Research

JAMA | Original Investigation

Single-Dose Psilocybin Treatment for Major Depressive Disorder
A Randomized Clinical Trial
Charles L. Raison, MD; Gerard Sanacora, MD, PhD; Joshua Woolley, MD, PhD; Keith Heinzerling, MD; Boadie W. Dunlop, MD, MS;
Randall T. Brown, MD, PhD; Rishi Kakar, MD; Michael Hassman, DO; Rupal P. Trivedi, MD; Reid Robison, MD; Natalie Gukasyan, MD;
Sandeep M. Nayak, MD; Xiaojue Hu, MD; Kelley C. O’Donnell, MD, PhD; Benjamin Kelmendi, MD; Jordan Sloshower, MD, MSc;
Andrew D. Penn, RN, MS, NP; Ellen Bradley, MD; Daniel F. Kelly, MD; Tanja Mletzko, MA; Christopher R. Nicholas, PhD; Paul R. Hutson, PharmD;
Gary Tarpley, PhD; Malynn Utzinger, MD; Kelsey Lenoch, BS; Kasia Warchol, BS; Theraysa Gapasin, MS, aMFT; Mike C. Davis, MD, PhD;
Courtney Nelson-Douthit, BS; Steffanie Wilson, PhD; Carrie Brown, MA; William Linton, BS; Stephen Ross, MD; Roland R. Griffiths, PhD
Visual Abstract
IMPORTANCE Psilocybin shows promise as a treatment for major depressive disorder (MDD).

Editorial page 813

OBJECTIVE To evaluate the magnitude, timing, and durability of antidepressant effects andMultimedia

safety of a single dose of psilocybin in patients with MDD.
DESIGN, SETTING, AND PARTICIPANTS In this phase 2 trial conducted between December 2019

and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio toreceive a single dose of psilocybin vs niacin placebo administered with psychological support.
Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition diagnosis of MDD of at least 60 days’ duration and moderate or greater
symptom severity. Exclusion criteria included history of psychosis or mania, active substanceuse disorder, and active suicidal ideation with intent. Participants taking psychotropic agents
who otherwise met inclusion/exclusion criteria were eligible following medication taper.
Primary and secondary outcomes and adverse events (AEs) were assessed at baseline(conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing.

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INTERVENTIONS Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of
niacin in identical-appearing capsules, each administered with psychological support.
MAIN OUTCOMES AND MEASURES The primary outcome was change in central rater–assessed
Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scoresindicate more severe depression) from baseline to day 43. The key secondary outcome
measure was change in MADRS score from baseline to day 8. Other secondary outcomes
were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-definedsustained response and remission. Participants, study site personnel, study sponsor, outcome
assessors (raters), and statisticians were blinded to treatment assignment.
RESULTS A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) wererandomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was
associated with significantly reduced MADRS scores compared with niacin from baseline today 43 (mean difference,−12.3 [95% CI, −17.5 to −7.2]; P <.001) and from baseline to day 8(mean difference, −12.0 [95% CI, −16.6 to −7.4]; P < .001). Psilocybin treatment was also
associated with significantly reduced Sheehan Disability Scale scores compared with niacin(mean difference, −2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. Moreparticipants receiving psilocybin had sustained response (but not remission) than thosereceiving niacin. There were no serious treatment-emergent AEs; however, psilocybin
treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs.
CONCLUSIONS AND RELEVANCE Psilocybin treatment was associated with a clinicallysignificant sustained reduction in depressive symptoms and functional disability, without
serious adverse events. These findings add to increasing evidence that psilocybin—when
administered with psychological support—may hold promise as a novel intervention for MDD.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03866174

JAMA. 2023;330(9):843-853. doi:10.1001/jama.2023.14530
Published online August 31, 2023.

Author Affiliations: Author
affiliations are listed at the end of thisarticle.
Corresponding Author: Charles L.
Raison, MD, Usona Institute,
2800 Woods Hollow Rd, Fitchburg,
WI 53711 (charles.raison@usonainstitute.org).

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Research Original Investigation

Single-Dose Psilocybin Treatment for Major Depressive DisorderInterest in the therapeutic potential of the psychedelic psilocybin has skyrocketed in recent years, spurred in partby increasing awareness of the limitations of currently
approved pharmacological treatments for major depressive
disorder (MDD)1-5 and in part by recent studies suggestingthat psilocybin engenders a rapid antidepressant responsethat far outlasts the presence of the drug in the body.6-15
However, recent critiques highlight notable limitations inmany of these studies,16-19 including small sample sizes,
assessments by raters likely to be functionally unblinded, an
open or waitlist comparator design, and an inadequate
assessment of adverse events (AEs). Larger recent studies
have addressed these issues to various degrees, but reportprimary end points of short duration,14,15 leaving open thequestion of the long-term clinical utility of psilocybin for anoften chronic condition such as MDD.
The current study seeks to address these issues using a randomized, multiblinded design that compared a single dose ofpsilocybin with an active placebo comparator (niacin), with outcome assessments conducted by blinded centralized raters to
examine the timing of onset of action, durability of benefit, andsafety profile of psilocybin over a 6-week period.

Methods
Study Design Overview and OversightThis randomized, 2-group, phase 2 clinical trial was designed
to evaluate the efficacy of psilocybin vs niacin (active placebo) administered with psychological support in patients with
MDD. The trial was conducted at 11 US sites from December
2019 to June 2022 (list of sites provided in eTable 1 in Supplement 3). The study was conducted in accordance with theInternational Conference on Harmonization Good Clinical
Practice Guideline. Participants provided written informed consent before engaging in study-specific procedures. The protocol was approved by a central institutional review board(Western Institutional Review Board Copernicus Group)
and/or site institutional review boards. The trial protocol isavailable in Supplement 1 and the statistical analysis planis available in Supplement 2.

Participants
Recruitment occurred through a study-specific website, clinical programs at participating institutions, advertisements,
and national clinician-focused and patient-advocate listservs. Eligible participants were medically healthy adults
aged 21 to 65 years who met Diagnostic and Statistical Manualof Mental Disorders, Fifth Edition (DSM-5) criteria for MDD
with a current depressive episode of at least 60 days assessedby the Structured Clinical Interview for DSM-5 Disorders Clinical Version.20 Participants were required to have a central
rater–assessed Montgomery-Asberg Depression Rating Scale(MADRS) total score greater than or equal to 28 at screening,with less than or equal to 30% improvement in MADRS score
during a 7- to 35-day period to allow for a psychiatric medication taper if indicated (including not receiving antidepressants for ≥2 weeks or 5 half-lives, whichever was longer), to844

Key Points
Question What are the efficacy and safety of psilocybin inpatients with major depressive disorder?
Findings In a randomized, placebo-controlled, 6-week trial in 104
adults, a 25-mg dose of psilocybin administered with psychologicalsupport was associated with a rapid and sustained antidepressanteffect, measured as change in depressive symptom scores,
compared with active placebo. No serious treatment-emergent
adverse events occurred.
Meaning A 25-mg dose of psilocybin was well tolerated and may
hold promise as a treatment for major depressive disorder whencombined with psychological support.

