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https://doi.org/10.1177/02698811211073759
Journal of Psychopharmacology
2022, Vol. 36(2) 151 –158
© The Author(s) 2022
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DOI: 10.1177/02698811211073759
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Major depressive disorder (MDD) affects over 260 million peo-
ple worldwide and is a leading cause of disability and healthcare
expenditures (James et al., 2018). First-line treatments, including
pharmacotherapy and psychotherapy, may take weeks or months
to produce clinically meaningful symptom reduction, and patients
can have difficulty with treatment adherence (Cuijpers et al.,
2008; Kolovos et al., 2017; Lam, 2012). At least 30% of patients
ultimately meet criteria for treatment-resistant depressive illness
after failing to respond to multiple attempts at treatment
(Nemeroff, 2007). MDD also has a highly recurrent course, with
40–60% of those diagnosed with a single episode eventually
relapsing, and rate of relapse increasing with each subsequent
episode (Richards, 2011; Solomon et al., 2000). Novel interven-
tions are needed that can act rapidly and produce sustained
remission.
Several preliminary studies suggest that psilocybin-assisted
treatment may have substantial antidepressant effects in patients
with MDD, with treatment response occurring within a week of
administration of just one or two doses in the context of psycho-
therapy (Carhart-Harris et al., 2018, 2021; Davis et al., 2021). In
an initial report of primary outcomes following two doses of
psilocybin using a randomized waitlist-control study design,
we reported a large effect size (Cohen d = 2.3) and high rates of
treatment response and remission (71% and 54%) at 1 month fol-
lowing intervention (Davis et al., 2021). Treatment-resistant
patients also appear to have a favorable response rate (Carhart-
Harris et al., 2018). A more recent study used a double-blind
Efficacy and safety of psilocybin-assisted
treatment for major depressive disorder:
Prospective 12-month follow-up
Natalie Gukasyan1, Alan K Davis1,2 , Frederick S Barrett1,
Mary P Cosimano1, Nathan D Sepeda1, Matthew W Johnson1
and Roland R Griffiths1,3
Abstract
Background: Preliminary data suggest that psilocybin-assisted treatment produces substantial and rapid antidepressant effects in patients with major
depressive disorder (MDD), but little is known about long-term outcomes.
Aims: This study sought to examine the efficacy and safety of psilocybin through 12 months in participants with moderate to severe MDD who received
psilocybin.
Methods: This randomized, waiting-list controlled study enrolled 27 patients aged 21–75 with moderate to severe unipolar depression (GRID-Hamilton
Depression Rating Scale (GRID-HAMD) ⩾ 17). Participants were randomized to an immediate or delayed (8 weeks) treatment condition in which they
received two doses of psilocybin with supportive psychotherapy. Twenty-four participants completed both psilocybin sessions and were followed
through 12 months following their second dose.
Results: All 24 participants attended all follow-up visits through the 12-month timepoint. Large decreases from baseline in GRID-HAMD scores were
observed at 1-, 3-, 6-, and 12-month follow-up (Cohen d = 2.3, 2.0, 2.6, and 2.4, respectively). Treatment response (⩾50% reduction in GRID-HAMD
score from baseline) and remission were 75% and 58%, respectively, at 12 months. There were no serious adverse events judged to be related to
psilocybin in the long-term follow-up period, and no participants reported psilocybin use outside of the context of the study. Participant ratings
of personal meaning, spiritual experience, and mystical experience after sessions predicted increased well-being at 12 months, but did not predict
improvement in depression.
Conclusions: These findings demonstrate that the substantial antidepressant effects of psilocybin-assisted therapy may be durable at least through
12 months following acute intervention in some patients.
Keywords
Insight, long-term effects, major depressive disorder, mystical experience, psilocybin
1 Center for Psychedelic and Consciousness Research, Department of
Psychiatry and Behavioral Sciences, Johns Hopkins University School
of Medicine, Baltimore, MD, USA
2College of Social Work, The Ohio State University, Columbus, OH, USA
3 Department of Neuroscience, Johns Hopkins University School of
Medicine, Baltimore, MD, USA
Corresponding authors:
Natalie Gukasyan, Center for Psychedelic and Consciousness Research,
Department of Psychiatry and Behavioral Sciences, Johns Hopkins
University School of Medicine, 5510 Nathan Shock Drive, Baltimore,
MD 21224, USA.
