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Psilocybin-assisted therapy for depression: A systematic review and dose-

response meta-analysis of human studies

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DOI: 10.1016/j.euroneuro.2023.07.011

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 European Neuropsychopharmacology 76 (2023) 61–76

www.elsevier.com/locate/euroneuro

REVIEW

Psilocybin-assisted therapy for depression:

A systematic review and dose-response
meta-analysis of human studies
Natacha Perez a, Florent Langlest a, Luc Mallet b,c,d, Marco De
Pieri a,e, Othman Sentissi a, Gabriel Thorens f,
Federico Seragnoli f,g, Daniele Zullino f, Matthias Kirschner a,h,
Stefan Kaiser a, Marco Solmi i,j,k,l,m,1, Michel Sabé a,1,∗

a
Division of Adult Psychiatry, Department of Psychiatry, University Hospitals of Geneva, 2, Chemin du
Petit-Bel-Air, CH-1226, Thonex, Switzerland
b
Univ Paris-Est Créteil, DMU IMPACT, Département Médical-Universitaire de Psychiatrie et
d’Addictologie, Hôpitaux Universitaires Henri Mondor - Albert Chenevier, Assistance Publique-Hôpitaux
de Paris, Créteil, France
c
Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Paris, France
d
Department of Mental Health and Psychiatry, Global Health Institute, University of Geneva, Geneva,
Switzerland
e
Center for Research in Medical Pharmacology, Varese, Italy
f
Division of Addiction Psychiatry, Department of Psychiatry, University Hospitals of Geneva, 70,
Grand-Pré, CH-1202 Geneva, Switzerland
g
Department of Political and Social Sciences, Institut of Psychology, University of Lausanne, Switzerland
h
Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of
Zurich, Switzerland
i
Department of Psychiatry, University of Ottawa, Ontario, Canada
j
On Track: The Champlain First Episode Psychosis Program, Department of Mental Health, The Ottawa
Hospital, Ontario, Canada
k
Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program University of Ottawa
Ontario, Canada
l
School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Canada
m
Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany

Received 3 June 2023; received in revised form 25 July 2023; accepted 28 July 2023

∗ Corresponding author at: Division of Adult Psychiatry, Department of Psychiatry, University Hospitals of Geneva, 2, Chemin du Petit-Bel-

Air, CH-1226, Thonex, Switzerland.

E-mail address: michel.sabe@hcuge.ch (M. Sabé).
1These authors have contributed equally to this work and share last co-authorship

https://doi.org/10.1016/j.euroneuro.2023.07.011
0924-977X/© 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/)
 N. Perez, F. Langlest, L. Mallet et al.

KEYWORDS Abstract
Psilocin; Psilocybin is increasingly studied for its antidepressant effect, but its optimal dosage for de-
Plant-base; pression remains unclear. We conducted a systematic review and a dose-response meta-analysis
Psychotherapy; to find the optimal dosage of psilocybin to reduce depression scores.
Mushroom; Following our protocol (CRD 42022220190) multiple electronic databases were searched from
Treatment; their inception until February 2023, to identify double-blind randomized placebo-controlled
Hallucinogen (RCTs) fixed-dose trials evaluating the use of psilocybin for adult patients with primary or sec-
ondary depression. A one-stage dose-response meta-analysis with restricted cubic splines was
used. Cochrane risk of bias was used to assess risk of bias.
Our analysis included seven studies with a total of 489 participants. Among these, four stud-
ies focused on primary depression (N = 366), including one study with patients suffering
from treatment-resistant depression. The remaining three studies examined secondary de-
pression (N = 123). The determined 95% effective doses per day (ED95) were 8.92, 24.68,
and 36.08 mg/70 kg for patients with secondary depression, primary depression, and both
subgroups, respectively. We observed significant dose-response associations for all curves,
each plateauing at different levels, except for the bell-shaped curve observed in the case of
secondary depression. Additionally, we found significant dose-response associations for var-
ious side effects, including physical discomfort, blood pressure increase, nausea/vomiting,
headache/migraine, and the risk of prolonged psychosis.
In conclusion, we discovered specific ED95 values for different populations, indicating higher
ED95 values for treatment-resistant depression, primary depression, and secondary depression
groups. Further RCTs are necessary for each population to determine the optimal dosage, al-
lowing for maximum efficacy while minimizing side effects.
© 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/)

1. Introduction classified as classics psychedelics, also called serotonergic

psychedelics (De Gregorio et al., 2021), typically produce
Depression is a prevalent mental disorder, affecting more perceptual distortions and mind-altering effects, mainly by
than 300 million people worldwide (WHO, 2017). It is one agonistic action at the serotonin (5-HT) 2A brain recep-
of the most debilitating illnesses with the most signifi- tor, with potential antidepressant properties (Kwan et al.,
cant impact on quality of life. The lifetime prevalence of 2022).
major depressive disorder (MDD) is between 10% and 20% Although the exact physiopathology of MDD has not been
(Lim et al., 2018), with an onset in a third of patients fully understood, it is widely accepted that dysregulation
by 25 years old, an median age at onset at 30 years old of the monoaminergic system, of which serotonin is a part,
(M. Solmi et al., 2021). A third of people suffering from contributes to affective symptoms (Otte et al., 2016). Con-
an MDD will experience more than one depressive episode sidering that both conventional antidepressants and psilo-
in their lifetime (Richards, 2011), and approximately half cybin act by modulating the serotonergic neurotransmission
of patients with depressive disorder lack adherence to an- system, this opens a door for the use of the latter in the
tidepressants as soon as 6 months after initiation of treat- treatment of MDD.
ment, with a further increase of non-adherence with com- Over the past decade, several RCTs have shown promis-
plex treatments regimens (Solmi et al., 2021). While most ing effects of psilocybin use in the treatment of mood dis-
prescribed antidepressants are superior to placebo in adults orders by reducing symptoms of anxiety and depression.
(Cipriani et al., 2018a) - but not in children and adolescents However, only one RCT has directly compared psilocybin-
- and are reasonably safe in the long term (Correll et al., assisted therapy with escitalopram (Carhart-Harris et al.,
2021), they do have a small effect size, can have lim- 2021).
ited tolerability, with associated discontinuation and high Animal studies have indicated that psilocybin has
relapse rates (Anagha et al., 2021; Locher et al., 2017; a low addiction and physical dependence potential
Solmi et al., 2021). Hence, novel treatments for depres- (Johnson et al., 2018), and national surveys report low rates
sion are needed, in particular for those that do not re- of abuse (European Monitoring centre for Drugs and Drug Ad-
spond to available antidepressants. As such, renewed inter- diction). In RCTs conditions, psilocybin appears to be well-
est in psychedelic-assisted therapy has emerged in recent tolerated in the long term (Roland R Griffiths et al., 2016;
years after being demonized in the early 1960s despite ini- Studerus et al., 2011).
tial promising research (Hofmann, 1980). This resurgence A recent meta-analysis conducted by Li and colleagues
of psychedelics started as therapeutic tools for resistant- focused on the clinical effects of classic psychedelics on de-
depression, mainly with lysergic acid diethylamide (LSD) pressive symptoms (Li et al., 2022). The analysis revealed
and psilocybin (Solmi et al., 2022). Both substances are that psilocybin had a small effect size on both acute and

