Optimal dosing for psilocybin pharmacotherapy: Considering weight-adjusted and fixed dosing approaches

This analysis of psilocybin dosages given in 10 previous studies (n=288) found no effect of weight, nor gender, on the effects (acute or long-term) of the dosage (20-30mg) of psilocybin used. The authors recommend a fixed dosing approach going forward to simplify dosing regimes.

Abstract

“Background: Growing evidence suggests psilocybin, a naturally occurring psychedelic, is a safe and promising pharmacotherapy for treatment of mood and substance use disorders when administered as part of a structured intervention. In most trials to date, psilocybin dose has been administered on a weight-adjusted basis rather than the more convenient procedure of administering a fixed dose.

Aims: The present post hoc analyses sought to determine whether the subjective effects of psilocybin are affected by body weight when psilocybin is administered on a weight-adjusted basis and when psilocybin is administered as a fixed dose.

Methods: We analyzed acute subjective drug effects (mystical, challenging, and intensity) associated with therapeutic outcomes from ten previous studies (total N=288) in which psilocybin was administered in the range 20 to 30mg/70 kg (inclusive). Separate multivariate regression analyses examined the relationships between demographic variables including body weight and subjective effects in participants receiving 20mg/70kg (n=120), participants receiving 30mg/70kg (n=182), and participants whose weight-adjusted dose was about 25mg (to approximate the fixed dose that is currently being evaluated in registration trials for major depressive disorder) (n=103).

Results: In the 20mg/70kg and 30mg/70 kg weight-adjusted groups, and in the fixed dose group, no significant associations were found between subjective effects and demographic variables including body weight or sex. Across a wide range of body weights (49 to 113kg) the present results showed no evidence that body weight affected subjective effects of psilocybin.

Conclusions: These results suggest that the convenience and lower cost of administering psilocybin as a fixed dose outweigh any potential advantage of weight-adjusted dosing.”

Authors: Albert Garcia-Romeu, Frederic S. Barrett, Theresa M. Carbonaro, Matthew W. Johnson & Roland R. Griffiths

Summary

Introduction

Psilocybin is a naturally occurring psychedelic that is primarily mediated via 5-HT2AR agonist activity. It has been found to be effective in treating depression, alcohol dependence, and tobacco dependence, as well as anxiety and depression in patients with life-threatening cancer diagnoses.

Most therapeutic studies of psilocybin use body weight-adjusted doses, but one open-label trial showed significant reductions in depressive symptoms when psilocybin was administered as a fixed dose. However, it will be important to determine whether weight-adjusted dosing is necessary for optimizing psilocybin’s therapeutic efficacy.

Psilocybin is a naturally occurring psychedelic.

Acute subjective drug effects such as a sense of unity, sacredness, and deeply felt positive mood are among the most robust predictors of psilocybin therapeutic efficacy and other enduring aftereffects. Challenging experiences during psilocybin administration can also be associated with increased well-being and perceived benefits in retrospect.

The present report provides post hoc analyses of acute subjective effect data in 288 participants from ten previous studies to examine whether weight-adjusted dosing of psilocybin leads to unintended differences between individuals in acute effects, or whether fixed dosing is more appropriate than weight-adjusted dosing.

Material and methods

Data were analyzed from ten studies conducted at Johns Hopkins University School of Medicine between 2001 and 2018 on adults who were administered body weight-adjusted doses of psilocybin between 20 and 30 mg/70 kg (inclusive).

Measures

Participants included healthy volunteers, cigarette smokers seeking to quit smoking, patients with a life-threatening cancer diagnosis and symptoms of anxiety or depression, novice meditators, religious professionals, and people with major depressive disorder.

The Mystical Experience Questionnaire is a 30-item scale designed to assess the occurrence and intensity of mystical-type experiences occasioned by psilocybin across four factors: mystical, positive mood, transcendence of time and space, and ineffability. A “complete mystical experience” was defined as a score 60% of the maximum possible score on each subscale.

The Challenging Experience Questionnaire (CEQ) is a 26-item measure assessing seven dimensions of psychedelic-occasioned challenging experiences. Participants rated the intensity of drug effects on a scale from 0 (Not at all) to 4 (Extreme) after completing the CEQ.

