ORIGINAL ARTICLE
`
`ONLINE FIRST
`Pilot Study of Psilocybin Treatment for Anxiety
`in Patients With Advanced-Stage Cancer
`
`Charles S. Grob, MD; Alicia L. Danforth, MA; Gurpreet S. Chopra, MD; Marycie Hagerty, RN, BSN, MA;
`Charles R. McKay, MD; Adam L. Halberstadt, PhD; George R. Greer, MD
`
`Context: Researchers conducted extensive investiga-
`tions of hallucinogens in the 1950s and 1960s. By the early
`1970s, however, political and cultural pressures forced
`the cessation of all projects. This investigation reexam-
`ines a potentially promising clinical application of hal-
`lucinogens in the treatment of anxiety reactive to ad-
`vanced-stage cancer.
`
`Objective: To explore the safety and efficacy of psilo-
`cybin in patients with advanced-stage cancer and reac-
`tive anxiety.
`
`Design: A double-blind, placebo-controlled study of pa-
`tients with advanced-stage cancer and anxiety, with sub-
`jects acting as their own control, using a moderate dose
`(0.2 mg/kg) of psilocybin.
`
`Setting: A clinical research unit within a large public
`sector academic medical center.
`
`Participants: Twelve adults with advanced-stage can-
`cer and anxiety.
`
`Main Outcome Measures: In addition to monitor-
`ing safety and subjective experience before and during
`experimental treatment sessions, follow-up data includ-
`ing results from the Beck Depression Inventory, Profile
`
`of Mood States, and State-Trait Anxiety Inventory were
`collected unblinded for 6 months after treatment.
`
`Results: Safe physiological and psychological re-
`sponses were documented during treatment sessions.
`There were no clinically significant adverse events with
`psilocybin. The State-Trait Anxiety Inventory trait anxi-
`ety subscale demonstrated a significant reduction in anxi-
`ety at 1 and 3 months after treatment. The Beck Depres-
`sion Inventory revealed an improvement of mood that
`reached significance at 6 months; the Profile of Mood States
`identified mood improvement after treatment with psi-
`locybin that approached but did not reach significance.
`
`Conclusions: This study established the feasibility and
`safety of administering moderate doses of psilocybin to
`patients with advanced-stage cancer and anxiety. Some
`of the data revealed a positive trend toward improved
`mood and anxiety. These results support the need for more
`research in this long-neglected field.
`
`Trial Registration: clinicaltrials.gov Identifier:
`NCT00302744
`
`Arch Gen Psychiatry. 2011;68(1):71-78.
`Published online September 6, 2010.
`doi:10.1001/archgenpsychiatry.2010.116
`
`I N RECENT YEARS, THERE HAS BEEN
`
`a growing awareness that the psy-
`chological, spiritual, and existen-
`tial crises often encountered by pa-
`tients with cancer and their
`families need to be addressed more vigor-
`ously.1-4 From the late 1950s to the early
`1970s, research was carried out exploring
`the use of hallucinogens to treat the exis-
`tential anxiety, despair, and isolation often
`associated with advanced-stage cancer.5-15
`Those studies described critically ill indi-
`viduals undergoing psychospiritual epipha-
`nies, often with powerful and sustained im-
`provement in mood and anxiety as well as
`diminished need for narcotic pain medica-
`tion. Despite these promising results, there
`has been no follow-up research.
`
`Today, the medical value of hallucino-
`gens is again being examined in formal
`psychiatric settings. One substance un-
`der investigation is psilocybin, 4-phos-
`phoryloxy-N,N-dimethyltryptamine,
`which occurs in nature in various species
`of mushrooms. Psilocybin is rapidly me-
`tabolized to psilocin, which is a potent ago-
`nist at serotonin 5-HT1A/2A/2C receptors, with
`5-HT2A receptor activation directly corre-
`lated with human hallucinogenic activ-
`ity.16 Psilocybin was studied during the
`1960s to establish its psychopharmaco-
`logical profile; it was found to be active
`orally at around 10 mg, with stronger ef-
`fects at higher doses, and to have a 4- to
`6-hour duration of experience. Psycho-
`logical effects were similar to those of ly-
`
`Author Affiliations:
`Departments of Psychiatry
`(Drs Grob and Chopra) and
`Internal Medicine (Dr McKay),
`Harbor-UCLA Medical Center
`and Los Angeles Biomedical
`Research Institute, Torrance
`(Drs Grob and McKay and
`Mss Danforth and Hagerty)
`and Department of Psychiatry,
`University of California,
`San Diego, La Jolla
`(Dr Halberstadt); and Heffter
`Research Institute, Santa Fe,
`New Mexico (Dr Greer).