ensure randomized participants met criteria for moderate tosevere MDD at the baseline assessment. Additional exclusion
criteria included personal or first-degree family history ofpsychosis or mania, moderate/severe alcohol or drug use disorder, being unable/unwilling to discontinue prohibited psychotropic medications, use of a psychedelic drug in the past 5
years or more than 10 lifetime uses, active suicidal ideation
with intent or plan, or suicidal behavior in the past 12
months. There were no exclusions for number of priordepressive episodes, length of current episode, maximum
symptom severity, or number of previous pharmacological or
behavioral treatments, with the exception of history of deepbrain or vagus nerve stimulation, which were exclusionary as
a proxy for severe treatment resistance. See the study protocol in Supplement 1 for a full list of inclusion and exclusion
criteria. Participants were queried regarding demographic
information by site personnel; race and ethnicity were collected in accordance with the US Food and Drug Administration guidance document Collection of Race and Ethnicity Data
in Clinical Trials.21

Study Procedures
Following the 7- to 35-day screening period to allow for a medication taper if needed, participants who continued to meet eligibility criteria completed baseline assessments followed by
6 to 8 hours of preparation. On the day of dosing (ie, receiptof the intervention), eligible participants were randomized ina 1:1 ratio using permuted blocks with random block sizes of
2, 4, and 6, with randomization stratified by site, to receive asingle 25-mg oral dose of psilocybin or 100-mg dose of niacin. Randomization was administered centrally by the study’s
clinical research organization via the Advantage eClinical datasystem. Statistical programs generated for randomization by
unblinded statistical staff at the clinical research organization included a master medication list program that generated a random blinded bottle number code and associated treatment for each bottle and a treatment assignment program thatassigned participants to a treatment. Bottles were labeled by
the drug distributor with a blinded bottle number prior to distribution to sites. On the day of dosing, after participants wereconfirmed to be eligible, the data system identified the participant’s treatment assignment based on the treatment table.

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Single-Dose Psilocybin Treatment for Major Depressive Disorder

The data system then identified a bottle shown to be available on site containing the appropriate treatment. Only theblinded bottle number was then displayed to site staff for treatment administration.
Niacin was used as an active placebo that produces an acutephysiological response (flushing) thought to aid in blinding.8,22
Study drug administration occurred on the same day as randomization (day 1), no later than 7 days following the baseline assessment. Postdosing assessments were conducted ondays 2, 8, 15, 29, and 43. Participants, study sponsor, and studysite personnel were blinded to treatment group until unblinding following data lock.
Study drugs were administered within a “set and setting”
protocol23 that was identical for participants randomized toreceive either psilocybin or niacin placebo and that included(1) 6 to 8 hours of preparatory sessions with 2 facilitators between the baseline assessment and the day of dosing, (2) a 7to 10-hour dosing session conducted in a comfortable room under the supervision of the same facilitators, and (3) 4 hours of
postdose integration sessions during which participants wereinvited to discuss their dosing experience with the facilitators. All set and setting sessions (eg, preparatory, dosing,integration) were protocolized and communicated via
instructions in a manual for clinical facilitators. During thedosing session, participants were encouraged to wear eyeshades and listen to a curated playlist on headphones. Leadfacilitators were doctoral-level psychologists or physicianswith MDD treatment experience and co-facilitators held aminimum of a bachelor’s degree in a mental health–related
field. All facilitators completed study-specific training prior
to engaging with participants.

Efficacy Assessments
The primary study outcome was between-group difference inmean change of central rater–assessed MADRS score from baseline to day 43. MADRS is a 10-item scale with a scoring range of
0 to 60, with higher scores indicating more severe depression.24
A minimal clinically important difference (MCID) in change in
MADRS score was not prespecified, although depression trial
literature supports a placebo-adjusted change in score as low
as 2 and as high as 9 and an absolute change from pretreatment of 6 as clinically meaningful and a change of 12 as clinically substantial.25,26 To reduce the risk of functional unblinding of raters, all MADRS assessments, including those at
screening and baseline, were conducted via telephone27,28 bytrained, remote central raters who maintained interrater reliability and were blinded to participant treatment assignment,
study visit, and the specifics of the protocol and study design.
The key secondary outcome was change in total MADRS
score from baseline to day 8. Additional secondary outcomes
included change in Sheehan Disability Scale (SDS) score frombaseline to day 43 and proportion of participants with a sustained depressive symptom response, defined a priori as at least
a 50% reduction from baseline MADRS score at days 8, 15, 29,
and 43, and sustained depressive symptom remission, defined a priori as MADRS score less than or equal to 10 at days
8, 15, 29, and 43. The SDS comprises self-rated items that measure the extent to which psychiatric symptoms have imjama.com

Original Investigation Researchpaired functioning in patients’ work/school, social, and family/
home responsibilities. Scores for each section range from 0 to
10,29 and the total score was calculated as the mean score of
all 3 sections. No MCID is defined for active vs control interventions. If the work/school section was not applicable, themean score was calculated as the mean of social life and family/
home responsibilities. Administration of the SDS at baseline
and postdosing assessments was overseen by trained andblinded site raters.
Exploratory outcomes included scores on the ClinicalGlobal Impressions Scale, Hamilton Anxiety Rating Scale,Quality of Life Enjoyment and Satisfaction Questionnaire,
Symptoms of Major Depressive Disorder Scale, and the Oxford
Depression Questionnaire (to assess emotional blunting). These
exploratory assessments were completed by self-report overseen by blinded and trained site raters at baseline and all postdosing assessments.

Safety Assessments
AEs were collected from enrollment through the end of study
and were graded for severity, seriousness, and relationship to
study product by site principal investigators. Treatmentemergent AEs (TEAEs) were considered any AE that occurred
after drug administration. Among TEAEs, an AE was classified as “related” if there was a reasonable possibility that the
study drug caused the event as judged by site principal investigators. Solicited adverse events included (1) active suicidal
ideation assessed with the Columbia Suicide Severity Rating
Scale (C-SSRS) administered by site personnel or MADRS
item 10 and verified by clinical assessment, (2) elevatedblood pressure or heart rate requiring medication, (3) drug
overdose with suicidal intent, (4) headache, (5) nausea, and(6) visual perceptual effects. Serious AEs were classified as
those resulting in any of a list of negative health outcomes(eg, death, inpatient hospitalization, significant or persistentincapacity, congenital birth defect/abnormality) following thestandard definition.30

Statistical Analysis
The US Food and Drug Administration initially recommended day 8 as the primary end point, so the study was powered on the assumption of a mean change in MADRS score frombaseline to day 8 of 18 points and from baseline to day 43 of 17
points in the psilocybin group. In the niacin group, a meanchange in MADRS score of 10 points was assumed for all postdosing assessments. An SD of 10 points was assumed for bothgroups. With the expectation of a 5% dropout rate by day 8 andan additional 7.5% dropout rate by day 43 and 2-sided α of .05,
a sample size of 100 participants resulted in 92% power for the
primary day 43 end point and 98% power for the key secondary day 8 end point. The US Food and Drug Administration subsequently recommended changing the primary end point to
day 43; in response, the sample size was increased from 80 to
100 to account for additional dropout expected with the longerterm primary outcome follow-up.
The primary efficacy analysis was a de facto estimand conducted on the intent-to-treat (ITT) population that included all
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Research Original Investigation