Data analysis

Multivariate regression analyses were used to test for associations between subjective drug effects and demographic variables. The analysis was conducted in three subsets of pooled data: drug administration sessions in which participants received 20 mg/70 kg of psilocybin, drug administration sessions in which participants received 30 mg/70 kg of psilocybin, and drug administration sessions in which participants received 23 to 27 mg.

Analysis included participant weight as an exogenous variable, but did not include the absolute dose of psilocybin that was administered as an exogenous variable. Race was coded as a dummy variable, and Bonferroni correction for multiple comparisons provided an alpha level of p 0.004.

Results

Subjective effects in weight-adjusted dosing (20 mg/70 kg)

Participants’ body weight varied across a 2.3-fold range from 49 to 111 kg, and subjective effects were moderately high MEQ30 scores and intensity ratings, with low to moderate CEQ scores overall. No statistically significant relationships were found between psilocybin subjective effects and demographic variables.

Subjective effects in weight-adjusted dosing (30 mg/70 kg)

Participants who received a weight-adjusted high dose of 30 mg/70 kg psilocybin had a mean age of 42.7 (12.2) years and 56% were female. On average, subjective effects were characterized by high MEQ30 scores and intensity ratings, and low to moderate CEQ scores overall.

Subjective effects in absolute doses

To approximate the effects of using a fixed dose regimen, 103 individuals were examined who received similar absolute doses of psilocybin. No significant associations were found between psilocybin subjective effects and demographic variables.

Discussion

Post hoc analyses of pooled data from several previous studies found no significant associations between age, race, sex, or weight of the participant and psilocybin subjective effects. Therefore, the results were somewhat mixed, and did not indicate an advantage of weight-adjusted dosing over the simpler method of fixed dosing. We did not find significant evidence that weight-adjusted dosing produced stronger effects in heavier individuals, but we did find significant evidence that fixed doses approximating 25 mg produced as strong an effect as weight-adjusted dosing.

To definitively demonstrate clinical superiority of either dosing strategy, prospective research comparing weight-adjusted to fixed doses would be necessary. However, current studies examining clinical populations with fixed doses may demonstrate efficacy of fixed dosing.

Results from this study are consistent with a recent pharmacokinetic study of psilocybin, which found that a fixed oral dose of 25 mg may result in similar exposures as a weight-adjusted oral dose.

Psilocybin-occasioned increases in mindfulness are negatively correlated with changes in 5-HT2AR binding, suggesting potential biological and psychological therapeutic mechanisms of psilocybin. It is unclear whether observed variability in subjective effects of psilocybin may be driven by psychological, neurological, or pharmacogenetic factors distinct from body weight and absolute dose administered.

This study has some limitations that limit the generalizability of the findings. Prospective research is needed to compare weight-adjusted and fixed psilocybin dosing, preferably among a well-defined clinical population.

The majority of study samples examined here were white, and this remains an important limitation for clinical hallucinogen research. Additional factors such as lack of sufficient funding for research on therapeutic effects of hallucinogens and distrust of biomedical research institutions are likely factors influencing the low prevalence of non-white participants.

The present analyses found no evidence for sex differences in subjective effects of psilocybin. However, women may score marginally higher on self-reported challenging effects (CEQ) than men, and may feel more comfortable disclosing these feelings due to cultural norms or expectations.

Previous studies in healthy volunteers showed that higher psilocybin doses were associated with stronger effects, but the current study found only a dose-related trend. Furthermore, lower age was associated with greater psilocybin-related cognitive impairment and loss of self-control, though we found no significant relationship between age and subjective effects.

Across a wide range of body weights, there was no evidence that body weight affected the subjective effects of psilocybin. However, there was substantial variability in response to psilocybin across individuals, independent of body weight, suggesting some patients may necessitate higher dosage in order to receive clinical benefit.

The present results suggest that body weight is not a major factor in determining the subjective effects of psilocybin across a range of populations, and that fixed dosing may provide comparable subjective effects and clinical efficacy.

Notes

The first author, Albert Garcia-Romeu, already spoke about these findings/recommendations all the way back in 2017.