62
 European Neuropsychopharmacology 76 (2023) 61–76

long-term reduction of depressive symptoms in patients depression occurs in the presence of an incapacitating or
dealing with MDD and secondary anxiety and depression life-threatening medical illness that precedes and parallels
related to cancer following psilocybin administration. Fur- the symptoms of depression (Florita and Barbini, 2005).
thermore, a sub-group meta-analysis investigating the dose-
effects of psilocybin on MDD and depression associated with
cancer indicated that the optimal therapeutic effect of 2.4. Outcomes measures and data extraction
psilocybin is achieved at a dose of 30–35 mg/70 kg (Galvão-
Coelho et al., 2021). The primary aim of our study was to establish the dose-
Considering the increase research and use of psilocybin, response profile of the effect of psilocybin on depressive
and the crucial aspect of the dose-relationship concerning symptoms for patients diagnosed with primary or secondary
efficacy and potential side-effects, we decided to perform depression. In order to determine the near maximum ef-
a dose-response meta-analysis of RCTs on psilocybin to de- fective dose of psilocybin needed to achieve a reduction
termine the near maximum effective doses of psilocybin on of depressive symptoms, we considered the mean changes
both primary and secondary depression, and the relative from each study by extracting the baseline and endpoint
risks of adverse events. score (mean±SD) of each study using the Hamilton Depres-
sion Rating Scale (Hamilton, 1960), the Montgomery-Åsberg
Depression Rating Scale (Montgomery and Asberg, 1979),
2. Methods or any other suitable scale to assess changes in depres-
sive symptoms. Missing standard deviations were estimated
2.1. Registration from p-values or by using the mean standard deviation from
other included studies with validated imputation methods
This systematic review was conducted according to the Pre- (Furukawa et al., 2005). Furthermore, considering the phe-
ferred Reported Items for Systematic Reviews and Meta- nomenological overlap between depression and anxiety, we
Analysis (PRISMA) (Supplementary Information 1). The re- also extracted the mean change on anxiety score using the
view protocol was registered on PROSPERO in December Beck Anxiety Inventory (Beck et al., 1988).
2022 (CRD 42022220190). The database was updated in The secondary aim of the study was to determine if pos-
February 2023. sible, psilocybin side-effects were dose-dependent, and to
assess tolerability by examining the relative risk of adverse
effects.
2.2. Search strategy

We conducted a systematic search for randomized

controlled trials (RCTs) comparing all serotoninergic 2.5. Risk of bias assessment
psychedelics in Embase, the Cochrane Database of System-
atic Reviews and PsycInfo. A combination of search terms The risk of bias was assessed independently by two review-
and MeSH terms that can be found in the published proto- ers (MS and NP) using the Cochrane risk-of-bias tool for ran-
col were used, such as ‘psilocibine’, ‘psilocybin’ and ‘hal- domized trials (RoB 2) (Sterne et al., 2019). RoB 2 evaluates
lucinogens’. Subsequently, we retrieved RCTs focusing on risk of bias in five different domains: generation of allo-
psilocybin for the treatment of primary or secondary de- cation sequence, allocation concealment, masking of study
pression. The results were limited to the adult population personnel and participants, masking of outcome assessor,
(18–65 years) without any language or time restrictions. Two attrition, and selective outcome reporting. We classified
reviewers (NP, FL) independently reviewed titles and ab- studies as having low risk of bias if none of these domains
stracts using Rayyan, a research collaboration web platform was rated as high risk of bias and three or fewer were rated
for systematic reviews. In case of disagreement, full texts as unclear risk; moderate if four or more were rated as un-
were analyzed until both reviewers reached a consensus. clear risk; and all other cases were assumed to have high
risk of bias.

2.3. Inclusion criteria and study selection

2.6. Statistical analysis
We included all double-blind RCTs and cross-over trials with
a minimum duration of one-week, comparing any fixed dose We used the one stage dose-response meta-analysis pack-
of psilocybin in any form of administration with placebo age ‘doresmeta’ published by Crippa & Orsini (Crippa et al.,
in patients diagnosed with primary or secondary depres- 2019). For our primary outcome, the objective was to ex-
sion (e.g.; cancer patients representing secondary depres- amine the relationship between the dose of psilocybin (in-
sive disorder). Diagnoses were based on versions of the DSM dependent variable) and the effect on depressive symptoms
or the SCID (e.g.; DSM-IV, DSM-V, and SCID-5) (APA, 2022; (dependent variable). We included all RCTs with fixed doses
First et al., 2016). Case-control studies, case reports, re- of psilocybin. We converted dose to total dose in mg/70 kg
views and uncontrolled clinical trials were excluded. We for all studies (e.g.; 0.2 mg/kg= total of 14 mg/70 kg
excluded case-control studies, case reports, reviews, and of psilocybin ingested). As a measure of effect size, the
uncontrolled clinical trials. Primary depression is defined as standardized mean difference (Cohen’s d) was used. We
MDD occurring in the absence of comorbid psychiatric dis- used a random-effects model with the standardized mean
orders, except for anxiety disorder. In contrast, secondary difference (SMD) to account for between-study variability