Email: gukasyan@jhmi.edu
Roland R Griffiths, Center for Psychedelic and Consciousness Research,
Department of Psychiatry and Behavioral Sciences, Johns Hopkins
University School of Medicine, 5510 Nathan Shock Drive, Baltimore,
MD 21224, USA.
Email: rgriff@jhmi.edu
1073759JOP0010.1177/02698811211073759Journal of PsychopharmacologyGukasyan et al.
research-article2022
Original Paper
152 Journal of Psychopharmacology 36(2)
double dummy design to compare high-dose psilocybin plus
6 weeks of placebo with very low dose psilocybin plus 6 weeks of
escitalopram (Carhart-Harris et al., 2021). The authors failed to
show a significant difference between the two groups at 6 weeks
in their designated primary outcome measure (Quick Inventory
of Depressive Symptoms). The majority of results for secondary
outcome measures including other depression severity scores
favored the high-dose psilocybin group, though analyses were
not corrected for multiple comparisons.
Although psilocybin treatment of MDD appears promising,
little is known about long-term efficacy and safety. The three
studies conducted to date demonstrated efficacy at their longest
follow-up assessments of 4 weeks (Davis et al., 2021), 6 weeks
(Carhart-Harris et al., 2021), and 6 months (Carhart-Harris et al.,
2018), although depression severity scores were trending upward
at 3- and 6-month follow-up timepoints. Carhart-Harris et al.
(2018), with the longest period of follow-up, had an open-label
design. Given the chronicity and relapsing disease course of
MDD (Richards, 2011), the present study represents a significant
extension of these previous findings by assessing efficacy and
safety of a psilocybin intervention throughout a 12-month fol-
low-up period.
Methods
Study design
Full details of the study design and inclusion criteria have been
described previously (Davis et al., 2021). All procedures involv-
ing subjects were approved by The Johns Hopkins Medicine
Institutional Review Board. Written informed consent was
obtained from all participants. Participants were 21–75 years of
age, medically stable, and met criteria for a moderate to severe
episode of MDD as defined by a score of ⩾17 on the GRID-
Hamilton Depression Rating Scale (GRID-HAMD) assessed by
blinded clinician raters. Individuals with personal or first- or
second-degree relative history of psychotic or bipolar I or II dis-
order were excluded. To avoid interactions with psychoactive
drugs including those used to treat depression, participants were
required to refrain from using such medications for at least five
half-lives before screening and for at least 1 month following the
second psilocybin session. Following medical and psychological
screening and baseline assessments, participants were rand-
omized to an immediate or delayed treatment condition.
Participants in the immediate treatment group began the inter-
vention after screening, while those in the delayed treatment
group began the intervention after an 8-week delay interval.
After participants entered the intervention period, they were
provided with 6–8 h of preparatory meetings with two facilita-
tors. At least one facilitator in each dyad had a master’s or doc-
toral level of clinical training in mental health (e.g. master of
social work, PhD in clinical psychology, MD specializing in psy-
chiatry). Following preparation, participants received two doses
of psilocybin at 20 mg/70 kg and 30 mg/70 kg spaced approxi-
mately 2 weeks apart. Psilocybin was administered in a comfort-
able room under the supervision of both facilitators following
established safety guidelines (Johnson et al., 2008). A nondirec-
tive psychotherapeutic approach was taken on session days.
Participants returned for follow-up at 1 day and 1 week following
each drug administration session, and then at 1, 3, 6, and
12 months following the second session, during which depression
severity was assessed with participant- and clinician-rated meas-
ures. Each follow-up visit included a 1–2 h meeting with at least
one of the therapist facilitators. Functional magnetic resonance
imaging was completed at baseline and 1 week after the second
psilocybin session (Doss et al., 2021).
Outcome measures
Measures of depression severity. The primary outcome mea-
sure was the GRID-HAMD (Depression Rating Scale Standard-
ization Team, 2003), which was assessed by blinded clinician
raters via telephone as described previously (Davis et al., 2021).
Inter-rater reliability at the 3-, 6-, and 12-month timepoints was
87.5% (see online supplement for additional information).
