Psilocybin
tion, and cognition.
GENERAL INFORMATION
In 1957, psilocybin was isolated from the Psilocybe mex-
icana mushroom and it has since been identified as a
component of over 75 distinct mushroom species [1].
Psilocybin-containing mushrooms, also called “magic
mushrooms”, are used recreationally, with an expanding
worldwide distribution. They are sold in “smart shops”
and over the internet. Psilocybin is also used in nightclubs,
although its use is not as popular as “club drugs” such as
ecstasy or amphetamines.
Psilocybin and psilocin are listed as Schedule I drugs
under the United Nations 1971 Convention on Psycho-
tropic Substances. Spore prints, which are distributed in
home-growing kits, are currently legal in several states of
the USA and can be purchased over the internet [2].
Psilocybin content varies based on such factors as spe-
cies and preparation. The most commonly used mushroom
is Psilocybe cubensis, which contains 10–12 mg of psilo-
cybin per gram of dried mushrooms; effective oral doses
range from 6 to 20 mg and about 40 micrograms/kg is
considered the threshold level for intoxication [3].
Structure
Psilocybin (N-phosphoryloxy-N,N-dimethyltryptamine),
a simple tryptamine, is dephosphorylated to psilocin
(4-hydroxy-N,N-dimethyltryptamine) by alkaline phos-
phatase in the gastrointestinal tract and kidneys during
first-pass metabolism. Psilocin, the pharmacologically
active compound, is an indole derivative with structural
similarities to serotonin. Psilocybin is detectable by high
performance liquid chromatography, but this is not avail-
able in most clinical settings.
Action
Psilocin is a high-affinity agonist at serotonin 5HT2A
receptors, which are especially prominent in the prefron-
tal cortex. The net result of 5HT2A agonism is increased
cortical activity secondary to down-stream postsynaptic
glutamate effects. Psilocin is also active at 5HT1A,
5HT1D, and 5HT2C receptors, although these are thought
to play a lesser role in its effects.
Additional evidence about the mechanism of action
comes from studies of receptor antagonists. In the presence
of the 5HT2A antagonist ketanserin, the mental status
changes typical of psilocybin do not occur, supporting the
notion that primary effects are due to action at presynaptic
5HT2A receptors [4]. Although psilocybin has no affinity
for dopamine D2 receptors, a PET study using the dopa-
mine D2 receptor ligand raclopride showed that psilocybin
increases dopamine transmission in the striatum, probably
through secondary increases in dopamine [5,6]. Some
psilocybin-containing mushrooms contain phenylethyl-
amine, which may contribute to sympathomimetic effects.
Psilocybin like other serotonergic hallucinogens,
such as lysergic acid diethylamide (LSD) and
ã 2016 Elsevier B.V. All rights reserved.
N,N-dimethyltryptamine (DMT), alters mood, percep-
In healthy volunteers, changes in emotion, conscious-
ness, perception and thought begin within 20–30 minutes
of ingestion and peak in 30–50 minutes. Peak effects per-
sist for 2 hours, with resolution of effect within 6 hours.
Lower doses may produce shorter lasting effects of 1–2
hours. Moderate oral doses (12–30 mg) alter conscious-
ness, increase introspection, and induce derealization,
dream-like states, illusions, complex hallucinations, synes-
thesia, and altered perceptions of time and space. Muscle
relaxation is also experienced with intoxication. Disrup-
tions in attention, such as difficulty in disengaging from
prior stimuli and impairment in monitoring several simul-
taneous visual stimuli, have been described [7]. Euphoria,
grandiosity, and other amplifications of affective experi-
ence are common. The majority of psilocybin users expe-
rience a pleasant alteration in mood, but some experience
panic or dysphoria. A user’s expectations and environ-
ment very strongly influence the hallucinogenic effects.
Settings with more interpersonal support reduce panic
and paranoia and increase positive experiences [8].
Psilocybin and psilocin are renally excreted, and about
2/3 of excretion occurs in the first 3 hours. The half-life is
about 50 minutes [6]. After 24 hours, the compound is
undetectable in the urine [9].
Uses
Psilocybin has been used in obsessive–compulsive disor-
der (OCD) and some studies support its efficacy in this
disorder. In a double-blind study, nine subjects received
four doses, low (100 micrograms/kg), medium (200 micro-
grams/kg), and high (300 micrograms/kg), in a series of
8-hour sessions with a very low dose (25 micrograms/kg)
inserted randomly in a double-blind manner. All the sub-
jects had a reduction in their symptoms (measured by the
Yale-Brown Obsessive Compulsive Scale) during at least
one of the sessions, and improvement lasted at least 24
hours. No dose effect was noted, probably because of the
small number of subjects studied and large interindividual
variability. With the exception of one subject who had
transient hypertension, psilocybin was well tolerated and
without adverse reactions [10,11].
