ARTICLE

Pharmacokinetics and Pharmacodynamics

of Oral Psilocybin Administration in Healthy
Participants
Friederike Holze1,2 , Anna M. Becker1,2 , Karolina E. Kolaczynska1,2, Urs Duthaler1,2
and Matthias E. Liechti1,2,*

Psilocybin is being investigated as a potential treatment for psychiatric and neurological disorders. Only a few studies
have evaluated the pharmacokinetics (PKs) of psilocybin and have used body weight-­adjusted dosing. Data on PKs
and the PK-­pharmacodynamic (PD) relationship of fixed doses that are commonly used are unavailable. The present
study characterized the PKs and PK-­PD relationship of 15, 25, and 30 mg of orally administered psilocybin in 28,
23, and 28 healthy subjects, respectively. Plasma levels of unconjugated psilocin (the psychoactive metabolite of
psilocybin) and corresponding subjective effects were repeatedly assessed up to 24 hours. PK parameters were
determined using compartmental modeling. Concentration-­subjective effect relationships were described using
PK-­PD modeling. Mean (95% confidence interval) maximal psilocin concentrations were 11 ng/mL (10-­13), 17 ng/
mL (16-­19), and 21 ng/mL (19-­24) after the administration of 15, 25, and 30 mg psilocybin, respectively. Maximal
concentrations were reached after an average of 2 hours. Elimination half-­lives were 1.8 hours (1.7–­2.0), 1.4 hours
(1.2–­1 .7), and 1.8 hours (1.6–­1 .9) for 15, 25, and 30 mg psilocybin, respectively. Mean (± SD) durations of subjective
effects were 5.6 ± 2.2 hours, 5.5 ± 1.6 hours, and 6.4 ± 2.2 hours, and maximal effects (“any drug” effects) were
58% ± 25%, 73% ± 27%, and 80% ± 18% after 15, 25, and 30 mg psilocybin, respectively. Psilocin exhibited dose-­
proportional PKs. The duration and intensity of subjective effects were dose-­dependent. Body weight did not influence
pharmacokinetics or the response to psilocybin. These data may serve as a reference for future clinical trials.

Study Highlights

WHAT IS THE CURRENT KNOWLEDGE ON THE were dose-­proportional. Body weight did not relevantly influ-
TOPIC? ence PKs.
; Psilocybin is currently under investigation as a treatment for HOW MIGHT THIS CHANGE CLINICAL PHARMA-
several psychiatric and neurological disorders. COLOGY OR TRANSLATIONAL SCIENCE?
WHAT QUESTION DID THIS STUDY ADDRESS? ; The present data support the design of further studies that
; The pharmacokinetics (PKs) and PK-­pharmacodynamic investigate psilocybin as a potential treatment.
(PK-­PD) relationship of commonly used fixed doses of 15, 25,
and 30 mg psilocybin were investigated in healthy participants.
WHAT DOES THIS STUDY ADD TO OUR
KNOWLEDGE?
; PK and PK-­PD characteristics of fixed psilocybin doses are
described for the first time. PKs of psilocybin and its metabolites

Psilocybin is a classic psychedelic and serotonin 5-­hydroxytryptamine-­2A
receptor agonist, similar to lysergic acid diethylamide (LSD).1,2
Psilocybin is currently being investigated in psilocybin-­assisted psycho-
therapy for several psychiatric and neurologic disorders, such as major
depression,3–­8 anxiety,6,7 cluster headache,9 and migraine,10 among
others.
After oral ingestion, psilocybin is rapidly dephosphorylated to
its active metabolite, psilocin.11 Maximal plasma psilocin concen-
trations are reached after 1.6–­2 hours.12,13 Psilocin is then metab-
olized to inactive psilocin glucuronide and eliminated via urine
and feces.14–­16 A large portion of psilocin is also metabolized to
inactive 4-­hydroxyindole-­3-­acetic acid (4-­HIAA) via monoamine

1
Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel and University of
Basel, Basel, Switzerland; 2Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland. *Correspondence: Matthias E. Liechti
(matthias.liechti@usb.ch)
Trial registry
Clini​calTr​ials.gov (NCT03912974 and NCT03604744).
Received August 25, 2022; accepted December 6, 2022. doi:10.1002/cpt.2821

