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 Can a psychedelic trip change the way people with life-threatening cancer face death? Results from two clinical trials suggest so. 
 
 Researchers have shown that a single dose of psilocybin – the active ingredient in magic mushrooms – combined with psychotherapy reduces depression and anxiety and increases feelings of wellbeing in people with cancer. What’s more, for most, these effects appeared to last for more than six months. 
 
 Psilocybin, along with other psychedelic drugs like LSD, was banned in the late 1960s. But an increased understanding of the drug’s physiological mechanisms has sparked a revival of research into its potential therapeutic benefits. Several small trials have shown its promise as a treatment for alcoholism, opiate addiction, depression and anxiety. 
 
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 People with cancer often develop chronic symptoms of depression and anxiety, and antidepressants appear to be of little help. Some small studies have suggested that psilocybin could be an alternative. 
 
 To investigate, teams from Johns Hopkins University in Baltimore and NYU Langone Medical Centre in New York carried out two trials involving 80 people with cancer and symptoms of depression and anxiety. 
 
 In one trial, each volunteer participated in a psychotherapy session aided by either a single high dose of psilocybin or a low placebo-like dose of psilocybin. Five to seven weeks after this session, they took part in a second session with the other drug. 
 
 The second trial was run in a similar manner, except it used Vitamin B3 as a placebo. 
 
 Inner experience 
 
 During each session, the subjects laid on a couch, wore a blindfold and listened to music. They were accompanied by two researchers and were encouraged to focus their attention on their inner experiences. 
 
 To assess the volunteers’ responses, the trials used a variety of psychological and physiological measures, including blood pressure and heart rate, clinician-based tests and self-reported questionnaires. These assessments were carried out before each session and at either two or three points over the next six months. At the end of the trial, their families, friends and work colleagues were also interviewed to gauge their thoughts on the participant’s wellbeing. 
 
 Results across the two trials showed that psilocybin produced immediate and significant decreases in measures of depression, anxiety and mood disturbance, and increases in measures of quality of life, life meaning, death acceptance and optimism. These benefits were still present in 80 per cent of participants after six months. 
 
 The core feature of a psilocybin experience is a sense of unity; a feeling that everything is connected at some level, says Roland Griffiths, who led the Hopkins trial. 
 
 “After this kind of experience, people feel that they’ve learned something that’s of deep meaning and value to them,” he says. “They attribute changes in how they approach life, interact with people and to their value systems to that experience.” 
 
 There were no serious adverse effects in either trial, although there were some reports of nausea, headache and transient anxiety. The results together form the most extensive trial of psilocybin for treatment of depression and anxiety. 
 
 Alternative treatment 
 
 Stephen Ross, lead investigator on the NYU Langone trial, highlights the need for an alternative to the available care for people with cancer. “Anywhere from 40 to 50 per cent of cancer patients will have diagnosable anxiety or depression,” he says. “The [current] treatments, like antidepressants, really don’t work any better than placebo.” 
 
 In a commentary published alongside the trials, Richard Shelton and Peter Hendricks, both at the University of Alabama, at Birmingham, call into question the integrity of the placebo design in both trials, as none of the participants were asked which drug they thought they had received after each session. 
 
 This is normally carried out to ensure that the placebo arm of a trial is realistic enough. If people cannot accurately guess which drug they were given, it ensures that the results are down to the drug and not any other factor. However, they note that due to the hallucinogenic effects of the real drug, it may be unfeasible to create a placebo that is indistinguishable from the real thing, as is often the case with studies of psychoactive drugs. 
 
 Ross says the study now needs to be carried out on a larger sample of people. “Even though our two trials together replicated the same study and would lead one to think this is a real effect, it needs to be done in a larger, nationally representative cancer sample,” he says. “And if that trial shows what we showed then psilocybin potentially could be rescheduled to become a prescription medication for cancer related anxiety and depression.” 
 
 Journal references: Journal of Psychopharmacology, DOI: 10.1177/0269881116675512; DOI: 10.1177/0269881116675513 

 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). 
 
 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. 
 
 Three measures of spirituality were assessed at three time-points: Baseline, 5 weeks after session 2, and at the 6-month follow-up: FACIT-Sp, a self-rated measure of the spiritual dimension of quality of life in chronic illness ( Peterman et al., 2002 ) assessed on how the participant felt “on average”; Spiritual-Religious Outcome Scale, a three-item measure used to assess spiritual and religious changes during illness ( Pargament et al., 2004 ); and Faith Maturity Scale, a 12-item scale assessing the degree to which a person’s priorities and perspectives align with “mainline” Protestant traditions ( Benson et al., 1993 ). 
 