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 68 (NO. 1), JAN 2011
`71
`
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`
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`EXHIBIT L
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`sergic acid diethylamide (LSD), with psilocybin consid-
`ered to be more strongly visual, less emotionally intense,
`more euphoric, and with fewer panic reactions and less
`chance of paranoia than LSD.17,18
`Recent clinical examinations of psilocybin have indi-
`cated that it is not hazardous to physical health.19 Posi-
`tron emission tomographic studies demonstrated that
`psilocybin produces a global increase in cerebral meta-
`bolic rate of glucose, most markedly in the frontomedial
`and frontolateral cortex, anterior cingulate, and tempo-
`romedial cortex. These changes were correlated with
`measures of psychological state and consistent with
`potential neurobiological substrates of major mental
`illnesses.20
`In one recent study, 36 healthy volunteers received a
`high dose (30 mg/70 kg) of psilocybin with no sus-
`tained deleterious physiological or psychological ef-
`fects. The investigators corroborated previous findings
`that psilocybin could reliably catalyze mystical experi-
`ences leading to significant and lasting improvements in
`quality of life.21 In another study, the effects of psilocy-
`bin were examined in patients with severe, refractory ob-
`sessive-compulsive disorder. Researchers concluded that
`psilocybin is safe and well tolerated in subjects with ob-
`sessive-compulsive disorder and may be associated with
`“robust acute reductions” in core obsessive-compulsive
`disorder symptoms, although there was no clear dose-
`response relationship.22
`During the first wave of hallucinogen research from
`the 1950s through the early 1970s, investigators who ad-
`ministered hallucinogens to patients with end-stage can-
`cers reported results that included improved mood and
`reduced anxiety, even in those with profound psycho-
`logical demoralization.23-26 The present study is the first
`in more than 35 years to explore the potential utility of
`a psilocybin treatment model for patients with reactive
`anxiety associated with advanced-stage cancer.27
`
`METHODS
`
`Twelve subjects with advanced-stage cancer and a DSM-IV28 di-
`agnosis of acute stress disorder, generalized anxiety disorder,
`anxiety disorder due to cancer, or adjustment disorder with anxi-
`ety were recruited into a within-subject, double-blind, placebo-
`controlled study to examine the safety and efficacy of psilocy-
`bin in the treatment of psychological distress associated with
`the existential crisis of terminal disease. Participants were re-
`cruited through Internet postings, flyer distribution, presen-
`tations at local hospitals and wellness centers, oncologist re-
`ferrals, and study registration on clinicaltrials.gov and by
`contacting local patient support agencies and health care pro-
`viders. Medical and psychiatric screening including brain mag-
`netic resonance imaging, communication with treating oncolo-
`gists, formal psychiatric diagnostic interviews, and informed
`consent were required for enrollment into the study. Subjects
`were not paid for their participation. The institutional review
`board of the Los Angeles Biomedical Research Institute, Harbor-
`UCLA Medical Center, Torrance, California, approved the pro-
`tocol and monitored the study.
`Of the 12 subjects, 11 were women. Subjects’ ages ranged from
`36 to 58 years. Primary cancers included breast cancer in 4 sub-
`jects, colon cancer in 3, ovarian cancer in 2, peritoneal cancer
`in 1, salivary gland cancer in 1, and multiple myeloma in 1. All
`
`subjects were in advanced stages of their illness. The duration
`of their primary cancers ranged from 2 months to 18 years. Eight
`subjects completed the 6-month follow-up assessment, 11 com-
`pleted at least the first 4 months of assessment, and all 12 com-
`pleted at least the first 3 months of follow-up. Two subjects died
`of their cancer during the follow-up period, and 2 others be-
`came too ill to continue participating. The study was conducted
`from June 2004 to May 2008. By the time of submission of this
`report in 2010, 10 of the 12 subjects had died.