822 CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 113 NUMBER 4 | April 2023

oxidase and aldehyde dehydrogenase.12,17 Previously reported half-­
lives of psilocin ranged between 2 and 3 hours.12,13
Some earlier trials used weight-­adjusted dosing,6,7 but psilocy-
bin is now mostly administered as single fixed doses of 15, 25, or
30 mg.3,5,18–­20 Although psilocybin has been intensively investi-
gated clinically for many years, very little pharmacokinetic (PK)
data and no data on the PK-­pharmacodynamic (PK-­PD) relation-
ship are available. Furthermore, descriptions of PKs and dose-­
effect relationships of the increasingly used fixed doses are lacking.
The few small previous PK studies used body weight-­adjusted dose
administrations,12,13 whereas therapeutic trials favor fixed doses of
psilocybin.13,21
Therefore, the present study investigated the PKs and acute ef-
fects of psilocin and the PK-­PD relationship of clinically represen-
tative fixed doses of 15, 25, and 30 mg psilocybin. For this purpose,
data from two separate phase I studies in healthy participants were
analyzed using a validated analytical method and established PK-­
PD modeling techniques.
METHODS AND MATERIALS
Study design
PK and PK-­PD modeling was conducted using data from two
separately conducted double-­ blind, placebo-­ controlled, cross-­
over studies. Other data from both studies were previously pub-
lished.19,20 In one study, 20 participants received a single dose of
25 mg psilocybin after pretreatment with placebo or escitalopram.
For the present analysis, only data from the placebo condition were
analyzed. In the other study,19 participants received single doses
of 15 and 30 mg psilocybin, 100 and 200 μg LSD, and placebo
on 5 separate test days. For the present analysis, both psilocybin
conditions were used. Both studies were conducted in accordance
with the Declaration of Helsinki and International Conference
on Harmonization Guidelines in Good Clinical Practice and
approved by the Ethics Committee of Northwest Switzerland
(EKNZ) and Swiss Federal Office for Public Health (FOPH).
Both studies were registered at Clini​calTr​ials.gov (NCT03912974
and NCT03604744).
Participants
The first study20 included 23 healthy participants (12 men and
11 women; 34 ± 10 years old (mean ± SD); range: 25–­55 years)
with a mean body weight of 70 ± 14 kg (50–­112 kg), a mean body
mass index (BMI) of 24 ± 3.5 (18–­32), and a mean glomerular
filtration rate (GFR) of 110 ± 13 mL/min/1.73 m2 (79–­129 mL/
min/1.73 m2). The second study19 included 28 healthy participants
(14 men and 14 women; 35 ± 9.4 years old (mean ± SD); range:
25–­52 years) with a mean body weight of 72 ± 12 kg (55–­104 kg),
a mean BMI of 23 ± 2.7,18–­29 and a mean GFR of 109 ± 14 mL/
min/1.73 m2 (79–­129 mL/min/1.73 m2). Participants were re-
cruited by word of mouth or from a pool of volunteers who had
contacted our research group because they were interested in
participating in a clinical trial that investigated psychedelics.
All participants provided written informed consent and were
paid for their participation. Participants aged between 25 and
65 years were included. The exclusion criteria were pregnancy
(urine pregnancy test at screening and before each test session),
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ARTICLE
personal history of major psychiatric disorders (assessed by the
Semi-­structured Clinical Interview for Diagnostic and Statistical
Manual of Mental Disorders, 4th edition, Axis I disorders), fam-
ily (first-­degree relative) history of psychotic disorders, the use of
medications that may interfere with the study medications (e.g.,
antidepressants, antipsychotics, and sedatives), chronic or acute
physical illness (e.g., abnormal physical examination, electrocar-
diogram, or hematological and chemical blood analyses), tobacco
smoking > 10 cigarettes/day, lifetime prevalence of illicit drug
use > 10 times (except Δ9-­tetrahydrocannabinol), illicit drug use
within the last 2 months, and illicit drug use during the study pe-
riod (determined by urine drug tests). The participants were asked
to consume no more than 10 standard alcoholic drinks/week and
have no more than one drink on the day before the test sessions.
Adverse events were previously reported in detail,19–­20 the most
common adverse events during the acute effect phase included
fatigue, headache, lack of concentration, lack of energy, dullness,
feeling of weakness, and loss of appetite. Subacute adverse events
included headache, migraine, low mood, and nausea. There were
no serious adverse events in regard to substance administration.
Study drugs
Psilocybin was customer synthesized for both studies with ap-
proval of the FOPH (99.7% high-­performance liquid chroma-
tography purity; ReseaChem GmbH, Burgdorf, Switzerland) and
administered as opaque capsules that contained a 5 mg dose of
psilocybin dihydrate and an exact analytically confirmed actual
psilocybin content of 4.61 ± 0.09 mg (mean ± SD, n = 10 samples).
All drug products were produced according to good manufactur-
ing practice by a licensed good manufacturing practice facility
(Apotheke Dr. Hysek, Biel, Switzerland). The formulation of psi-
locybin and its use in humans were authorized by the FOPH.
Study procedures
The first study20 included a screening visit, two 10-­hour test
sessions, and an end-­of-­study visit. The test sessions began at
7:30 am. Psilocybin was administered at 10:00 am. Outcome
measures were assessed for 7 hours after psilocybin adminis-
tration. The second study19 included a screening visit, five 25-­
hour test sessions, and an end-­of-­study visit. The test sessions
began at 8:00 am. Psilocybin was administered at 9:00 am.
In both studies, participants received a standardized breakfast
(two croissants) ~ 30 minutes before psilocybin administration.
Outcome measures were assessed for 24 hours after psilocybin
administration. For both studies, sessions were conducted in a
calm hospital room. Only one research subject and one or two
investigators were present during each test session. Before drug
administration, a urine sample was taken to verify abstinence
from drugs of abuse, and a urine pregnancy test was performed
in women. Standardized lunches were served at 1:30 pm. In the
first study, 20 participants were never alone during the test ses-
sions. The subjects were sent home at 5:30 pm with a partner
or friend. In the second study,19 the participants were never
alone during the first 8 hours or until effects had subsided.
Participants stayed overnight at the research facility with an in-
vestigator always available in the adjacent room.
823
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ARTICLE