 Structured telephone interviews with community observers (e.g. family members, friends, or work colleagues) provided ratings of participant attitudes and behavior reflecting healthy psychosocial functioning ( Griffiths et al., 2011 ). The interviewer provided no information to the rater about the participant or the nature of the research study. The structured interview (Community Observer Questionnaire) consisted of asking the rater to rate the participant’s behavior and attitudes using a 10-point scale (from 1 = not at all, to 10 = extremely) on 13 items reflecting healthy psychosocial functioning: inner peace; patience; good-natured humor/playfulness; mental flexibility; optimism; anxiety (scored negatively); interpersonal perceptiveness and caring; negative expression of anger (scored negatively); compassion/social concern; expression of positive emotions (e.g. joy, love, appreciation); self-confidence; forgiveness of others; and forgiveness of self. On the first rating occasion, which occurred soon after acceptance into the study, raters were instructed to base their ratings on observations of and conversations with the participant over the past 3 months. On two subsequent assessments, raters were told their previous ratings and were instructed to rate the participant based on interactions over the last month (post-session 2 assessment) or since beginning in the study (6-month follow-up). Data from each interview with each rater were calculated as a total score. Changes in each participant’s behavior and attitudes after drug sessions were expressed as a mean change score (i.e. difference score) from the baseline rating across the raters. Of 438 scheduled ratings by community observers, 25 (<6%) were missed due to failure to return calls or to the rater not having contact with the participant over the rating period. 
 
 The two primary therapeutic outcome measures were the widely used clinician-rated measures of depression, GRID-HAM-D-17 ( ISCDD, 2003 ) and anxiety, HAM-A assessed with the SIGH-A ( Shear et al., 2001 ). For these clinician-rated measures, a clinically significant response was defined as ⩾50% decrease in measure relative to Baseline; symptom remission was defined as ⩾50% decrease in measure relative to Baseline and a score of ⩽7 on the GRID-HAMD or HAM-A ( Gao et al., 2014 ; Matza et al., 2010 ). 
 
 Seventeen measures focused on mood states, attitudes, disposition, and behaviors thought to be therapeutically relevant in psychologically distressed cancer patients were assessed at four time-points over the study: immediately after study enrollment (Baseline assessment), about 5 weeks (mean 37 days) after each session (Post-session 1 and 2 assessments), and about 6 months (mean 211 days) after session 2 (6-month follow-up). 
 
 Ten minutes before and 30, 60, 90, 120, 180, 240, 300, and 360 min after capsule administration, blood pressure, heart rate, and monitor ratings were obtained as described previously ( Griffiths et al., 2006 ). The two session monitors completed the Monitor Rating Questionnaire, which involved rating or scoring several dimensions of the participant’s behavior or mood. The dimensions, which are expressed as peak scores in Table 2 , were rated on a 5-point scale from 0 to 4. Data were the mean of the two monitor ratings at each time-point. 
 
 Statistical analysis 
 
 Differences in demographic data between the two dose sequence groups were examined with t-tests and chi-square tests with continuous and categorical variables, respectively. 
 
 Data analyses were conducted to demonstrate the appropriateness of combining data for the 1 and 3 mg/70 kg doses in the low-dose condition and for including data for the one participant who received 30 mg/70 kg. To determine if the two different psilocybin doses differed in the low-dose condition, t-tests were used to compare participants who received 3 mg/70 kg (n = 12) with those who received 1 mg/70 kg (n = 38) on participant ratings of peak intensity of effect (HRS intensity item completed 7 h after administration) and peak monitor ratings of overall drug effect across the session. Because neither of these were significantly different, data from the 1 and 3 mg/70 kg doses were combined in the low-dose condition for all analyses. 
 
 Of the 50 participants who completed the high-dose condition, one received 30 mg/70 kg and 49 received 22 mg/70 kg. To determine if inclusion of the data from the one participant who received 30 mg/70 kg affected conclusions about the most therapeutically relevant outcome measures, the analyses for the 17 measures shown in Tables 4 and 5 were conducted with and without that participant. Because there were few differences in significance (72 of 75 tests remained the same), that participant’s data were included in all the analyses. 
 