`Exclusion criteria included central nervous system involve-
`ment of the cancer, severe cardiovascular illness, untreated hy-
`pertension, abnormal hepatic or renal function, diabetes, life-
`time history of schizophrenia, bipolar disease, other psychotic
`illness, and anxiety or affective disorders within 1 year prior
`to the onset of cancer. Medication contraindications included
`active cancer chemotherapy, antiseizure medications, insulin
`and oral hypoglycemics, and psychotropic medications in the
`previous 2 weeks. Subjects also were asked to refrain from tak-
`ing any medications the day of and the day after the experi-
`mental treatment sessions, except for prescription or over-the-
`counter nonnarcotic pain medications at any time and narcotic
`pain medications up to 8 hours before and 6 hours after ad-
`ministration of the experimental medicine.
`Four subjects had no prior hallucinogen experience. Of the
`remaining 8, 4 had hallucinogen experience more than 30 years
`ago. Two had their last experience more than 5 years ago, and
`the other 2 had taken a hallucinogen within the year prior to
`their participation in the study. Hallucinogens taken included
`LSD (7 subjects), hallucinogenic mushrooms (5 subjects), peyote
`(2 subjects), and ayahuasca (2 subjects).
`Subjects met with study staff to review the purpose and
`intention of participation in the study, the treatment goals,
`the structure of the experimental treatment sessions, and criti-
`cal issues to be examined during the course of the treatments.
`Subjects were informed of the range of emotional reaction
`that might be experienced while under the influence of psilo-
`cybin, including challenging psychological issues that might
`arise, and were informed that the purpose of the investigation
`was to determine whether psilocybin could ameliorate the
`anxiety associated with their advanced-stage cancer. Addi-
`tional goals of these meetings included establishing a comfort-
`able level of rapport and trust between the patient and
`research personnel, reviewing significant life issues in the
`patient’s history, and the nature and status of present relation-
`ships and concerns.
`All experimental sessions took place in a hospital clinical
`research unit in a room decorated with fabric wall hangings and
`fresh flowers to provide a pleasing and comfortable environ-
`ment. Subjects were admitted on the afternoon of the day prior
`to treatment. A Holter cardiac monitor was attached for 24 hours
`beginning at admission. Following medical and nursing evalu-
`ations, the treatment team met with the subject to review the
`procedure for the treatment session (described later), confirm
`the subject’s personal intentions, and answer any additional ques-
`tions. Subjects spent the night in the room on the research unit
`and were provided dinner and a light breakfast before 06:30
`hours. On the morning of treatment, the therapeutic team met
`with the subject to administer presession instruments, attend
`to patient comfort, and review treatment procedures for the ses-
`sion one final time.
`Each subject acted as his or her own control and was pro-
`vided 2 experimental treatment sessions spaced several weeks
`apart. They were informed that they would receive active psi-
`locybin (0.2 mg/kg) on one occasion and the placebo, niacin
`(250 mg), on the other occasion. Psilocybin and placebo were
`administered in clear 00 capsules with corn starch and swal-
`lowed with 100 mL of water. A niacin placebo was chosen be-
`cause it often induces a mild physiological reaction (eg, flush-
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 68 (NO. 1), JAN 2011
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`ing) without altering the psychological state. The order in which
`subjects received the 2 different treatments was randomized and
`known only by the research pharmacist. Treatment team per-
`sonnel remained at the bedside with the subject for the entire
`6-hour session.
`Psilocybin or placebo was administered at 10:00 hours. The
`subject was encouraged to lie in bed wearing eye shades during
`the first few hours as well as to put on headphones to listen to
`preselected music. Subjects were allowed to remain undisturbed
`until each hour point, when treatment staff checked to inquire
`how they were doing. Contact was generally brief; subjects had
`been advised that there would be ample opportunity after the ses-
`sion and in subsequent days, weeks, and months to discuss the
`content of the experience. During hourly check-ins, heart rate (HR)
`and blood pressure (BP) measurements also were taken. Non-
`caffeinated clear liquids or juices were permitted.
