Psilocybin – Summary of knowledge
and new perspectives
Filip Tylša,b,n, Tomáš Páleníčeka,b, Jiří Horáčeka,b
aPrague Psychiatric Center, Prague, Czech Republic
b3rd Faculty of Medicine, Charles University in Prague, Czech Republic
Received 1 August 2013; received in revised form 17 November 2013; accepted 2 December 2013
Psilocybin, a psychoactive alkaloid contained in hallucinogenic mushrooms, is nowadays given a lot of
attention in the scientific community as a research tool for modeling psychosis as well as due to its
potential therapeutic effects. However, it is also a very popular and frequently abused natural
hallucinogen. This review summarizes all the past and recent knowledge on psilocybin. It briefly deals
with its history, discusses the pharmacokinetics and pharmacodynamics, and compares its action in
humans and animals. It attempts to describe the mechanism of psychedelic effects and objectify its
action using modern imaging and psychometric methods. Finally, it describes its therapeutic and
& 2013 Elsevier B.V. and ECNP . All rights reserved.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
Structural and chemical characteristics of psilocybin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
Metabolism and pharmacokinetics of psilocybin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
Behavioral effects of psilocybin/psilocin in animals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
Human studies with psilocybin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
6.1. Dosage and time course of effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
6.2. Effects on somatic, physiological and endocrine functions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
6.3. Psychotropic and neuropsychological effects of psilocybin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
0924-977X/$-see front matter & 2013 Elsevier B.V. and ECNP. All rights reserved.
nCorresponding author at: Prague Psychiatric Center, Prague, Laboratory of Brain Pathophysiology and Biochemistry, Ústavní 91, Praha 8 –
Bohnice 181 03, Czech Republic. Tel.: +420 266003175.
E-mail address: firstname.lastname@example.org (F. Tylš).
European Neuropsychopharmacology (2014) 24, 342–356
Acute somatic toxicity of psilocybin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
Risks and side effects of psilocybin, long-term toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Functional brain imaging studies of psilocybin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
9.1. Electroencephalography (EEG), Magnetoencephalography (MEG) . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
9.2. Positron emission tomography (PET), Functional magnetic resonance imaging (fMRI) . . . . . . . . . . . . . . 350
Psilocybin as a model of psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
Therapeutic uses and recent clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
Psilocybin and psilocin, the main psychedelic ingredients of
hallucinogenic mushrooms (Guzman et al., 1998; Laussmann
and Meier-Giebing, 2010) (Table 1), have recently been
given a lot of attention as a research tools (Geyer and
Vollenweider, 2008) as well as a potential therapeutic
agents (Grob et al., 2011; Moreno et al., 2006; Sewell
et al., 2006). History of the ritual use of hallucinogenic
mushrooms dates back 3000 years in Mexico and regionally
its use is still conventional practice today (Carod-Artal,
2011; Hofmann, 2005). Western science was introduced
to these mushrooms in 1957 by Robert G. Wasson and
they were later systematically ranked by Roger Heim
(Aboul-Enein, 1974). Psilocybin was first isolated and iden-
tified in 1958 and synthesized in 1959 by Albert Hofmann
(Hofmann et al., 1958). The content of psilocybin and
psilocin in hallucinogenic mushrooms varies in the range
from 0.2% to 1% of dry weight (Table 2.).
In the 1960s psilocybin was widely used in the experimental
research of mental disorders and even in psychotherapy
(Metzner, 2005). Soon, however, psilocybin containing mush-
rooms spread amongst the general public and became a popular
recreational drug. Consequently, psilocybin (and psilocin) was
classed as a schedule I drug in 1970 (Nichols, 2004) and all
human experiments were gradually discontinued. Since the late
1990s, interest in human experimental research into psilocybin
and other psychedelics has become revived (Figure 1). Nowa-
days, psilocybin is one of the most used psychedelics in human
studies due to its relative safety, moderately long duration of
action and good absorption after oral administration (Hasler
et al., 2004; Johnson et al., 2008).
The aim of this paper is to bring together the most
detailed and up to date list of known properties and effects
species currently freely distributed in the SmartShop network in the Netherlands are depicted in bold.
Systematic classification and the selected representatives of mushrooms containing psilocybin. Representatives of
Mushrooms containing psilocybin
DivisionClass Order FamilyGenus Best know representative
343Psilocybin – Knowledge and perspectives
of psilocybin, starting with its chemical characteristics,
metabolism, pharmacokinetics and ending with the use of
psilocybin in human research and therapy.