Depression was also assessed with two self-report question-
naires: the Quick Inventory of Depressive Symptoms (QIDS)
(Rush et al., 2003), and the Beck Depression Inventory II (BDI-
II) (Beck et al., 1996). Depression severity was assessed at base-
line and at each of the follow-up timepoints.
Participant-rated measures of acute psilocybin effects.
Various measures of acute psilocybin effects assessed at the end
of the session or the following day were reported previously
(Davis et al., 2021). Of interest in this follow-up analysis was
whether a subset of these acute measures would predict subse-
quent follow-up results. Based on previous studies showing asso-
ciations between acute psilocybin measures and subsequent
positive effects in healthy and patient samples (Bogenschutz
et al., 2015; Davis et al., 2020; Garcia-Romeu et al., 2014;
Griffiths et al., 2008, 2016, 2018), the following measures were
examined: the Mystical Experience Questionnaire (MEQ30)
(Barrett et al., 2015) and four single-item measures (Carbonaro
et al., 2020) on which participants rated the degree to which the
session experience was personally meaningful, spiritually sig-
nificant, psychologically insightful, and psychologically chal-
lenging on a scale from 1 = no more than routine, everyday
experiences to 8 = the single most (meaningful, spiritually sig-
nificant, psychologically insightful, or psychologically challeng-
ing experience) of my life. The psychological challenge item was
included as a comparison because it was not expected to predict
subsequent positive outcomes. The MEQ30 was completed at the
conclusion of each psilocybin session and the single-item mea-
sures were completed on the day following each session.
Overall well-being attributed to psilocybin. At the 1-, 3-, 6-,
and 12-month follow-up timepoints, participants completed the
Persisting Effects Questionnaire (Griffiths et al., 2018), which
involved rating on a 6-point scale current persisting effects that
they attributed to their psilocybin experiences (see online supple-
ment for more information). For this study, an overall well-being
score was calculated as the grand mean of the five subscales of
positive change: attitudes about life, attitudes about self, mood,
relationships, and behavior, with each expressed as a percentage
of maximum possible score.
Safety measures. At each follow-up timepoint, adverse events
were recorded, suicidal ideation was assessed using the Colum-
bia Suicide Severity Rating Scale (C-SSRS) (Posner et al., 2008),
Gukasyan et al. 153
and symptoms indicative of hallucinogen persisting perceptual
disorder (HPPD) were solicited (e.g. “Since your drug session
have you experienced any uncontrolled or disturbing return of
drug-like effects?”).
Statistical analyses
A repeated-measures analysis of variance was conducted with
time (baseline, 1 week post-treatment, and 1, 3, 6, and 12 months
post-treatment) and condition (immediate and delayed treatment)
as factors on the primary depression outcome (GRID-HAMD
score), with effect sizes calculated using partial eta squared (
η
p
2).
This analysis showed a significant effect of time, but no signifi-
cant effect of condition or a time-by-condition interaction.
Therefore, data were collapsed across the conditions and a series
of paired t tests compared baseline scores with scores at each of
the follow-up timepoints with Bonferroni adjustment for multiple
comparisons. Paired t test effect sizes were calculated using
Cohen d. Descriptive statistics of follow-up measures were calcu-
lated, including treatment response (⩾50% reduction in depres-
sion scores from baseline) and remission (GRID-HAMD ⩽ 7,
QIDS ⩽ 5, BDI-II ⩽ 9) for measures of depression (Beck et al.,
1996; Rush et al., 2003; Zimmerman et al., 2013). The relation-
ship between acute measures of session experiences and follow-
up measures of acute psilocybin effects (MEQ30 and ratings of
meaning, insight, spiritual significance and psychological chal-
lenge) were examined with Spearman’s correlations (rs). For
these calculations, the highest ratings or scores from Session 1
and Session 2 for each participant were used. For the follow-up
measures, the overall well-being score was expressed as a per-
centage of maximum possible score, and the depression measures
were expressed as percentage change from the baseline score for
each participant. Analyses of several group-based comparisons
were conducted using χ2 for categorical variables and t test for
continuous variables. A two-tailed significance level of p < .05
was used for between-group comparisons and correlations.
Analyses were completed using SPSS 26 and 27.