 To examine acute drug effects from sessions, the drug dose conditions were collapsed across the two dose sequence groups. The appropriateness of this approach was supported by an absence of any significant group effects and any group-by-dose interactions on the cardiovascular measures (peak systolic and diastolic pressures and heart rate) and on several key monitor- and participant-rated measures: peak monitor ratings of drug strength and joy/intense happiness, and end-of-session participant ratings on the Mysticism Scale. 
 
 Six participants reported initiating medication treatment with an anxiolytic (2 participants), antidepressant (3), or both (1) between the Post-session 2 and the 6-month follow-up assessments. To determine if inclusion of these participants affected statistical outcomes in the analyses of the 6-month assessment, the analyses summarized in Tables 4, 5, 6, 7 and 8 were conducted with and without these six participants. All statistical outcomes remained identical. Thus, data from these six participants were retained in the data analyses. 
 
 For cardiovascular measures and monitor ratings assessed repeatedly during sessions, repeated measures regressions were conducted in SAS PROC MIXED using an AR(1) covariance structure and fixed effects of dose and time. Planned comparison t-tests were used to assess differences between the high- and low-dose condition at each time-point. 
 
 Peak scores for cardiovascular measures and monitor ratings during sessions were defined as the maximum value from pre-capsule to 6 h post-capsule. These peak scores and the end-of-session ratings (Tables 2 and 3) were analyzed using repeated measures regressions in SAS PROC MIXED with a CS covariance structure and fixed effects of group and dose. 
 
 View this table: Download to PowerPoint Slide Table 3. Participant ratings on questionnaires completed 7 hours after psilocybin administration+. 
 
 For the analyses of continuous measures described below, repeated measures regressions were conducted in SAS PROC MIXED using an AR(1) covariance structure and fixed effects of group and time. Planned comparison t-tests (specified below) from these analyses are reported. For dichotomous measures, Friedman’s Test was conducted in SPSS for both the overall analysis and planned comparisons as specified below. All results are expressed as unadjusted scores. 
 
 For the measures that were assessed in the two dose sequence groups at Baseline, Post-session 1, Post-session 2, and 6 months (Tables 4 and 5), the following planned comparisons most relevant to examining the effects of psilocybin dose were conducted: Between-group comparisons at Baseline, Post 1, and Post 2; and within-group comparisons of Baseline versus Post 1 in both dose sequence groups, and Post 1 versus Post 2 in the Low-Dose-1st (High-Dose-2nd) Group. A planned comparison between Baseline and 6 months collapsed across groups was also conducted. Effects sizes were calculated using Cohen’s d. 
 
 View this table: Download to PowerPoint Slide Table 4. Effects of psilocybin on the 11 therapeutically relevant outcome measures assessed at Baseline, Post-session 1 (5 weeks after Session 1), Post-session 2 (5 weeks after Session 2), and 6 months follow-up that fulfilled conservative criteria for demonstrating an effect of psilocybin+. 
 
 View this table: Download to PowerPoint Slide Table 5. Effects of psilocybin on six therapeutically relevant outcome measures assessed at Baseline, Post-session 1 (5 weeks after Session 1), Post-session 2 (5 weeks after Session 2), and 6 months that did not fulfill conservative criteria for demonstrating an effect of psilocybin+. 
 
 For measures assessed only at Baseline, Post 2, and 6 months (Table 7), between-group planned comparisons were conducted at Baseline, Post 2, and 6 months. Because measures assessed only at these time-points cannot provide information about the psilocybin dose, data were collapsed across the two dose sequence groups and planned comparisons were conducted comparing Baseline with Post 2 and Baseline with 6 months. 
 
 For participant ratings of persisting effects attributed to the session (e.g. Table 8), planned comparisons for continuous and dichotomous measures were conducted between: (1) ratings at 5 weeks after the low versus high-dose sessions; (2) ratings of low dose at 5 weeks versus ratings of high dose at the 6-month follow-up; (3) ratings of high dose at 5 weeks versus ratings of high dose at the 6-month follow-up. 
 
 As described above, clinician-rated measures of depression (GRID-HAMD) and anxiety (HAM-A) were analyzed as continuous measures. In addition for both measures, a clinically significant response was defined as ⩾50% decrease in measure relative to Baseline; symptom remission was defined as ⩾50% decrease in measure relative to Baseline and a score of ⩽7. Planned comparisons were conducted via independent z-tests of proportions between the two dose sequence groups at Post-session 1, Post-session 2, and 6 months. To determine if effects were sustained at 6 months, planned comparisons were also conducted via dependent z-tests of proportions between Post-session 2 versus 6 months in the Low-Dose-1st (High-Dose-2nd) Group, and between Post-session 1 versus 6 months in the High-Dose-1st (Low-Dose-2nd) Group. 
 