Measures can be found in the Supplementary Methods online (Table S1,

Blood and urine sampling. Blood was collected into lithium hep-
arin tubes before and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and
7 hours after psilocybin administration in the first study20 and
before and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12,
14, 16, and 24 hours after psilocybin administration in the second
study.19 The blood samples were immediately centrifuged, and
the plasma was stored at −20°C. Urine was collected only in the
second study19 for time intervals of 0–­8, 8–­16, and 16–­24 hours
after psilocybin ingestion. Urine samples were frozen and stored
at −20°C. For long-­term storage (1–­18 months), the samples were
kept at −80°C until analysis. Stability has been shown for psilocin
and 4-­HIAA for repetitive freeze–­thaw cycles.11
Analysis of psilocin and metabolite concentrations. Plasma psilocin
and 4-­HIAA concentrations were analyzed using a validated ultra-­
high-­performance liquid chromatography tandem mass spectrom-
etry method as described previously.11 Urine psilocin and 4-­HIAA
concentrations were analyzed with the aforementioned method,
with adaptation, to process urine samples. A detailed description
Figure S1). All samples were re-­analyzed after deglucuronidation
with Escherichia coli β-­glucuronidase,11 thereby allowing the deter-
mination of concentrations of unconjugated psilocin and psilocin
glucuronide, which corresponds to the difference between samples
that were incubated with and without β-­glucuronidase.11,22
Subjective mood. Visual Analog Scales (VASs) were repeatedly
used to assess subjective effects over time. The VASs included sep-
arate measures for “any drug effect,” “good drug effect,” “bad drug
effect,”, and “ego dissolution”20,23,24 and were presented as 100 mm
horizontal lines (0–­100%), marked from “not at all” on the left to
“extremely” on the right. The VASs were administered simultane-
ously with plasma sample collection.
Pharmacokinetic analyses and pharmacokinetic-­
pharmacodynamic modeling
All of the analyses were performed using Phoenix WinNonlin
8.3 (Certara, Princeton, NJ). PK parameters were estimated
using compartmental modeling. A one-­compartment model was

Figure 1 Pharmacokinetics (PKs) of 3 doses of psilocybin, 15, 25, and 30 mg, in 28, 22, and 28 subjects, respectively. (a–­c) Predicted
individual plasma psilocin concentration-­time curves shown separately for each subject, with the mean marked in bold to illustrate the
between-­subject variability of psilocin concentrations after the administration of a 15 mg, b 25 mg, and c 30 mg psilocybin. (d) Plasma psilocin
concentration-­time curves that represent the mean of individual PK model predictions. The observed data are expressed as symbols and the
mean ± SEM. Dose-­linear increases in psilocin concentrations were observed. Psilocybin was administered at t = 0 hours. PK parameters are
listed in Table 1.