Structural and chemical characteristics
mine) and its active dephosphorylated metabolite psilocin
(N,N-dimetyltryptamine) structurally belong to the group of
tryptamine/indolamine hallucinogens and are structurally
related to serotonin (Hasler et al., 1997; Horita and Weber,
1961a) (Figure 1). An equimolar dose to 1 mol of psilocin is
1.4 mol of psilocybin (Wolbach et al., 1962). Substitution of
the indole nucleus in position 4 probably plays a substantial
role in its hallucinogenic effects (Nichols, 2004; Troxler
et al., 1959).
Psilocybin and psilocin in their pure forms are white
crystalline powders. While psilocybin is soluble in water,
psilocin on the other hand is more lipid-soluble (Ballesteros
et al., 2006). However, psilocin can be also diluted in an
acidified aqueous solution and in dimethylsulfoxide (DMSO; up
to 100 mM). Furthermore, both substances are soluble in
(source PubMed dated 06/02/2013. Advanced searched terms were “psilocybin”[Title/Abstract] OR “psilocin”[Title/Abstract] AND
Date “YYYY-YYYY”[Date – Publication]; for human studies available selection box was checked).
Number of publications dealing with psilocybin/psilocin (y axis) in five-year intervals from its synthesis to the present day
x=content is not known.
Content of psilocybin and psilocin in the dry state of selected representatives of psychoactive mushrooms,
Species Psilocybin (%) Psilocin (%)Study
Stamets and Gartz (1995)
Gartz and Moller (1989) and Gartz (1993, 1994)
Psilocybe semilanceata 0.98/0.96
Gartz (1994, 1993)
Repke et al. (1977) and Beug and Bigwood (1982)
Repke et al. (1977), Stijve and Kuyper (1985), and Gartz (1993,
Gartz (1994) and Stijve and De Meijer (1993)
Hofmann et al. (1959)
Heim and Hofamnn (1958)
Repke et al. (1977) and Beug and Bigwood (1982)
Stamets et al. (1980)
Gymnopilus Purpuratus 0.34
Stijve and Kuyper (1985)
F. Tylš et al.344
methanol and ethanol, but almost insoluble in petroleum
ether and chloroform (Barceloux, 2012; Berle, 1974). Both
drugs are unstable in light (in particular in the form of
solutions), their stability at low temperatures in the dark
under an inert atmosphere is very good (Anastos et al., 2006).
Metabolism and pharmacokinetics
Psilocybin is rapidly dephosphorylated to psilocin in the
intestinal mucosa by alkaline phosphatase and nonspecific
esterase. After ingestion, about 50% of the total volume of
psilocin is absorbed from the digestive tract of the rat
(Kalberer et al., 1962). After systemic parenteral adminis-
tration of psilocybin tissue phosphatases play the same role
with the kidneys being among the most active (Horita and
Weber, 1961b, 1962). Given that the competitive blockade
of dephosphorylation (beta-glycerolphosphate) blocks the
psychotropic effects of psilocybin, it is clear that psilocin is
the main active metabolite of psilocybin (Horita, 1963).
Psilocin is further glucuronidated by endoplasmic enzymes
UDP-glucuronosyltransferase (UGTs) to psilocin-O-glucuronide
(Manevski et al., 2010) and in this form 80% of it is excreted
from the body (Grieshaber et al., 2001; Sticht and Kaferstein,
2000). Of the 19 tested recombinant UGTs (from the families
1A, 2A and 2B) UGT1A10 in the small intestine and UGT1A9 in
the liver have the greatest activity (Manevski et al., 2010).
In addition to the above-described metabolic pathway,
psilocin itself is subject to oxidative metabolism. Psilocin
undergoes a demethylation and deamination to 4-hydroxyin-
dol-3-yl-acetaldehyde (4-HIA) and subsequent oxidation (pre-
sumably by hepatic aldehyde dehydrogenase and monoamine
oxidase) to 4-hydroxyindol-3-acetic acid (4-HIAA) and 4-
hydroxytryptofol (4-HT) (Hasler et al., 1997; Passie et al.,
2002). These minor metabolites (about 4% psilocin being
degraded in this way) can also be detected in vivo in human
plasma (Hofmann, 1968; Lindenblatt et al., 1998). The third
possible pathway is the oxidation of psilocin by hydroxyindol
oxidases to a product with an o-quinone or iminochinon
structure (Kovacic, 2009).
In rats and mice after oral administration of extracts from
mushrooms (Chen et al., 2011) maximum plasma levels are
achieved after approximately 90 min. Psilocin is distributed
to all tissues, including the brain, and is excreted within
24 h – the majority in the first 8 h (65% in the urine and
15–20% in the bile and feces); small amounts can be
detected in the urine even after a week (Hofmann, 1968).