Synthetic psilocybin (Indocybin) was used for investiga-
tional and psychotherapeutic purposes in the 1960s. The
serotonin hypothesis of schizophrenia grew in part from
the psychotomimetic effects of psilocybin seen in these
investigations, as well as similar observations in studies
of LSD. Psilocybin impairs thalamic sensory gating, result-
ing in an inability to screen out extraneous stimuli and
difficulties attending to appropriate stimuli, which over-
whelms frontal organizational capacities and is thought to
result in the observed psychotomimetic effects [6,12].
ORGANS AND SYSTEMS
Cardiovascular
An 18-year-old man developed Wolff–Parkinson–White
syndrome and had a myocardial infarction during

psilocybin intoxication [13]. The mechanism for myocar-
dial infarction is not known, although it is theorized
that serotonin-induced changes in platelet aggregation
and sympathetically-induced vasospasm may play a
role [14].
In a study of the dose-dependent effects of psilocybin
45–315 micrograms/kg in eight subjects, there was no
effect on the electrocardiogram or heart rate [15]. At the
highest doses, mean arterial blood pressure rose signifi-
cantly in the 60 minutes after psilocybin ingestion, leading
the authors to recommend that those with untreated
hypertension should abstain from psilocybin.
An acute coronary syndrome with ST-segment eleva-
tion has been reported in the absence of coronary artery
disease after abuse of psychoactive fungi (“magic mush-
rooms”) [16].
 A 17-year-old boy developed chest pain and dyspnea at rest
after consuming Psilocybe semilanceata. His blood pressure was
120/60 mmHg and his heart rate 93/minute. In a 12-lead elec-
trocardiogram there were right bundle branch block and ST-
segment elevation in leads I, II, aVL, aVF, and V3–V6. Serum
troponin T concentration and creatine kinase (CK) activity
were raised, as was the CK-MB fraction. Drug screening
excluded other substances. He had no cardiovascular risk
factors. Coronary angiography showed normal coronary arter-
ies, but left ventriculography showed a regional wall motion
abnormality in the apical segment and a reduced ejection frac-
tion. Cardiovascular MRI scanning confirmed the contractile
pattern. There was a pericardial effusion. Left ventricular func-
tion normalized after 6 days and the pericardial effusion
resolved with anti-inflammatory drug therapy.
The authors attributed this presentation to takotsubo car-
diomyopathy (left ventricular ballooning syndrome) due
to psilocybin, probably resulting from its catecholamine-
like action.
Nervous system
In an interview study of 53 subjects with cluster headaches
who were using psilocybin or LSD to treat their symp-
toms, 32 had episodic cluster headache and 21 had chronic
cluster headaches; 17 of 19 who tried sublingual psilocybin
reported that it terminated the headache within 20
minutes [17]. Of the 29 who used psilocybin as prophy-
laxis, 15 described it as completely effective in avoiding
headaches and 12 (42%) reported that it reduced the
frequency or intensity of headaches. Of the 21 subjects
with chronic cluster headaches, seven tried psilocybin to
abort a headache and five felt that it was effective; 20 tried
psilocybin as prophylaxis and 10 reported a complete
response, while eight reported partial efficacy. This small
study used a retrospective design and may have been
affected by recall bias, selection bias, and by its unblinded
and uncontrolled design.
In a double-blind study of a range of psilocybin doses
(0, 5, 10, 20, and 30 mg/70 kg) in 18 healthy participants
headache was common, with an incidence, duration, and
severity that increased dose-dependently [18]. The head-
aches were of delayed onset and were transient, lasting
no more than a day. Nitric oxide release was suggested as a
possible mechanism.
ã 2016 Elsevier B.V. All rights reserved.
Psilocybin 1049
Psychological
Psilocybin and other hallucinogenic drugs cause alter-
ations of time perception, such as “time standing still”
and mystical or ecstatic states. In a placebo-controlled
study of two doses of psilocybin (115 and 250 micro-
grams/kg) on temporal processing, using tasks of temporal
reproduction, sensorimotor synchronization, and tapping
tempo in 12 healthy volunteers, psilocybin significantly
impaired their ability to reproduce interval durations lon-
ger than 2.5 seconds and to synchronize to inter-beat
intervals longer than 2 seconds; it also caused subjects to
be slower in their preferred tapping rate [19]. These
effects were accompanied by deficits in working memory
and subjective changes in conscious state (increased
reports of depersonalization and derealization, including
disturbances in subjective time sense). The authors pro-
posed that these results suggest that the serotonin system
is selectively involved in duration processing of intervals
longer than 2–3 seconds and in the voluntary control of the
speed of movement. They speculated that selective dis-
ruption of longer intervals by psilocybin is likely to result
from interactions with cognitive dimensions of temporal
processing, presumably via 5HT2A receptor stimulation.
