In a within-subject study of 12 healthy volunteers given three escalating oral psilocybin doses (0.3–0.6 mg/kg), higher doses produced greater Mystical Experience Questionnaire scores—particularly on the transcendence of time and space subscale—and positive persisting effects 30 days later. Pharmacokinetics scaled with dose but did not predict mystical scores, and a complete mystical experience was not necessary for positive outcomes.
Aim
The aim of the current study was to investigate the relationship between escalating higher doses of psilocybin and the potential psilocybin occasioned positive subjective effects.
Methods
Healthy participants ( n=12) were given three escalating doses of oral psilocybin (0.3 mg/kg; 0.45 mg/kg; 0.6 mg/kg) or (18.8–36.6 mg; 27.1–54.0 mg; 36.3–59.2 mg) a minimum of four weeks apart in a supervised setting. Blood and urine samples, vital signs, and electrocardiograms were obtained. Subjective effects were assessed using the Mystical Experience Questionnaire and Persisting Effects Questionnaire.
Results
There was a significant linear dose-related response in Mystical Experience Questionnaire total score and the transcendence of time and space subscale, but not in the rate of a complete mystical experience. There was also a significant difference between dose 3 compared to dose 1 on the transcendence of time and space subscale, while no dose-related differences were found for Mystical Experience Questionnaire total scores or rate of a mystical experience. Persisting Effects Questionnaire positive composite scores 30 days after completion of the last dose were significantly higher than negative composite scores. Persisting Effects Questionnaire results revealed a moderate increase in sense of well-being or life satisfaction on average that was associated with the maximum Mystical Experience Questionnaire total score. Pharmacokinetic measures were associated with dose but not with Mystical Experience Questionnaire total scores or rate of a mystical experience.
Conclusions
High doses of psilocybin elicited subjective effects at least as strong as the lower doses and resulted in positive persisting subjective effects 30 days after, indicating that a complete mystical experience was not a prerequisite for positive outcomes.
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Barrett, F. S., Johnson, M. W., Griffiths, R. R. · Journal of Psychopharmacology (2015)
Barrett, F. S., Bradstreet, M. P., Leoutsakos, J. M. S. et al. · Journal of Psychopharmacology (2016)
Brown, R. T., Nicholas, C. R., Cozzi, N. V. et al. · Clinical Pharmacokinetics (2017)
Carbonaro, T. M., Bradstreet, M. P., Barrett, F. S. et al. · Journal of Psychopharmacology (2016)
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.
dose consisted of the four subscales of the MEQ (mystical, positive mood, transcendence of time and space, and ineffability), total MEQ score, rate of mystical experience, and pharmacokinetic AUC and C max values. Dichotomous outcomes consisted of occurrence of headache, tachycardia or hypertension, and attainment of a full mystical experience. Continuous outcomes were compared between dose groups with repeated analysis of variance (ANOVA) models using dose group as a fixed effect and participant as a random effect. Incidence of the dichotomous variable between dose groups was compared with mixed-effects logisticregression models with dose group as a fixed effect and participant as a random effect. If significant differences were found between dose groups then a post-hoc mixed effects analysis with Tukey adjusted p-values was used to determine differences between dose groups. Data from the PEQ were collected once per participant 30 days after each participant's last dose of psilocybin. Paired t-tests were used to determine if positive PEQ composite scores were significantly different than the analogous negative PEQ composite scores. Analyses were conducted using R for statistical computing (R Core Team, 2013) with packages nlme,, geepack, ppcor. All tests were conducted at an a-priori 0.05 significance level.