`At the conclusion of the 6-hour session, subjects discussed
`the subjective aesthetic, cognitive, affective, and psychospiri-
`tual experiences they had during the session and completed rat-
`ing instruments. Various self-report inventories and question-
`naires were administered from 2 weeks prior to the first treatment
`session to up to 6 months after the second. Treatment team per-
`sonnel maintained contact with subjects for the entire 6-month
`follow-up period, including regularly scheduled monthly tele-
`phone calls to update data on adverse events, concomitant medi-
`cations, and evolving medical and psychological status.
`
`ASSESSMENT MEASURES
`
`Subjects’ BP and HR were measured 30 minutes before drug
`ingestion, immediately before drug administration, and at hourly
`intervals for the next 6 hours. Temperature was measured just
`prior to drug administration and 6 hours later at the conclu-
`sion of the session.
`The following psychological measures were administered
`the day before each of the experimental sessions: the Beck De-
`pression Inventory (BDI), Profile of Mood States (POMS), and
`State-Trait Anxiety Inventory (STAI). The POMS, STAI, 5-Di-
`mension Altered States of Consciousness profile (5D-ASC), and
`Brief Psychiatric Rating Scale were administered at the conclu-
`sion of the experimental sessions. The day after the session, the
`BDI, POMS, and STAI were readministered. Finally, the BDI,
`POMS, and STAI were administered again 2 weeks after each
`session and at monthly intervals for 6 months after the final
`session.
`
`INSTRUMENTS
`
`Beck Depression Inventory
`
`The BDI consists of a series of questions developed to measure
`the intensity, severity, and depth of depression.29
`
`Profile of Mood States
`
`The POMS describes feelings individuals have, with the sub-
`ject indicating his or her mood during the past week, includ-
`ing the present day. The POMS Brief, used for this study, is a
`shorter version of the original POMS Standard.30 Subjects were
`instructed to fill out the POMS and BDI in reference to their
`feelings during the past week.
`
`State-Trait Anxiety Inventory
`
`The STAI Form Y is a widely used self-report instrument for
`assessing anxiety in adults. It includes separate measures of
`
`state and trait anxiety.31 The STAI evaluates the essential
`qualities of feelings of apprehension, tension, nervousness,
`and worry. The STAI differentiates between the temporary
`condition of state anxiety and the more general and long-
`standing quality of trait anxiety. The STAI state anxiety sub-
`scale asks for feelings at the moment of filling out the ques-
`tionnaire, and the STAI trait anxiety subscale asks subjects
`to indicate how they generally view themselves.
`
`Brief Psychiatric Rating Scale
`
`The Brief Psychiatric Rating Scale provides clinician assess-
`ment of the level of symptoms such as hostility, suspicious-
`ness, hallucination, and grandiosity.32
`
`5-Dimension Altered States
`of Consciousness Profile
`
`The 5D-ASC rating scale measures alterations in mood, per-
`ception, experience of self in relation to environment, and
`thought disorder.33 The ASC items are grouped into 5 sub-
`scales comprising several items, including the following:
`(1) oceanic boundlessness, measuring derealization and
`depersonalization accompanied by changes in affect ranging
`from elevated mood to euphoria; (2) anxious ego dissolution,
`measuring ego disintegration associated with loss of self-
`control, thought disorder, arousal, and anxiety; (3) visionary
`restructuralization, including hallucinations, pseudohalluci-
`nations, synesthesia, changed meaning of perceptions, and
`facilitated recollection and imagination; (4) auditory alter-
`ations, with acoustic alterations and alterations of auditory
`experiences; and (5) reduction of vigilance, associated with
`drowsiness, reduced alertness, and related impairment of
`cognition. Subjects filled out the 5D-ASC at the conclusion
`of the session.
`
`DATA ANALYSIS
`
`Raw BDI, POMS, and STAI data were analyzed using 2-way
`analysis of variance (ANOVA) with drug as the within-
`subject factor and day as a repeated measure. When the
`2-way ANOVA detected significant main effects of drug or
`interactions between day and drug, post hoc pairwise com-
`parisons were performed by 1-way ANOVA for each day.