The action of psilocybin on internal time representation
has been investigated in two double-blind, placebo-
controlled studies, in 12 subjects with graded doses and
in 9 subjects at a very low dose [20]. The effects were
assessed by measuring k, a parameter of the dual klepsy-
dra model of internal time representation, fitted to indi-
vidual response data and intraindividually normalized
with respect to initial values. In both experiments, k was
significantly prolonged by psilocybin at 90 minutes, indi-
cating a higher loss rate of internal duration representa-
tion. The authors suggested that this effect may be linked
to the effects of psilocybin on subjective time.
Psilocybin-containing mushrooms can sometimes cause
a “bad trip”, a psychotic reaction accompanied by fear,
panic, and dangerous behavior, especially when used in
combination with other drugs and alcohol or by psychiat-
rically unstable patients. Two young men, aged 25 and 32
years automutilated with knives after consuming halluci-
nogenic mushrooms; the first had also used cocaine, can-
nabis, and alcohol, but the second had used only the
mushrooms [21].
Psychiatric
Two cases of exacerbation of pre-existing psychosis have
been reported [22].
 A 35-year-old man with a history of schizophrenia developed
anxiety, irritability, agitation, and aggression while using “a
handful” of psilocybin-containing mushrooms plus cannabis
twice daily. He also reported delusions of external control and
persecution as well as auditory, olfactory, and gustatory hallu-
cinations. He was given risperidone 3 mg/day and his symptoms
gradually improved over 2 weeks.
 A 35-year-old man with a 10-year history of paranoid schizo-
phrenia experienced mood elevation, anxiety, and psychomotor
agitation as well as illusions, hallucinations, “sensory dysper-
ceptions”, paranoia, compulsive thinking, and poor attention
after taking psilocybin (amount and duration of exposure not
specified). The symptoms resolved within days without phar-
macologic treatment.
1050 Psilocybin
While these case studies suggest a possible role for psilo-
cybin in exacerbating psychosis, the small number of cases
and factors such as the simultaneous use of cannabis in the
first case make it difficult to draw a more definitive
conclusion.
Hallucinogen persisting perceptual disorder (HPDD)
has been reported after psilocybin [23].
 An 18-year-old man with no prior psychiatric history who
smoked cannabis weekly and took a single dose of 40
psilocybin-containing mushrooms, after which he experienced
visual distortions, temporal and spatial distortions, depersonal-
ization, and derealization. These symptoms remitted, but
recurred the next day in conjunction with cannabis use and
continued daily thereafter. His symptoms, including hallucina-
tions, depersonalization, derealization, and dysphoric mood,
remitted 8 months later, after discontinuation of cannabis and
treatment with sertraline 150 mg/day and risperidone 2 mg/day.
The authors commented that both cannabis and psilocybin
may play a role in triggering HPDD.
There have been anecdotal reports that hallucinogens
induce religious experiences and heightened spirituality.
This has been investigated in a double-blind study in 36
healthy hallucinogen-naı̈ve volunteers, who were assigned
to either psilocybin (30 mg per 70 kg) or methylphenidate
(40 mg per 70 kg) in an 8-hour drug session, returning at a
later date for a session with the other drug [8]. Monitors
were assigned to provide support throughout the sessions
and a comfortable environment was maintained. Based on
criteria from the Mysticism Scale and the States of Con-
sciousness Questionnaire, 22 of 36 volunteers had a “com-
plete” mystical experience with psilocybin, compared with
four of 36 in response to methylphenidate. The authors
noted that 33% of participants described the psilocybin
experience as their most significant spiritual experience in
life and another 38% rated the experience within their top
10 most significant experiences. Dysphoria or anxiety in the
6 hours after psilocybin was reported by eight of the 36
participants; these reactions responded to reassurance and
did not persist beyond the duration of the session. Of these
healthy volunteers without a history of psychosis, 17%
reported transient ideas of reference or paranoia in
response to psilocybin; there were no lasting adverse effects.