The highest levels of psilocin in various animals were
detected in the neocortex, hippocampus, extrapyramidal
motor system and reticular formation (Hopf and Eckert,
1974). In mice, preceding the brain, psilocin accumulates in
the kidneys, and the liver (Horita and Weber, 1962).
In humans, psilocybin and psilocin can be found in blood
plasma 20–40 min after oral administration of psilocybin,
maximum levels of psilocin are achieved between 80 and
105 min and can be detected for up to 6 h (Hasler et al.,
1997; Passie et al., 2002). The half-life of psilocin in plasma is
2.5 h after oral ingestion of psilocybin, following intravenous
administration the half-life is 1.23 h. Eighty percent of
psilocin in plasma was found to be in a conjugated form.
Both psilocin (at 90–97%) and psilocybin (3–10%), are detect-
able in human urine, unmodified (only 3–10%) and particularly
conjugated with glucoronic acid (Hasler et al., 2002; Kamata
et al., 2006; Passie et al., 2002). The elimination half-life of
psilocybin is 50 min and the elimination constant is 0.307/h
(Lindenblatt et al., 1998). The majority is excreted within 3 h
after oral administration and is completely eliminated from
the body within 24 h (Hasler et al., 2002; Holzmann, 1995).
Psilocybin and psilocin are the substances with predominant
agonist activity on serotonin 5HT2A/Cand 5HT1Areceptors (for
specific affinities see Table 3). Interestingly, psilocybin's affinity
to human 5HT2A receptors is 15-fold higher than in rats
(Gallaher et al., 1993). While the 5HT2A receptor agonism
is considered necessary for hallucinogenic effects (Nichols,
2004), the role of other receptor subtypes is much less
understood. Contrary to the previous report (Creese et al.,
1975), a recent study found that psilocin binds to many
different receptors including dopamine in the following order:
Affinity of psilocin to serotonin receptors. x=missing data.
Constant Subtypes of serotonin receptorsStudy
5HT1A 5HT1B 5HT1D 5HT1E 5HT1F 5HT2A 5HT2B
2.88 2.19 3.43.03
567.4 219.6 36.4 x
5HT4 5HT5A 5HT5B 5HT6 5HT7
xxxKi (nM)xxxx 25,
Blair et al.
Ki (nM)xxxx 6,
et al. (1990)
x2.83 x2.82 2.82 Ray (2010)
anpKi is logarithmated and normalized value of Ki. It is calculated as follows: npKi=4+pKi?pKiMax, where pKi=?log 10(Ki).
345 Psilocybin – Knowledge and perspectives
5HT2C45HT1B45HT2A. According to this data it also weakly
binds to the receptors for Imidazoline1, Alpha2A/B/Cand 5HT
transporters (Ray, 2010).
Using selective agonists and antagonists 5HT1Aand 5HT2A
activity has also been confirmed in rodents in discrimination
studies with hallucinogens (Appel and Callahan, 1989;
Fantegrossi et al., 2008; Winter et al., 2007) and in studies
on head twitch behavior and wet dog shakes (typical signs
of the stimulation of the 5-HT2A receptor) (Fantegrossi
et al., 2008; Halberstadt et al., 2011). On the other hand,
restored by antagonists 5-HT1A and 5-HT2B/C receptors
(Halberstadt et al., 2011; Palenicek et al., 2006; unpub-
lished data). Finally, inhibition of dorsal raphe nucleus
activity by psilocybin was shown to be mediated via agonism
at 5-HT1Aautoreceptors (Aghajanian and Hailgler, 1975) and
electroencephalographic changes induced by psilocin were
partly normalized by antagonists of 5-HT1A, 5HT2A/Cas well
as dopamine D2receptors (Tyls et al., 2012a).
The effects of psilocybin in humans are also blocked by
the 5-HT2A/Cantagonists (Vollenweider et al., 1998). The
role of 5-HT1Areceptors in human psilocybin studies is yet to
be investigated, certain clues can be derived from a study
of a related hallucinogen N,N-dimethyltryptamine (DMT).
Here the 5-HT1Apartial antagonist pindolol magnified the
hallucinogenic effects by two to three times (Strassman,
1996). Psilocybin also indirectly increased (via 5HT recep-
tors) the release of dopamine in the ventral striatum in
humans, an effect that correlated with symptoms of deper-
sonalization and euphoria (Vollenweider et al., 1999).