`The 5D-ASC data were analyzed using 1-way ANOVA with
`drug as a within-subject factor. Item clusters comprising the
`oceanic boundlessness, anxious ego dissolution, and vision-
`ary restructuralization dimensions also were analyzed using
`1-way ANOVA.34 The Brief Psychiatric Rating Scale data
`were analyzed using 1-way ANOVA with drug as a within-
`subject factor. The HR and BP data were analyzed using
`2-way ANOVA with drug as a within-subject factor and time
`as a repeated measure. When the 2-way ANOVA detected
`significant main effects of drug or interactions between time
`and drug, pairwise post hoc comparisons were performed by
`1-way ANOVA at each time. For the measures listed earlier,
`significance was demonstrated by surpassing an ␣ level of
`.05. Paired t tests were used to assess whether niacin placebo
`and psilocybin produced effects on HR and BP compared
`with the predrug time, and significance was demonstrated
`for these multiple comparisons by surpassing an ␣ level of
`.025. For the BDI, POMS, and STAI, data from each of the 6
`follow-up times were compared with the baseline value
`obtained on the day before the first treatment session, using
`t tests. For the follow-up data, significance was demon-
`strated by surpassing an ␣ level of .05.
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 68 (NO. 1), JAN 2011
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`administration, with a mean (SEM) peak effect of 81.5
`(5.8) beats/min, which was statistically significant
`(F1,11=11.31, P ⬍.007) compared with 70.4 (4.3) beats/
`min during placebo sessions (Figure 1A).
`Blood pressure also peaked at the 2-hour point, with
`mean (SEM) peak systolic BP during psilocybin ses-
`sions measuring 138.9 (6.4) mm Hg (compared with 117.0
`[4.3] mm Hg during niacin placebo sessions) (Figure 1B)
`and mean (SEM) peak diastolic BP of 75.9 (3.4) mm Hg
`during psilocybin sessions (compared with 69.6 [2.7]
`mm Hg during niacin placebo sessions) (Figure 1C).
`Holter monitor recordings during the psilocybin ses-
`sions showed no sustained tachyarrhythmias or heart
`block and were consistent with findings during active pla-
`cebo sessions. Compared with the predrug time, niacin
`modestly depressed diastolic BP 1 hour after adminis-
`tration (Figure 1C) with a rebound over the next hour
`but had no effect at other times.
`
`Placebo
`Psilocybin, 0.2 mg/kg
`
`†
`
`∗
`
`†
`
`PSYCHOLOGICAL MEASURES
`
`†
`
`†
`
`†
`
`The 5D-ASC demonstrated marked subjective differ-
`ences between the psilocybin and placebo experiences.
`Psilocybin particularly affected the oceanic boundless-
`ness (F1,11=33.12, P ⬍.001) and visionary restructural-
`ization (F1,11=18.95, P=.001) dimensions (Figure 2A).
`Psilocybin had smaller but significant effects on anx-
`ious ego dissolution (F1,11=4.91, P=.049) and auditory
`alterations (F1,11=5.93, P=.03). The item clusters with
`marked differences between the subjective states pro-
`duced by psilocybin and niacin included a significant in-
`crease (P ⬍.05) in psilocybin-invoked states of positive
`derealization, positive depersonalization, altered sense
`of time, positive mood, manialike experiences, elemen-
`tary hallucinations, visual pseudohallucinations, synes-
`thesia, changed meaning of percepts, facilitated recol-
`lection, and facilitated imagination. Subscales with no
`appreciable differences between intrasubjective states in-
`duced by the 2 treatments included anxious derealiza-
`tion, thought disorder, delusion, fear of loss of thought
`control, and fear of loss of body control (Figure 2B).
`For the BDI, there was an overall interaction of psi-
`locybin and day that approached but did not attain sta-
`tistical significance (F1,11=3.75, P=.08). There was no ap-
`preciable change from 1 day prior to placebo
`administration to 2 weeks after experimental treatment,
`whereas a trend was observed after psilocybin adminis-
`tration, from a mean (SEM) score of 16.1 (3.6) one day
`before treatment to 10.0 (2.7) two weeks after treat-
`ment (Figure 3A). As shown in Figure 3B, BDI scores
`dropped by almost 30% from the first session to 1 month
`after the second treatment session (t11=−2.17, P=.05), a
`difference that was sustained and became significant at
`the 6-month follow-up point (t7=2.71, P=.03).