Endocrine
In a double-blind, placebo-controlled study of psilocybin in
32 healthy volunteers, drug exposure did not affect prolac-
tin, cortisol, or growth hormone concentrations [24].
In a study of the dose-dependent effects of psilocybin 45–
315 micrograms/kg in eight subjects, there were transient
rises in thyroid stimulating hormone, prolactin, ACTH, and
cortisol [15]. These effects were unlikely to be clinically
relevant, since all values returned to baseline by 300
minutes after ingestion. The authors noted that only the
prolactin concentrations fell outside the reference range.
Electrolyte balance
Psilocybin has no effect on electrolyte balance (measured
at 105 and 300 minutes after exposure to 45–315 micro-
grams/kg) [15].
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Liver
Psilocybin has no clinically relevant effects on liver func-
tion [15]. Brief, statistically significant increases in
gamma-glutamyltransferase and aspartate aminotransfer-
ase activity resolved within 300 minutes of exposure.
Body temperature
Psilocybin has no effect on axillary body temperature [15].
Trauma
Hallucinogen intoxication can result in traumatic injury if
people believe that they have superhuman powers [25].
Death
Psilocybin mushrooms are not known to cause major
organ toxicity or death, but mis-identification can lead to
the ingestion of toxic species with potentially fatal out-
comes. For example, there have been reports of renal
failure after ingestion of Cortinarius mushrooms that
were mistaken for Psilocybe species [26,27].
LONG-TERM EFFECTS
Drug abuse and tolerance
Psilocybin and other hallucinogens are not considered
classic drugs of abuse because they do not have reinforcing
properties and do not produce drug-seeking behaviors [8].
Use tends to be episodic and is generally short-term and
experimental [24]. Tolerance occurs with repeated dosing
and is thought to be due to down-regulation of 5HT2A
receptors [24]. There may also be cross-tolerance between
LSD and psilocybin [2,6]. Psilocybin, like other hallucino-
gens, is not known to cause dependence, craving, or
withdrawal.
INTERFERENCE WITH DIAGNOSTIC
TESTS
Urine toxicology may be falsely positive for amphet-
amines because of the phenylethylamine in psilocybin-
containing mushrooms [1].
MANAGEMENT OF ADVERSE DRUG
REACTIONS
Treatment should begin with reassurance and observation
in a low-stimulation environment. Benzodiazepines are
considered first line for agitation. Most symptoms of
intoxication resolve within 6 hours of ingestion [1,28]. If
it is suspected that another, potentially toxic, type of
mushroom was ingested, activated charcoal should be
administered [1].

REFERENCES
[1] Berger KJ, Guss DA. Mycotoxins revisited: Part II.
J Emerg Med 2005; 28(2): 175–83.
[2] Halpern JH. Hallucinogens and dissociative agents natu-
rally growing in the United States. Pharmacol Ther 2004;
102(2): 131–8.
[3] Halpern JH, Sewell RA. Hallucinogenic botanicals of
America: a growing need for focused drug education and
research. Life Sci 2005; 78(5): 519–26.
[4] Vollenweider FX, Leenders KL, Scharfetter C, Maguire P,
Stadelmann O, Angst J. Positron emission tomography and
fluorodeoxyglucose studies of metabolic hyperfrontality
and psychopathology in the psilocybin model of psychosis.
Neuropsychopharmacology 1997; 16(5): 357–72.
[5] Vollenweider FX, Vontobel P, Hell D, Leenders KL. 5-HT
modulation of dopamine release in basal ganglia with
psilocybin-induced psychosis in man—a PET study with
(11C) raclopride. Neuropsychopharmacology 1999; 20(5):
424–33.
[6] Passie T, Seifert J, Schneider U, Emrich HM. The pharma-
cology of psilocybin. Addict Biol 2002; 7(4): 357–64.
[7] Carter OL, Burr DC, Pettigrew JD, Wallis GM, Hasler F,
Vollenweider FX. Using psilocybin to investigate the rela-
tionship between attention, working memory, and the sero-
tonin 1A and 2A receptors. J Cogn Neurosci 2005; 17(10):
1497–508.
[8] Griffiths RR, Richards WA, McCann U, Jesse R. Psilocy-
bin can occasion mystical-type experiences having substan-
tial and sustained personal meaning and significance.
Psychopharmacology 2006; 187(3): 268–83.
[9] Hasler F, Bourquin D, Brenneisen R, Vollenweider FX.
Renal excretion profiles of psilocin following oral adminis-
tration of psilocybin: a controlled study in man. J Pharm
Biomed Anal 2002; 30(2): 331–9.