 Exploratory analyses used Pearson’s correlations to examine the relationship between total scores on the Mystical Experience Questionnaire (MEQ30) assessed at the end of session 1 and enduring effects assessed 5 weeks after session 1. The Post-session 1 measures were ratings on three items from the Persisting Effects Questionnaire (meaningfulness, spiritual significance, and life satisfaction) and 17 therapeutically relevant measures assessed at Baseline and Post 1 (Tables 4 and 5) expressed as difference from baseline scores. Significant relationships were further examined using partial correlations to control for end-of-session participant-rated “Intensity” (item 98 from the HRS). To examine MEQ30 scores as a mediator of the effect of psilocybin dose on therapeutic effects, a bootstrap analysis was done using the PROCESS macro (Hayes, 2013) in SPSS. Bootstrapping is a non-parametric method appropriate for small samples, which was used to estimate 95% confidence intervals for the mediation effect. The PROCESS macro also calculated direct effects on outcome for both group effects and MEQ30. 

 Dr. Stephen Ross, the lead investigator and chief of addiction psychiatry at N.Y.U., pointed out that antidepressants, by contrast, can take weeks to show benefit. 
 
 “Cancer patients with anxiety and depression need help immediately,” he said, “especially if you consider that they are at elevated risk for completed suicide.” 
 
 Image A chalice used in a study on psilocybin, an ingredient found in hallucinogenic mushrooms. Credit N.Y.U. Langone Medical Center 
 
 Some experts questioned the reliability of the results. Dr. Breitbart said that because diagnoses ranged from early-stage cancer to imminent terminal illness, it was impossible to know which patients might have come through their psychological ordeal without psilocybin — whether some might have adapted to the new norms of their disease; felt stronger once chemotherapy side effects, including depression, had abated; or even experienced an improvement in health. 
 
 None of those possibilities fit Kevin, who had a bone-marrow transplant for acute myeloid leukemia. It sent his cancer into remission, but left him with graft-versus-host disease. 
 
 Suffering from chronic pain and fatigue, Kevin, 57, who lives in central Michigan and asked that his last name be withheld because he had been in law enforcement, had to retire. Four years after the transplant, he despaired. 
 
 “Going through a near-death illness is similar to returning from combat,” he said. “It damages who you are, to the core of what it is to be human.” 
 
 “I was hoping to get out of this funk of waiting for the other shoe to drop,” he added. “You’re looking up to the heavens, saying ‘What else can I try?’ ” 

 Prep PT: preparatory psychotherapy; 1-day pre-D1: 1 day prior to dose 1; Dose 1: dosing session 1; 1-day post-D1: 1 day after dose 1; Post-integrative PT: post-integrative psychotherapy; 2-wks post-D1: 2 weeks after dose 1; 6-wks post-D1: 6 weeks after dose 1; Safety prep for D2: safety preparation for dosing dose 2; 1-day pre-D2: 1 day prior to dose 2; Dose 2: dosing session 2; 1-day post-D2: 1 day after dose 2; 6-wks post-D2: 6 weeks after dose 2; 26-wks post-D2: 2 weeks after dose 2. 
 
 This randomized, blinded, controlled, crossover, study was designed to investigate the efficacy of a single psilocybin dosing session (0.3 mg/kg) versus one dosing session of an active control (niacin 250 mg), administered in conjunction with psychotherapy, to treat clinically significant anxiety or depression in patients with life-threatening cancer (see Supplementary Methods for information on inclusion/exclusion criteria, blinding procedures, medication sessions and psychotherapy procedures). The trial employed a two-session, double-blind, crossover (7 weeks after administration of dose 1) design to compare groups. Participants were randomly assigned to two oral dosing session sequences: psilocybin (0.3 mg/kg) first then niacin (250 mg) second, or niacin (250 mg) first then psilocybin (0.3 mg/kg) second ( Figures 1 and 2 ). Randomization did not stratify for any demographic (i.e. gender, race, spiritual/religious affiliation) or clinical characteristics (i.e. stage of cancer, prior hallucinogen use). Drug administration dose 1 (psilocybin or control) occurred 2–4 weeks (mean 18 days) after baseline assessments and the crossover occurred 7 weeks (mean 52 days) after dose 1, at which point drug administration dose 2 occurred. Data assessments occurred at baseline (2–4 weeks prior to dose 1), 1 day prior to dose 1, day of dose 1 (7 hours post-dose), 1 day after dose 1, 2 weeks after dose 1, 6 weeks after dose 1, 7 weeks after dose 1 (1 day prior to dose 2), day of dose 2 (7 hours post-dose), 1 day after dose 2, 6 weeks after dose 2, and 26 weeks after dose 2 ( Figure 2 ). The total duration of study participation was approximately 9 months (mean 253 days). The primary outcome variables were anxiety and depression assessed prior to the crossover. Secondary outcome measures (assessed before and after the crossover) included assessments of existential distress, quality of life, and spirituality, as well as measures assessing immediate and sustained effects of psilocybin administration on subjective (e.g. mystical) experience, cognition, affect, spirituality, and behavior. 
 