Psilocybin has been shown to produce dose-dependent positive subjective changes in mood, perception, and psychological states in healthy participants. Results from the current study, in which the immediate and persisting subjective effects of psilocybin were evaluated, revealed a significant linear dose-related response in MEQ total score and the transcendence of time and space subscale, but not in the rate of a complete mystical experience. Comparisons between the three doses revealed a significant difference between dose 3 and dose 1 on the transcendence of time and space subscale, though there were no differences in MEQ total scores or rate of a mystical experience. PEQ positive composite scores 30 days after completion of the last dose were significantly higher than negative composite scores. PEQ results also revealed a moderate increase in sense of well-being or life satisfaction on average that was associated with the maximum MEQ total score. AUC and C max were associated with dose; and with the exception of a positive association between AUC and the transcendence of time and space subscale, there were no other associations between pharmacokinetic and subjective measures. Results of the current study suggest that even without differential effects of dose on the rate of a "complete" mystical experience, positive persisting effects were achieved following these higher doses of psilocybin. The results of the current study showed a slightly lower rate of complete mystical experiences compared with some previous studies using psilocybinbut are similar to those of LSD in healthy participants and patients. A complete mystical experience was defined as scoring ⩾60% on each of the four subscales: mystical, transcendence of time and space, positive mood, and ineffability. Only 36% of the doses (12 of 33) facilitated a complete mystical experience. There was no significant difference in the rate of complete mystical experience across the three high doses with four (33.3%) occurring after dose 1, five (45.5%) after dose 2, and three (30.0%) after dose 3 (p=0.547). A number of considerations for our findings are offered below. It would be reasonable to infer from previous reports of doserelated mystical-type experiences) that a similar pattern would have been observed in the current study. While we did observe a dose-related response on the MEQ total score, the rate of mystical experiences was not associated with dose, nor did it differ between doses. One possible explanation for these findings, particularly at 0.60 mg/kg, could be the result of a ceiling effect: for some participants, maximum subjective effects were achieved at the 0.30 mg/kg or 0.45 mg/kg doses. Specifically, three out of four participants who had a mystical experience at 0.30 mg/kg achieved one at 0.45 mg/kg, however, only one of these participants had a mystical experience at 0.60 mg/kg (see Supplementary Material Table). This may also be the case for the two participants who only had one mystical experience at either 0.30 mg/kg. or 0.45 mg/kg, respectively. Participants were exposed to higher concentrations of psilocybin with each escalating dose, as shown by the significant positive linear increase in AUC and C max of psilocin with increasing doses of psilocybin. Future research investigating underlying causes of a ceiling effect in psilocybin will be important, particularly when developing therapeutic protocols. The requirements that each participant not only be non-naive to psychedelics, but also that at least one of their prior experiences was deemed to be meaningful could have also contributed to a lower rate of mystical experience. We speculate that while findings from the PEQ (see below) indicated that the majority of participants rated their psilocybin experience in the study to be highly positive and meaningful, it is possible that some of our participants were relatively less sensitized to the effects of psilocybin compared to psychedelic naïve individuals. This notion may be consistent with pooled data across 23 experimental psilocybin studies showing significantly increased visual changes, disembodiment, and changed meaning of perceptsin psychedelic-naïve participants. In contrast, no difference in the acute effects of LSD was found between naïve participants and those with up to 10 previous experiences. It is also possible that the PEQ results were affected by their prior positive experience (e.g. expectancy; learned ability to achieve meaning). Thus, more direct comparisons between non-naive and naïve participants with regard to the intensity of the acute effects, expectations, and their subsequent ability and/or efforts to personally integrate their experience would be informative. Another characteristic of our sample which could have affected the validity of their responses on the SOCQ and the embedded MEQ, is that several of the participants in our study were proclaimed atheists, had limited or no involvement in a spiritual practice, or had belief systems outside the Judeo-Christian traditions. The MEQ includes several items referring to Judeo-Christian phenomena. These include the "sacredness" dimension of the mystical factor (e.g. "sense of reverence;" "sacred and holy") in addition to other SOCQ items not included in the MEQ (e.g. "visions of events in the life of Christ") that may be incongruous to the belief system of some of our participants. While sensitivity analysis involving recalculation of the MEQ without the "sacredness" dimension did not change the rate of a mystical experience, it is possible that frustration when encountering some of these items affected their pattern of responding on these measures. Additionally, the fact that some of our participants did not engage in a spiritual practice also limits our comparisons to studies where engagement in a spiritual practice was part of their inclusion criteria. Given the exploratory nature and novelty of progressing to a never-reported high dose of psilocybin (i.e. 0.60 mg/kg), an important methodological decision based on our cautious approach to the study design was to implement an escalating weight-based dose design without controlling for dose sequence effects through counterbalancing. Thus, it is unknown whether a first dose at 0.60 mg/kg would have been associated with different scores on subjective measures., observed dose sequence effects on follow-up measures, though not acutely on the