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ARTICLE

used with first-­order input, first-­order elimination, and lag time
to account for oral administration in gelatin capsules. Initial esti-
mates for apparent volume of distribution and λ were derived from
noncompartmental analyses. The model fit was not relevantly im-
proved by a 2-­compartment model but by a 1/y weighting when
sampling up to 24 hours, based on visual inspection of the plots.
The one-­compartment model also resulted in smaller Akaike
information criterion values in all subjects compared with a two-­
compartment model. The PK model was first fitted and evaluated.
The predicted concentrations were then used as an input to the PD
model by treating the PK parameters as fixed and using the clas-
sic PK-­PD link model module in WinNonlin. The model used a
first-­order equilibrium rate constant that related the observed PD
effects of psilocin to the estimated psilocin concentrations at the
effect site and accounted for the lag between the plasma and effect
site concentration curves.25,26 A sigmoid maximum effect (Emax)
model (half-­maximal effective concentration (EC50), Emax, and γ)
was selected for all PD effects. Lower and upper limits for Emax
were set to 0% and 100%, respectively, for all VASs scores. The sig-
moidal Emax model best described the relationship between esti-
mated effect-­site concentrations and psilocybin effects compared
with a simple Emax model (plot inspection (Figure S2) and Akaike
information criteria). Renal clearance (mL/h) was calculated as
urinary recovery (ng)/24-­hour area under the concentration-­time
curve (AUC24; ng × h/mL).
Statistical analyses
The onset, time to maximum concentration (Cmax; Tmax), offset,
and effect duration were assessed for the model-­predicted “any
drug effect” VAS effect-­time plots after psilocybin administration
using a threshold of 10% of the maximum individual response
using Phoenix WinNonlin 8.3. Pearson’s correlations between
body weight, BMI, GFR, and age and plasma concentrations were
calculated using Statistica 12 software (StatSoft, Tulsa, OK).
RESULTS
Pharmacokinetics of psilocin and its metabolites in plasma
and urine
Plasma concentrations of psilocin and 4-­HIAA were quantified
before and at all time points after treatment. All samples were re-­
analyzed after deglucuronidation. Plasma levels of psilocin glucu-
ronide were determined based on the difference between samples

Figure 2 Pharmacokinetics (PKs) of free psilocin (unconjugated), psilocin glucuronide, and 4-­hydroxyindole-­3 -­acetic acid (4-­HIAA) for three
doses of psilocybin, 15, 25, and 30 mg, in 28, 22, and 28 subjects, respectively. The graphs show observed plasma concentrations for
(a) 15 mg, (b) 25 mg, and (c) 30 mg psilocybin. The data are expressed as the mean ± SEM. Psilocybin was administered at t = 0 hours. PK
parameters are listed in Table S2.

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ARTICLE

that were incubated with and without glucuronidase, correspond-

(156–­190)

(159–­193)
(175–­225)
CL/F (L/h)

119– ­335

110–­309
108–­359
ing to the total amount of conjugated metabolites.

AUC∞, area under the plasma concentration-­time curve from time zero to infinity; CI, confidence interval; CL/F apparent total clearance; Cmax, estimated maximum plasma concentration; t1/2, estimated plasma
199

175
172
The plasma concentration-­time curves for psilocin, includ-
ing individual PK model-­predicted psilocin concentration-­time
curves, are shown in Figure 1. The individual observed psilocin
concentrations are shown in Figures S3-­S5, together with their

(103–­125)
(ng·h/mL)

64–­180
49–­140
(52–­64)

(74–­94)
28– ­92
individual model-­predicted curves. Predicted curves could not

AUC∞

113
83
58
be modeled in one participant, thus leading to a sample of 22
participants in the first study (25 mg dose of psilocybin). Plasma
concentration-­time curves for psilocin glucuronide and 4-­HIAA

0.94–­4.3

(1.6–­1.9)
(1.2–­1.7)
(1.7–­2.0)
1.2–­3.0

1.2–­2.7
are shown in Figure 2. Corresponding PK parameters are shown

t1/2 (h)
1.8

1.8
1.4
in Table 1. Parameters based on the noncompartmental analysis

terminal elimination half-­life; Tmax, estimated time to reach Cmax; k01, first-­order absorption coefficient; λ z, first order elimination coefficient; Vz/F volume of distribution.
are summarized in Table S2. Figure 1a–­c also illustrate between-­
subjects variance in the concentrations of psilocin for each dose.

0.99–­3.4
(1.8–­2.2)

(2.0–­2.4)
0.81–­3.1

(1.7–­2.2)
Coefficients of variation for Cmax values (Table 1) were 23%, 20%,

1.1–­3.2
Tmax (h)

2.2
1.9
2.0
and 27% for the 15, 25, and 30 mg psilocybin doses, respectively.
Values indicate overall moderate variance and greater variance at

Table 1 Pharmacokinetic parameters for different doses of unconjugated psilocin based on compartmental modeling
the highest dose.
Unconjugated psilocin was rapidly metabolized to 4-­HIAA or

(ng/mL)

(10–­13)

(16–­19)

(19–­24)
6.2–­17

12–­33
11–­25
Cmax
glucuronidated (Figure 2). Psilocin and its metabolites displayed

11

21
17
dose-­proportional increases in plasma concentrations. Maximal
plasma concentrations of unconjugated psilocin were reached after