 Nearly two-thirds of participants (62%) had advanced cancers (stages III or IV). The types of cancer included: breast or reproductive (59%); gastrointestinal (17%); hematologic (14%); other (10%). In accordance with the study’s inclusion criteria, all participants carried an anxiety-related diagnosis per the severe combined immunodeficiency (SCID) (Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV) with the majority meeting criteria for an adjustment disorder (26, 90%) and the rest for generalized anxiety disorder (three, 10%). Nearly two-thirds (59%) had previously been treated with anti-depressant or anxiolytic medication, but none were on any psychotropics at the time of study enrollment, per the inclusion/exclusion criteria. 
 
 Of 108 participants pre-screened, 42 gave informed consent and of these 29 patients were randomly assigned and received treatment with single-dose psilocybin or single-dose niacin control ( Table 1 and Figure 1 ). The study was approved and monitored by the institutional review board of the New York University (NYU) School of Medicine. The majority of participants were recruited from a clinical cancer center at an academic medical facility (NYU Langone’s Perlmutter Cancer Center). Data were collected from 18 February 2009 to 22 October 2014 and the analysis was conducted from 3 November 2014 to 11 December 2015. 
 
 Persisting effects of psilocybin were assessed at 2 weeks post-dose 1 and 26 weeks post-dose 2: the Persisting Effects Questionnaire (PEQ), a self-report measure of changes in attitudes, moods, behaviors and spiritual experiences, sensitive to the longitudinal effects of psilocybin administration ( Griffiths et al., 2006 , 2008 , 2011 ). All participants (including in both the psilocybin first and niacin first groups) were asked at 26 weeks after dose 2 to reflect on the meaningfulness, spiritual significance and changes in wellbeing relative to what they guessed was their psilocybin dosing experience (see Supplementary Methods secondary outcome measures). 
 
 Subjective drug effects/mystical experience was assessed at 7 hours after drug administration sessions and retrospectively at 26 weeks post-dose 2: the Mystical Experience Questionnaire (MEQ 30) ( Barrett et al., 2015 ) is a self-report questionnaire that evaluates discrete mystical experiences induced by serotoninergic psychedelics and is sensitive to detecting psilocybin-induced mystical experiences ( MacLean et al., 2012 ). In addition to an MEQ total score, the questionnaire generates four empirically derived factors: mystical; positive mood; transcendence of time and space; and ineffability. A retrospective version of the MEQ 30 (MEQ retrospective scale) was administered at 26 weeks post-dose 2. See Supplementary Methods section for more information on the MEQ 30 and for other measures of subjective drug effects/mystical experience measured 7 hours after drug administration sessions. 
 
 Spirituality was assessed at baseline, 2 weeks post-dose 1 and 26 weeks post-dose 2: Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being (FACIT-SWB) ( Brady et al., 1999 ) a self-report measure of spiritual wellbeing generating three scales: meaning/peace, faith, total spiritual wellbeing score. The meaning/peace scale assesses one’s sense of inner peace, meaning, and purpose in life and corresponds to the more existential components of religious or spiritual practice. The faith scale measures strength and comfort derived from one’s faith and emphasizes the more ritualized components of religious/spiritual practice. 
 
 Quality of life was assessed at baseline, 2 weeks post-dose 1 and 26 weeks post-dose 2: World Health Organization Qualify of Life scale, brief version (WHO-Bref) ( WHO, 1994 ), self-report measure of quality of life in four domains (physical, psychological, social relationships, environment). 
 