MEQ when participants were randomized to either an ascending or a decending dose sequence. Also, the highest dose in that study was equivalent to 0.45 mg/kg; and consistent with our study, did not find a significant difference from 0.30 mg/kg to 0.45 mg/kg in the total MEQ score, or on any of the subscales, except transcendence of time and space. It also remains unknown if the interval between consecutive doses is associated the subjective effects of psilocybin. Consecutive doses were administered on average four weeks apart for each participant, thus a shorter or longer interval between doses may be important to consider in future studies. Another possibility was the invasive nature of our sampling procedure, including frequent blood sampling through an IV catheter or using venipuncture, blood pressure, and temperature measurements, urine collection, and intermittent use of a 12-lead ECG monitoring system. Anecdotally, however, participants reported that these measures were not explicitly disruptive, often welcoming these measurements as a tangible reminder of their contribution to science. Consistent with, the only MEQ subscale that showed a significant increased effect at dose 3 relative to dose 1 and positive association with AUC in our study, was transcendence of time and space. It is possible that the subjective effects of time were the only aspects of the psychedelic experience that became distinguishably stronger, relative to the remaining MEQ subscales (mystical, positive mood, ineffability). In addition to the reasons described above (ceiling effect, nonnaïvety of the participants; not explicitly spiritual), this may be related to the transcendence of time and space subscale, which contains less religious and/or spiritual wording and thus may be less affected by any possible validity issue in our sample. Despite the lower rate of a complete mystical experience, participants reported profound positive changes evidenced by the PEQ results and as similarly reported in a study using LSD. Average positive composite scores were significantly higher (range: 0.58-0.67) than the corresponding average negative composite scores (range: 0.03-0.7) in all response categories (all p<0.001). In addition, while the majority of PEQ variables did not correlate significantly with minimum, maximum, or mean MEQ, the PEQ Final Question 3 ("Did the experience change your sense of well-being or life satisfaction?") was associated with maximum MEQ (p=0.05), in effect suggesting that it may not be solely the "complete" mystical experience itself that leads to important positive effects and outcomes. Additional limitations are worth considering. With only 12 volunteers and 33 evaluable sessions, we likely had limited statistical power to capture possible differences between doses and larger dose related effects on subjective measures. Also, given that the probability that difficult and challenging psychological experiences increase at higher doses, it would be informative to measure these experiencesfuture studies to examine their impact on the rate of mystical experience. In the current study, every dose was considered a "high dose" based on previous research, with dose 3 (0.60 mg/kg,) providing the highest dose of psilocybin recorded in a research setting. Studying high doses may be relevant for substance-use disorders (e.g. alcoholism and opioid addiction), in which these individuals may need higher doses of psilocybin to benefit from its effects. Importantly, the results of this study show that the 0.60 mg/kg dose elicited results at least as strong as the 0.30 and 0.45 mg/kg doses, and resulted in no serious adverse events despite the invasive nature of the pharmacokinetic sampling in this study. Notably, this study also continues to underscore how careful screening and spending adequate time to develop trust and rapport allowed for highly positive outcomes. In conclusion, while there were no statistically significant differences in the rate of complete mystical experiences at 0.60 mg/ kg versus 0.45 mg/kg or 0.30 mg/kg doses of oral psilocybin, there were significant dose-related differences on the transcendence of time and space MEQ subscale. Multiple factors may have contributed to the lack of dose-related difference in rates of mystical experience including ceiling effects, sample characteristics, and limitations of the MEQ. Participants reported significant positive persisting effects 30 days after their final dose and an average moderate increase in their overall sense of well-being or life satisfaction, which suggests that the "complete" mystical experience may not necessarily be a prerequisite for positive outcomes in certain samples. Further research discerning the complex relationship between methodological and sample characteristics and the underlying mechanisms (e.g. neurochemical and biological, psychological, and psycho-spiritual) associated with the positive effects of psilocybin will be important, particularly when developing therapeutic protocols for clinical populations.
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Doblin, R. · Journal of Transpersonal Psychology (1991)
Griffiths, R. R. · Journal of Psychopharmacology (2008)
Griffiths, R. R., Richards, W. A., Mccann, U. et al. · Journal of Psychopharmacology (2006)
Grob, C. S., Danforth, A. L., Chopra, G. S. et al. · JAMA Psychiatry (2011)
Johnson, M. W., Garcia-Romeu, A., Cosimano, M. P. et al. · Journal of Psychopharmacology (2014)
Johnson, M. W., Richards, W. A., Griffiths, R. R. · Journal of Psychopharmacology (2008)
Leary, T., Litwin, G. H., Metzner, R. · Journal of Nervous and Mental Disease (1977)
Liechti, M. E. · Neuropsychopharmacology (2017)
Liechti, M. E., Dolder, P. C., Schmid, Y. · Psychopharmacology (2016)
Maclean, K. A., Johnson, M. W., Griffiths, R. R. · Journal of Psychopharmacology (2011)
MacLean, K. A., Leoutsakos, J. S., Johnson, M. W. et al. · Journal for the Scientific Study of Religion (2012)
Richards, W. A., Rhead, J. C., Dileo, F. B. et al. · Journal of Psychedelic Drugs (1997)
Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)
Schmid, Y., Enzler, F., Gasser, P. et al. · Biological Psychiatry (2015)
Schmid, Y., Liechti, M. E. · Psychopharmacology (2017)
Studerus, E., Gamma, A., Kometer, M. et al. · PLOS ONE (2012)
Studerus, E., Kometer, M., Hasler, F. et al. · Journal of Psychopharmacology (2010)
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