`The POMS similarly revealed a trend for reduced ad-
`verse mood tone from 1 day before treatment with psi-
`locybin to 2 weeks later, a difference that was not seen
`after placebo (drug⫻time interaction: F3,33=2.71, P=.06)
`(Figure 4A). Paired post hoc tests revealed that mean
`(SEM) POMS scores were elevated (F1,11=7.48, P=.02) 1
`day before psilocybin treatment (11.3 [3.1]) compared
`with 1 day before placebo (4.5 [2.0]) and demonstrated
`
`∗
`
`∗
`
`∗
`
`†
`
`90
`
`80
`
`70
`
`60
`
`0
`
`150
`
`140
`
`130
`
`120
`
`110
`
`100
`
`0
`
`A
`
`Heart Rate, Beats/min
`
`B
`
`Systolic Blood Pressure, mm Hg
`
`C
`
`80
`
`70
`
`60
`
`0
`
`–1
`
`Diastolic Blood Pressure, mm Hg
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Time, h
`
`Figure 1. Effect of psilocybin or niacin placebo on mean (SEM) heart rate
`(A), systolic blood pressure (B), and diastolic blood pressure (C). Psilocybin
`or niacin placebo was administered at 0 hours.*P ⬍.01, †P ⬍.05 for
`psilocybin vs niacin placebo control (1-way analyses of variance were used
`to compare niacin and psilocybin effects at individual times).
`
`RESULTS
`
`CARDIOVASCULAR FUNCTION
`
`The administration of psilocybin at a dose of 0.2 mg/kg
`induced a mild but statistically significant elevation of
`HR (psilocybin⫻time interaction: F7,70=2.40, P=.03), sys-
`tolic BP (F1,11 = 25.39, P ⬍ .001), and diastolic BP
`(F1,11= 5.94, P = .03) when compared with niacin pla-
`cebo. Elevation of HR peaked 2 hours after psilocybin
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 68 (NO. 1), JAN 2011
`74
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`

`†
`
`†
`
`†
`
`†
`
`†
`
`††
`
`†
`
`†
`
`†
`
`†
`
`†
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`B
`
`% of Maximum Score
`
`0
`
`Positive Depersonalization
`Positive Derealization
`Ele m entary Hallucinations
`Visual Pseudohallucinations
`M anialike Experience
`Fear of Loss of Body Control
`Anxious Derealization
`Fear of Loss of Thought Control
`Thought Disorder
`Facilitated Recollection
`Changed M eaning of Percepts
`Altered Sense of Tim e
`Synesthesia
`Positive M ood
`Facilitated Im agination
`
`Delusion
`
`∗
`
`Placebo
`Psilocybin, 0.2 mg/kg
`
`∗
`
`†
`
`†
`
`OB
`
`AA
`VR
`AED
`5D-ASC Dimension
`
`RV
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`A
`
`% of Maximum Score
`
`Figure 2. Subjective effects of psilocybin as measured by the 5-Dimension Altered States of Consciousness profile (5D-ASC). A, Five main 5D-ASC dimensions are
`shown: oceanic boundlessness (OB), anxious ego dissolution (AED), visionary restructuralization (VR), auditory alterations (AA), and reduced vigilance (RV). B, Item
`clusters comprising the OB, AED, and VR dimensions are shown. Values are the mean (SEM) percentages of the total possible score. *P⬍.01, †P⬍.05 for psilocybin
`vs niacin placebo control (1-way analyses of variance were used to compare niacin and psilocybin effects on individual 5D-ASC dimensions and 5D-ASC item clusters).
