The present study demonstrated orderly dose-related increases in the effects of psilocybin on volunteer and observer ratings of drug effect and on the cardiovascular measures of blood pressure and heart rate. Notably, even the 5 mg/70 kg (71 μg/kg) dose of psilocybin produced significant subjective, physiological, and observer-rated effects. This is the lowest dose of psilocybin demonstrated to produce significant effects. A previous study showed dose-related effects of psilocybin at doses of 45, 115, 215, and 315 μg/kg, however did not show statistically significant effects at the lowest dose (Hasler et al. 2004
). Consistent with previous findings, the present study showed orderly time-related observer-rated and cardiovascular effects during the session, with significant effects at the highest doses generally occurring at 30-60 minutes, peaking at 90-180 minutes, and decreasing toward pre-drug levels over the remainder of the session (Griffiths et al. 2006
The present study extends previous observations showing that psilocybin can occasion mystical-type experiences having sustained personal and spiritual significance (Pahnke 1963
; Doblin 1991
; Griffiths et al. 2006
). Two volunteer-rated measures of mystical-type experience completed at the end of the session days showed dose-related increases, with 72% of volunteers fulfilling criteria for having had a “complete” mystical experience at either or both of the two highest dose sessions. Retrospective ratings of mystical experience and spiritual significance did not diminish in time. One month after either or both the two highest dose sessions, 83% of participants rated the experience as the single most or among the 5 most spiritually significant experiences of their life. At the 14-month follow-up, this number was even higher (94%). Likewise, at 14 months, retrospective ratings of mystical experience at the highest dose were generally slightly higher than at the 1-month rating time. Finally, longitudinal measures of lifetime mystical experience and of death transcendence (Religious subscale) were significantly increased over screening levels at both one month and 14 months after the final session. The significant increase in the Religious subscale of the Death Transcendence Scale is notable in this group of healthy volunteers because questions in this subscale assess a sense of continuity after death (e.g. Death is a transition to something even greater than this life; Death is never just an ending, but a part of a process). This effect may be relevant to the proposed palliative effects of psilocybin and similar hallucinogens in treating existential anxiety in terminal illness (Kast 1967
; Richards et al. 1972
; Grob et al. 2011
The present study also extends previous observations indicating that psilocybin can occasion persisting positive changes in attitudes, mood, life satisfaction, behavior, and altruism/social effects (Griffiths et al. 2006
). All of these domains showed dose-related increases one month after sessions, with effects at the highest doses sustained at the 14-month follow-up. One month after sessions at either or both the two highest dose sessions, 94% of volunteers endorsed that the experience increased their sense of well-being or life satisfaction moderately or very much, and 89% rated moderate or higher changes in positive behavior. At the 14-month follow-up, these ratings remained high. The types of behavior change most frequently cited by volunteers were better social relationships with family and others, increased physical and psychological self-care, and increased spiritual practice (). Ratings by community observers before and after the study as well as ratings by study monitors after the study were consistent with the persisting positive changes in behavior and attitudes claimed by the volunteers. The persisting positive changes, particularly in attitudes, mood, and life satisfaction, occasioned by psilocybin appear similar in kind and breadth to the enduring changes reported in case studies of individuals who have had spontaneously-occurring mystical- or insightful-types of experiences (Miller and C’ de Baca, 2001
A novel aspect of the present study was that it compared effects in volunteers who received the four active psilocybin doses in either an ascending or a descending dose sequence. Although the acute measures of psilocybin effects were not affected by the dose sequence, volunteer-rated positive changes in attitudes and behavior assessed 1 month after each session showed Dose x Dose Sequence interactions reflecting relatively larger effects at the highest psilocybin doses than the lower doses in the ascending dose sequence compared to the descending sequence (). Analogous differences occurred at the 14-month follow-up assessment on the mystical experience items of the States of Consciousness Questionnaire and on retrospective ratings of the personal meaning and spiritual significance associated with various session doses. Overall, these findings suggest that the ascending dose sequence is somewhat more likely than the descending sequence to produce long-lasting positive changes in attitudes, behavior, and remembered mystical-type experiences. Thus it appears that having experience with lower doses facilitates the likelihood of having sustained positive effects after a high dose of psilocybin. The biological or psychological mechanisms underlying this effect are unknown. This finding suggesting an advantage of an ascending dose sequence may have clinical application in the design of therapeutic studies of psilocybin (Griffiths and Grob, 2010
; Grob et al. 2011
). It is noteworthy, however, that this finding is contrary to some older recommendations of psychotherapists who administered classic hallucinogens. Specifically, in one report (Blewett and Chwelos, 1959
) psychotherapists inferred from their clinical experience that a single high-dose overwhelming experience was more therapeutic than an approach that began with a small doses and gradually increased the dose over successive experiences.