63
 N. Perez, F. Langlest, L. Mallet et al.

(Higgins et al., 2003). In dose-response models, the null hy- Davis et al., 2021; Goodwin et al., 2022; von Rotz et al.,
pothesis states that there is no dose-response relationship, 2023), with one study including patients with treatment-
meaning that the outcome does not vary significantly with resistant depression comparing different doses of psilocybin
different doses of the intervention or exposure (flat curve). (Goodwin et al., 2022). In most studies, treatment resistant
If the p-value is below a pre-defined significance level (e.g., episode was defined by lack of response to two to four an-
0.05), the null hypothesis is rejected, leading to a signifi- tidepressant trials at sufficient dose of ≥ 8 weeks duration.
cant dose-response relationship. One study included both patients with MDD (30% of patients)
The dose–response relationship was characterized using and patients with depression and anxiety disorders sec-
a restricted cubic spline model (nonlinear model) knot at ondary to cancer (dysthymic disorder, adjustment disorder
the 25th, 50th, and 75th percentiles (Crippa et al., 2018; with anxiety and depressed mood, other anxiety disorder)
Hamza et al., 2021). Estimations of 50% (ED50) and 95% (Griffiths et al., 2016). One study included patients with
(ED95) effective doses were extracted from the estimated anxiety disorder secondary to cancer (acute stress disorder,
dose–response curves. The ED50 was the mean dose at which generalized anxiety disorder, adjustment disorder with anx-
half of the possible psilocybin antidepressant effect would iety) (Grob et al., 2011). One study included patients with
occur. adjustment disorder (90%) and generalized anxiety disorder
Furthermore, for the secondary outcome regarding psilo- (10%) secondary to cancer (Ross et al., 2016). For studies
cybin side effects, we estimated the association between including patients with MDD, 2 studies delivered 2 doses,
the dose and the logarithm of risk ratio (RR) for physical and 2 studies delivered one of psilocybin (Table 1). For the
(physical discomfort, blood pressure increase, tachycardia, 3 studies focusing on secondary depression (and anxiety) to
nausea or vomiting, headache, or migraine) or psychological cancer, one study delivered two doses, and 2 studies deliv-
adverse events (psychological distress, prolonged psychosis) ered 2 doses.
across studies. In all included studies, psilocybin was manufactured by
We further conducted separate analysis regarding the di- pharmaceutical companies and administered orally in cap-
agnosis of primary and secondary depression. We quanti- sules. The mean dose used in studies that delivered a unique
fied heterogeneity using the variance partition coefficient dose of psilocybin was 16.5 mg/70 kg, and for studies with
(VPC), a multivariate extension of the I2 value. The VPC 2 doses, of 31.5 mg/70 kg.
can be defined as the ratio of the between-studies com- Prior hallucinogen use was reported in all studies, with a
ponent by the total residual. All analyses were conducted prevalence of 26.3% of patients having already experienced
using R statistical software v4.2.2 (metafor and dores- the use of psychedelics at least once in their life. How-
meta packages) (Crippa et al., 2019; R Core Team, 2019; ever, almost no studies provided information on the years
Viechtbauer, 2010). Moreover, if suitable we will conduct since last psychedelic use, except for one study that re-
a subgroup analysis and leave-one-out analysis to explore ported a mean length of 30 years since last psychedelic use
residual heterogeneity. (Griffiths et al., 2016).
In all studies, participants had not been taking antide-
pressants for at least 2 weeks prior to psilocybin intake. The
3. Results substance intake involved only one patient at a time, in an
individual psychedelic-assisted psychotherapy setting (IPAP)
3.1. Search results (Ponomarenko et al., 2023).
Furthermore, all studies delivered non-directive support-
The systematic search yielded 5196 references. We ive psychotherapy, albeit one study delivered a psychedelic
searched for additional articles by conducting a snowball psychotherapy training program (Ross et al., 2016).
search in identified reviews. Following our protocol, we re-
tained 260 clinical trials on psilocybin that were screened
for eligibility (Supplementary Fig 1). Overall, 7 studies were
included in the final dataset (Carhart-Harris et al., 2021; 3.2. Dose-response curve of the psilocybin effect
Davis et al., 2021; Goodwin et al., 2022; Griffiths et al., on depressive symptom
2016; Grob et al., 2011; Ross et al., 2016; von Rotz et al.,
2023). Studies including healthy participants or without con- A total of 7 RCTs (N = 489) examined the effect of psilocybin
trol groups were excluded (Becker et al., 2022; Carhart- on depression, with doses between 1.5 mg and 50 mg/70 kg.
Harris et al., 2016; Rucker et al., 2022). These studies were conducted between 2011 and 2023.
Follow-ups of various length (up to 33 weeks, mean 14.14 Study durations greatly differed considering that follow-up
weeks) was present for several studies (Table 1). When was up to a year after inclusion, however the mean length
considering all studies, 53.2% of included patients were between first and second dose of psilocybin was 3.54 weeks
women. Furthermore, all studies reported the age albeit (range 2 to 8 weeks). A detail of all results for primary out-
one study (Grob et al., 2011), and thus the mean age was come is reported in Table 2.
of 44.1(±12.8) years, and of 39.2(±11.6) and 56.3(±5.3) A significant dose-response association was found
years for the primary and secondary depression subgroups (p<0.0001) (Fig. 1). The visual inspection of the curve shows
respectively. an ascending curve that starts to plateau at the highest ex-
Although some patients presented treatment-resistant amined dose in presence of a considerable heterogeneity
depression, all patients were considered as stable out- (I2 =85%) (Supplementary Table S1.a). The ED95 was reached
patients. Of the 7 studies included, four studies in- at the dose of 41.14 mg/70 kg (95%IC 26.37–47.80), and the
cluded patients with MDD (Carhart-Harris et al., 2021; ED50 was 10.13 mg/70kg(95%IC 6.6–14.5). These results sug-