In neurons expressing the 5HT2A receptor, but not in
5HT2A knockouts, psilocybin increases the expression of
early genes (erg-1, erg-2, c-fos, jun-B, period-1, gpcr-26,
fra-1, N-10, I-κBα) and reduces the expression of sty-kinase
(Gonzalez-Maeso et al., 2007; Gonzalez-Maeso and Sealfon,
2009). Needless to say, the precise signaling pathway
leading from the receptor to the activation of early genes
is not yet known. Given that a non-hallucinogenic lisuride
also activates the c-fos, it is likely that the expression of c-
fos only reflects increased neuronal activity (Day et al.,
2008), while the expression of egr-1/egr-2 is specific for the
Gonzales-Meaeso explained this selectivity with the “ago-
nist trafficking of receptor signaling theory”, where hallu-
cinogens activate the 5HT2A/mGlu2receptor heterocomplex
and different G proteins compared to non-halucinogenic
5-HT2A agonists (Gonzalez-Maeso et al., 2003). This hypoth-
esis is supported in a study where the mice with the
knockout gene for the mGlu2receptor do not display any
head twitch behavior (Moreno et al., 2011).
locomotor inhibition was
Behavioral effects of psilocybin/psilocin
Psilocybin and psilocin are used in animal behavioral experi-
ments in the range of 0.25–10 mg/kg; however doses up to
80 mg/kg have also been used. Psilocybin dose of 10 mg/kg
has mild sympathomimetic effects (piloerection and hyper-
ventilation) in rodents and small carnivores (Passie et al.,
2002). Characteristic effect of psilocybin is enhancement of
monosynaptic spinal reflexes in cats (Hofmann, 1968).
Peak of behavioral changes are typically observed within
30–90 min after drug administration. Locomotor behavior of
rodents is dose-dependently inhibited by the drug with signs
of ataxia (Halberstadt et al., 2011; Palenicek et al., 2005).
Psilocin also suppresses exploration and habituation ele-
ments and induces manifestations of behavioral serotonin
syndrome (e.g. head twitch behavior) and in a very high
doses (80 mg/kg) also induces atypical behavioral of back-
ward walking (Geyer et al., 1979; Halberstadt et al., 2011).
Behavioral excitation was observed anecdotally (Chauchard,
1967; Sugrue, 1969). Furthermore, psilocybin decreases
aggressive behavior in rodents (Kostowski et al., 1972;
Uyeno, 1978) and inhibits normal dominance behavior
(Uyeno, 1967, 1972).
Psilocybin has increased prepulse inhibition of acoustic
startle response (PPI)1up to doses of 4.5 mg/kg in mice
(Halberstadt and Geyer, 2011). Using a lower dose of psilocin
(1 mg/kg), it attenuated PPI (via 5-HT2Aagonism predomi-
nantly) and with 4 mg/kg had no effect in Wistar rats
(Palenicek et al., 2011, unpublished data). Psilocin also
seems to have biphasic effects on startle reaction per
se, with lower doses slightly increasing and higher doses
(4–8 mg/kg) decreasing startle (Davis and Walters, 1977;
Palenicek et al., 2011). Psilocybin also increased the
starting latency in a special conditioned task (swimming
through an underwater tube) (Uyeno, 1971) and attenuated
responses in a passive avoidance task (Collins et al., 1966;
Sugrue, 1969). It is probable that attenuation of startle
response as well as altered performance in cognitive tasks
could be related to the motor inhibition and ataxia produced
by the drug as well as to an altered perception of the
In psilocybin self-administration experiments with maca-
ques at sufficiently high doses the drug provoked stereo-
typical visual scanning, head shaking, bizarre postures,
hyperactivity and focusing on an empty spot in a room with
catching non-existent flies (Fantegrossi et al., 2004b). It is
therefore very likely that this is a direct manifestation of an
altered perception, especially visual hallucinations.
6.Human studies with psilocybin
6.1. Dosage and time course of effects
In terms of efficacy, psilocybin is 45 times less potent than
LSD and 66 times more potent than mescaline (Isbell, 1959;
Wolbach et al., 1962). Clinical studies indicate that the
effective dose of oral (p.o.) psilocybin is 0.045–0.429 mg/kg
1PPI is a commonly evaluated parameter, which reflects sensor-
imotor processing. It is the evaluation of the startle response to a
sudden unexpected stimulus (usually tactile or audio) and the
prepulse inhibition of startle response. The principle of prepulse
inhibition relies on the ability of slightly supraliminal stimulus
(prepulse; cannot be consciously processed) preceding in an order
of milliseconds the startle stimulus (pulse) to reduce the extent of
the startle response. These measurements can be used to evaluate
a number of parameters, such as latency response and amplitude. A
frequently evaluated parameter is the habituation to a startle
response and PPI.