Also of relevance to the design of future research trials with psilocybin, the present study provides information about the relative likelihood of different doses of psilocybin to occasion acute adverse subjective effects as well as mystical-type effects having persisting positive effects. The acute anxiety/fear-producing effects of psilocybin, as assessed by monitor and volunteer ratings, increased with increasing doses. Thirty-nine percent of volunteers reported extreme fear, fear of insanity, or feeling trapped sometime during the session (0 at placebo or the two lower doses, 1 at 20 mg/70 kg, and 6 at 30 mg/70 kg). Furthermore, 44% of volunteers reported delusions or paranoid thinking sometime during the session (0 at placebo and the two lower doses, 1 at 20 mg/70 kg, and 7 at 30 mg/70 kg). In the present study, such negative effects were well managed with reassurance in the highly supportive setting. Interestingly, these psychological struggles did not generally affect rates of having “complete” mystical experiences, possibly because the negative feelings were most often of short duration. However, under conditions in which volunteers are less well screened and psychologically prepared, or sessions are not as well supervised, there could be a possibility that extreme anxiety and/or delusion could be prolonged and result in dangerous behavior. Under such conditions, administration of doses higher than about 20 mg/70 would be inadvisable. The unpredictable time-course across the session of anxiety or fear () underscores the importance that session monitors remain vigilant throughout the session. Furthermore, the unpredictable time-course of anxiety, in combination with the finding that even experienced session monitors cannot rate with high reliability whether or not psilocybin has been administered (Griffiths et al., 2006
), suggests the potential risk of the recommendation by some psychotherapists that a “booster” dose of a classic hallucinogen should be administered relatively shortly after the initial dose if the effects are less than expected (Blewett and Chwelos, 1959
; Stolaroff 1997
In a therapeutic or other research trial, the possibility of such potentially adverse effects should be considered in relationship to the potential persisting positive effects. The proportion of volunteers having “complete” mystical-type experiences, which likely mediate persisting positive effects (Richards et al. 1977
; Griffiths et al. 2008
), as well as the persisting positive effects ( and ) were generally an increasing function of dose, with the percentage change from 20 to 30 mg/70 kg varying widely (−23% to a +99%), with a mean of +17%. However, endorsement of having had a “complete” mystical experience, or of having had the single most spiritually significant experience of his/her life increased 25% and 60%, respectively from 20 to 30 mg/70 kg. Likewise, endorsement of moderate to extreme positive behavioral change, which may be the most relevant outcome measure in some therapeutic trials, increased 45% from 20 to 30 mg/70 kg. Thus, in addition to considering the extent of screening and support provided to volunteers, the decision to administer psilocybin doses higher than about 20 mg/70 kg should be made on the basis of the type of outcome desired.
The present study provided no evidence of adverse effects of high dose psilocybin exposure other than the episodes of psychological struggle during some portion of the time of psilocybin action. This should not be interpreted to suggest that casual use of high dose psilocybin is safe. It is important to recognize that the present study was conducted in carefully screened volunteers who received ample preparation before sessions, were closely monitored during sessions, and had some continuing contact with study staff after sessions (see Johnson et al., 2008
for detailed safety guidelines for minimizing risks of high dose hallucinogen exposure in human research). The reported potential risks of hallucinogen exposure include: (1) panic or fear reactions resulting in dangerous behavior during the time of drug action; (2) precipitation or exacerbation of enduring psychiatric conditions; (3) long-lasting perceptual disturbances and (4) development of an abusive pattern of hallucinogen use (Abraham, et al., 1996
; Halpern and Pope, 1999
; Johnson, et al., 2008
The generalizability of the results of the present study is limited by the study population, a group of hallucinogen-naïve, well-educated, psychologically stable, mostly middle-aged adults, most of whom reported at least weekly participation in religious or spiritual activity. It would be particularly interesting to determine whether volunteers who identified as atheist or agnostic would be as likely to have mystical-type experiences and whether they would ascribe spiritual significance to such experiences. It would also be interesting to compare hallucinogen-naïve volunteers with past users to provide information about whether the novelty of effects in naïve volunteers contributes to the high persisting ratings of personal meaning and spiritual significances.
Overall, the present study shows that psilocybin can dose-dependently occasion mystical-type experiences having persisting positive effects on attitudes, mood, and behavior. The observations that episodes of extreme fear, feeling trapped, or delusions occur at the highest dose in almost 40% of volunteers, that anxiety and fear have an unpredictable time-course across the session, and that an ascending sequence of dose exposure may be associated with long-lasting positive changes have implications for the design of therapeutic trials with psilocybin. Considering the rarity of spontaneous mystical experiences in the general population, the finding that more than 70% of volunteers in the current study had “complete” mystical experiences suggests that most people have the capacity for such experiences under appropriate conditions and, therefore, such experiences are biologically normal.