 Cancer-related existential distress (demoralization, hopelessness, attitudes and affect associated with disease progression and death) was assessed at baseline, 2 weeks post-dose 1, and 26 weeks post-dose 2: Demoralization (DEM) scale ( Kissane et al., 2004 ), self-report measure of the cancer-related demoralization syndrome (e.g. despair, helplessness, existential distress such as loss of hope/meaning/purpose in life, a sense of ‘giving up’, desire for hastened death); Hopelessness Assessment and Illness (HAI) scale ( Rosenfeld et al., 2011 ) self-report measure of hopelessness in advanced cancer; Death Anxiety Scale (DAS) ( Templer, 1970 ) a self-report questionnaire assessing the level of death anxiety; Death Transcendence Scale (DTS) ( VandeCreek, 1999 ) a self-report measure of positive attitudes and adaptations to the finitude of life. 
 
 Clinical primary outcome measures (anxiety, depression) were assessed at baseline, 1 day prior to dose 1, 1 day after dose 1, 2-weeks after dose 1, 6 weeks after dose 1, 7 weeks after dose 1 (corresponding to 1 day prior to dose 2), 1 day after dose 2, 6 weeks after dose 2, and 26 weeks after dose 2: Hospital Anxiety and Depression Scale (HADS) ( Zigmond and Snaith, 1983 ), self-rated subscales of anxiety (HADS anxiety or HAD A), depression (HADS depression or HAD D) and total (HADS total or HAD T) combined score in patients with physical health problems (e.g. cancer); Beck Depression Inventory (BDI) ( Beck et al., 1988 ) self-report depression measure; Spielberger State-Trait Anxiety Inventory (STAI) ( Spielberger, 1983 ) self-report measure of state (STAI state or STAI S) and trait (STAI trait or STAI T) anxiety. 
 
 Cardiovascular measures were assessed during medication sessions. Systolic and diastolic blood pressure (BP) and heart rate (HR) were measured at the following time points during the medication dosing sessions: baseline, 30, 60, 90, 120, 180, 240, 300, 360 minutes post-dose administration. 
 
 Statistical analysis 
 
 Whenever multiple time points were included in the analysis for continuous measures, repeated measures regressions, from the mixed effect repeated measurement (MMRM) model, were performed in SAS PROC MIXED using an AR(1) covariance structure and fixed effects of group and time. Comparison t-tests from the MMRM analyses are reported for the primary and the continuous secondary outcome measures (see below). 
 
 For the primary outcome measures (anxiety, depression) in the two dosing sequences, planned between-group comparisons were made at the following time points: prior to the crossover at baseline, 1 day pre-dose 1, 1 day post-dose 1, 2 weeks post-dose 1, 6 weeks post-dose 1, 7 weeks post-dose 1 (corresponding to 1 day pre-dose 2) (Figure 3) and after the crossover at 1 day post-dose 2, 6 weeks post-dose 2, and 26 weeks post-dose 2 (Figure 4). Between-group effect sizes were calculated using Cohen’s d. Planned within-group comparison t-tests were conducted for each of the dosing sequences comparing the baseline to each of the following time points: 1 day pre-dose 1, 1 day post-dose 1, 2 weeks post-dose 1, 6 weeks post-dose 1, 7 weeks post-dose 1 (1 day pre-dose 2), 1 day post-dose 2, 6 weeks post-dose 2, 26 weeks post-dose 2 (Figures 3 and 4). Within-group effect sizes for the dosing sequences were calculated at each time point, compared to baseline, using Cohen’s d (Supplementary Table 1). To assess whether the magnitude of psilocybin-induced change in anxiety and depression differed across treatment groups, we compared change scores on the six primary outcome measures across each participant’s active (psilocybin) treatment session (from 1 day prior to psilocybin treatment to 1 day after psilocybin treatment) with one-way analysis of variance (ANOVA). 
 
 View larger version: Download to PowerPoint Slide Figure 3. Primary outcome variables: cancer-related anxiety and depression (pre-crossover). Means (±SE) for primary outcome measures are shown in the two treatment groups at the following time points: baseline (psilocybin first n=14, niacin first n=15), 1 day pre-dose 1 (psilocybin first n=14, niacin first n=15), 1 day post-dose 1 (psilocybin first n=14, niacin first n=15), 2 weeks post-dose 1 (psilocybin first n=14, niacin first n=14), 6 weeks post-dose 1 (psilocybin first n=14, niacin first n=14), 7 weeks post-dose 1 (psilocybin first n=12, niacin first n=14). Asterisks indicate significance level of between-group t-tests. Effect sizes, represented as Cohen’s d, are shown above time points at which the treatment groups differ. Closed points represent significant within-group differences relative to scores at baseline. 
 