64
 Table 1 Characteristics of included studies.
Study (country) Methods, aim Population characteristic Inclusions (Female gender%) Dose range of Prior Sessions design and Adverse
of the study Mean age (mean ± SD) psilocybin (Psia ) experience psychological support physical or
(mg/70 kg) / Dose with psychological
of placebo psychedelics effects
Primary depression
∗ ∗
1- Davis et al., 8 weeks Outpatients with Intervention 9(69%) Psi 20 mg 4(44%) 2–3 h of meeting after each The most
2021 waiting-list moderate to severe group 43.6 ± 13 (1st dose) 7 (100%) session common

European Neuropsychopharmacology 76 (2023) 61–76

∗
randomized major depressive Waiting-list 7(64%) Psi 30 mg One day session with adverse event
controlled trial disorder episode (SCID-5 group 35.2 ± 9.9 (2nd dose) non-directive supportive was mild-to-
(RCT) with 1 criteria); no use of psychotherapy moderate
∗
month follow ketamine or classic Participants were headache and
up. hallucinogens during the instructed to lie on a couch challenging
Two doses of past 6 months; no in a living room–like emotions that
psilocybin current environment with were limited to
delivered. pharmacotherapy for eyeshades and headphones the time of
depression. (n = 27; and were encouraged by sessions
65

21–75) facilitators to focus their

attention inward and stay
with any experience that
arose
∗ ∗
2- Carhart- 6 weeks RCT, Oupatients with Intervention 11(37%) Two separate dose 8 (27%) 2 sessions of unknown The most
Harris et al., with no follow moderate-to-severe group 43.3 ± 11.7 of Psi 25 mg, or Psi 9 (28%) duration common
∗
2021 up, comparing major depressive Control group 9(31%) 1 mg Psychological support adverse event
psilocybin with disorder assessed by a 39.1 ± 9.7 Escitalopram during sessions consisted of was transient
escitalopram. score ≥17 on the 10 mg for 3 weeks, caring for the physical and headache
Two doses of HAM-D-17b , with no then escitalopram psychological well-being of within 24 h
psilocybin current use of 20 mg daily subjects and responding to after the
delivered. psychotropic medication signs of discomfort during psilocybin
nor psychotherapy and immediately after the session
(DSM-IV criteria). 73% of administration
subjects were psilocybin
naïve.
(n = 59;21–64)
(continued on next page)
 Table 1 (continued)
Study (country) Methods, aim Population characteristic Inclusions (Female gender%) Dose range of Prior Sessions design and Adverse
of the study Mean age (mean ± SD) psilocybin (Psia ) experience psychological support physical or
(mg/70 kg) / Dose with psychological
of placebo psychedelics effects
∗ ∗
3- 3 weeks phase Outpatients with High dose 44(56%) Psi 25 mg 5 (6%) 6–8 h session Adverse
∗
Goodwin et al., 2, dose-finding treatment-resistant group 40.2 ± 12.2 Psi 10 mg 5 (7%) Subjects were in a quiet events
2022 RCT, that assess depression (DSM-V Low dose 41(55%) Psi 1 mg (Placebo) 4 (5%) room and listened to music occurred in 77%
of the safety criteria). Treatment group 40.6 ± 12.8 wearing eyeshades, and of subjects
and efficacy of resistance is defined by Control group 36(46%) returned home once the (headache,
various doses no response after two to 38.7 ± 11.7 psychedelic experience nausea and
of synthetic four adequate trials ≥ 8 fully dissipated dizziness) in

N. Perez, F. Langlest, L. Mallet et al.

∗
psilocybin, weeks duration. Drugs 3 meetings with a therapist particular in
with 12 weeks affecting the central before the psilocybin the high dose
follow up. nervous system were session to build trust and to group, as for
Unique dose of discontinued two weeks prepare for the psychedelic the severe
psilocybin before psilocybin experience adverse event
∗
(1, 10 or 25 mg) administration. 2 integration sessions after such as suicidal
(n = 233; 36–58) the psilocybin experience to ideation,
66

integrate the psychedelic behavior or

experience self-injury
∗ ∗
4- Von Rotz 3 weeks RCT. Outpatients diagnosed Psilocybin 26 (61.5%) Psi 15.05 mg 5 (19.02%) 6–8 h session Of a total of
∗
et al. 2023 Unique dose of with major depressive Group 37.6 ± 10.9 Pure mannitol 11(42.3%) Subjects were instructed eight
psilocybin. disorder (DSM-V) and Control 26 (65.4%) to immerse themselves in adverse events,
no unstable somatic group 35.9 ± 9.80 an introspective focus. A the most
conditions were standardized playlist with frequently
allocated to receive music was played via reported was
either a single, moderate headphones or speakers. mild
dose (0.215 mg/kg body One trained therapist was headache (11%)
weight) of psilocybin or present in the room which resolved
placebo in conjunction throughout the completely
with psychological administration day to within two days
support. Prior respond to the participants’ after drug
experience with needs. administration
∗
psychedelics. (n = 52; One integration session
20–60) after the psilocybin
experience
(continued on next page)
 Table 1 (continued)
Study (country) Methods, aim Population characteristic Inclusions (Female gender%) Dose range of Prior Sessions design and Adverse
of the study Mean age (mean ± SD) psilocybin (Psia ) experience psychological support physical or
(mg/70 kg) / Dose with psychological
of placebo psychedelics effects
Secondary depression
∗ ∗
5-Grob et al., 2 weeks RCT Outpatients with Intervention 6(91.7%) Psi 10–15 mg 4 (66.6%) 6 h session Safe
∗
2011 (USA) and 6 months secondary depression group n.a. Niacin 4(66.6%) Subjects were encouraged physiological
follow-up. (acute stress disorder, Control group 6(100%) 250 mg to lie in bed wearing eye and
Unique dose of generalized anxiety n.a. shades and were able to psychological
psilocybin disorder, anxiety listen to preselected music. responses
disorder due to cancer, A debriefing was proposed

European Neuropsychopharmacology 76 (2023) 61–76

or adjustment disorder after the session
with anxiety; DSM-IV
criteria). (n = 12; 36–58)
∗ ∗
6- 5 weeks Outpatients with Intervention 25(48%) Psi 22–30 mg 23 (45%) 7 h sessions Safe
∗
Griffiths et al., crossover study secondary depression group 56.1 ± 2.3 Psi 1–3 mg 23 (45%) Subjects were encouraged physiological
2016 (USA) with 6 months (dysthymic disorder, or Waiting-list 26(50%) to lie in bed wearing eye and
follow-up. adjustment disorder with group 56.5 ± 1.8 shades and were able to psychological
Two doses anxiety and depressed listen to music. responses
delivered. mood, chronic) or A debriefing was proposed
67

anxiety disorders using after the session.