Single-Dose Psilocybin Treatment for Major Depressive DisorderFigure 1. Participant Flow in a Study of Single-Dose Psilocybin Treatment for Major Depressive Disorder
1529 Assessed for eligibilitya
1425 Excluded
1182 Excluded at telephone screening
240 Excluded at screening after providing
informed consent
195 Did not meet eligibility criteria
32 Voluntary withdrawal by participant
7 Lost to follow-up
3 Voluntary withdrawal by investigator
3 Other
3 Excluded at early preparation phase
2 Voluntary withdrawal by investigator
1 Voluntary withdrawal by participant

104 Randomized

51 Randomized to receive psilocybinb
50 Received intervention as randomized
1 Did not receive intervention as
randomized

53 Randomized to receive niacin andreceived intervention as randomized

51 Completed day 8 assessment visit

48 Completed day 8 assessment visit
1 Lost to follow-up before day 8
2 Missed day 8 visit
2 Incomplete day 8 visit

50 Completed day 43 assessment visit
1 Lost to follow-up before day 43

42 Completed day 43 assessment visit
9 Lost to follow-up before day 43
2 Incomplete day 43 visit
51 Included in the intent-to-treat analysis

53 Included in the intent-to-treat analysis

45 Included in the per-protocol analysis
6 Excluded from the per-protocol analysisc

36 Included in the per-protocol analysis
17 Excluded from the per-protocol analysisb

50 Received psilocybin and were includedin the safety analysis

54 Received niacin and were includedin the safety analysis

treatment group. Analyses of other efficacy outcomes used asimilar approach. The per-protocol (PP) population included
a subset of the ITT population that received study drug, completed day 8 and day 43 MADRS assessments, and had no major protocol deviations affecting the primary or secondary outcomes. The safety population included all randomized
participants who received a study drug. Safety data were analyzed according to the intervention received.
Analysis of continuous outcomes used a mixed-effects
model for repeated measures with an unstructured covariance matrix, adjusted for the baseline score of the relevant
outcome assessment, site, sex, and treatment-resistantdepression (TRD) status as fixed effects with no imputationof missing data. Time was included as a categorical variable,
and a treatment × time effect was included to evaluate
between-group differences in mean scores at each point.
Sensitivity analyses using multiple imputation methods
were run for the primary and key secondary outcomes. Sustained depressive symptom response and remission wereassessed using logistic regression models adjusted for sex
and TRD, with site excluded due to low participant counts atsome sites resulting in model convergence issues. In addition to odds ratios (ORs) with 95% CIs, absolute differenceswith 95% CIs were also calculated.
846

Includes all potential participantsfrom the point of telephone
screening.

b

One participant randomized toreceive psilocybin received niacin
and was included in the niacin groupfor the safety population.

cReasons for exclusion included
missing day 8 or day 43 central rater
Montgomery-Asberg Depression
Rating Scale assessments or major
protocol deviations.

See eFigure 1 in Supplement 3 foradditional details.

A sequential significance testing procedure was used to control the overall α level at .05 for primary and secondary end
points. Two-sided tests were used in the following prespecified order with testing halted the first time the null hypothesis
is not rejected (ie, first P value ≥.05): change in MADRS score frombaseline to day 43, change in MADRS score from baseline to day
8, change in SDS score from baseline to day 43, sustained depressive symptom response, and sustained depressive symptom remission. No procedure for α-level control was applied for
exploratory end points, therefore P values reported for these outcomes in eTables 4-8 in Supplement 3 should be considerednominal (ie, not adjusted for multiple comparisons).
Incidence of AEs was summarized using counts, percentages, and Clopper-Pearson 95% CIs for the following protocoldefined study periods: enrollment through day 43, dosing(day 1) through day 9, and day 10 through day 43. Relative incidence for TEAEs was calculated by dividing the percentageof participants experiencing an event in the psilocybin treatment group by the percentage in the niacin group and were presented with Wald 95% CIs. Percent difference in AEs between
groups with 95% CIs were also calculated.
All statistical analyses were performed using SAS, version 9.4 (SAS Institute). See the statistical analysis plan in
Supplement 2 for additional details.

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Single-Dose Psilocybin Treatment for Major Depressive Disorder

Original Investigation Research

Table 1. Baseline Participant Characteristics

Results

Psilocybin(n = 51)

Niacin(n = 53)Men

27 (53)25 (47)Women

24 (47)28 (53)Age, mean (SD), y

40.4 (10.9)

41.8 (11.7)

Ethnicity, No. (%)

n = 50Characteristic

ParticipantsSex, No. (%)

Among 1529 potential participants who completed prescreening, 347 signed informed consent, 240 were excluded at screening, 3 were excluded prior to randomization, and 104 were randomized, received the study drug, and comprised the ITT
population (51 in the psilocybin group and 53 in the niacingroup) (Figure 1). Median (IQR) time between enrollment andrandomization on the morning of dosing was comparable forthe 2 groups (28 [21-36] days for psilocybin and 28 [20-35] days
for niacin). Enrollment by study site is detailed in eTable 1 in
Supplement 3.
One participant randomized to receive psilocybin received the incorrect treatment, resulting in 50 participants receiving psilocybin and 54 receiving niacin. Baseline characteristics of the ITT population are provided in Table 1. Mean
(SD) participant age was 40.4 (10.9) years in the psilocybingroup and 41.8 (11.7) years in the niacin group; half were men
and the majority (89%) were White. Ten participants (19.6%)
in the psilocybin group and 13 (24.5%) in the niacin group reported previous lifetime use of a psychedelic. Median (IQR)
length of the current depressive episode was 53 (25-135) weeks
for psilocybin vs 81 (26-145) weeks for niacin; 4 participants(8%) in the psilocybin group vs 10 (19%) in the niacin groupwere experiencing a first episode (the remainder were experiencing a recurrent disorder). Seven participants in the psilocybin group vs 6 in the niacin group (12.5% of the ITT sample)
met criteria for TRD. The median (IQR) number of prior pharmacologic treatments in the current episode was 1 (0-2) for bothgroups. Fifteen participants (29%) in the psilocybin group and
8 (15%) in the niacin group completed a medication taper prior
to dosing. By 6 weeks, 1 participant in the psilocybin group and
9 in the niacin group had withdrawn or been lost to followup; 3 participants in the psilocybin group and 3 in the niacingroup started antidepressant medication prior to study completion at day 43, of whom 2 participants in the psilocybin groupand 1 in the niacin group also commenced psychotherapy prior
to study completion. No participants withdrew due to an AE.