Results
Participants
As described in more detail previously (Davis et al., 2021), 27
participants were randomized and 24 completed both psilocybin
sessions, with 13 and 11 assigned to the immediate and delayed
treatment groups, respectively. All 24 participants completed all
long-term follow-up assessment visits (see online supplement,
CONSORT diagram). The group was 67% female and 92%
Caucasian. One participant identified as Black and another as
Asian; none identified as Hispanic. Participants had a mean (SD)
age of 39.8 (12.2) years. Mean duration of illness (years since
diagnosis of MDD) was 21.5 (12.2) years, and mean time in cur-
rent major depressive episode was 24.4 (22.0) months. Of the
participants, 88% had previously attempted treatment with an
antidepressant (e.g. a selective serotonin, norepinephrine, or
dopamine reuptake inhibitor, etc.) and 58% reported previous use
of such medication in the current depressive episode. Twenty-
five percent had previously used a psychedelic drug, with an
average of 3.3 previous uses and an average time of 9.2 years
since last use.
Changes in depressive symptoms
As reported previously (Davis et al., 2021), GRID-HAMD scores
were significantly lower in the immediate treatment group at 1
and 4 weeks post treatment when compared with corresponding
timepoints after randomization in the delayed treatment group.
After completing the delay period, participants in the delayed
treatment group completed the psilocybin intervention and fol-
low-up assessments. In this follow-up study, analysis of variance
with GRID-HAMD scores showed a significant effect of time
(baseline and 5 post-treatment timepoints) (F(4.4, 96.3) = 34.9,
p < 0.001;
η
p
2 = .61), but no significant effect of condition
(immediate vs delayed treatment) or a time-by-condition interac-
tion. Thus, the following results are from data collapsed across
conditions.
As shown in Figure 1, mean GRID-HAMD scores for the
overall treatment sample decreased from a mean (SD) of 22.8
(3.9) at pretreatment baseline to 8.7 (7.6) at 1 week, 8.9 (7.4) at
4 weeks, 9.3 (8.8) at 3 months, 7.0 (7.7) at 6 months, and 7.7 (7.9)
at 12 months post-treatment (p > .001 at all timepoints, paired t
tests with Bonferroni correction). The effect sizes for these dif-
ferences were large, with Cohen d (95% CI) being 2.3 (1.5, 3.1)
at 1 week, 2.3 (1.5, 3.1) at 4 weeks, 2.0 (1.3, 2.7) at 3 months, 2.6
(1.7, 3.4) at 6 months, and 2.4 (1.6, 3.2) at 12 months. Similar
significant, large magnitude, and sustained decreases in depres-
sion from pretreatment across the five follow-up assessments
occurred with the two patient-rated depression assessment ques-
tionnaires (QIDS and BDI-II, online supplement Table S1,
Figures S1 and S2).
As previously reported (Davis et al., 2021), at 1 week after
treatment, 17 of the 24 participants (71%) showed a clinical
response rate on the GRID-HAMD (⩾50% reduction from pre-
treatment) and 14 (58%) were in remission (GRID-HAMD
score ⩽ 7) (Zimmerman et al., 2013). As shown in Table 1, the
response and remission rates were generally sustained through
the 12-month follow-up assessment, with final response and
remission rates of 75% and 58%, respectively. Table 1 shows
similar or greater response and remission rates with the two
patient-rated measures of depression (QIDS and BDI-II).
Figure 2 shows GRID-HAMD depression scores for each of
the 24 study participants from pretreatment through the 12-month
follow-up assessment. Most participants showed large decreases
in their depression score at the first follow-up interval at 1-week
post-treatment, consistent with the 71% response rate and 58%
remission rate shown in Table 1. The figure shows that psilocybin
did not exacerbate depression in any participant and that 3 of 24
participants (13%) did not meet criteria for a treatment response
at any post-treatment timepoint.