DSM-IV criteria.
Participants were not
taking antidepressants.
Almost all participants
were hallucinogens
naïve. (n = 51; 29–62)
∗ ∗
7-Ross et al., 7 weeks RCT Outpatients of which the Intervention 15(62%) Psi 21 mg 7 (50%) 4 h session Most common
∗
2016 (USA) with a majority meeting group 56.3 ± 7.3 Niacin 250 mg 9 (60%) Subjects were encouraged psychiatric AEs
crossover criteria for an Waiting-list 16(62%) to lie in bed wearing eye were transient
design, and adjustment disorder group 56.3 ± 9.5 shades and were able to anxiety (17%)
with a (90%) and the rest for listen to music. and transient
follow-up at 33 generalized anxiety A debriefing was proposed psychotic-
weeks. disorder (10%) DSM-IV after the session. like symptoms
∗
Unique dose of criteria. Stanislas Grof method of (7%)
psilocybin 55% prior hallucinogens preparatory psychotherapy,
use. All participants and post—dosing integrative
were hallucinogens psychotherapy
naïve. (n = 29; 22–75)
Abbreviations.
n.a.: not available.
a Psi: Psilocybin.
b HAM- D -17: Hamilton depression rating scale (17 items).
 N. Perez, F. Langlest, L. Mallet et al.

Table 2 Results for the primary outcome: psilocybin effect on depressive and anxiety symptoms.
Psilocybin effect on Results Primary and Primary depression Secondary depression
secondary depression
Depressive Inclusions n = 7, N = 489 n = 4, N = 366 n = 3, N = 123
symptoms
ED50 10.13 mg/70kg 8.23 mg/70kg 3.20 mg/70kg
ED95 36.08 mg/70kg 24.68 mg/70kg 8.92 mg/70kg
Curve shape Plateau Plateau Bell-shape
Significancy; I2 p<0.0001; I2 =85% p< 0.0001; I2 = 80% p = 0.07; I2 = 80%
Anxiety symptoms Inclusions n = 6; N = 258 n = 3; N = 135 n = 3; N = 123
ED50 7.58 mg/70kg 11.94 mg/70kg 4.08 mg/70kg
ED95 22.78 mg/70kg 24.68 mg/70kg 8.86 mg/70kg
Curve shape Plateau Plateau Plateau
Significancy; I2 p<0.0001; I2 =85% p<0.0001; I2 =85% p<0.0001; I2 =85%

Fig. 1 Dose-response curve of psilocybin for patients with both primary and secondary depression (X2= 31.56 (df = 2), p< 0.0001,
I2 = 85%). The maximum reduction of depressive symptoms (ED95%) was reached for the dose of 41.14 mg/70 kg (95CI%: 26.37–
47.80), n = 7, N = 489; mean duration of 3.71 weeks. ED50 was reached at 10.13 mg/70 kg. Each circle represents one study, and
the size of a circle is proportional to the number of patients that have received a single dose of psilocybin. The dose-response curve
represents the standardized mean differences reduction of depressive symptoms for the treatments arm compared to the placebo
arm. Y-axis represents the standardized mean differences of reduction of depressive symptoms for the dose-response curve. X-axis
represents doses (total mg/70 kg received). The dotted lines are 95% confidence intervals. We used knot locations at the 25th, 50th,
and 75th percentiles to anchor the curves.

gested that higher dose that the ED95 might not be more a leave-one-out analysis, which found no significant modifi-
efficient on depressive scores reduction. cation of results with range of ED50 from 8 to 14 mg/70 kg
We performed a sensitivity analysis, excluding studies and range of ED95 from 24 to 45 mg/70 kg (Supplementary
with that presented an overall risk different than low risk Table 3).
(Supplementary Table 2). Only the Grob et al. (2011) study
was excluded. The dose-response association did not signifi-
cantly change (p<0.0001), the ED50 was 10.13 and the ED95 3.3. Subgroup analysis for patients with primary
was 36.08 mg/70 kg. and secondary depression
Furthermore, we excluded the Goodwin et al. (2022) that
administered only one dose of psilocybin to patients with Considering the heterogeneity of included population
treatment-resistant depression. Results were unchanged among retained studies we conducted a subgroup analysis
(p<0.0001) (Supplementary Fig S2), however both lowest to distinguish the effects of psilocybin for patients with MDD
ED50 and ED95 were reached at 8.23 and 24.05 mg/70 kg and patients’ depression secondary to cancer (Fig. 2).
respectively. We complemented our sensitivity analysis with For primary depression (n = 4; N = 366), a significant
dose-response association was found (p< 0.0001), in pres-

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 European Neuropsychopharmacology 76 (2023) 61–76

Fig. 2 Subgroup analysis with dose-response curve of psilocybin for depressive symptoms, when considering patients with only
primary depression (A) and only with secondary depression (B) without distinction of the number of sessions. For primary depression,
the maximum reduction of depressive symptoms (ED95%) was reached for the dose of 24.68 mg/70 kg (95CI%: 19.29–48.73), n = 4,
N = 366; mean duration of 3 weeks. The effect size at the maximum dose reaches a 95% CI of 1.62 ([1.15, 1.8]. For secondary
depression, the maximum reduction of depressive symptoms (ED95%) was reached for the dose of 8.92 mg/70 kg (95CI%: 7.15–
22.42), n = 3, N = 123; mean duration of 4.6 weeks. The effect size at the maximum dose reaches a 95% CI of 1.0 ([0.85, 1.25].