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4 (8)Not Hispanic or Latino

46 (92)

Race, No. (%)

12 (23)41 (77)n = 51

Black or African American

3 (6)

0

White

44 (86)49 (96)

Multiracial

4 (8)

2 (4)

Annual income, No. (%), $n = 45n = 44≤24 999

8 (18)

6 (14)

25 000-49 999

3 (7)8 (18)

50 000-74 999

5 (11)3 (7)75 000-99 999

6 (13)

8 (18)≥100 000

23 (51)19 (43)Treatment-resistant depression, No. (%)a7 (14)

6 (11)

Underwent a medication taper prior to
randomization, No./total No. (%)b15 (29)8 (15)

Baseline MADRS score, mean (SD)c35.5 (5.7)

35.0 (4.5)

Baseline SDS score, mean (SD)c

6.69 (1.99)

7.14 (1.61)

Length of current depressive episode,median (IQR), wkd

53 (25-135)

81 (26-145)

0

4 (8)

10 (19)1

10 (20)5 (9)28 (16)

15 (28)3

9 (18)3 (6)4

6 (12)

9 (17)

54 (8)

6 (11)>5

10 (20)5 (9)1 (0-2)

1 (0-2)

Prior depressive episodes, No. (%)dPrior pharmacological treatments for
current depressive episode, median (IQR)ea

Based on Massachusetts General Hospital Antidepressant Treatment History
Questionnaire as meeting the following criteria: self-report of receiving
treatment with ⱖ2 antidepressant medications (or 1 antidepressant with ⱖ1
augmenting agent) for this current depressive episode for ⱖ8 weeks, dose of
medication is equal to or greater than minimally adequate dose, and responseto these medications is <50% improvement.

bParticipants underwent medication taper if they met all other study
inclusion/exclusion criteria, except for use of a prohibited psychotropic
medication, and were willing to undergo tapering.

c

Score from the Montgomery-Asberg Depression Rating Scale (MADRS)
assessment completed at the baseline visit. For participants with a repeatedbaseline visit, the score from the repeated visit was used for analysis. The
median value is based on all participants in the intent-to-treat population. The
total sample median score of 35.5 is consistent with a severe major depressive
episode. Maximal change score on the MADRS is 60 points; maximal change
score on the Sheehan Disability Scale (SDS) is 10 points, with lower scoresindicating clinical improvement. Minimal clinically important difference (MCID)
from baseline is a 6-point improvement for the MADRS and a 1.33-point
improvement on the SDS as scored in this study.

dLength of current depressive episode and number of unique lifetime
depressive episodes were determined via the clinician-administered
Structured Interview for DSM-5 Disorders-Clinical Trials Version.

e

Pharmacological treatments taken for ⱖ8 weeks reported on the Massachusetts
General Hospital Antidepressant Treatment History Questionnaire.

Efficacy
The psilocybin-treated group showed greater change vs niacin in central rater–assessed MADRS score from baseline to day
43 (mean difference, −12.3 [95% CI, −17.5 to −7.2]; P <.001)(Table 2 and Figure 2) and from baseline to day 8 (key secondary end point) (mean difference, −12.0 [95% CI, −16.6 to −7.4];
P < .001). Similar results were observed for day 15 and day 29(Figure 2) and in multiple imputation sensitivity analyses accounting for missing data (1 psilocybin and 9 niacin participant measures missing and imputed at day 43 and 0 psilocybin and 3 niacin participant measures missing and imputed atday 8; see eTable 2 and eAppendix in Supplement 3 for full details). More participants receiving psilocybin than niacin hadsustained depressive symptom response (20/48 [42%] vs 5/44
[11%]; adjusted absolute difference, 30.3 [95% CI, 13.5-47.1];
P = .002; OR, 5.6 [95% CI, 1.9-16.7]; P = .002) (Table 2). Sustained depressive symptom remission rate appeared greater

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Single-Dose Psilocybin Treatment for Major Depressive Disorder

Table 2. Overall Summary of Primary, Secondary, and Select Exploratory Efficacy Outcomes
Mean change from baseline (95% CI)a

Mean difference (95% CI)a

Psilocybin(n = 51)

Niacin(n = 53)

Psilocybin vs niacin

P value

Day 2−2.7 (−4.1 to −1.3)−2.7 (−4.1 to −1.3)−0.1 (−2.1 to 1.9)

.95

Day 8 (key secondary outcome)−17.8 (−21.1 to −14.6)−5.8 (−9.1 to −2.6)−12.0 (−16.6 to −7.4)<.001cDay 15−18.0 (−21.3 to −14.7)−6.9 (−10.3 to −3.5)−11.1 (−15.8 to −6.3)<.001

Day 29−19.2 (−22.6 to −15.8)−5.5 (−9.0 to −2.0)−13.7 (−18.6 to −8.8)<.001

Day 43 (primary outcome)−19.1 (−22.7 to −15.5)−6.8 (−10.5 to −3.1)−12.3 (−17.5 to −7.2)<.001cDay 8−3.85 (−4.60 to −3.10)−1.49 (−2.27 to −0.72)−2.36 (−3.46 to −1.26)<.001

Day 15−3.97 (−4.73 to −3.21)−1.76 (−2.56 to −0.97)−2.21 (−3.33 to −1.09)<.001

Day 29−4.26 (−5.08 to −3.45)−1.78 (−2.64 to −0.93)−2.48 (−3.68 to −1.28)<.001

Day 43 (secondary outcome)−4.07 (−4.88 to −3.26)−1.76 (−2.62 to −0.91)−2.31 (−3.50 to −1.11)<.001cOther secondary outcomes

No./total No. (%)dNo./total No. (%)dDifference (95% CI)e

Sustained depressive symptom
responsef

20/48 (41.7)

5/44 (11.4)

30.3 (13.5 to 47.1)g.002c,dSustained depressive symptom
remissionh

12/48 (25.0)

4/44 (9.1)

15.9 (1.0 to 30.8)i.05d

Outcome
MADRS total scoreb

SDS mean scoreb

depression, predicting odds of response or remissions for psilocybin comparedwith niacin. Wald 95% CIs are provided for difference in difference in response
and remission rates.

Abbreviations: MADRS, Montgomery-Asberg Depression Rating Scale;
SDS, Sheehan Disability Scale.
aMixed model for repeated measures with an unstructured covariancestructure adjusted for baseline score, site, sex, and treatment-resistantdepression. Negative values indicate an improvement in symptom severity.
For additional information, see footnote c in Table 1.

Sustained depressive symptom response is defined as ⱖ50% reduction frombaseline central rater MADRS total score at each of the postdose assessments
on days 8, 15, 29, and 43.

b

All outcomes are exploratory unless otherwise noted.

g

Odds ratio, 5.60 (95% CI, 1.87-16.74).

cStatistically significant based on sequential testing procedure.

hdRestricted to participants in the intent-to-treat population with MADRS
assessments at baseline, and days 8, 15, 29, and 43 after baseline.