F. Tylš et al. 346
and 1–2 mg per adult intravenously (i.v.) (Table 4). Psyche-
delic effects occur at doses above 15 mg of oral psilocybin
(Hasler et al., 2004) or plasma psilocin levels of 4–6 ng/ml
(Hasler et al., 1997). Safety guidelines for the experimental
use of hallucinogens state high but not dangerous oral doses
of psilocybin as being anything higher than 25 mg (Johnson
et al., 2008).
The psilocybin onset of action is between 20 and 40 min,
maximum is 60–90 min and the duration is 4–6 h after oral
administration. The main effects disappear entirely within
6–8 h, completely in 24 h (Hasler et al., 2004; Vollenweider
et al., 1998). For i.v. application, the effect starts after 1–
2 min, peaks at 4–5 min and lasts for about 20 min (Carhart-
Harris et al., 2011; Hasler et al., 1997). Evaluation of the
effects of psilocybin after one week of administration did
(Gouzoulis-Mayfrank et al., 1999b).
and endocrine functions
Effects on somatic, physiological
Analogously as in animals, in humans psilocybin slightly
stimulates sympathetic activity (mydriasis, mild increase in
blood pressure and increased heart rate) at doses higher
than 3–5 mg p.o. with the full effect at 8–25 mg p.o.
(Griffiths et al., 2006; Hasler et al., 2004; Isbell, 1959).
The increase of systolic and diastolic pressure is approxi-
mately 10–30 mmHg each. The average heart rate was in the
range of 82–87, maximal values reached 140 beats per
minute. Furthermore, psilocybin had no effect on electro-
cardiograph (ECG) or body temperature (Hasler et al.,
2004). Other common somatic symptoms are as follow:
dizziness, weakness, tremor, nausea and vomiting (mainly
after ingestion of psilocybin-containing mushrooms (Peden
and Pringle, 1982), drowsiness, yawning, paresthesia,
blurred vision, and increased tendon reflexes (Hollister,
1961; Johnson et al., 2008).
Psilocybin does not acutely affect the ionic balance, blood
glucose or cholesterol, and even in high doses has only a
negligible effect on plasma concentration or the activity of
various enzymes (lactate dehydrogenase, alanine transami-
nase, alkaline phosphatase and cholinesterase, mild elevation
of aspartate aminotransferase and γ-glutamyl transferase)
(Hasler et al., 2004; Hollister, 1961). However, psilocybin
increases levels of prolactin, and in high doses also cortico-
tropin, cortisol and thyreotropin. Hormone levels have
returned to normal within 5 h (Gouzoulis-Mayfrank et al.,
1999b; Hasler et al., 2004).
of significance. Number of arrows indicates significance (p values – 0.05, 0.01, 0.001) according to corresponding studies,
↑ – increase, ↓ – decrease. Abbreviations: OSE=Oceanic Boundlessness, AED=Anxious Ego Dissolution, VUS=Visionary
Restructuralization, AA=Auditory Alterations, RV=Reduction of Vigilance, Psi=psilocybin, Pla=placebo, Ket=ketanserine,
Risp=risperidone, Hal=haloperidol, n/a=not analyzed, n.s.=not significant, x=versus.
Subjective effects after administration of psilocybin versus placebo in the Dittrich scale of ASCs shown as a measure
OSE AEDVUS AARV
Example of symptoms Euphoria
Drugs and dosage
Psi 0.045 mg/kg p.o. xPla
Psi 0.115 mg/kg p.o. xPla
Psi 0.215 mg/kg p.o. xPla
Psi 0.315 mg/kg p.o. xPla
Hasler et al.
Psi 5 mg/70 kg p.o. xPla
Psi 10 mg/70 kg p.o. xPla
Psi 20 mg/70 kg p.o. xPla
Psi 30 mg/70 kg p.o. xPla
et al. (2011)
Psi 1.5 mg i.v. xPla
Psi 2 mg i.v. xPla
Harris et al.
Psi 0.25 mg/kg p.o. xPla
Psi 0.25 mg/kg p.o.+Ket 40 mg p.o.
xPsi 0.25 mg/kg p.o.
Psi 0.25 mg/kg p.o.+Risp 1 mg p.o.
xPsi 0.25 mg/kg p.o.
Psi 0.25 mg/kg p.o.+Hal 0.021 mg/kg
i.v.xPsi 0.25 mg/kg p.o.
et al. (1998)
347Psilocybin – Knowledge and perspectives
Psychotropic and neuropsychological effects
Very low doses cause drowsiness and emphasize the pre-
existing mood (Hasler et al., 2004). Medium doses induce a
well controllable altered state of consciousness (Passie et al.,
2002) and higher doses evoke a strong psychedelic experience.
