Participants with a potentially life-threatening cancer diagnosis and a DSM-IV diagnosis that included anxiety and/or mood symptoms were recruited through flyers, internet, and physician referral. Of 566 individuals who were screened by telephone, 56 were randomized. Figure 1 shows a CONSORT flow diagram. Table 1 shows demographics for the 51 participants who completed at least one session. The two randomized groups did not significantly differ demographically. All 51 participants had a potentially life-threatening cancer diagnosis, with 65% having recurrent or metastatic disease. Types of cancer included breast (13 participants), upper aerodigestive (7), gastrointestinal (4), genitourinary (18), hematologic malignancies (8), other (1). All had a DSM-IV diagnosis: chronic adjustment disorder with anxiety (11 participants), chronic adjustment disorder with mixed anxiety and depressed mood (11), dysthymic disorder (5), generalized anxiety disorder (GAD) (5), major depressive disorder (MDD) (14), or a dual diagnosis of GAD and MDD (4), or GAD and dysthymic disorder (1). Detailed inclusion/exclusion criteria are in the online Supplementary material. The Johns Hopkins IRB approved the study. Written informed consent was obtained from participants.
A two-session, double-blind cross-over design compared the effects of a low versus high psilocybin dose on measures of depressed mood, anxiety, and quality of life, as well as measures of short-term and enduring changes in attitudes and behavior. Participants were randomly assigned to one of two groups. The Low-Dose-1st Group received the low dose of psilocybin on the first session and the high dose on the second session, whereas the High-Dose-1st Group received the high dose on the first session and the low dose on the second session. The duration of each participant’s participation was approximately 9 months (mean 275 days). Psilocybin session 1 occurred, on average, approximately 1 month after study enrollment (mean 28 days), with session 2 occurring approximately 5 weeks later (mean 38 days). Data assessments occurred: (1) immediately after study enrollment (Baseline assessment); (2) on both session days (during and at the end of the session); (3) approximately 5 weeks (mean 37 days) after each session (Post-session 1 and Post-session 2 assessments); (4) approximately 6 months (mean 211 days) after Session 2 (6-month follow-up).
The study compared a high psilocybin dose (22 or 30 mg/70 kg) with a low dose (1 or 3 mg/70 kg) administered in identically appearing capsules. When this study was designed, we had little past experience with a range of psilocybin doses. We decreased the high dose from 30 to 22 mg/70 kg after two of the first three participants who received a high dose of 30 mg/70 kg were discontinued from the study (one from vomiting shortly after capsule administration and one for personal reasons). Related to this decision, preliminary data from a dose-effect study in healthy participants suggested that rates of psychologically challenging experiences were substantially greater at 30 than at 20 mg/70 kg ( Griffiths et al., 2011 ). The low dose of psilocybin was decreased from 3 to 1 mg/70 kg after 12 participants because data from the same dose-effect study showed significant psilocybin effects at 5 mg/70 kg, which raised concern that 3 mg/70 kg might not serve as an inactive placebo.
Expectancies, on part of both participants and monitors, are believed to play a large role in the qualitative effects of psilocybin-like drugs ( Griffiths et al., 2006 ; Metzner et al., 1965 ). Although double-blind methods are usually used to protect against such effects, expectancy is likely to be significantly operative in a standard drug versus placebo design when the drug being evaluated produces highly discriminable effects and participants and staff know the specific drug conditions to be tested. For these reasons, in the present study a low dose of psilocybin was compared with a high dose of psilocybin, and participants and monitors were given instructions that obscured the actual dose conditions to be tested. Specifically, they were told that psilocybin would be administered in both sessions, the psilocybin doses administered in the two sessions might range anywhere from very low to high, the doses in the two sessions might or might not be the same, sensitivity to psilocybin dose varies widely across individuals, and that at least one dose would be moderate to high. Participants and monitors were further strongly encouraged to try to attain maximal therapeutic and personal benefit from each session.