Sustained depressive symptom remission is defined as a central rater MADRS
total score ⱕ10 at each of the postdose assessments on days 8, 15, 29, and 43.

i

Odds ratio, 3.37 (95% CI, 0.99-11.47).

e

P value from logistic regression model adjusted for sex and treatment-resistantwith psilocybin, but the difference was not statistically significant (12/48 [25%] for psilocybin vs 4/44 [9.1%] for niacin;
adjusted absolute difference, 15.9 [95% CI, 1.0-30.8]; P = .05;
OR, 3.4 [95% CI, 1.0-11.5]) (Table 2). Rates of response andremission at each postdosing assessment are shown ineTable 3 in Supplement 3. Mean change difference in SDSassessed functional disability score from baseline to day 43
was greater in the psilocybin vs niacin group (−2.31 [95% CI,
3.50-1.11]; P < .001) (Table 2). Psilocybin treatment was associated with improvements in various exploratory end points,
including reductions in global disease severity, self-reported
depressive and anxiety symptoms, and improvement in quality of life, while having no effect on emotional blunting(eTables 4-8 in Supplement 3).
Results in the PP population of 81 participants (45 in the
psilocybin group and 36 in the niacin group, excluding 5 [10%]in the psilocybin and 8 [15%] in the niacin group, due to major protocol deviations likely to impact primary or secondary
outcomes; see eAppendix and eFigure 1 in Supplement 3 fordetails) were similar in direction, magnitude, and significance to results in the ITT population, with the exception thatthe difference in sustained remission between psilocybin- andniacin-treated participants became statistically significant(12/44 [27%] with psilocybin vs 3/36 [8%] with niacin; adjusted absolute difference, 18.9% [95% CI, 3.0%-34.9%]; OR,
4.0 [95% CI, 1.0-15.7]; P = .04) (eTable 9 in Supplement 3).
848

f

SafetyIn the safety population (Figure 1), 44 of 50 participants (88%)
receiving psilocybin and 33 of 54 (61%) receiving niacin reported at least 1 AE through day 43. Three serious AEs occurred between enrollment and randomization (nephrolithiasis; incisional hernia, obstructive; and appendicitis; Table 3).
From randomization on the day of dosing (day 1) through day
9, a total of 41 of 50 participants (82%) in the psilocybin groupexperienced at least 1 drug-related TEAE vs 24 of 54 (44%) in
the niacin group (difference, 38% [95% CI, 20.6%-41.3%]; relative incidence [RI], 1.8 [95% CI, 1.3-1.8]). Severe related AEs
through day 9 were reported by 4 of 50 participants (8%) receiving psilocybin (migraine in 1 participant, headache in 1 participant, illusion in 1 participant [all solicited], and panic attack
and paranoia in 1 participant) vs 0 in the niacin group. The ratesof mild and moderate drug-related TEAEs in the same period
were higher for psilocybin vs niacin (mild: difference, 35%[95% CI, 17.9%-52.9%]; RI, 1.8 [95% CI, 1.1-1.8]); moderate: difference, 18% [95% CI, 5.8%-30.8%]; RI, 2.3 [95% CI, 1.0-5.7]).
From day 10 through day 43, related TEAEs were reported by
2 of 50 participants (4%) in the psilocybin group vs 1 of 53 (2%)
receiving niacin (difference, 2% [95% CI, −4.4% to 8.7%];
RI, 2.1 [95% CI, 0.2-22.7]) (Table 3).
Solicited AEs were reported by 38 of 50 participants (76%)
receiving psilocybin vs 16 of 54 (30%) receiving niacin (difference, 46% [95% CI, 29.4%-63.4%]; RI, 2.6 [95% CI, 1.7-4.0]).

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Single-Dose Psilocybin Treatment for Major Depressive Disorder

Original Investigation Research

Figure 2. Change in Montgomery-Asberg Depression Rating Scale (MADRS) Score by Treatment GroupA MADRS score

Change from baseline in central
rater MADRS score

0–5
Niacin–10–15
Psilocybin–20–25
Baseline 2

8

15

29

43

49
44

50
44

Follow-up, dNo. of participants at risk
Psilocybin 51 51
53 52
Niacin

B

51
50

50
45

Depressive symptom reduction
50

50

Change in total MADRS scorefrom baseline to day 43

Central rater MADRS total score

40
40

30

20

10

30
20
10
0
–10
–20
–30
–40
–50

0
Baseline Day
43

50

11

Patient

44

Baseline Day
43

Psilocybin

NiacinGroup

Patient

Psilocybin

NiacinGroup

The majority of solicited events were mild (73 of 91 total events[80%] in the psilocybin group and 22 of 23 total events [96%]in the niacin group). Severe solicited events were reported by
3 participants receiving psilocybin (2 headaches and 1 visual
perceptual effects) and 1 headache was reported in a participant receiving niacin. The most common solicited AE washeadache in 33 of 50 participants (66%) receiving psilocybinand 13 of 54 participants (24%) receiving niacin (difference,
42% [95% CI, 27.3%-57.6%]; RI, 2.7 [95% CI, 1.6-4.6]), followed by nausea in 24 of 50 participants (48%) receiving psilocybin and 3 of 54 participants (6%) receiving niacin (difference, 42% [95% CI, 24.5%-59.3%]; RI, 8.6 [95% CI, 2.8-26.9]).
Visual perceptual effects (assessed following resolution of acutedrug effects) were reported by 22/50 (44%) psilocybin participants on the day of dosing and by 3/50 (6%) after the dosing
day, all resolved by study conclusion (See Table 3 for details).
Based on C-SSRS or MADRS Item 10 scores and confirmed byclinical assessment, no suicidal or self-injurious behavior occurred during the trial and all instances of suicidal ideation were
jama.com

A, Results from mixed model for
repeated measures adjusted
for baseline score, site, sex, andtreatment-resistant depression. Error
bars represent 95% CIs; point labels
are P values for treatment difference
for primary (day 43) and key (day 8)
secondary end points in theintent-to-treat population. B, Rawvalue participant change values withmeans indicated with diamonds andmedians indicated by the bar in theboxes. The boxes show the IQR andthe whiskers extend from the boxes
to indicate the most extreme pointthat is less than or equal to 1.5 times
the IQR. See eFigure 2 in
Supplement 3 for additional details.

considered passive. One participant receiving psilocybin and
5 in the niacin group had an increase in C-SSRS suicidal ideation score from baseline to end of trial (eTables 10 and 11 in
Supplement). No clinically significant changes in vital signs or
clinical laboratory tests were observed.

Discussion
In this phase 2 study, treatment with a 25-mg dose of psilocybin administered with psychological support was associatedwith a statistically and clinically significant reduction in depressive symptoms compared with a niacin placebo, assessed as change in total MADRS score and as rates of sustained response. The 15.9% difference in sustained remission
rates between the groups was not significantly different. Improvements in depression were apparent within 8 days of psilocybin dosing, consistent with a rapid onset of action, andwere maintained across the 6-week follow-up period, without(Reprinted) JAMA September 5, 2023 Volume 330, Number 9© 2023 American Medical Association. All rights reserved.

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849

Research Original Investigation

Single-Dose Psilocybin Treatment for Major Depressive Disorder

Table 3. Summary of Safety Events in the Safety PopulationaAdverse event (AE)

Enrollment through day 43, No. (%)

Randomization through day 9

Day 10 through day 43

Psilocybin(n = 50)

Psilocybin(n = 50),
No. (%)

Psilocybin(n = 50),
No. (%)

Niacin(n = 54)

Niacin(n = 54),
No. (%)

Difference(95% CI), %b

Niacin(n = 53),
No. (%)

Difference(95% CI), %b

At least 1 AE

44 (88)33 (61)42 (84)32 (59)25 (8.2 to 41.3)

18 (36)13 (25)11 (−6.2 to 29.1)

At least 1 related AEc

41 (82)24 (44)41 (82)24 (44)38 (20.6 to 54.6)

2 (4)

1 (2)

2 (−4.4 to 8.7)

At least 1 serious AE

1 (2)

2 (4)

Mild

39 (78)23 (43)39 (78)23 (43)35 (17.9 to 52.9)

1 (2)Moderate

11 (22)2 (4)

11 (22)2 (4)18 (5.8 to 30.8)

1 (2)

NC

NC

1 (2)