Thephenomenology of psilocybin
changes in perception (dream-like states, illusions, hallucina-
tions, synesthesiae) including changes in body image (e.g.
paraesthesia in the form of a tingling, dreaminess or somatic
hallucinations), altered self-perception, derealization and
depersonalization, impaired perception of time and space,
impaired attention, thought content disorder (magical think-
ing, unusual ideas or delusions), change of intuition and
sometimes also mood swings, symptoms of anxiety or elation,
Vollenweider, 2008; Hasler et al., 2004; Hollister, 1961).
Emotions during intoxication can vary greatly from ecstatic
and pleasant feelings to anxiety (Vollenweider et al., 1997).
The effects of psilocybin as with other hallucinogens are
quantified with five subscales of the Altered States of
Consciousness scale (ASCs) (Dittrich, 1998) (Table 4). Compar-
ing psilocybin with the dissociative anesthetic ketamine it was
found that psilocybin has greater visual hallucinatory effects
(VUS scale) but feelings of loss of physical integrity (AED scale)
are more pronounced in ketamine (Studerus et al., 2012;
Vollenweider and Geyer, 2001; Vollenweider and Kometer,
2010). Psilocybin-induced changes were uniformly normalized
by ketanserin (5-HT2A/Cantagonist) and risperidone (mixed 5-
HT2A/Cand D2antagonist). On the other hand, an antagonist of
the D2receptor, haloperidol, normalized only euphoric symp-
toms, derealization and depersonalization (OSE scale) and had
no effect on the visual hallucinations (VUS scale) and even
slightly potentiated the feeling of a loss of self-control (AIA
scale) (Vollenweider et al., 1998). A positive correlation
between psilocybin-induced reduction of visually evoked
potentials and score on the VUS scale was also described
(Kometer et al., 2013).
According to the Adjective Mood Rating Scale (AMRS)2
(Janke and Debus, 1978) psilocybin induced an overall inacti-
vation and tiredness, dazed state, introversion, increased
emotional excitability, increased sensitivity and persisting
dreaminess for up to 24 h (Hasler et al., 2004; Studerus
et al., 2011). Psilocybin altered several domains of cognitive
function and information processing. It selectively reduced the
ability to visually distinguish between faces with negative and
neutral expressions but not positive-neutral faces (Schmidt
et al., 2012), disrupted sustained attention (Umbricht et al.,
2003; Vollenweider et al., 2007) and altered visual information
processing (Carter et al., 2004; Gouzoulis-Mayfrank et al.,
2002; Wittmann et al., 2007). Interestingly, some of the
alterations in a binocular rivalry test (visual processing) were
also observed during deep meditative states realized by
experienced meditation practitioners (Vollenweider, 2013).
Effect of psilocybin on sensorimotor gating (PPI) was found
to be dependent on the parameter “prepulse–pulse interval”,
with PPI disruption for short intervals (30 ms) and PPI increase
in longer intervals (120–2000 ms) (Gouzoulis-Mayfrank et al.,
1998; Vollenweider et al., 2007).
Psilocybin intoxication also brings about numerous spiri-
tual and mystical experiences, as first documented in the
famed Good Friday Experiment3(Pahnke, 1963). Positive
long-term changes in life attitudes of participants were
reported 25 years later (Doblin, 1991). These pioneering
experiments have recently been confirmed by double-blind
placebo and active comparator controlled studies. Volun-
teers without any previous experience with psychedelics,
two months after taking psilocybin rated the experience as
having substantial personal meaning and spiritual signifi-
cance with sustained positive changes in attitudes and
behavior (Griffiths et al., 2006). A 14 months follow-up
revealed it as being one of the most significant spiritual
experiences (Griffiths et al., 2008). In another follow-up
survey with subjects from studies carried out in Switzerland
between 1999 and 2008, most described the experience as
pleasurable, enriching and non-threatening (Studerus et al.,
2011). A third of subjects positively evaluated their experi-
ence 8–16 months after the session (positive change in world
view, values, awareness of personal problems, relationships
to one's body as well as to other people, relationships to
nature, aesthetic experiences and their attitude to altered
states of consciousness). Only 8% of the subjects reported
moderate negative changes in their psychological well-
being, however no subsequent long-term impairment of
functioning was detected. Another recent study, assessing
domains of personality in order to objectify long term
subjective changes, found a significant increase in “open-
ness” after psilocybin in participants who had mystical
experiences during the session which remained for more
than one year (MacLean et al., 2011).
