High dose psilocybin is associated with positive subjective effects in healthy volunteers

Psilocybin is a classical psychedelic compound reported to produce intense alterations in perception, mood and sense of self, and in some people to occasion a so-called mystical or spiritual experience characterised by unity, sacredness, ineffability and transcendence of time and space. Early clinical and experimental work suggests that psilocybin can produce lasting positive psychological effects and improvements in mood and substance use outcomes when administered in supportive settings. Most contemporary human studies, however, have used a relatively narrow dose range (about 20–30 mg per 70 kg, roughly 0.28–0.43 mg/kg), leaving uncertainty about subjective and persisting effects at higher doses and whether a full mystical experience is necessary for beneficial outcomes. Nicholas and colleagues set out to examine the relationship between escalating, higher oral doses of psilocybin and acute and persisting positive subjective effects in healthy volunteers. The primary aim reported here was to relate dose and pharmacokinetic measures to scores on the Mystical Experience Questionnaire (MEQ30) and on the Persisting Effects Questionnaire (PEQ) collected up to 30 days after the last dose; the data derive from an open-label Phase I study that also characterised pharmacokinetics and safety of weight‑based dose escalation up to 0.60 mg/kg.

The study was an open-label, single-site Phase I investigation in medically and psychologically healthy adults who also reported at least one prior meaningful psychedelic experience. Thirteen participants were enrolled and 12 were included in the analyses. Each participant received up to three weight‑based oral psilocybin capsules in an ascending sequence with a minimum interval of four weeks between doses: 0.30 mg/kg (dose 1), 0.45 mg/kg (dose 2) and 0.60 mg/kg (dose 3), corresponding to ranges of roughly 18.8–36.6 mg, 27.1–54.0 mg and 36.3–59.2 mg respectively. Sessions were supervised in a designed setting, with two trained guides present for eight hours post‑ingestion and an overnight hospital stay for observation and pharmacokinetic sampling. Preparation emphasised set and setting: participants completed about 6–8 hours of preparatory counselling spread across several meetings to build rapport and practise coping strategies. Sessions were conducted in a comfortable, quiet room with a standardised music playlist and options such as eye‑shades and headphones. Rescue medications and a physician were available, although no rescue medications were required. Post‑session integration meetings occurred after each dose, and safety follow‑up calls were made at seven days and 30 days after dosing; the end‑of‑study visit occurred 30 days after the final dose. Subjective measures included the 30‑item MEQ30 embedded in a larger States of Consciousness Questionnaire administered on the evening of each session, and the 143‑item PEQ completed once at 30 days after the participant's last dose. A “complete” mystical experience was defined a priori as scoring ≥60% on each of the four MEQ30 subscales (mystical, positive mood, transcendence of time and space, ineffability). Physiological monitoring included blood pressure, pulse, temperature and ECG; blood and urine were collected over 24 hours for pharmacokinetic assays. Plasma psilocin concentrations (psilocybin is rapidly dephosphorylated) were measured by HPLC‑mass spectrometry; Cmax (maximum plasma concentration) was determined by inspection and AUC (area under the concentration–time curve) through 24 hours was calculated by the trapezoidal method. Statistical analyses used repeated measures ANOVA for continuous dose‑related outcomes with participant as a random effect, mixed‑effects logistic regression for dichotomous outcomes, and paired t‑tests for PEQ positive versus negative composites. Analyses were conducted in R with an a priori alpha of 0.05.

Twelve participants (median age 43 years, range 24–61; 83.3% male; 75.0% Caucasian) provided data. Twelve completed dose 1, eleven completed dose 2, and ten completed dose 3. There were no serious adverse events reported. On the MEQ30, mean total scores rose across doses from 0.58 (95% CI 0.46–0.71) at dose 1 to 0.64 (0.51–0.77) at dose 2 and 0.70 (0.56–0.83) at dose 3, but this upward trend in total MEQ score did not reach statistical significance (p=0.209). The transcendence of time and space subscale showed a significant dose effect: scores were significantly higher after dose 3 (mean 0.73, 95% CI 0.58–0.88) than after dose 1. By contrast, the rate of a “complete” mystical experience was not associated with dose. Across the 33 evaluable dosing sessions, 12 (36%) met the complete mystical experience criterion: 4 of 12 doses after dose 1 (33.3%), 5 of 11 after dose 2 (45.5%) and 3 of 10 after dose 3 (30.0%), with no significant difference between doses (p=0.547). Persisting effects measured by the PEQ at 30 days showed that positive composite scores were significantly higher than corresponding negative composite scores across all response categories (positive range 0.58–0.67 versus negative range 0.03–0.7; all p<0.001). On the PEQ global items, 2 participants (16.7%) rated the experience as the single most meaningful of their lives and 7 (58.3%) among the five most meaningful; regarding spiritual significance, 4 (33.3%) rated it as the single most spiritually significant and 6 (50.0%) among the five most spiritually significant. For the question on change in well‑being or life satisfaction (scale −3 to +3), the mean response was 2.1 (SD 1.6), significantly greater than zero (p=0.001): 7 participants (58.3%) reported “increased very much,” 3 (25.0%) “increased moderately,” 1 reported no change and 1 reported “decreased moderately.” Pharmacokinetic measures (AUC and Cmax of psilocin) increased linearly with dose. AUC showed a positive association with the transcendence of time and space subscale, but otherwise pharmacokinetic parameters were not associated with total MEQ score or the rate of a mystical experience. An association was observed between PEQ final question on well‑being and the maximum MEQ score across doses (p=0.05), but this association lost significance when controlling for the dose number associated with the maximum MEQ score (p<0.096).

Nicholas and colleagues interpret their findings as indicating that higher, weight‑based psilocybin doses up to 0.60 mg/kg produce strong acute subjective effects and positive persisting changes at 30 days, even though the incidence of a complete mystical experience did not increase with dose. The study found a significant dose‑related increase on the transcendence of time and space subscale of the MEQ and a non‑significant upward trend in total MEQ score, while only 36% of sessions met the criterion for a complete mystical experience. Persisting positive outcomes on the PEQ were robust and, on average, participants reported moderate increases in life satisfaction; these persisting effects were not wholly dependent on a complete mystical experience. The investigators offer several explanations for the lack of a dose‑related increase in complete mystical experiences: a possible ceiling effect in which some participants reached maximal subjective response at the lower doses; the non‑naïve status of participants (all had prior meaningful psychedelic experience) which might attenuate some acute effects; cultural or spiritual mismatch between participants and MEQ item wording (for example the ‘‘sacredness’’ items); and methodological factors such as the ascending, non‑counterbalanced dose sequence, the four‑week inter‑dose interval, and the invasive sampling procedures. The authors note that only the transcendence of time and space subscale—containing relatively less religious language—showed a consistent dose effect, which may reflect measurement sensitivity in this sample. Key limitations acknowledged include the small sample size (12 volunteers, 33 sessions) and limited statistical power to detect dose differences, potential sample bias from requiring prior meaningful psychedelic experience, possible expectancy effects, and measurement constraints of the MEQ in diverse samples. The investigators stress that despite these limitations the highest dose studied (0.60 mg/kg) produced effects at least as strong as the lower doses and was not associated with serious adverse events under careful screening and supervised conditions. They conclude that a complete mystical experience may not be a prerequisite for positive persisting outcomes in certain populations and recommend further research to disentangle dose, participant characteristics, sequence and interval effects, and underlying neurobiological and psychological mechanisms when developing therapeutic protocols.