NC

NC

NC

Drug-related AE severityc

SevereAt least 1 solicited AEd

4 (8)

4 (8)

0 (−5.2 to 5.5)

38 (76)16 (30)38 (76)16 (30)46 (29.4 to 63.4)

Headachee

33 (66)13 (24)33 (66)13 (24)42 (27.3 to 57.6)

NA

NA

NA

Nauseae24 (48)3 (6)24 (48)3 (6)42 (24.5 to 59.3)

NA

NA

NA

Visual perceptual
effects on dosing day

22 (44)3 (6)22 (44)3 (6)38 (23.4 to 53.5)

NA

NA

NA

Visual perceptual
effects after dosing day

3 (6)

3 (6)

At least 1 AE requiring
psychiatric attention

2 (4)

1 (2)

At least 1 psychiatricconcomitant medication
reportedf

8 (16)

7 (13)

NC

NC

3 (6)

NC

1 (2)

NC

2 (4)

1 (2)

2 (−4.4 to 8.7)4 (7)−1 (−11.0 to 8.2)

5 (10)4 (8)

2 (−8.5 to 13.4)

relationship to study drug or procedure were determined by the site principal
investigator.

Abbreviations: NA, not applicable (event not solicited during period); NC, notcalculable.
aParticipants are counted once for each category regardless of the numberof events.

d

Only solicited events with any occurrences during the study are summarized.
See eTable 2 in Supplement 3 for a full list of events solicited during the study.

b

Wald 95% CIs for difference in incidences between treatment groups(psilocybin – niacin).

e

Headache and nausea were only collected as solicited events during
randomization through postdose day 9.

c

An AE was classified as “related” if there was a reasonable possibility
that the study drug or procedure caused the event. Severity andfDefined as concomitant medications with WHODRUG ATC2 codes N05 –Psycholeptics or N06 – Psychoanaleptics.

attenuation of the effect, and with higher point prevalence ratesof MADRS-defined response and remission than has been observed in recent psilocybin studies of TRD.10,14 Although an
MCID was not specified a priori for this study, the 12.3-point
difference in change in score between the psilocybin and niacin groups is larger than the upper limit active placebo difference in the literature of 9 points and the 19.1-point reductionin MADRS score from baseline to day 43 in the psilocybin groupis larger than the 12-point difference shown to reflect substantial clinical improvement in patients with TRD.25 In contrast
to prior psilocybin trials for depression,8,14,15 there was not asignificant reduction in depressive symptoms or a psilocybin/placebo difference in depressive symptom status at the day 2
assessment (ie, 1 day after dosing) (Figure 2 and Table 2). This
may reflect the fact that to maintain central rater blinding, the7-day recall period used for all other MADRS assessments wasmaintained at day 2, with the result that the majority of recall
period for the day 2 assessment covered the predosing period
during which depressive symptoms remained elevated, basedon results from the Symptoms of Major Depressive Disorder
Scale (eTable 7 in Supplement 3).
Psilocybin also improved psychosocial functioning compared with niacin as shown by mean difference in SDS scorechange. Similar results were observed in the per-protocol population and in sensitivity analyses. Psilocybin treatment was associated with improvement in various exploratory end points,
including reduced overall disease severity, anxiety and self850

1 (2)reported depressive symptoms, and improved quality of life(eTables 4-7 in Supplement 3). Psilocybin treatment did not
evince the type of emotional blunting reported with standard
antidepressant medicines (eTable 8 in Supplement 3).31
Psilocybin was generally well-tolerated, with most AEs
being of mild or moderate severity and generally limited to theacute dosing period. The 8% rate of severe adverse events inparticipants receiving psilocybin was similar to the 10% ratereported in the study by Goodwin et al in participants with TRD
treated with a single 25-mg dose of psilocybin.14 However, incontradistinction to the study by Goodwin et al, no clinicallyconfirmed active suicidal ideation or suicidal behavior occurred in either randomized group. No serious TEAEs were reported in the current study; however, psilocybin treatment was
associated with a higher rate of overall AEs and a higher rateof severe AEs compared with niacin, with these severe AEs
being known effects of psilocybin.17 Moreover, psychedelics
may produce AEs not captured by standard rating scales or may
induce unrecognized new psychiatric conditions even as they
improve target syndromes.32

Limitations
Several limitations in this study warrant consideration. First,
the success of allocation blinding was not assessed, and it
is likely that the acute psychoactive effects of psilocybin
produced some degree of functional unblinding that may
have contributed to the observed effect in psilocybin-treated

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Single-Dose Psilocybin Treatment for Major Depressive Disorderparticipants and the increased dropout rate in niacin-treatedparticipants.33 To help address this issue, the current study
used off-site centralized raters to reduce the potential impactof unblinding on the assessment of outcomes. Nonetheless,recent data demonstrating high rates of functional unblinding in a randomized, placebo-controlled trial of psilocybin foralcohol use disorder highlight a possible role for measuring
blinding effectiveness in future studies of agents with acute
psychoactive effects.33
Second, the use of niacin as active placebo may haveincreased believability of the comparator condition andenhanced the placebo response, given that placebo response
rates in the current study were equivalent to those seen in
response to a low-dose psilocybin comparator in participants
with TRD and larger than the effect of an inactive placebo in a
recent study in participants with MDD.14,15 Nonetheless, placebo response rates in the current study are smaller than are
typically observed with daily placebo pills,34 which may haveinflated the placebo-adjusted effect size compared withstudies of standard antidepressants in patients with MDD. As
a complement to traditional placebo-controlled trials, a better understanding of the contribution that placebo effects
make to the antidepressant efficacy of psilocybin might begained via use of novel comparators (eg, ketamine) thatinduce acute effects to aid with blinding while failing to generally produce the type of sustained antidepressant response
observed with psilocybin.
Third, relevant to the important question of durability ofeffect with time-limited treatments, the 6-week (day 43) postdosing primary end point in the current study is longer than
primary end points in recent randomized, double-blind,placebo-controlled trials of single-dose psilocybin for TRD(3 weeks) or MDD (2 weeks),14,15 although one of these studies included a longer, 12-week, overall follow-up period during which the antidepressant effect of psilocybin waned in the
TRD study group.14 Whether the sustained antidepressant effect observed in the current study reflects the low rate of treatment resistance (13%) or some other factor is unknown. Similarly, the current study does not allow inferences to be drawn
regarding whether the antidepressant effect would have diminished over subsequent weeks or been maintained, although it is intriguing that a small open trial of two doses ofpsilocybin in MDD—as opposed to TRD—found evidence
for maintenance of effect in many participants out to a year

ARTICLE INFORMATION
Accepted for Publication: July 13, 2023.
Published Online: August 31, 2023.
doi:10.1001/jama.2023.14530
Author Affiliations: Usona Institute, Fitchburg,
Wisconsin (Raison, Tarpley, Utzinger, Lenoch,
Warchol, Gapasin, Davis, Linton); Departmentof Psychiatry, School of Medicine, Yale
University, New Haven, Connecticut (Sanacora,
Kelmendi, Sloshower); Department of
Psychiatry and Behavioral Sciences, Universityof California San Francisco (Woolley, Penn,
Bradley); San Francisco Veterans Affairs Medical
Center, San Francisco, California (Woolley, Bradley);jama.com