7. Acute somatic toxicity of psilocybin
According to a number of toxicological and clinical studies
psilocybin has a very low toxicity (Nichols, 2004; Passie et al.,
2002). Psilocybin showed no specific signs of toxicity in the
isolated organs (intestine, heart) of rats and pigs (Cerletti,
1958), it is also not neurotoxic (Johnson et al., 2008).
Psilocybin LD50for rats and mice is 280–285 mg/kg, and for
rabbits it is 12.5 mg/kg. Psilocin LD50is significantly lower for
mice and rats 75 mg/kg and for rabbits 7 mg/kg (Usdin and
Efron, 1972). The LD50/ED50 ratio is 641 according to the
National Institute for Occupational Safety and Health Registry
of Toxic Effects (compare this with 9637 for vitamin A, 4816
for LSD, 199 for aspirin and 21 for nicotine). Fatalities
associated with ingestion of psilocybin containing mushrooms
have been described, however these were not linked to direct
toxicity of psilocybin but most victims died after jumping out
of the window or committing suicide (van Amsterdam et al.,
2011). The only reported fatality was described after ingestion
2AMRS: this subjective scale, allowing repeated assessment of the
current state of mind, is based on the principle of assigning the
degree of conformity to various adjectives that are typical for a
certain mental disposition (Janke and Debus, 1978).
3Experiment performed by Walter N. Pahnke, a graduate student
in theology at Harvard Divinity School, under the supervision of
Timothy Leary in 1962, in which theology students were adminis-
tered psilocybin or a placebo during divine service. Those intoxi-
cated with the drug had a much greater spiritual and mystical
experience than those with the placebo (Pahnke, 1963).
F. Tylš et al. 348
of an extreme dose (psilocin plasma level was 4 μg/ml) of
Psilocybe semilanceata (Gerault and Picart, 1996).
A human lethal dose of psilocybin is difficult to estimate,
it is clear that it is much higher than the psychoactive dose.
One would have to eat approximately 19 g of the pure drug
or consume their body weight in fresh psilocybin containing
mushrooms to bring on death (www.erowid.org). Doses have
not exceeded 0.429 mg/kg in clinical trials (Griffiths et al.,
2006), which is approximately 30? less than the LD50for
Theoretically, hypertension and tachycardia may affect
predisposed individuals and extremely high doses of psilo-
cybin (several times higher than in clinical trials) can cause
coma, hyperthermia, and respiratory failure (symptoms of
serotonin syndrome), similar to high doses of LSD (Klock
et al., 1975). However, no such case has been reported to-
date. During the long history of psilocybin use in the form of
hallucinogenic mushrooms there have been no documented
cases of somatic toxicity (Hofmann, 2005). Organ damage
(e.g. renal failure) only occurs due to confusion between
psilocybin mushrooms and other morphologically similar
mushrooms (Franz et al., 1996).
Risks and side effects of psilocybin,
The safety of psilocybin use is given mainly by personal
expectations (set) and the nature of the environment
(setting), which is the cause of the great variability of the
subjective effects (Nichols, 2004). Due to the altered
perception, hallucinations and intensified emotions, dan-
gerous behavior may occur during non-medical administra-
tion (Johnson et al., 2008). These complications can be
significantly reduced by educating an individual, creating a
safe environment and building rapport with an experienced
intoxication guide (sitter). (Johnson et al., 2008; Leary
et al., 1963). Thus well-prepared hallucinogen-naïve parti-
cipants can safely take higher doses of psilocybin (over
25 mg) (Johnson et al., 2008) and experienced volunteers
can be administered with psilocybin even in magnetic
resonance (Carhart-Harris et al., 2011).
Approximately 2000 subjects had received psilocybin under
controlled experimental conditions during psychological and
psychiatric research by 2005 (Metzner, 2005), without causing
any serious side effects (Johnson et al., 2008). Anxiety,
paranoid experiences, derealization, depersonalization, long
lasting unpleasant experiences (bad trips), psychotic reactions
and rare hallucinogen persisting perception disorder (HPPD)4
are the main side effects described (Strassman, 1984) and are
more likely than any physical risks (Johnson et al., 2008).
Psychological interventions are mostly sufficient, anxiolytics
and/or atypical antipsychotics can be used in extreme cases,
and commitment is only very rarely required (Johnson et al.,
2008; Strassman et al., 1994).