ence of a considerable heterogeneity (I2 = 80%) (Supple- group analysis, a visual inspection of VPC curves suggested
mentary Table S1). The curve plateaued at the ED95 of that heterogeneity was essentially found for the highest
24.68 mg/70kg(95%IC 19.29–48.73). dose of psilocybin.
For the subgroup focusing only on secondary depression
to cancer (n = 3; N = 123), the dose-response association
was not statistically significant (p = 0.07), and these results 3.4. Dose-response curve of the psilocybin effect
were found in presence of a considerable heterogeneity (I2 = on anxiety symptoms
80%) (Supplementary Table S1). Nevertheless, the visual in-
spection revealed a bell-shape curve, suggesting that higher All studies, albeit one study (Goodwin et al., 2022) re-
dose than the ED95 of 8.92 mg/70kg(95%IC 7.15–22.42), was ported anxiety symptoms change using the BDI scale to-
no more beneficial on depressive symptoms. For both sub- tal of (n = 6 RCTs; N = 258), with doses between 1.5

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 N. Perez, F. Langlest, L. Mallet et al.

to 50 mg/70 kg. When considering both primary and sec- sidered an adverse event differed across studies. Further-
ondary depression, a significant dose-response association more, certain adverse events, such as ’psychological dis-
was found (p<0.0001) with a curve that plateaued (Supple- tress,’ were not consistently retained due to ambiguous def-
mentary Fig S3.A.B.C). Highest doses were associated with a initions between studies and highly variable rates of events,
considerable heterogeneity (I2 =85%). The ED95 was reached particularly in the placebo groups.
at the dose of 22.78 mg/70kg(95%IC 15.82–47.2) and the
ED50 at 7.58 mg/70kg(95%IC 3.3–11.7). The subgroup of pri-
mary and secondary depression revealed that although both 4. Discussion
curve that plateaued also present significant dose-response
association in favor of a decrease of anxiety, ED50 and ED95 To the best of our knowledge, this is the first dose-response
were very different. The ED95 was of 24.68 mg/70kg(95%IC meta-analysis conducted for psilocybin and depression. Our
17.09–47.47), and 11.94 mg/70kg(95%IC 2.91–22.42), and analysis included 7 RCTs with a total of 489 participants, and
the ED50 of 8.86 mg/70 kg and 4.08 mg/70 kg, for primary the findings revealed that psilocybin significantly reduced
and secondary depression respectively in presence of con- depressive symptoms in both primary and secondary de-
siderable heterogeneity (I2 =80–85%). pression. For primary depression, the dose-response curve
plateaued, while for secondary depression, a bell-shaped
curve was observed. Notably, the near maximal effective
3.5. Secondary outcome: relative risks of adverse dose was much lower for secondary depression than for pri-
events mary depression.
Furthermore, the analysis also yielded significant results
We examined the relationship between psilocybin dose and for anxiety scores, and specific dose-response associations
the occurrence of physical or psychological adverse events were identified regarding somatic and psychological adverse
using linear model of binary sample data with the one-stage events. These findings provide valuable insights into the
random-effects meta-analysis and the covariance approxi- therapeutic potential of psilocybin for depression and its as-
mation of Greenland & Longnecker (Greenland and Long- sociated effects, enhancing our understanding of its efficacy
necker, 1992). All results are reported in Fig. 3. and safety profile.
For somatic adverse events, we found a significant
dose-association for physical discomfort (p = 0.023), with
a curve that continues to increase. On the exponential 4.1. Dose response association of the
scale, the relative risk was +2.35% suggesting that the antidepressant effect of psilocybin
risk of physical discomfort event increase by 1.0235 times
(exp(0.0235)=1.0235), or increase by +2.35% with each Our results are somewhat different from those of a recent
1 mg/70Kg of psilocybin ingested. We also found a simi- meta-analysis studying the dose effects of psilocybin on
lar curve for the relative risk of blood pressure increase primary and secondary depression (Li et al., 2022), which
(p = 0.042), with a relative risk of +1.04%. pointed out that the antidepressive effect of psilocybin de-
For tachycardia, although the visual inspection of the cline from a dose of 10–15 mg/70 kg to 20–25 mg/70 kg, be-
curve suggested that a dose-response association similar to fore increasing at the dose of 30–35 mg/70 kg, being the op-
the two previous one described was present, this associa- timal therapeutic dose. This meta-analysis included fewer
tion was not significant (p = 0.09), with the presence of a studies and does not use a dose-response model. When con-
major uncertainty. The relative risk was +2.02%. sidering both primary and secondary depression, we found
Furthermore, for nausea and vomiting, as for headache that half of psilocybin antidepressant effect occurs at doses
and migraine, two bell shaped curves were obtained, of 10.13 mg/70 kg, and 95% of the antidepressant effect oc-
with significant dose-response associations (p<0.001 and curs at doses of 41.14 mg/70 kg, achieving the optimal ther-
p<0.05), with relative risk of +1.25% and +1.42% respec- apeutic effect. However, these results must be interpreted
tively. Of importance, vomiting and migraine where only re- with caution, as with the exclusion of the only study in-
ported in a few cases, with mostly nausea and headache cluding treatment-resistant patients (Goodwin et al., 2022),
occurring. the ED95 for depressive symptoms reduction dropped to
Regarding psychiatric adverse events, for the combined 24.05 mg/70 kg, suggesting that resistant patients mostly
risk of prolonged psychosis (>24 h) and the risk of hal- respond to higher dose of psilocybin (40 mg/kg).
lucinogen persisting perception disorder (HPPD), we ob- Furthermore, the bell-shaped curve obtained for patients
tained a significant dose-response relation with a curve that with secondary depression, with a low E95% (24.68 mg/kg)
plateaued (p = 0.001), although in presence of a consider- also points out the importance of the type of population
able heterogeneity. The relative risk was +2.51% suggest- considered. Among the pool of patients with secondary de-
ing that the risk of such adverse event increase by 1.025, pression, only 16% of patients presented MDD as a ‘pri-
times with each additional 1 mg/70 kg dose of psilocybin mary’ diagnosis, other patients presenting adjustment and
is ingested. However, the occurrence of such events was anxiety disorders. We hypothesize that patients with co-
relatively rare, and the author’s consideration of psychotic morbid, or with ‘primary’ anxiety disorders will be more
symptoms varies between studies (N = 12 cases on a total likely to only respond to a lower dose of psilocybin, at
of 465 subjects) (Supplementary Table S4). least in the first psilocybin sessions. Similarly, the results
Of importance, it should be noted that the definitions of regarding the decrease of BDI score, and the different ED50
different outcomes varied between studies. For instance, and ED95 values between both subgroups of patients point
the threshold at which blood pressure increase was con- out that patients with comorbid anxiety symptoms seem