 View larger version: Download to PowerPoint Slide Figure 4. Primary outcome variables: cancer-related anxiety and depression (post-crossover). Means (±SE) for primary outcome measures are shown in the two treatment groups at the following time points: baseline (psilocybin first n=14, niacin first n=15), 1-day pre dose-1 (psilocybin first n=14, niacin first n=15), 1 day post-dose 1 (psilocybin first n=14, niacin first n=15), 6 weeks post-dose 1 (psilocybin first n=14, niacin first n=14), 7 weeks post-dose 1 (1 day pre-dose 2) (psilocybin first n=12, niacin first n=14), 1 day post-dose 2, 6 weeks post-dose 2 (psilocybin first n=12, niacin first n=11), 26 weeks post-dose 2 (psilocybin first n=11, niacin first n=12). Asterisks indicate significance level of between-group t-tests. Closed points represent significant within-group differences relative to scores at baseline. 
 
 For primary outcome measures (HAD D, BDI, HAD A, HAD T) that have empirical support in defining anti-depressant or anxiolytic response, clinically significant responses rates were defined as a 50% or greater reduction in the measure at a particular assessment point relative to baseline. Anti-depressant symptom remission (HAD D, BDI) was defined as 50% or greater reduction in depressive symptoms plus HADS D ⩽7 (Hung et al., 2012) or BDI ⩽12 (Reeves et al., 2012; Riedel et al., 2010), respectively. Planned chi-square analyses were performed to compare the percentage of participants, in the psilocybin first versus the niacin first groups, who met criteria for anxiolytic or anti-depressant response, or anti-depressant remission (BDI, HAD D) at the following time points: 1 day post-dose 1, 7 weeks post-dose 1, and 26 weeks post-dose 2 (Figure 5). 
 
 View larger version: Download to PowerPoint Slide Figure 5. Percentage of participants with anti-depressant or anxiolytic response rates and anti-depressant symptom remission. Percentages of participants in each treatment group who met criteria for anti-depressant or anxiolytic response or anti-depressant symptom remission (BDI, HAD D) at 1 day post-dose 1 (psilocybin first n=14, niacin first n=15), 7 weeks post-dose 1 (psilocybin first n=12, niacin first n=14) and at 26 weeks post-dose 2 (psilocybin first n=11, niacin first n=12). Asterisks indicate significance level of between-group comparisons at each time point. 
 
 For cardiovascular measures assessed during the medication sessions, repeated measures regressions, from the mixed effect repeat measurement (MMRM) model, were conducted in SAS PROC MIXED using an AR(1) covariance structure and fixed effects of time, drug (psilocybin vs. niacin) and group (niacin first vs. psilocybin first) collapsed across treatment order at time points: baseline, 30, 60, 90, 120, 180, 240, 300, 360 post-dosing (Supplementary Figure 1). 
 
 For the secondary outcome measures (cancer-related existential distress, quality of life, spirituality, persisting effects of psilocybin), planned between-group comparisons were conducted generating the following comparisons: 1. niacin first group 2 weeks post-dose 1 versus psilocybin first group 2 weeks post-dose 1; 2. niacin first group 2 weeks post-dose 1 versus niacin first group 26 weeks post-dose 2; 3. niacin first group 2 weeks post-dose 1 versus psilocybin first group 26 weeks post-dose 2; 4. psilocybin first group 2 weeks post-dose 1 versus psilocybin first group 26 weeks post-dose 2 (Figure 6 (bottom), Supplementary Table 2). 
 
 View larger version: Download to PowerPoint Slide Figure 6. Secondary outcome measures: existential distress, quality of life, spirituality, persisting effects attributed to psilocybin administration. (Top) Percentage of participants that reported ‘among the top 5’ or ‘the single most’ personally meaningful and spiritually significant experiences, ‘moderate’, ‘strong’ or ‘extreme’ positive behavioral change, and ‘increased moderately’ or ‘increased very much’ wellbeing or life satisfaction on the Persisting Effects Questionnaire (PEQ). Asterisks indicate significance level of comparison to the niacin first group at 2 weeks post-dose 1. There were no significant differences between the psilocybin first group at 2 weeks post-dose 1 versus the psilocybin first group at 26 weeks post-dose 2. (Bottom) Secondary measures of cancer-related existential distress (DEM, HAI, DAS, DTS), quality of life (WHO-Bref) and spirituality (FACIT). Measures are shown at 2 weeks post-dose 1 (psilocybin first n=14, niacin first n=14) and at 26 weeks post-dose 2 (psilocybin first n=11, niacin first n=12); asterisks indicate significance level of comparison to the niacin first group at 2 weeks post-dose 1. There were no significant differences between the psilocybin first group at 2 weeks post-dose 1 versus the psilocybin first group at 26 weeks post-dose 2. 
 