Original Investigation Research

post-dosing.12 Regardless, it will be essential to conduct rigorous, large-scale, longer-term, follow-up studies to better understand how to best use psilocybin in often chronic conditions such as MDD or TRD.
Fourth, that psilocybin and niacin were administered
within an identical, fully protocolized program of psychological support is a strength of the current study. All study facilitators received extensive training; however, fidelity to the psychological support protocol by study facilitators was notassessed, leaving open the possibility that at least some degree of between-participant variability in response may be attributable to unknown differences in psychological support
provided by facilitators, rather than direct biological effectsof psilocybin per se. This study limitation highlights the importance of better understanding potential benefits and harmsthat may be engendered by the psychological/psychotherapeutic components of psilocybin assisted therapy.
Fifth, as with the majority of recent clinical trials of
psychedelics,35 a major limitation of the current study is a lackof participant ethnic and racial diversity. The current study
sample was predominantly White, non-Hispanic, and from upper socioeconomic echelons. Whether psilocybin would be
more, less, or equivalently effective in a more ethnically, racially, and socioeconomically diverse sample is an urgent question that must be addressed in future studies by actively employing strategies shown to increase recruitment and retentionof racial and ethnic minoritized populations and other underrepresented groups in clinical trials of psychedelic agents.36

Conclusions
In this randomized trial, a single 25-mg dose of psilocybin administered with psychosocial support was associated with clinically and statistically significant reductions in depressive symptoms and improvement in measures of functional disability
compared with a 100-mg dose of niacin placebo administered under an identical protocol. No serious TEAEs occurred
during the study, but psilocybin treatment was associated withan increase rate of overall, solicited, and severe TEAEs, mostof which occurred during or immediately after the dosing period. These findings add to evidence that psilocybin—when administered with psychological support—may hold promise asa novel intervention for MDD.

Pacific Neuroscience Institute, Santa Monica,
California (Heinzerling, Kelly); Department of
Psychiatry and Behavioral Sciences, Emory
University School of Medicine, Atlanta, Georgia(Dunlop, Mletzko); Department of Family Medicine& Community Health, University of Wisconsin
School of Medicine & Public Health, Madison(R. T. Brown, Nicholas); Center for Psychedelic
Research, Segal Trials, Lauderhill, Florida (Kakar);
Hassman Research Institute, Berlin, New Jersey(Hassman); Flourish Research, Chicago, Illinois(Trivedi); Numinus Wellness, Draper, Utah
(Robison); Department of Psychiatry, University of
Utah School of Medicine, Salt Lake City (Robison);
Department of Psychiatry and Behavioral Sciences,

Johns Hopkins University School of Medicine,
Baltimore, Maryland (Gukasyan, Nayak, Griffiths);
NYU Langone Center for Psychedelic Medicine,
Department of Psychiatry, NYU Grossman School of
Medicine, New York, New York (Hu, O’Donnell,Ross); School of Nursing, University of California
San Francisco (Penn); Pharmacy Practice &Translational Research Division, School of
Pharmacy, University of Wisconsin-Madison(Hutson); The Emmes Company, Inc, Rockville,
Maryland (Nelson-Douthit, Wilson, C. Brown);
Department of Neuroscience, Johns Hopkins
University School of Medicine, Baltimore, Maryland(Griffiths).

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Research Original Investigation

Single-Dose Psilocybin Treatment for Major Depressive Disorder

Author Contributions: Drs Raison and Davis had
full access to all of the data in the study and takeresponsibility for the integrity of the data and theaccuracy of the data analysis. Drs Griffiths and Ross
contributed equally.
Concept and design: Raison, Kakar, Kelmendi,
Tarpley, Utzinger, Linton, Ross.
Acquisition, analysis, or interpretation of data:
Raison, Sanacora, Woolley, Heinzerling, Dunlop,
R. Brown, Hassman, Trivedi, Robison, Gukasyan,
Nayak, Hu, O'Donnell, Sloshower, Penn, Bradley,
Kelly, Mletzko, Nicholas, Hutson, Lenoch, Warchol,
Gapasin, Davis, Nelson-Douthit, Wilson, C. Brown,
Griffiths.
Drafting of the manuscript: Raison, Woolley,
Kelmendi, Mletzko, Nicholas, Gapasin,
Nelson-Douthit, C. Brown.
Critical review of the manuscript for important
intellectual content: Sanacora, Woolley, Heinzerling,
Dunlop, R. Brown, Kakar, Hassman, Trivedi,
Robison, Gukasyan, Nayak, Hu, O'Donnell,
Sloshower, Penn, Bradley, Kelly, Hutson, Tarpley,
Utzinger, Lenoch, Warchol, Gapasin, Davis, Wilson,
C. Brown, Linton, Ross, Griffiths.
Statistical analysis: Raison, Wilson, C. Brown.
Obtained funding: Woolley, Linton.
Administrative, technical, or material support:
Raison, Woolley, R. Brown, Hassman, Trivedi,
Robison, Nayak, Hu, O'Donnell, Kelmendi, Bradley,
Kelly, Mletzko, Nicholas, Hutson, Tarpley, Utzinger,
Lenoch, Warchol, Gapasin, Davis, Nelson-Douthit,
Linton, Ross.
Supervision: Raison, Woolley, Heinzerling, R. Brown,
Trivedi, Robison, Nayak, Sloshower, Penn, Nicholas,
Griffiths.
Other - study therapist, co-PI of study at NYU site: Hu.
Other - participated in training research site staff/
facilitators: Utzinger.
Conflict of Interest Disclosures: Dr Raison
reported receiving personal fees from Usona
Institute and grants to Usona Institute fromDr. Bronner's All-One, Fournier Family Foundation,
Good Ventures, Steven and Alexandra Cohen
Foundation, Tiny Blue Dot Foundation, Turnbull
Family Foundation, and William A. Linton during the
conduct of the study and personal fees from
Novartis, Sage/Biogen, Emory Healthcare, and Vail
Health outside the submitted work. Dr Sanacora
reported receiving grants from Usona Instituteduring the conduct of the study and personal feesfrom Ancora/Embark, Aptinyx, Atai, Axsome
Therapeutics, Biogen, Boehringer Ingelheim,
Bristol-Myers Squibb, Clexio, Cowen, Denovo
Biopharma, ECR1, EMA Wellness, Engrail
Therapeutics, Gilgamesh, Intra-Cellular Therapies,
Janssen, KOA Health, Levo Therapeutics,
Lundbeck, Merck, MiCure, Navitor Pharmaceuticals,
Neurocrine, Novartis, Noven Pharmaceuticals,
Otsuka, Perception Neuroscience, Praxis
Therapeutics, Relmada Therapeutics, Sage
Pharmaceuticals, Seelos Pharmaceuticals, Taisho
Pharmaceuticals, Valeant, Vistagen Therapeutics,
and XW Labs; equity in Freedom Biosciences,
Biohaven Pharmaceuticals, and Tetricus; and grants
from Janssen and Merck outside the submitted
work and having a patent for #8,778,979 issued
from Biohaven for glutmatergic drugs and a patent
for 047162-7177P1 (00754) pending from Freedom
for combination of immunemodulating andglutamatergic treatments. Dr Woolley reported
receiving grants from UCSF Research Allocation
Program during the conduct of the study andpersonal fees from Alexander Shulgin Research