Figure 2 also provides detailed information about participants
who started or resumed daily use of an antidepressant medication
for depression (i.e. a selective serotonin reuptake inhibitor, a
serotonin-norepinephrine reuptake inhibitor, or a norepineph-
rine-dopamine reuptake inhibitor) after psilocybin treatment. Of
the 24 participants, 0 (0%), 3 (12.5%), 5 (20.8%), 8 (33.3%), and
8 (33.3%), respectively, reported daily antidepressant use at the
4-week and 3-, 6-, and 12-month follow-up assessments. The 8
participants who started antidepressant treatment by the 12-month
timepoint had higher baseline GRID-HAMD scores (mean 25.3
vs 21.5, p = .02) compared with those who did not report antide-
pressant use; however, they were not statistically different in age,
sex, years with depression, duration of current depressive
154 Journal of Psychopharmacology 36(2)
0
10
20
30
Depression Scores
(GRID-HAMD)
Post-Treatment
d=2.3d=2.3d=2.0
d=2.6d=2.4
Pretreatment
Baseline
1 4
weeks
3 months 6 months 12 months
Figure 1. Decrease in GRID-HAMD depression scores over time from baseline through the 12-month follow-up (N = 24).
Data points are means and brackets are ±1 SD; lower brackets are truncated at GRID-HAMD scores of 0. Mean GRID-HAMD was 22.8 (3.9) at baseline, 8.7 (7.6) at 1 week,
8.9 (7.4) at 4 weeks, 9.3 (8.8) at 3 months, 7.0 (7.7) at 6 months, and 7.7 (7.9) at 12 months post-treatment. All timepoints were significantly different from baseline
(p < 0.001). Cohen d effect size is shown for each timepoint. Cohen d (95% CI) was 2.3 (1.5–3.1) at 1 week, 2.3 (1.5–3.1) at 4 weeks, 2.0 (1.3–2.7) at 3 months, 2.6
(1.7–3.4) at 6 months, and 2.4 (1.6–3.2) at 12 months.
Table 1. Percentage of total sample (N = 24) meeting criteria for treatment response (reduction in depression ⩾ 50% from pretreatment baseline) or
remission.
Post-Treatment Follow-Up Time
1 week 4 weeks 3 months 6 months 12 months
GRID-HAMD
Response rate 71% 71% 67% 79% 75%
Remission ratea58% 54% 54% 71% 58%
QIDS
Response rate 79% 71% 79% 79% 79%
Remission rateb54% 54% 58% 67% 67%
BDI-II
Response rate 79% 79% 79% 88% 83%
Remission ratec67% 63% 58% 75% 75%
GRID-HAMD: Hamilton Depression Rating Scale; QIDS: Quick Inventory of Depressive Symptoms; BDI-II: Beck Depression Inventory II.
aRemission = GRID-HAMD score ⩽ 7 (Zimmerman etal., 2013).
bRemission = QIDS score ⩽ 5 (Rush etal., 2003).
cRemission = BDI-II score ⩽ 9 (Beck etal., 1996).
Gukasyan et al. 155
episode, or history of medication use in the current depressive
episode. Mean GRID-HAMD scores and overall well-being
scores at 12 months did not significantly differ between those
who did and did not begin antidepressant treatment.
Overall well-being attributed to psilocybin across the 1-, 3-,
6-, and 12-month follow-up timepoints was intermediate and sta-
ble. The grand mean (SD) overall well-being score, expressed as
percentage of maximum possible score, was 63.9 (22.6), 60.0
(21.3), 59.0 (24.0), and 65.0 (20.0), respectively.
Participant-rated measures of session
experiences as predictors of subsequent
overall well-being and changes in depression
severity
Correlations between participant-rated measures of psilocybin
experiences at the time of the session and subsequent measures of
well-being and depression were examined. At the first long-term
follow-up assessment (Table 2, Week 4), ratings of personal
meaning, psychological insight, spiritual significance, and the
mystical experience (MEQ30) correlated significantly with
well-being, and ratings of personal meaning and spiritual signifi-
cance correlated significantly with improvement in depression
(GRID-HAMD). However, at subsequent follow-up timepoints,
none of these session experience measures were significantly
correlated with improvements in depression (Table 2). The
MEQ30 significantly correlated with well-being at all four fol-
low-up timepoints, and ratings of personal meaning and spiritual
significance were significantly correlated at three of four time-
points. Ratings of psychological challenge during the session
were not significantly correlated with subsequent measures of
well-being or depression at any follow-up timepoint.
Safety outcomes
During the follow-up period, there were no serious adverse
events, suicidal ideation remained low, there were no instances of
self-injurious behavior, no reported use of psilocybin or other
psychedelics, and no participant met criteria for HPPD. Further
details on adverse events are available in the online supplement.
