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

This open-label study (n=12) investigates the positive subjective effects in response to escalating doses of oral psilocybin (21, 31.5, 42 mg/70k) in healthy participants and found that both the highest and the low doses induced equally strong mystical experiences and persisting positive effects that lasted 30 days after ingestion.

Abstract

“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.“

Authors: Christopher R Nicholas, Kelsey M Henriquez, Michele C Gassman, Karen M Cooper, Daniel Muller, Scott Hetzel, Randall T Brown, Nicholas V Cozzi, Chantelle Thomas & Paul R Hutson

Summary

Introduction and background

Psilocybin is a naturally-occurring tryptamine that was first isolated from Psilocybe mushrooms in 1958. It produces psychoactive effects that include an intense dream-like state, changes in auditory, tactile, olfactory, gustatory, and kinesthetic perceptions, altered perceptions of time and space, and ego dissolution.

Psilocybin was classified as a controlled substance in 1970, and was removed from clinical use and scientific study. However, scientific interest has grown in the resumption of research exploring the clinical safety and efficacy of psilocybin.

The current study investigated the relationship between escalating higher doses of psilocybin and positive subjective effects.

Psilocybin has been shown to produce positive effects in healthy volunteers, including increased openness, decreased depressive and anxiety symptoms, and abstinence from addictive substances. However, little is known about the potential positive effects achieved beyond the 20 – 30 mg/70 kg dose range.

The University of Wisconsin-Madison completed a Phase I study to determine the pharmacokinetics and safety of escalating doses of psilocybin.

Participants

Participants were required to be medically and psychologically healthy and have at least one self-reported prior positive or meaningful psychedelic drug experience. They were recruited by word of mouth and through ClinicalTrials.gov. Participants underwent a physical examination, blood draw, urinalysis, drug screen, and ECG at the Clinical Research Unit (CRU) at the University of Wisconsin Institute for Clinical and Translational Research (ICTR).

Seventeen people were excluded from the study due to inadequate venous access, lack of meaningful prior experience, staff clinical judgment, uncontrolled hypertension, positive psychiatric family history, abnormal ECG, or having another disqualifying disorder.

Human subjects and safety

The study was conducted in accordance with the protocol approved by the University of Wisconsin Health Sciences Institutional Review Board.

Study design and overview

The data for the current analyses come from a recently published open-label study with psilocybin given to healthy adult volunteers. The dose of psilocybin was increased by 0.3 mg/kg, 0.45 mg/kg, and 0.60 mg/kg, with a minimum of four weeks between each dose.

Drug synthesis and qualification

NV Cozzi synthesized psilocybin, which was tested for purity and potency at the University of Wisconsin-Madison School of Pharmacy Zeeh Pharmaceutical Experiment Station.

Preparation for drug sessions

The preparation of the participant and the environment are important for maximizing participant safety, especially psychologically, during, and after a psilocybin session.

Psilocybin sessions took place in a room at the University of Wisconsin-Madison School of Pharmacy that was equipped with comfortable living room furniture, an audio system, and wireless headphones. Rescue medications were available on-site but were not used by any participants.

A group of participants underwent preparatory counseling with two trained guides, one male and one female, prior to taking psilocybin. The counseling sessions included life review, generous listening with unconditional positive regard, and discussion of past psychedelic experiences and any immediate or late adverse effects. The nurses at the CRU were instructed on how to maintain the atmosphere of the study during the participant’s hospital stay.

Participants attended integration sessions with the guides the morning after each dose, and likewise the morning after the second dose.

Drug sessions

Participants were admitted to the University of Wisconsin Hospital CRU, received vital signs, a urine sample for pregnancy testing and drug screening, and an IV catheter with saline lock extension. They then listened to a pre-selected musical program while lying down on the sofa. Participants were assessed at the close of the session to ensure readiness for transfer to the hospital CRU. They were seen by a nurse practitioner or study physician and discharged the following morning.

Participant follow-up

Participants were contacted seven days after each psilocybin session and again 30 days post-dose. They completed a final end of study visit in person 30 days after completing the final psilocybin dose.

Questionnaires

Participants completed the States of Consciousness Questionnaire (SOCQ) after each psilocybin dose. The SOCQ is a 100-item assessment used to characterize the consciousness-altering effects of psilocybin. Thirty items were derived from the SOCQ to make up the 30-item revised Mystical Experience Questionnaire (MEQ30), which was validated in experimental sessions with psilocybin and LSD. The MEQ30 contains four subscales: mystical, deeply felt positive mood, transcendence of time and space, and ineffability.