[10] Moreno FA, Wiegand CB, Taitano EK, Delgado PL.
Safety, tolerability, and efficacy of psilocybin in 9 patients
with obsessive–compulsive disorder. J Clin Psychiatry 2006;
67(11): 1735–40.
[11] El Mansari M, Blier P. Mechanisms of action of current and
potential pharmacotherapies of obsessive–compulsive dis-
order. Prog Neuropsychopharmacol Biol Psychiatry 2006;
30(3): 362–73.
[12] Vollenweider FX, Geyer MA. A systems model of altered
consciousness: integrating natural and drug-induced psy-
chosis. Brain Res Bull 2001; 56(5): 495–507.
[13] Borowiak KS, Ciechanowski K, Walsoszczyk P. Psilocybin
mushroom (Psilocybe semilanceata) intoxication with myo-
cardial infarction. J Toxicol Clin Toxicol 1998; 36(1–2): 47–9.
[14] Ghuran A, Nolan J. Recreational drug misuse: issues for
the cardiologist. Heart 2000; 83(6): 627–33.
[15] Hasler F, Grimberg U, Benz MA, Huber T,
Vollenweider FX. Acute physiological effects of psilocybin
in healthy humans: a double-blind, placebo-controlled
ã 2016 Elsevier B.V. All rights reserved.
Psilocybin 1051
dose-effect study. Psychopharmacology 2004; 172(2):
145–56.
[16] Nef HM, Möllmann H, Hilpert P, Krause N, Troidl C,
Weber M, Rolf A, Dill T, Hamm C, Elsässer A. Apical
regional wall motion abnormalities reminiscent to tako-
tsubo cardiomyopathy following consumption of psychoac-
tive fungi. Int J Cardiol 2009; 134(1): e39–41.
[17] Sewell RA, Halpern JH, Pope HG. Response of cluster
headaches to psilocybin and LSD. Neurology 2006; 66(12):
1920–2.
[18] Johnson MW, Sewell RA, Griffiths RR. Psilocybin dose-
dependently causes delayed, transient headaches in healthy
volunteers. Drug Alcohol Depend 2012; 123(1–3): 132–40.
[19] Wittmann M, Carter O, Hasler F, Cahn BR, Grimberg U,
Spring P, Hell D, Flohr H, Vollenweider FX. Effects of
psilocybin on time perception and temporal control of
behaviour in humans. J Psychopharmacol 2007; 21(1):
50–64.
[20] Wackermann J, Wittmann M, Hasler F, Vollenweider FX.
Effects of varied doses of psilocybin on time interval repro-
duction in human subjects. Neurosci Lett 2008; 435(1):
51–5.
[21] Attema-de Jonge ME, Portier CB, Franssen EJ. Auto-
mutilatie na gebruik van hallucinogene paddenstoelen.
[Automutilation after consumption of hallucinogenic
mushrooms.] Ned Tijdschr Geneeskd 2007; 151(52):
2869–72.
[22] Nielen RJ, van der Heijden FM, Tuinier S,
Verhoeven WM. Khat and mushrooms associated with psy-
chosis. World J Biol Psychiatry 2004; 5(1): 49–53.
[23] Espiard M, Lecardeur L, Abadie P, Halbecq, Dollfus S.
Hallucinogen persisting perception disorder after psilo-
cybin consumption: a case study. Eur Psychiatry 2005;
20(5–6): 458–60.
[24] Gouzoulis-Mayfrank E, Thelen B, Habermeyer E,
Kunert HJ, Kovar KA, Lindenblatt H, Hermle L,
Spitzer M, Sass H. Psychopathological, neuroendocrine
and autonomic effects of 3,4-
methylenedioxyethylamphetamine (MDE), psilocybin,
and D-methamphetamine in healthy volunteers: results of
an experimental double-blind placebo-controlled study.
Psychopharmacology 1999; 142(1): 41–50.
[25] Nichols DE. Hallucinogens. Pharmacol Ther 2004; 101(2):
131–81.
[26] Franz M, Regele H, Kirchmair M, Kletzmayr J, Sunder-
Plassmann G, Hörl WH, Pohanka E. Magic mushrooms:
hope for a “cheap high” resulting in end-stage renal failure.
Nephrol Dial Transplant 1996; 11(11): 2324–7.
[27] Raff E, Halloran PF, Kjellstrand CM. Renal failure after
eating “magic” mushrooms. Can Med Assoc J 1992; 147(9):
1339–41.
[28] Persson H. Mushrooms. Medicine 2007; 35(12): 635–7.