Discussion
The present study suggests that two doses of psilocybin provided
in the context of supportive therapy for MDD produced large and
stable antidepressant effects throughout a 12-month follow-up
0
5
10
15
20
25
30
35
DepressionScores
(GRID-HAMD)
Post-Treatment
Pretreatment
Baseline
1 4
weeks
3 months 6 months 12 months
Figure 2. Depression scores (GRID-HAMD) for each of 24 study participants at baseline and each of 5 follow-up assessment timepoints.
Individual participants are represented with different colors. Dashed lines indicate three participants who did not fulfill criteria for a treatment response at any post-
treatment timepoint. Enlarged data points indicate participants who reported treatment with antidepressant medication, with the left-most enlarged data points showing
the first follow-up timepoint at which medication use was reported.
156 Journal of Psychopharmacology 36(2)
period. More specifically, depression, as measured by blinded
clinician-rated assessments (GRID-HAMD), decreased substan-
tially after treatment and remained low at 1, 3, 6, and 12 months
post-treatment. The effect size at 12 months was very large
(Cohen d = 2.4). Likewise, high and stable rates of response and
remission occurred throughout the follow-up period (75%
response and 58% remission at 12 months). Two patient-rated
measures of depression (QIDS and BDI-II) showed similar large
magnitude and stable antidepressant effects on mean scores and
on response and remission rates. These findings suggesting
enduring antidepressant effects of psilocybin 1 year after treat-
ment significantly extend the previous results in this and two
other trials that showed antidepressant effects through 4 weeks
(Davis et al., 2021), 6 weeks (Carhart-Harris et al., 2021), and
6 months (Carhart-Harris et al., 2018). Notably, the remission
rate and magnitude of the effect in the current study at both 6 and
12 months were substantially greater than those in a previous
study at 6 months (QIDS, remission rate 67% and 67% vs 32%,
Cohen d 2.2 and 2.3 vs 1.6, respectively) (Carhart-Harris et al.,
2018). Whether this difference reflects population differences in
severity of illness or procedural differences is unknown. Future
research is needed to explore the possibility that efficacy of psilo-
cybin treatment in MDD may be substantially longer than the
12 months observed in the present study, as has been suggested in
a study that documented decreases in depressive symptoms up to
4.5 years following psilocybin treatment in patients with cancer-
related distress (Agin-Liebes et al., 2020).
Of note, eight patients (33%) reported beginning a new course
of treatment with a daily antidepressant drug at some point dur-
ing the 12-month follow-up period, which is similar to the 32%
of patients in a previous trial that did so by 6 months (Carhart-
Harris et al., 2018). Although patients who used antidepressants
during the follow-up period had higher GRID-HAMD scores at
baseline, at 12 months they did not significantly differ from those
who did not initiate medications. Determining the extent of the
contribution of psilocybin vs other medications to clinical
improvement in those who resumed antidepressant use is not
possible. However, participant ratings of persisting well-being
attributed to the psilocybin sessions were not significantly differ-
ent from those who did not use antidepressant medications, sug-
gesting that psilocybin treatment resulted in some independent
benefit.
Although relapse and remission rates at 12 months were
favorable, the ability to accurately compare the long-term effi-
cacy of psilocybin-assisted treatment to that of standard antide-
pressant treatment is limited. The majority of recent studies of
long-term antidepressant efficacy drop non-responders from fol-
low-up and focus on rate of relapse among those who respond to
a particular drug, which is often a minority of the intention-to-
treat sample (McGrath et al., 2006; Trivedi et al., 2006). In our
sample, of the 17 participants who met criteria for treatment
response at 1-month follow-up, 12 (71%) continued to meet cri-
teria for treatment response at all subsequent timepoints. An
additional 3 participants who responded at 1 month also met cri-
teria for treatment response at 12 months, but had one or more
interim assessments during which their GRID-HAMD score was
elevated out of the range for treatment response. The 71% con-
tinuous treatment response at 12 months is somewhat higher than
the 54% rate reported in a study of fluoxetine responders who
were maintained on fluoxetine, and much higher than those
switched to placebo (28%) (McGrath et al., 2006).