Participants completed the PEQ 30 days after the last psilocybin session, and were scored on 12 items in 6 categories. A high positive score means that the participant experienced significant positive changes in that area, whereas a high negative score means that the participant experienced significant negative changes in that area.

The questionnaire asks about how personally meaningful the experience was to you, how spiritually significant it was to you, and whether the experience has led to increased or decreased sense of personal well-being or life satisfaction.

Analysis

Psilocybin and psilocin concentrations were measured in plasma and urine using a validated assay incorporating high-performance liquid chromatography (HPLC) and mass spectrometry. No psilocybin was detected in either plasma or urine, and the maximum plasma concentration of psilocin (Cmax) was determined by inspection.

Statistical analyses were conducted using R for statistical computing with packages nlme, (Lenth), geepack, and ppcor. Incidence of headache, tachycardia or hypertension, and attainment of a full mystical experience was compared between dose groups using mixed-effects logistic-regression models.

Participants

Participants’ median age was 43 years and they were predominately male and Caucasian. There were no serious adverse events.

Mystical experience questionnaire

Estimated means from the MEQ show that total MEQ scores increased with each dose from dose 1 to dose 2, but this difference was not statistically significant. The transcendence of time and space subscale was significantly higher after dose 3 than after dose 1.

Pharmacokinetics

The pharmacokinetics of dose 3 was proportional to dose, with an AUC of 151 ug*h/mL (0 – 12 h) being significantly higher than dose 2 and dose 1, and a Cmax of 35.9 ug/mL being not significantly different between dose 2 and dose 3.

Persisting effects questionnaire

The average positive PEQ composite scores were significantly higher than the corresponding average negative composite scores in all response categories. Two participants rated the experience as the single most meaningful experience. The final question of the PEQ was associated with the maximum MEQ score across all three doses (p=0.05), though the dose number was not associated with the MEQ (minimum, maximum, or mean across all three doses).

Discussion

Psilocybin has been shown to produce dose-dependent positive subjective changes in mood, perception, and psychological states in healthy participants. The higher the dose, the greater the increase in sense of well-being or life satisfaction, but there were no differences in the rate of a complete mystical experience.

The results showed that 36% of doses facilitated a complete mystical experience, similar to LSD in healthy participants and patients. There was no significant difference in the rate of complete mystical experience across the three high doses.

In this study, participants experienced dose-related mystical-type experiences, but the rate of mystical experiences was not associated with dose, nor did it differ between doses. This could be because of a ceiling effect, or because participants were exposed to higher concentrations of psilocybin with each escalating dose.

The requirement that participants be non-naive to psychedelics and have at least one prior meaningful experience could have contributed to a lower rate of mystical experience. It is also possible that some participants were less sensitized to the effects of psilocybin compared to psychedelic naive individuals.

The fact that some participants were atheists or had no spiritual practice could have affected their responses on the SOCQ and the embedded MEQ, and their responses may have been influenced by frustration when encountering items referring to Judeo-Christian phenomena.

We used an escalating weight-based dose design without controlling for dose sequence effects through counterbalancing, and did not find a significant difference in the total MEQ score or on any of the subscales, except transcendence of time and space.

It remains unknown if the interval between consecutive doses of psilocybin is associated with the subjective effects of psilocybin, but participants reported that the sampling procedure was not disruptive.

Consistent with Griffiths et al. (2011), the transcendence of time and space subscale showed a significant increase in effect at dose 3 relative to dose 1 and positive association with AUC.

Participants reported profound positive changes after a mystical experience, as evidenced by the PEQ results. The PEQ Final Question 3 was associated with maximum positive effects.

Additional limitations include limited statistical power, the probability that difficult and challenging psychological experiences increase at higher doses, and the lack of measurement of mystical experiences.

In the current study, every dose of psilocybin was considered a high dose, and the 0.60 mg/kg dose elicited results at least as strong as the 0.30 and 0.45 mg/kg doses, with no serious adverse events.

While there were no significant dose-related differences in rates of complete mystical experiences, there were significant dose-related differences on the transcendence of time and space MEQ subscale. Participants reported significant positive persisting effects 30 days after their final dose.