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 European Neuropsychopharmacology 76 (2023) 61–76

Fig. 3 Dose-response association for adverse events reported with psilocybin RR=risk ratio. Each tick on the x-axis represents the
dose examined in a treatment group. The dotted lines represent 95% CIs.

to benefit from lower doses (almost half dose) of psilocy- anxiety and psychotic symptoms). Cahart-Harris and col-
bin than when considering patients with primary depres- leagues propose the notion of ‘increased cognitive entropy’
sion. For such patients presenting a proneness of anxiety, or (‘entropic brain’ hypothesis) to explain the possible occur-
even for patients with a proneness for psychotic symptoms, rence of such paradoxical psychological effects (Carhart-
we could assume that higher doses might mitigate response Harris et al., 2014; Rankaduwa and Owen, 2023). In oppo-
due to subsume dysphoric mood states such as anxiety site, oceanic boundlessness, usually associated with positive
and fearful delusions, arising mainly from ego-disintegration emotional states is an indirect measure of derealization and
and loss of self-control phenomena (Stoliker et al., 2022; depersonalization, which might be difficult to apprehend for
Studerus et al., 2011). such patients (Preller and Vollenweider, 2018).
Indeed, it is important to remind the frequent paradoxi- Considering these unforeseen reactions caused by sero-
cal effect of serotonergic psychedelics to increase feelings toninergic psychedelics, we can only stipulate that for first
of anxiety (Carhart-Harris et al., 2016), and the very na- sessions, patients prone to anxiety or psychotic symptoms
ture of psychedelics trips with dose-dependent effect for are very likely to reach the ED95% for depressive symp-
ego dissolution that can be associated with a sense of loss of toms reduction at lower dose, as indicated by our re-
control with subsequent levels of anxiety or even short-term sults. The optimal dose of psilocybin for depression there-
psychosis-like symptoms (Hirschfeld and Schmidt, 2021). fore clearly varies between the subgroup of patient con-
On the neurobiological level, 5-HT2A R stimulation has sidered. By extension, caution regarding the dose of psilo-
been associated with both positive and negative facets of cybin used should be applied for all patients presenting
the acute psychedelic state (e.g., positive mood but also different core psychiatric disorder than depression, and

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 N. Perez, F. Langlest, L. Mallet et al.

that would be eligible to psilocybin-assisted psychotherapy combined with psychotherapy from escitalopram, possibly
for their comorbid depression. As mentioned, lower dose by modulating neuroplasticity. In a recent analysis of the
than 25 mg/70 kg should even be considered – with for fMRI data of this study, Daws and colleagues propose that
instance a first threshold at the ED50% for secondary de- 5-HT2A receptor-rich higher-order functional networks be-
pression (ED95 of 9 mg/70 kg) – in most disorders where came more functionally interconnected and flexible after
anxiety of psychotic symptoms might occur (e.g.; anxiety psilocybin treatment – which is not the case with escitalo-
disorders; schizoaffective disorders (Arnovitz et al., 2022); pram – suggesting a specific antidepressant mechanism for
bipolar depression (Gard et al., 2021); autism spectrum psilocybin therapy, the global increases in brain network in-
disorders (Markopoulos et al., 2022); borderline person- tegration (Daws et al., 2022).
ality (NCT05399498). Although some clinical trials includ-
ing patients with borderline personality have started, sev-
eral years might be needed before such population of pa- 4.3. Dose response association of the occurrence
tients could benefit of the proper optimal dose of psilocybin of adverse events
(MacCallum et al., 2022).
Finally, it is important to acknowledge that other con- Our results are consistent with good tolerability of psilocy-
founding parameters, such as age and the novelty of the bin, with no serious adverse physical or psychological re-
psychedelic experience, might interact with the ED95. For actions (MacCallum et al., 2022). For overall physical dis-
instance, the mean age of patients with secondary depres- comfort and elevation of blood pressure, we encountered a
sion is higher than that of the primary depression sub- significant dose-association with an increasing curve. Most
group, which could reasonably impact the near maximum common adverse events were transient, mild to moderate
dose (39.2 and 56.2 years). Additionally, Li and colleagues, headache and nausea, and we found a significant dose-
in their meta-analysis, reported that the first or unique association with mostly ascending curve, suggesting that
dose of psilocybin received was generally more impact- highest doses are most likely to generate most side ef-
ful in decreasing depressive symptoms compared to subse- fects. Of importance, the definition of psychological dis-
quent doses (Li et al., 2022). Hallucinogens-naïve patients comfort and ‘long-lasting psychotic symptoms’ varied across
may potentially exhibit a more significant response to psilo- included trials which limit the interpretation of both curves.
cybin due to the novelty of the psychedelic experience For psychological discomfort, all panic reactions reported
(Haijen et al., 2018). However, in most studies, there was occurred during the psychedelic trips (potentially associ-
limited to no information available on the lifetime use of ated to the anxious ego dissolution phenomena, or increased
hallucinogens among the participants. disorganization), and were easily handled with immediate
psychological support with no requirement of specific med-
ication. These common adverse events during psychedelics
4.2. Real-world clinical relevance of results trips mostly occur at the highest dose but were not con-
sistently reported in all clinical trials. For instance, in Von
Our dose-response meta-analysis suggests that the optimal Rotz and colleague trials (dose of 15 mg), there were no
dose of psilocybin significantly varies among patients with report of such reactions. On the opposite, in the Davis and
resistant depression, those with MDD, and individuals with colleague trial where the Challenging Experience Question-
anxiety disorders. In most cases, the results indicate a very naire is used (Barrett et al., 2016), many patients exper-
large effect size for the standardized mean difference (1.62 imented episode of anxiety (26% and 15% for high 30 mg,
for primary depression and 1.0 for secondary depression). In and low doses 20 mg, respectively), and 2% of patients ex-
Li and colleagues’ meta-analysis, the effect size observed perimented transient episodes of paranoid ideation (Supple-
for psilocybin is also very large but presents a bit more mentary Table S4). Long-lasting possible psychotic reactions
uncertainty (2.19 for primary depression and 1.0 for sec- that last the day following the psilocybin trial, were only de-
ondary depressed patients) (Li et al., 2022). In both anal- scribed in the Carhart-Harris and colleague trial (illusions,
yses, the results are much more important that the one abnormal dreams) (Carhart-Harris et al., 2021). Although
communally accepted for conventional antidepressants ef- these adverse events are rare and dose-dependent, these
fect size on depression (0.3) (Cipriani et al., 2018b). In- inconsistent definitions and measures limit our conclusions.
deed, while neurobiological mechanisms play a crucial role,
it is essential to acknowledge that part of the very large
effect size observed in our dose-response meta-analysis 4.4. Limitations
could also be attributed to factors such as the intensity
of the psychedelic experience induced by relevant doses This current meta-analysis has several limitations that con-
of psilocybin and the supportive psychotherapeutic setting tribute to the considerable heterogeneity found in the re-
(Yaden and Griffiths, 2021). To note, only a quarter of in- sults. First, although most studies were of good quality, the
cluded patients had previously experimented with at least total number of patients included with primary depression
one psychedelic trip, and in most cases many decades be- is adequate for dose-response models (>300 inclusions),
fore the trials. Although we here focus on single or two ses- but not for secondary depression, which limits the strength
sions of psychedelic-assisted psychotherapy, only Carhart- of our findings. Studies with negative results might also
Harris and colleagues have compared psilocybin with daily not have been published, which could affect the accuracy
escitalopram treatment and found no significant difference of the dose-response model. Moreover, while these robust
in depression score (Carhart-Harris et al., 2021). This fMRI findings allow us to extract a dose-response curve for effi-
study supports a specific antidepressant effect of psilocybin cacy, there is often significant heterogeneity in the depres-