`
`A
`
`25
`
`20
`
`Placebo
`Psilocybin, 0.2 mg/kg
`
`A
`
`14
`
`12
`
`10
`
`†
`
`Placebo
`Psilocybin, 0.2 mg/kg
`
`1 d Before
`
`6 h After
`
`1 d After
`
`2 wk After
`
`1 d
`Before
`
`1 mo
`
`2 mo
`
`3 mo
`
`4 mo
`
`5 mo
`
`6 mo
`
`Assessment Time
`
`8 6 4 2
`
`0
`
`14
`
`12
`
`10
`
`8 6 4 2
`
`0
`
`POMS Score
`
`B
`
`POMS Score
`
`1 d Before
`
`1 d After
`
`2 wk After
`
`†
`
`1 mo
`
`2 mo
`
`3 mo
`
`4 mo
`
`5 mo
`
`6 mo
`
`1 d
`Before
`
`Assessment Time
`
`15
`
`10
`
`BDI Score
`
`5 0
`
`25
`
`20
`
`15
`
`10
`
`5 0
`
`B
`
`BDI Score
`
`Figure 3. Beck Depression Inventory (BDI) scores. A, Mean (SEM) BDI
`scores 1 day before, 1 day after, and 2 weeks after administration of
`psilocybin or niacin placebo are shown. B, Six months of mean (SEM) BDI
`follow-up data are shown. The BDI was administered at monthly intervals for
`6 months after the second treatment session, and the 6 sets of monthly
`follow-up data were compared with the scores obtained the first time the
`participants filled out the instruments (ie, 1 day before the first treatment
`session). †P ⬍.05 for psilocybin vs the value from 1 day before the first
`treatment session (t tests were used to compare individual monthly
`follow-up values with values on the day before the first session).
`
`Figure 4. Profile of Mood States (POMS) scores. A, Mean (SEM) POMS
`scores 1 day before, 6 hours after, 1 day after, and 2 weeks after
`administration of psilocybin or niacin placebo are shown. B, Six months of
`mean (SEM) POMS follow-up data are shown. The POMS was administered
`at monthly intervals for 6 months after the second treatment session, and
`the 6 sets of monthly follow-up data were compared with the scores
`obtained the first time the participants filled out the instruments (ie, 1 day
`before the first treatment session). †P ⬍.05 for psilocybin vs niacin placebo
`control (1-way analyses of variance were used to compare niacin and
`placebo effects at individual times).
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 68 (NO. 1), JAN 2011
`75
`
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`
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`

`

`Placebo
`Psilocybin, 0.2 mg/kg
`
`1 d Before
`
`6 h After
`
`1 d After
`
`2 wk After
`
`∗
`
`†
`
`1 d
`Before
`
`1 mo
`
`2 mo
`
`3 mo
`
`4 mo
`
`5 mo
`
`6 mo
`
`Assessment Time
`
`50
`
`45
`
`40
`
`35
`
`30
`
`25
`
`20
`
`50
`
`45
`
`40
`
`35
`
`30
`
`25
`
`20
`
`STAI Trait Anxiety Score
`
`STAI Trait Anxiety Score
`
`B
`
`D
`
`1 d Before
`
`6 h After
`
`1 d After
`
`2 wk After
`
`1 d
`Before
`
`1 mo
`
`2 mo
`
`3 mo
`
`4 mo
`
`5 mo
`
`6 mo
`
`Assessment Time
`
`50
`
`45
`
`40
`
`35
`
`30
`
`25
`
`20
`
`50
`
`45
`
`40
`
`35
`
`30
`
`25
`
`20
`
`STAI State Anxiety Score
`
`STAI State Anxiety Score
`
`A
`
`C
`
`Figure 5. Mean (SEM) State-Trait Anxiety Index (STAI) state anxiety scores (A) and trait anxiety scores (B) 1 day before, 6 hours after, 1 day after, and 2 weeks
`after administration of psilocybin or niacin placebo are shown. Six months of mean (SEM) STAI state anxiety follow-up data (C) and trait anxiety follow-up data
`(D) are shown. The STAI was administered at monthly intervals for 6 months after the second treatment session, and the 6 sets of monthly follow-up data were
`compared with the scores obtained the first time the participants filled out the instruments (ie, 1 day before the first treatment session). *P ⬍.01, †P ⬍.05 for
`psilocybin vs the value from 1 day before the first treatment session (t tests were used to compare individual monthly follow-up values with values on the day
`before the first session).