241–­1,319
(348–­4 89)
(394–­509)
a mean of 2.0, 1.9, and 2.2 hours for the 15, 25, and 30 mg psilo-

(393–­515)
254– ­853

248–­813
Vz/F (L)
448

450
cybin doses, respectively. Elimination occurred according to first-­

413
order kinetics. Elimination half-­lives were 1.8, 1.4, and 1.8 hours
for the 15, 25, and 30 mg psilocybin doses, respectively, defined
using compartmental analysis (Table 1). Neither plasma concen-
(0.24–­0.38)

(0.19–­0.40)

(0.24–­0.42)
0.09–­1.33

0.03–­0.73

0.05–­1.3
trations (Cmax or AUC values) nor subjective effects (Emax values)
Tlag (h)
0.30

0.28

0.31
correlated significantly with body weight, BMI, GFR, or age.
Concentrations and molar concentrations of psilocin (molecu-
lar weight: 204.3), psilocin glucuronide, and 4-­HIAA (molecular
(0.35–­0.42)

(0.36–­0.42)
(0.41–­0.56)
0.23–­0.60

0.26–­0.57
0.16–­0.74
weight: 191.2) in urine and corresponding urinary recovery are
λ z (1/h)
0.38

0.48

0.39
shown in Table 2. Urinary recovery was obtained in 27 and 26 par-
ticipants for the 15 and 30 mg psilocybin doses, respectively. An
average of 75%, 61%, and 81% of the nonmetabolized psilocin, psi-
locin glucuronide, and 4-­HIAA, respectively, that was recovered
(0.61–­0.92)
(0.58–­1.0)
(0.73–­1.1)

0.33–­4.4
0.43–­5.7

0.35–­2.7
K01 (1/h)

from urine appeared in urine within the first 8 hours after adminis-
0.89

0.77

0.75

tration. Of the orally administered psilocybin (9.9 mg or 48.7 μmol

psilocin in the 15 mg dose or 19.9 mg or 97.3 μmol in the 30 mg
dose), an average of 20% was eliminated in urine as psilocin glu-
curonide and 33% was eliminated as 4-­HIAA. Only 1.5% of the
28

22

28
N

orally administered psilocybin was eliminated in urine as unconju-

gated psychoactive psilocin within 24 hours. The renal clearance of
mean (95% CI)

mean (95% CI)

mean (95% CI)

psilocin was 42 ± 30 mL/min.

Geometric

Geometric
Geometric
Range

Range

Range

Subjective effects
The PK-­PD model-­predicted subjective effect-­time curves for VAS
ratings of “any drug effect,” “good drug effect,” “bad drug effect,”
and “ego dissolution” are shown in Figures 3 and 4. Psilocybin
Dose (mg)

dose-­dependently increased “any drug effect” (Figure 3) and

30
15

25

“good drug effect” (Figure 4a–­d). Transient “bad drug effect” was
reported in some subjects, resulting in a moderate increase in mean
group ratings (Figure 4e–­h). Psilocybin also dose-­dependently
Psilocybin

increased “ego dissolution” (Figure 4i-­l). Variability in the inten-

sity of subjective drug effects is illustrated in the “any drug effect,”
“good drug effect,” bad drug effect,” and “ego dissolution” curves in

826 VOLUME 113 NUMBER 4 | April 2023 | www.cpt-journal.com

 Table 2 Urinary elimination of psilocin, psilocin glucuronide, and 4-­HIAA
Psilocin (unconjugated) Psilocin glucuronide 4- ­HIAA

0-­8 hours 8-­16 hours 16-­24 hours 0–­24 hours 0-­8 hours 8-­16 hours 16-­24 hours 0–­24 hours 0-­8 hours 8-­16 hours 16-­24 hours 0–­24 hours

N=
Urinary concentrations Ae0-­24
ng/mL
15 mg 27 96 ± 100 46 ± 42 19 ± 19 1,100 ± 721 1,240 ± 1,073 270 ± 227 2,198 ± 1,370 812 ± 801 179 ± 158
30 mg 26 163 ± 139 87 ± 70 46 ± 46 2,131 ± 1708 2,386 ± 1734 732 ± 802 4,240 ± 2,532 1870 ± 430 ± 438
2,305
nmol/mL
15 mg 27 0.47 ± 0.49 0.23 ± 0.20 0.09 ± 0.10 5.4 ± 3.5 6.1 ± 5.3 6.1 ± 2.4 11 ± 7.2 4.2 ± 4.2 0.94 ± 0.83
30 mg 26 0.80 ± 0.68 0.43 ± 0.34 0.22 ± 0.22 10 ± 8.4 12 ± 8.5 3.6 ± 3.9 21 ± 14 9.6 ± 12 2.2 ± 2.3
Urinary volume (mL)

CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 113 NUMBER 4 | April 2023

15 mg 27 1,455 ± 644 775 ± 495 673 ± 437
30 mg 26 1,398 ± 575 702 ± 448 565 ± 464
Urinary recovery Ae0-­24
μg
15 mg 27 109 ± 97 29 ± 26 8.4 ± 5.1 145 ± 98 1,244 ± 490 669 ± 378 128 ± 64 2040 ± 527 2,498 ± 898 480 ± 484 88 ± 57 3,066 ± 951
30 mg 26 223 ± 194 48 ± 33 17 ± 11 279 ± 209 2,396 ± 816 1,208 ± 490 295 ± 221 3,899 ± 807 5,080 ± 2,313 906 ± 640 162 ± 104 6,148 ± 2,382
μmol
15 mg 27 0.53 ± 0.48 0.14 ± 0.13 0.04 ± 0.03 0.71 ± 0.48 6.1 ± 2.4 3.3 ± 1.9 0.62 ± 0.31 10 ± 2.6 13 ± 4.7 2.5 ± 2.5 0.46 ± 0.30 16 ± 5.0
30 mg 26 1.1 ± 0.95 0.23 ± 0.16 0.08 ± 0.05 1.4 ± 1.0 12 ± 4.0 5.9 ± 2.4 1.4 ± 1.1 19 ± 4.0 27 ± 12 4.7 ± 3.3 0.85 ± 0.55 32 ± 12
Values are mean ± SD; 15 mg psilocybin (exact content: 13.8 mg) = 9.9 mg psilocin (48.7 μmol); 30 mg psilocybin (exact content: 27.7 mg) = 19.9 mg psilocin (97.3 μmol).
Ae, amount eliminated.

827
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Figure 3 Subjective effects of psilocybin over time based on Visual Analog Scale (VAS) ratings from 0 to 100 for “any drug effect” for the
15, 25, and 30 mg psilocybin doses. (a–­c) Individual psilocybin effect-­time curves for a 15 mg, b 25 mg, and c 30 mg. Predicted individual
effect-­time curves are shown separately for each subject, with the mean marked in bold to illustrate the between-­subject variability of
psilocybin effects after the administration of a 15 mg, b 25 mg, and c 30 mg psilocybin. (d) Effect-­time curves represent the mean of individual
pharmacokinetic model predictions. The observed data are expressed as symbols and the mean ± SEM. Psilocybin was administered at
t = 0 hours.

Figures 3 and 4. Individual ratings for each subject and time point
are shown in Figures S6-­S17, together with the modeled curves.
Effect durations, assessed by the “any drug effect” VAS, are
shown in Table 3. Effect durations dose-­proportionally increased,
with higher doses resulting in a longer duration of effects. Time
to onset was similar for all three doses, and effects peaked after
~ 2 hours for all doses.
The PK-­PD modeling parameters are shown in Table S3.
Predicted concentrations of psilocin that produced half-­maximal
effects (EC50 values) were in the same range for all drug effects.
However, Emax values were 3–­5 times lower for “bad drug effects”
than for all other subjective effects.
DISCUSSION
The present study comprehensively described the PKs, PK-­PD re-
lationship, and urinary recovery of clinically representative fixed
doses of psilocybin (15–­30 mg) for the first time. Previous PK
studies investigated body weight-­adjusted doses.12,13,27 In the pres-
ent study, psilocybin administration resulted in dose-­proportional
changes in plasma psilocin (unconjugated), psilocin glucuron-
ide, and 4-­HIAA concentrations and dose-­proportional urinary
recovery. The average plasma elimination half-­lives were 1.8, 1.4,
and 1.8 hours according to the compartmental analysis and 2.4,
1.8, and 2.7 hours according to the noncompartmental analysis for
the 15, 25, and 30 mg doses, respectively. The noncompartmen-
tal analysis provides the best estimate of the terminal elimination
half-­life (t½), whereas the compartmental analysis best reflects the
clinically relevant plasma half-­life during the first 8 hours when
psychotropic effects occur. The modeled elimination half-­lives
were shorter than the 3–­5 hour half-­lives that were previously
reported.12,13,27 The shorter half-­lives of psilocin in the present
analysis align well with the short duration of the acute action
of psilocybin as also documented in the PK-­PD analysis and are
consistent with the PK-­PD of LSD, in which longer-­lasting effects
mirror a longer plasma half-­life of LSD (t1/2 = 3.5–­4 hours).23,28
Previous studies of the PKs of psilocybin were small, and unclear
is whether unconjugated or total concentrations of psilocin were
measured. Furthermore, the present study found no associations
between body weight and plasma concentrations of unconjugated
(free) psilocin for the body weight and dose range included in this
study, indicating that body weight-­adjusted dosing is very likely
unnecessary and may actually result in doses that are too high in