The present study provides new information about qualitative
features of the acute psilocybin experience that predict subse-
quent enduring effects. Patient ratings of personal meaning, spir-
itual significance, and MEQ30 scores after psilocybin sessions
significantly correlated with a measure of overall well-being at
most follow-up timepoints. However, except for ratings of per-
sonal meaning and spiritual significance at the first long-term
follow-up assessment at 4 weeks, none of patient ratings of psilo-
cybin experience at the time of the session were predictive of
improvements in depression. Notably, two previous studies in
individuals with cancer-related depression and anxiety (Griffiths
et al., 2016; Ross et al., 2016) showed positive associations of
MEQ30 session experiences with improvements in depression
symptoms at 5 or 6 weeks. Considering that the direction of cor-
relation at 4 weeks was in the predicted direction (rs = 0.38,
p = .066), it is possible that the present study was underpowered
to detect such an effect with MEQ30 or other measures of psil-
ocybin experience. Alternatively, this difference may reflect a
lack of such relationship in a sample of individuals with MDD
as opposed to depressive symptoms secondary to a cancer
diagnosis.
There were no serious adverse events, depression symptoms
were not significantly exacerbated in any participant, and there
Table 2. Relationship between measures of psilocybin experiences assessed at the end of the session or the following day with the follow-up
measures of well-being and improvement in depression assessed at 4 weeks and 3, 6, and 12 months.a
Session measuresb4 weeks Follow-up 3 months Follow-up 6 months Follow-up 12 months Follow-up
Well-beingcGRID-HAMDdWell-beingcGRID-HAMDdWell-beingcGRID-HAMDdWell-beingcGRID-HAMDd
Personal Meaninge0.70* 0.67* 0.43 0.34 0.51 0.44 0.45 0.43
Psychological Insighte0.49 0.36 0.35 0.04 0.27 0.34 0.39 0.25
Spiritual Significancee0.67* 0.56* 0.54 0.16 0.44 0.28 0.60* 0.40
Psychological Challengee0.12 0.32 0.09 0.18 0.13 0.31 0.06 0.13
Mystical Experience MEQ30 0.71* 0.38 0.43 0.17 0.50 0.05 0.50 0.19
HAMD: Hamilton Depression Rating Scale; MEQ30: Mystical Experience Questionnaire.
aData show Spearman’s correlations (rs); bold font indicates p < .05 and asterisks indicate p < .01.
bAssessments shown in this column were the highest rating or score from Sessions 1 and 2 for each participant.
cWell-being scores were expressed as percentage of maximum possible score.
dGRID-HAMD depression scores were expressed as percentage change from baseline for each participant.
eOnly 20 of 24 participants completed these measures due to an error in the survey programming.
Gukasyan et al. 157
was no reported use of psilocybin or other psychedelic drugs dur-
ing the follow-up period. This latter observation contrasts with a
previous study in which 5 of 19 participants reported use of psilo-
cybin outside of the research setting by the end of the 6-month
follow-up period (Carhart-Harris et al., 2018). Reasons for this
difference are unknown, but the observation indicates the impor-
tance of assessing use of psychedelics outside of a clinical trial.
Although the safety results presented herein are favorable, larger
phase 3 and 4 studies will be needed to more fully assess safety.
Strengths and limitations
Strengths of this study of psilocybin-facilitated treatment of
depression include a primary outcome measure that was assessed
by blinded clinician raters, the longest post-treatment follow-up
interval to date, and excellent participant retention. Although no
participants reported extraneous psilocybin use, 33% reported
using antidepressants during the follow-up period, which pre-
cludes determination of the effects of psilocybin alone in those
patients. Although the randomized waiting list-control design of
the study allowed for comparison of short-term treatment effects
to the control group, as described previously (Davis et al., 2021),
the design did not allow for a comparison group at long-term
follow-up. A recent study suggests that expectancy effects and
psychotherapy may account for some of the clinical benefit of
psychedelic-assisted therapy (Carhart-Harris et al., 2021). In
that study, which utilized a double-blind, double dummy design,
both the high-dose and very low-dose psilocybin groups showed
significant immediate decreases in depression, suggesting that
the preparation and drug administration day procedures may
reduce depressive symptoms even in the absence of high-dose
psilocybin. Studies of other types of interventions for patients
with MDD have demonstrated that placebo effects may last for
weeks or months beyond intervention, and a lack of a compara-
tor group makes it difficult to account for such effects in our
study (Khan et al., 2008). Other limitations include the small
sample size, the predominately Caucasian, non-Hispanic study
sample, and exclusion of those judged to be at elevated risk of
suicide.
