observation window. Body weight, BMI and GFR were not associated with plasma concentrations of unconjugated psilocin in the studied ranges, leading the authors to conclude that body weight–adjusted dosing is likely unnecessary for typical clinical populations and that fixed dosing may produce more consistent exposures. The metabolic data indicate extensive biotransformation, with only about 1.5% of the administered dose excreted as unchanged psilocin and roughly 54% of the dose recovered renally within 24 h as measurable metabolites; on this basis the authors suggest dose adjustment for renal impairment is unlikely to be required, although explicit clinical recommendations are not asserted. Strengths highlighted include use of two randomised trials conducted in a controlled laboratory setting, balanced sex representation, use of identically manufactured and well-characterised psilocybin capsules, validated assays for free and conjugated analytes, and dense sampling including urine measurement in one study. Limitations acknowledged in the extracted text include pooling data from two different participant samples and differences in sampling/configuration between studies: the 25 mg study lacked urine recovery data and had plasma/effect assessments only up to 7 h, which necessitated slightly different PK model configurations to achieve best fit. The authors conclude that the presented PK and PK–PD characterisation for fixed-dose oral psilocybin should serve as a reference for future clinical studies.