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ARTICLE

Figure 4 Subjective effects of psilocybin over time based on Visual Analog Scale (VAS) ratings from 0 to 100 for (a–­d) “good drug effect,” (e, f)
“bad drug effect,” and (i-­l) “ego dissolution” for the 15, 25, and 30 mg psilocybin doses. a “Good drug effect”-­time curves represent the mean
of individual model predictions and observed data. b-­d Predicted individual “good drug effect”-­time curves for b 15 mg, c 25 mg, and d 30 mg.
(e) “Bad drug effect”-­time curves represent the mean of individual model predictions and observed data. (f–­h) Predicted individual “bad drug
effect”-­time curves for f 15 mg, g 25 mg, and h 30 mg. (i) “Ego dissolution”-­time curves represent the mean of individual model predictions and
observed data. (j-­l) Predicted individual “ego dissolution”-­time curves for j 15 mg, k 25 mg, and l 30 mg. Predicted individual effect-­time curves
are shown separately for each subject, with the mean marked in bold to illustrate the between-­subject variability of psilocybin effects after
administration. The observed data are expressed as symbols and the mean ± SEM. Psilocybin was administered at t = 0 hours.

very heavy patients. This aligns with a previous study that investi-
gated associations between subjective effects and body weight and
recommended fixed doses.21
In the present study, we also described the PKs and urinary
recovery of the main metabolites of psilocin, 4-­HIAA, and psi-
locin glucuronide. Psilocin undergoes extensive metabolism,
with only ~ 1.5% of psilocin eliminated unchanged in urine.
This finding indicates that likely no dose adjustment is required
in patients with renal impairment as previously noted.13 The
largest portion of psilocin is rapidly metabolized to 4-­HIAA or
undergoes glucuronidation. 4-­HIAA has an elimination half-­life
that is similar to unconjugated psilocin, whereas psilocin glucu-
ronide has a significantly longer half-­life and remains in the body
longer. In line, the largest portions of unconjugated psilocin and
4-­HIAA are eliminated within the first 8 hours, whereas the
largest portion of psilocin glucuronide is eliminated 8–­16 hours
after oral ingestion. Amounts of unchanged eliminated psilocin
are small (1.5%) and similar to a previous study (< 2%)13 but
slightly lower than in another study (3.4%).14 However, these
previous studies were small and used body weight-­adjusted dos-
ing. Here, we report the urinary recovery of 4-­HIAA for the first
time. Combined, ~ 54% of the administered dose of psilocybin
is excreted renally within 24 hours as 4-­HIAA, free psilocin, or
psilocin glucuronide.
The plasma concentration-­time curve of unconjugated psi-
locin is consistent with the within-­subject effect-­time curve as
documented with PK-­PD modeling in this study. Subjective ef-
fects of psilocin closely mirror unconjugated psilocin concentra-
tions in healthy participants, indicating that effects are generally
present as long as psilocin is not further metabolized, and there
was no sign of acute tolerance. This was similarly described for
LSD in previous PK-­PD studies,28,29 with LSD having a longer
plasma half-­life and longer duration of subjective action com-
pared with psilocybin.19 Therefore, the subjective effects of psi-
locybin and its plasma concentrations are closely linked within
subjects as evidenced by the PK-­PD model fit. Greater variance
in subjective effects of psilocybin can be observed between indi-
viduals. However, the variance in plasma concentrations between

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ARTICLE

Table 3 Characteristics of the subjective response to different doses of psilocybin

15 mg Psilocybin 25 mg psilocybin 30 mg Psilocybin
Effect n = 28 n = 21* n = 28
Time to onset (hours) 0.8 ± 0.3 0.7 ± 0.4 0.7 ± 0.3
(0.3–­1.5) (0.2–­1.5) (0.1–­1.5)
Time to offset (hours) 6.3 ± 2.1 6.2 ± 1.4 7.1 ± 2.1
(3.7–­11) (2.7–­8) (4.1–­12)
Time to maximal effect (hours) 2.1 ± 0.5 1.9 ± 0.5 2.2 ± 0.7
(1.5–­3.4) (0.9–­2.7) (0.5–­3.3)
Effect duration (hours) 5.6 ± 2.2 5.5 ± 1.6 6.4 ± 2.2
(2.5–­10) (1.9–­7.8) (3.7–­12)
Maximal effect (%) 58 ± 25 76 ± 22 79 ± 19
(13–­98) (8.0–­99) (42–­100)
Parameters are for “any drug effects” as predicted by the PK-­PD link model. The threshold to determine times to onset and offset was set individually at 10% of
the individual maximal response. Values are mean ± SD (range). *Only for 21 subjects (instead of 22) due to one subject not showing any response, and therefore
failed to fit the model.
PD, pharmacodynamic; PK, pharmacokinetic.