852

Institute, Alvarius, Boxer Capital, Filament Health,Gilgamesh Pharmaceuticals, Guidepoint, Silo
Pharmaceuticals, and Travistock Company outside
the submitted work. Dr Heinzerling reported
working for Usona Institute as a site primary
investigator during the conduct of the study andreceiving personal fees from MindMed outside thesubmitted work. Dr Dunlop reported receiving
grants from Usona Institute during the conduct of
the study and grants from Compass Pathways andBoehringer Ingelheim and personal fees from
Cerebral Therapeutics, Otsuka, NRx
Pharmaceuticals, Myriad Neuroscience, Sage, andthe Department of Defense outside the submitted
work. Dr R. Brown reported receiving grants from
Usona Institute during the conduct of the study.
Dr Robison reported receiving grants from Usona
Institute during the conduct of the study and grants
from MindMed, Janssen, Merck, Neurocrine
Biosciences, Alto Neuroscience, Clexio Biosciences,and Otsuka and personal fees from Janssen and
MAPS Public Benefit Corporation outside thesubmitted work. Dr Gukasyan reported receiving
grants from Usona Institute during the conduct of
the study and grants to support the Center for
Psychedelic and Consciousness Research from
Steven and Alexandra Cohen Foundation, Tim
Ferriss, Matt Mullenweg, Craig Nerenberg, andBlake Mycoskie outside the submitted work.
Dr Nayak reported receiving philanthropic supportfor Hopkins Center for Psychedelic andConsciousness Research from Steven andAlexandra Cohen Foundation, Tim Ferriss, Matt
Mullenweg, Blake Mycoskie, and Craig Nerenberg
outside the submitted work. Dr Kelmendi reported
receiving nonfinancial support from Usona Instituteand grants from Yale University during the conductof the study and grants from NIMH outside thesubmitted work. Dr Sloshower reported receiving
personal fees from Usona Institute outside thesubmitted work. Dr Penn reported receiving grants
from Usona Institute during the conduct of thestudy and grants from Multidisciplinary Association
for Psychedelics Studies, Filament; personal feesfrom Compass Pathways, Mindmed, and Alexander
Shulgin Research Institute; and serving on anadvisory board or steering committee or teaching
for Tactogen, Osmind, North American Center for
Continuing Medical Education, California Institutefor Integral Studies, and Berkeley Center for
Psychedelics outside the submitted work. Dr Kelly
reported having stock in MindMed, Numinus
Wellness, and Noetic Fund outside the submitted
work. Dr Nicholas reported receiving funding
support from Usona Institute during the conduct of
the study and personal fees from MindMed andMultidisciplinary Association for Psychedelic
Studies Public Benefit Corp outside the submitted
work. Dr Tarpley reported receiving grants to Usona
Institute from Dr. Bronner's All-One, Fournier
Family Foundation, Good Ventures, Steven andAlexandra Cohen, Tiny Blue Dot Foundation,
Turnbull Family Foundation, and William A. Lintonand personal fees from Usona Institute (salaried
employee) during the conduct of the study.
Dr Utzinger reported receiving grants fromDr. Bronner’s All-One, Fournier Family Foundation,
Good Ventures, Steven and Alexandra Cohen
Foundation, Tiny Blue Dot Foundation, Turnbull
Family Foundation, William A. Linton and personal
fees from Usona Institute as a salaried employee
during the conduct of the study and personal feesfrom Promega Corporation as a salaried employee;and spouse being a board member of or owningshares in Cylerity Corporation, HealthBridge
Financial, Concord Health, and Ambershore Groupand being a board member on the Board of
Psychedelic Medicines and Therapies, which aims
to develop a credentialing process for licensed
health care professionals, and a guest faculty
member for CIIS and Synthesis, both educationalorganizations that developed training programs to
educate future clinicians/facilitators in psychedelic
medicine. Dr Lenoch reported receiving grants to
Usona Institute from Dr. Bronner's All-One, Fournier
Family Foundation, Good Ventures, Steven andAlexandra Cohen Foundation, Tiny Blue Dot
Foundation, Turnbull Family Foundation, andWilliam A. Linton and personal fees from Usona
Institute as a salaried employee during the conductof the study. Dr Warchol reported receiving grants
from Dr. Bronner's All-One, Fournier Family
Foundation, Good Ventures, Steven and Alexandra
Cohen Foundation, Tiny Blue Dot Foundation,
Turnbull Family Foundation, and William A. Lintonand personal fees from Usona Institute as a salaried
employee during the conduct of the study.
Dr Gapasin reported receiving grants fromDr. Bronner's All-One, Fournier Family Foundation,
Good Ventures, Steven and Alexandra Cohen
Foundation, Turnbull Family Foundation, andWilliam A. Linton and personal fees from Usona
Institute as a salaried employee during the conductof the study. Dr Davis reported receiving grants to
Usona Institute from Dr. Bronner's All-One, Fournier
Family Foundation, Good Ventures, Steven andAlexandra Cohen Foundation, Tiny Blue Dot
Foundation, Turnbull Family Foundation, andWilliam A. Linton and personal fees from Usona
Institute as a salaried employee during the conductof the study. Dr Nelson-Douthit reported receiving
personal fees from Usona Institute during the
conduct of the study. Dr Linton reported receiving
grants to Usona Institute from Dr. Bronner's
All-One, Fournier Family Foundation, Good
Ventures, Steven and Alexandra Cohen Foundation,
Tiny Blue Dot Foundation, Turnbull Family
Foundation, and William A. Linton during the
conduct of the study; receiving travel expenses
from Usona Institute outside the submitted work;and being executive director of Usona Institute and
CEO and chairman of Promega Corporation (Life
Science supplier). Dr Ross reported receiving grants
from Usona Institute during the conduct of thestudy and grants from National Institute on Drug
Abuse, National Cancer Institute, Heffter ResearchInstitute, Council on Spiritual Practices,
Multidisciplinary Association of Psychedelic
Studies, Reset Pharmaceuticals, and MindMed
outside the submitted work and being listed as aco-inventor in patent applications related to the useof psilocybin to treat psychiatric and existential
distress in cancer, filed by New York University
Grossman School of Medicine and licensed by Reset
Pharmaceuticals (N420838US and N419987US).
Dr Griffiths reported receiving grants and partialsalary support from Johns Hopkins Center for
Psychedelic and Consciousness Research during the
conduct of the study and personal fees fromHeffter Research Institute for serving on the boardof directors outside the submitted work. No otherdisclosures were reported.
Funding/Support: Usona Institute Inc, a 501(c)(3)
medical research organization, sponsored thestudy, supplied psilocybin synthesized under

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Single-Dose Psilocybin Treatment for Major Depressive Disordercurrent Good Manufacturing Practice regulations,and funded the study.
Role of the Funder/Sponsors: The sponsor
designed the study and oversaw a clinical researchorganization (Emmes Company, Inc) thatsupervised the study, managed the collection andanalysis of study data, and provided an initial draftof the manuscript Methods and Results sections.
The sponsor interpreted study data, wrote themanuscript, and made the decision to submit themanuscript for publication.
Data Sharing Statement: See Supplement 4.
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