 Ratings of persisting effects attributed to the medication sessions were expressed as proportions for four items (see Supplemental Methods): positive behavioral change; meaningfulness, spiritual significance, and increases in personal wellbeing. Planned chi-square analyses were performed: niacin first group at 2 weeks post-dose 1 and psilocybin first at 2 weeks post-dose 1, niacin first at 2 weeks post-dose 1 and psilocybin first at 26 weeks post-dose 2. McNemar tests were used to compare these proportions between the psilocybin first group at 2 weeks post-dose 1 and the psilocybin first group at 26 weeks post-dose 2 and between the niacin first group at 2 weeks post-dose 1 and the niacin first group at 26 weeks post-dose 2 (Figure 6 (top)). 
 
 Subjective drug effects/mystical experiences were compared between groups using an independent sample t-test run in SAS at three time points: 7 hours post-medication administration in sessions 1 and 2; and at 26 weeks post-dose 2 (Figure 7 (top)). Anxiety and depression change scores for the primary outcome measures (ΔHADS T, ΔHADS A, ΔHADS D, ΔBDI, ΔSTAI S, ΔSTAI T) were calculated from baseline to 6 weeks post-dose 1 with either psilocybin or niacin. Spearman rank correlation coefficients were calculated between the change scores and participant ratings on the MEQ total at 7 hours post-dose 1 to assess the relationship between subjective mystical experience and change in clinical outcomes. Significant relationships were further examined using partial correlations to control for end of session participant-rated ‘intensity’ (item 98 from the HRS). In order to examine the mystical experience (using MEQ 30 scores) as a mediator of psilocybin versus niacin treatment on anxiety/depression outcomes, a bootstrap analysis was performed using the PROCESS macro (Hayes, 2013, Figure 7 (bottom)). The bootstrapping method is a non-parametric approach that does not assume a normal distribution of the mediated effect, is appropriate with small sample sizes, and was used to estimate 95% confidence intervals (CIs) for the mediation effect (Hayes, 2013). See Supplemental Methods. 
 
 View larger version: Download to PowerPoint Slide Figure 7. Subjective effects of psilocybin and relationship of mystical experience to clinical outcomes. (Top) Subjective effects as measured by the Mystical Experience Questionnaire (MEQ 30) in each treatment group at 7 hours post-session 1 (psilocybin first n=14, niacin first n=15), 7 hours post-session 2 (psilocybin first n=12, niacin first n=14), and 26 weeks post-dose 2 (psilocybin first n=11, niacin first n=12). Asterisks indicate significance level of between-group differences. (Bottom) Mediation model in which total scores on the MEQ transmit a portion of the effects of psilocybin versus niacin treatment on change in anxiety and depression is shown. 
 
 See Supplementary Methods for additional statistical analysis.
– Hallucinogens are back on the table—at least when it comes to clinical trials. Hundreds of trials in the 1940s and 1950s studied their effects, but since their ban in the late '60s the research all but stopped, reports the New York Times. Nowadays, though, drugs like MDMA (think Ecstasy) and psilocybin (magic mushrooms) are once again the subject of multiple studies: Two trials out of Johns Hopkins and NYU Langone Medical Center involving 80 cancer patients with symptoms of depression and anxiety suggest that a single dose of psilocybin has immediate positive effects, ones that persisted more than 6 months later among 80% of the patients, both teams report in the Journal of Psychopharmacology (second trial here). One participant treated for Stage 3 Hodgkin's lymphoma remained terrified of his own mortality; he tells the Times that after swallowing a capsule of psilocybin in a dimly lit room, he laid down, put on headphones and an eye mask, and began tripping (a psychiatrist and social worker monitored). "I had an epiphany," he says of his eight-hour session, where he watched black smoke rise from his body; three years later, the crippling anxiety remains absent. The New Scientist, which calls the studies the "most extensive trial of psilocybin," reports that antidepressants haven't been overly successful in treating cancer patients, up to 40% of whom can develop depression and anxiety. The jury is out on how exactly psilocybin works, but one theory is that it disrupts the circuitry of self-absorbed thoughts common in people with depression. (Similar findings have come out of the UK.)