subjects was relatively small, indicated by coefficients of variation
for Cmax values of 20–­26%, and clearly smaller than the variance
in PK parameters between subjects in a study that used weight-­
adjusted dosing and another formulation of psilocybin.13 The low
variance in PK parameters was previously reported for fixed doses
of LSD in 2 similar studies that assessed PK-­PD relationships for
5–­200 μg doses of LSD.28,29 The relatively low variance may in-
dicate that formulations with a consistent and stable content of
psilocybin as used in the present study likely results in relatively
similar exposure to the drug and more consistent responses across
different healthy volunteers and potentially patients. This is likely
relevant for clinical trials that investigate potential therapeutic ef-
fects of psilocybin.
In the present study, we assessed dose-­effect relationships for
subjective drug effects. Overall, subjective effects and effect dura-
tions increased dose-­proportionally in the dose range of 15–­30 mg
psilocybin. “Any drug effects,” “good drug effects,” and “ego disso-
lution” dose-­dependently increased, although data were combined
from two different studies. In contrast, no clear dose–­response
was found for “bad drug effects.” “Bad drug effects” were higher in
the study20 that used 25 mg compared with the 30 mg dose in the
other study,19 possibly attributable to study-­specific differences.
Generally, “bad drug effect” ratings were very low, and EC50 values
were within a similar range for all doses.
We also assessed effect durations using the PK-­PD model.
Overall and as expected, effect durations were dose-­dependent.
However, durations of subjective effects of 15 and 25 mg psilocy-
bin were similar, most likely because of methodological differences
between studies because in the first study20 that used 25 mg, ses-
sions ended after 7 hours and effects were not assessed at later time
points, whereas in the second study19 that used 15 and 30 mg, ef-
fects were assessed up to 24 hours.
The present study has several strengths. We used data from two
randomized trials that were conducted within the same highly con-
trolled laboratory setting. Both studies included similar numbers
of male and female participants and used psilocybin capsules from
the same batch that was well-­characterized pharmaceutically with a
known exact drug content. Plasma concentrations of free psilocin,
psilocin glucuronide, and 4-­HIAA were determined using a val-
idated analytical method. Urine concentrations of analytes were
determined using the same, slightly adapted method to process
higher concentrations that accumulate in urine.
The present study also has limitations. We used data from two
different participant populations, and the 25 mg study20 assessed
no urine recovery or plasma concentrations and assessed effects
only up to 7 hours after psilocybin administration. Thus, two
slightly different configurations within the PKs model had to be
used for the best fit.
In conclusion, we described the PKs and PK-­PD relationship of
fixed doses of oral psilocybin in healthy participants. Subjective ef-
fects were closely related to plasma concentrations of unconjugated
psilocin, and body weight did not influence plasma concentrations
of psilocin. These findings are important for further clinical stud-
ies of psilocybin.
SUPPORTING INFORMATION
Supplementary information accompanies this paper on the Clinical
Pharmacology & Therapeutics website (www.cpt-journal.com).
ACKNOWLEDGMENTS
The authors thank Michael Arends for proofreading the manuscript.
AUTHOR CONTRIBUTIONS
F.H. and M.E.L. wrote the manuscript. F.H. and M.E.L. designed the
research. A.M.B., K.E.K., F.H., and U.D. performed the research. F.H.,
A.M.B., K.E.K., U.D., and M.E.L. analyzed the data.
CONFLICT OF INTEREST
M.E.L. is a consultant for Mind Medicine, Inc. All other authors declared
no competing interests for this work.
FUNDING
This work was supported by the Swiss National Science Foundation
(grant no. 32003B_185111 to M.E.L.), University Hospital Basel, and
Mind Medicine, Inc. Knowhow and data associated with this work and
owned by the University Hospital Basel were licensed by Mind Medicine,
Inc. Mind Medicine, Inc., had no role in planning or conducting the
present study or the present publication.

830 VOLUME 113 NUMBER 4 | April 2023 | www.cpt-journal.com


© 2022 The Authors. Clinical Pharmacology & Therapeutics published
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Pharmacology and Therapeutics.
This is an open access article under the terms of the Creative Commons
Attribution-NonCommercial License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited
and is not used for commercial purposes.
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