Clinical implications
As novel antidepressants, classic psychedelics are commonly
compared to ketamine and its analogues. Despite distinct mecha-
nisms of pharmacologic action, both have rapid antidepressant
effects and both have garnered concern about their potential for
non-medical use (Schak et al., 2016; Shalit et al., 2019). Ketamine
has nontrivial abuse potential and there may be overlap between
mechanisms underlying its antidepressant effects and abuse
potential, which may be exacerbated by the requirement for
repeated administration to maintain therapeutic efficacy (Kokane
et al., 2020; Liu et al., 2016). Although evidence to date suggests
that psilocybin has relatively low abuse potential (Johnson et al.,
2018), there remains concern for its potential to cause harm or
encourage substance misuse in vulnerable populations (Reiff
et al., 2020; Schatzberg, 2020). The present study highlights a
key potential advantage of psilocybin treatment over ketamine in
that antidepressant effects after just two administrations of psilo-
cybin paired with psychological support appear to be sustained
through 12 months, which is well beyond the duration of effects
reported with ketamine (McIntyre et al., 2021; Salloum et al.,
2020). It will be important for future research to determine the
risks and benefits of additional psilocybin administration for
those who failed to respond or experienced early relapse.
Conclusions
The results of this long-term follow-up of participants who were
not blinded to the drug condition suggest that psilocybin-assisted
treatment for MDD produces large and stable antidepressant
effects throughout at least 12 months after treatment. These data
document larger effects of longer duration than previous studies
of psilocybin in depressed patients. Further studies are needed
with active treatment or placebo comparison controls in larger
and more diverse populations.
Acknowledgements
Darrick May, MD, Annie Umbricht, MD, and Eric Strain, MD, provided
medical oversight during the study sessions. Patrick H. Finan, PhD, Jessiy
Salwen, PhD, and Mary Bailes, LCPC, served as blinded clinician raters.
Laura Doyle, BA, John Clifton, BS, Kasey Cox, MS, and Rhiannon
Mayhugh, PhD, facilitated the intervention sessions and data collection.
We thank Darrick G. May, MD, for help in the design and conduct of the
study, and James B. Potash, MD, for his helpful comments on this article.
These individuals, from Johns Hopkins University, received no additional
compensation, outside of their usual salary, for their contributions.
Declaration of conflicting interests
The author(s) declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this article:
AKD is a board member of Source Research Foundation. MWJ has
received grant support from the Heffter Research Institute unrelated to
this study and he is an advisor to the following companies: AJNA Labs
LLC, AWAKN Life Sciences Inc., Beckley Psytech Ltd., Entheon
Biomedical Corp., Field Trip Psychedelics Inc., Mind Medicine Inc.,
Otsuka Pharmaceutical Development & Commercialization Inc., and Silo
Pharma, Inc. RRG is a board member of the Heffter Research Institute
and has received grant support from the Heffter Research Institute unre-
lated to this study. RRG is site principal investigator, and MWJ and NG
are co-investigators for a multi-site trial of psilocybin-assisted therapy for
major depressive disorder sponsored by Usona Institute.
Funding
The author(s) disclosed receipt of the following financial support for the
research, authorship, and/or publication of this article: This study was
supported in part by a crowd-sourced funding campaign organized by
Tim Ferriss and by grants from the Riverstyx Foundation and Dave
Morin. Effort for AKD and NG was provided by NIH grant T32DA07209
from NIDA. Effort for authors was also provided by The Center for
Psychedelic and Consciousness Research which is funded by the Steven
and Alexandra Cohen Foundation, Tim Ferriss, Matt Mullenweg, Craig
Nerenberg, and Blake Mycoskie. The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the
manuscript.
ORCID iDs
Natalie Gukasyan https://orcid.org/0000-0003-3567-1421
Alan K Davis https://orcid.org/0000-0003-4770-8893
Roland R Griffiths https://orcid.org/0000-0001-5185-7854
158 Journal of Psychopharmacology 36(2)
Supplemental material
Supplemental material for this article is available online.
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