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 European Neuropsychopharmacology 76 (2023) 61–76

sive syndromes included in clinical trials (Østergaard et al., treating primary depression, with a curve that reaches a
2011). plateau. The optimal therapeutic dose, beyond which no
Secondly, for the studies including patients with sec- further therapeutic gain is observed, depends on the spe-
ondary depression, whose pathophysiology is distinct from cific patient population and potential confounding factors
that of MDD and present a different drug response, con- like age and previous psychedelic experience. In the short
siderable heterogeneity is found. These studies encompass term and in clinical settings, psilocybin demonstrates a rea-
various levels of depressive symptoms, such as acute stress sonable safety profile with transient and mostly benign ad-
disorder, generalized anxiety disorder, adjustment disorder verse events. This dose-response curve for the efficacy of
with anxiety and depressed mood, and dysthymic disorder, psilocybin will aid in designing future clinical trials, partic-
due to cancer. We were not able to isolate each diagnosis, ularly for populations with treatment-resistant depression
making it difficult to address psilocybin efficacy in each di- and other co-morbid diagnoses related to depression.
agnosis separately. Furthermore, acute depression was not
addressed, limiting extrapolation to such population. Ad-
ditional double-blind RCTs are warranted to examine the Availability of the code and other materials
efficacy of psilocybin in treatment-resistant depression, as
only one study focused on this population (Goodwin et al., The code used for analysis is available via open access at the
2022). Although we gathered 7 studies, the long-lasting following link: https://cran.r-project.org/web/packages/
(>1 months) antidepressant effect of psychedelics is also dosresmeta/index.html
still a matter of debate. Furthermore, only one study com-
pared psilocybin-assisted psychotherapy to antidepressants, Role of the funding source
and no comparison to other add-on psychotherapy is avail-
able. Long-term safety has also not been studied. Neverthe- Internal funding only
less, one RCT with 12-months follow-up (Gukasyan et al.,
2022) found that the antidepressant effects of two psilo-
cybin doses (total of 50 mg/70 kg) on patients with MDD Author contributions
were sustained during a 12 month follow up. However,
the current main questions debated is whether classical NP and FL screened papers and extracted data. NP and
placebo are adequate agents for blinding of psychedelics Mis ran analyses and wrote the first draft of the paper. MS
agents (Butler et al., 2022; Nayak et al., 2023), and whether and MiS designed the study, provided supervision, ran analy-
the generalization of results to all populations is coherent ses, and critically revised the paper. All authors contributed
(Michaels et al., 2018). equally to the final version of this paper.

4.5. Consideration for future studies Conflict of interest

Despite the mentioned limitations, our results offer in- Internal fundings only.
novative insights into approaching the optimal psilocy- Sentissi O has received advisory board honoraria from
bin dose for treating MDD. However, important aspects of Otsuka, Lilly, Lundbeck, Sandoz, and Janssen in an in-
psychedelic-assisted therapy need further consideration. stitutional account for research and teaching. Solmi M
The absence of concrete psychedelic-assisted psychother- has received honoraria/has been a consultant for AbbVie,
apy, as most studies only provided psychological support, Angelini, Lundbeck. Kaiser S has received honoraria for
and the use of intensity scales to quantify the subjective Boehringer Ingelheim. All other authors declare no conflict
psychedelic effects of the trip (e.g., the five-dimensional of interest.
altered states of consciousness) are questionable. Future
studies should aim to report factors that may significantly
impact the intensity of psychedelic sessions, such as safety Acknowledgement
and screening, set, setting, therapeutic relationship, open
or closed eyes, expectations, and preparation. None
In the current studies, the dose-response curves are lim-
ited to the total dose administered in each trial for patients
with depression. More studies are needed to identify the Supplementary materials
most effective dosing pattern in terms of efficacy and risk.
In particular, future studies should examine the influence Supplementary material associated with this article can be
of non-pharmacological factors (e.g., subjective aspects of found, in the online version, at doi:10.1016/j.euroneuro.
the psychedelic experience) that could mediate the effect 2023.07.011.
of the clinical response (Preller and Vollenweider, 2018).

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