`
`that this difference disappeared 6 hours after psilocybin
`administration. Improvement of mood, indicated by re-
`duced POMS scores, was observed in 11 subjects after
`administration of psilocybin. The elevation of POMS scores
`1 day before psilocybin treatment occurred regardless of
`whether the subjects were treated with placebo or psi-
`locybin first (ie, there was no interaction between treat-
`ment order and drug). As shown in Figure 4B, POMS
`scores were not altered during the 6 months of fol-
`low-up compared with the day before the first treatment
`session.
`The STAI revealed no significant changes from 1 day
`before to 2 weeks after treatment, although a substan-
`tial but nonsignificant decrease was evident for the state
`anxiety subscale 6 hours after psilocybin administra-
`tion, which was not observed after placebo (Figure 5A
`and C). Although minimal change was observed in the
`STAI state anxiety score for follow-up data, a sustained
`decrease in STAI trait anxiety was observed for the en-
`tire 6-month follow-up, reaching significance at the
`1-month (t11= 4.36, P = .001) and 3-month (t10= 2.55,
`P = .03) points after the second treatment session
`(Figure 5B and D).
`The Brief Psychiatric Rating Scale at the end of the ex-
`perimental session revealed no appreciable difference be-
`tween psilocybin and placebo administration.
`
`COMMENT
`
`The initial goals of this research project were to estab-
`lish feasibility and safety for a hallucinogen treatment
`model in patients with advanced-stage cancer and anxi-
`ety. Following discussion with federal and state regula-
`tory agencies as well as hospital institutional review board
`and research committees, a modest 0.2-mg/kg psilocy-
`bin dose was chosen. Although not comparable to higher
`doses of hallucinogens administered in the past to se-
`verely ill patients, the dose used here was still believed
`capable of inducing an alteration of consciousness with
`potential therapeutic benefit while optimizing patient
`safety. Determining safe parameters with this novel treat-
`ment paradigm is critical to establishing a strong foun-
`dation for this field of study that would allow for future
`investigations.
`Consistent with previous research, we found no unto-
`ward cardiovascular sequelae in our subject popula-
`tion.19 Minor HR and BP elevations after psilocybin ad-
`ministration were evidence only of a mild sympathomimetic
`effect. Holter monitoring did not identify increased car-
`diac arrhythmias in comparison with niacin placebo, even
`in subjects who presented with some baseline cardiac ar-
`rhythmia. Niacin may acutely lower BP through vasodi-
`
`(REPRINTED) ARCH GEN PSYCHIATRY/ VOL 68 (NO. 1), JAN 2011
`76
`
`WWW.ARCHGENPSYCHIATRY.COM
`
`©2011 American Medical Association. All rights reserved.
`Downloaded From: http://archpsyc.jamanetwork.com/ by a Yale University User on 06/29/2015
`
`

`

`lation35 but had minimal effects on BP and HR in our sub-
`jects, except for a reduction in diastolic BP that was noted
`1 hour after administration of niacin. This transient effect
`may have contributed to our detection of a significant psi-
`locybin effect at that time but cannot explain the signifi-
`cant effects of psilocybin over the subsequent intervals be-
`cause the initial niacin-induced reduction of diastolic BP
`did not persist. We also observed no adverse psychologi-
`cal effects from the treatment. All subjects tolerated the
`treatment sessions well, with no indication of severe anxi-
`ety or a “bad trip.” The fact that psilocybin produced only
`modest effects on the anxious ego dissolution scale of the
`5D-ASC confirmed this conclusion.
`When hallucinogens were administered to patients
`with terminal cancer in the 1960s and early 1970s, the
`occurrence of a profound psychospiritual experience was
`correlated with therapeutic outcome.10,12 Such transcen-
`dent states of consciousness are usually associated with
`higher doses of hallucinogens, so our expectation of dem-
`onstrating efficacy was limited.21 Common themes re-
`ported by subjects included examining how their illness
`had impacted their lives, relationships with family and
`close friends, and sense of ontological security. In addi-
`tion, subjects reported powerful empathic cathexis to close
`friends and family members and examined how they
`wished to address their limited life expectancy. In monthly
`follow-up discussions, subjects reflected on insights and
`new perspectives gained during their psilocybin treat-
`ment. However, the frequency of these reports was not
`quantified.
`Although past researchers reported more pro-
`nounced therapeutic effects with a higher-dose model,
`even the lower dose of psilocybin used in the current study
`gave so