Drug sessions were conducted in an aesthetic living-room-like environment with two monitors present. Participants were instructed to consume a low-fat breakfast before coming to the research unit. A urine sample was taken to verify abstinence from common drugs of abuse (cocaine, benzodiazepines, and opioids including methadone). Participants who reported use of cannabis or dronabinol were instructed not to use for at least 24 h before sessions. Psilocybin doses were administered in identically appearing opaque, size 0 gelatin capsules, with lactose as the inactive capsule filler. For most of the time during the session, participants were encouraged to lie down on the couch, use an eye mask to block external visual distraction, and use headphones through which a music program was played. The same music program was played for all participants in both sessions. Participants were encouraged to focus their attention on their inner experiences throughout the session. Thus, there was no explicit instruction for participants to focus on their attitudes, ideas, or emotions related to their cancer. A more detailed description of the study room and procedures followed on session days is provided elsewhere ( Griffiths et al., 2006 ; Johnson et al., 2008 ).
A description of session monitor roles and the content and rationale for meetings between participants and monitors is provided elsewhere ( Johnson et al., 2008 ). Briefly, preparation meetings before the first session, which included discussion of meaningful aspects of the participant’s life, served to establish rapport and prepare the participant for the psilocybin sessions. During sessions, monitors were nondirective and supportive, and they encouraged participants to “trust, let go and be open” to the experience. Meetings after sessions generally focused on novel thoughts and feelings that arose during sessions. Session monitors were study staff originally trained by William Richards PhD, a clinical psychologist with extensive experience conducting studies with classic hallucinogens. Monitor education varied from college graduate to PhD. Formal clinical training varied from none to clinical psychologist. Monitors were selected as having significant human relations skills and self-described experience with altered states of consciousness induced by means such as meditation, yogic breathing, or relaxation techniques.
After study enrollment and assessment of baseline measures, and before the first psilocybin session, each participant met with the two session monitors (staff who would be present during session days) on two or more occasions (mean of 3.0 occasions for a mean total of 7.9 hours). The day after each psilocybin session participants met with the session monitors (mean 1.2 hours). Participants met with monitors on two or more occasions between the first and second psilocybin session (mean of 2.7 occasions for a mean total of 3.4 hours) and on two or more occasions between the second session and 6-month follow-up (mean of 2.5 occasions for a mean total of 2.4 hours). Preparation meetings, the first meeting following each session, and the last meeting before the second session were always in person. For the 37 participants (73%) who did not reside within commuting distance of the research facility, 49% of the Post-session 1 meetings with monitors occurred via telephone or video calls.
The questionnaire included three final questions (see Griffiths et al. 2006 for more specific wording): (1) How personally meaningful was the experience? (rated from 1 to 8, with 1 = no more than routine, everyday experiences; 7 = among the five most meaningful experiences of my life; and 8 = the single most meaningful experience of my life). (2) Indicate the degree to which the experience was spiritually significant to you? (rated from 1 to 6, with 1 = not at all; 5 = among the five most spiritually significant experiences of my life; 6 = the single most spiritually significant experience of my life). (3) Do you believe that the experience and your contemplation of that experience have led to change in your current sense of personal well-being or life satisfaction? (rated from +3 = increased very much; +2 = increased moderately; 0 = no change; –3 = decreased very much).
Participant ratings of persisting effects attributed to the session on ratings completed 5 weeks after the low-dose and high-dose psilocybin sessions, and, again, retrospectively for the high-dose session 6 months after the second session + .
The Persisting Effects Questionnaire assessed self-rated positive and negative changes in attitudes, moods, behavior, and spiritual experience attributed to the most recent psilocybin session ( Griffiths et al., 2006 , 2011 ). At the 6-month follow-up, the questionnaire was completed on the basis of the high-dose session, which was identified as the session in which the participant experienced the most pronounced changes in their ordinary mental processes. Twelve subscales (described in Table 8 ) were scored.
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