Generally, although the use of hallucinogens can trigger
nonspecific psychoticepisodesor accentuate psychotic
symptoms in patients (Roubicek and Drvota, 1960), these
Mayfrank et al., 1994; Parashos, 1976). The risk of prolonged
psychosis (lasting longer than 48 h) in otherwise healthy
subjects after a single dose of psilocybin is rare and in most
cases it is associated with personality predisposition (Johnson
et al., 2008). The prevalence of prolonged psychiatric symp-
toms after serotonergic hallucinogens in thousands of healthy
subjects and psychiatric patients was 0.08–0.09% and 0.18%,
respectively. Attempts to commit suicide occurred in psychia-
tric patients only (in 0.12%) with few (0.04%) succeeding
(Cohen, 1960; Malleson, 1971; Perala et al., 2007). Finally,
incidence of HPPD is estimated to be in only a few cases per
million users (Johnson et al., 2008). Since chronic administra-
tion of hallucinogens reduces the number of 5HT2Areceptors
leading to a rapid onset of short-lasting tolerance (Roth et al.,
1998) the risk of addiction to hallucinogens, including psilo-
cybin is very low. Furthermore, monkeys did not seek psilocy-
bin as a reward (Fantegrossi et al., 2004a), and in the case of
LSD they even reacted aversely (Hoffmeister, 1975). In
humans, psilocybin does not cause craving or withdrawal
(Johnson et al., 2008) and it does not directly affect the
mesolimbic dopaminergic pathway and therefore does not
activate the reward system (Nichols, 2004).
Psilocybin is very likely to have no genotoxic effects. One
study that directly focused on the mutagenic potential of
psilocybin did not prove this type of toxicity (van Went,
1978). However, due to the lack of direct data on the
teratogenicity of psilocybin, this substance should not be
administered to pregnant women.
Despite the high level of safety and absence of risk of
addiction psilocybin is included in the U.S. list of “Schedule I”
controlled substances (Jerome, 2007; Nichols, 2004). However,
substances on this list must have the following three char-
acteristics: the drug or other substance has no currently
accepted medical use in treatment, there is a lack of accepted
safety for use of the drug or other substance under medical
supervision, the drug or other substance has a high potential
for abuse. It is clear from this text that psilocybin does not
meet the first two criteria and the third point is disputable.
Functional brain imaging studies
Early electrophysiological studies (limited to a visual assess-
ment) documented increases of fast activity, reduction of
amplitude and desynchronization in both primates and
humans (Fink, 1969; Horibe, 1974; Meldrum and Naquet,
1971). Changes in visually evoked potentials and a decrease
in alpha and theta activity were also described in humans
(Da Fonseca et al., 1965; Rynearson et al., 1968).
Recent findings with psilocin and other hallucinogens in
rats showed an overall reduction in EEG absolute power and
coherence (fronto-temporal mainly); relative power was
decreased in the delta and theta bands and increased in
the alpha, beta, high beta and gamma bands (Palenicek
et al., 2013; Tyls et al., 2012b, 2013, unpublished data).
Since the theta band in rats is the main basic activity, this
4DSM IV code 292.89, ICD10 code is F16.7. – psychotic reminis-
cence or flashback. HPPD manifests itself as persistent changes in
visual perception after the pharmacological effects of the sub-
stance have worn off (Halpern and Pope, 2003).
349Psilocybin – Knowledge and perspectives
may be analogous to the aforementioned EEG desynchroni-
zation in primates and humans. As similar patterns of
coherence were also observed for dissociative anesthetics
(Tyls et al., 2012b) we hypothesize that the reduction of
coherence might nonspecifically reflect the hallucinogenic
effects. Observed fronto-temporal disconnection is also a
characteristic finding correlating with the distortion of
several cognitive parameters and might also reflect sensor-
imotor processing deficits that are typically induced by
hallucinogens (Friston and Frith, 1995; Palenicek et al.,
Recent quantitative EEG analysis in healthy volunteers
revealed that psilocybin (0.215 mg/kg p.o.) decreased basal
alpha power precluding a subsequent stimulus-induced α-
power decrease and attenuated VEP N170 in the parieto-
occipital area (Kometer et al., 2013). Psilocybin (2 mg i.v.)
also decreased broadband spontaneous cortical oscillatory
power during resting state in MEG, with large decreases being
in the areas of the default-mode network (DMN) and other
resting state networks. On the other hand, visually and motor-
induced gamma activity remained unchanged. Subsequent
effective connectivity analysis revealed that posterior cingu-
late (central hub of DMN) desynchronization can be explained
by increased excitability of deep-layer pyramidal neurons
(Muthukumaraswamy et al., 2013).
The assumption that all these findings could be generalized
to hallucinogens is supported by a human Ayahuasca5study with
low-resolution brain electromagnetic tomography (LORETA),
where a global current density reduction was observed (Riba
et al., 2004).
Functional magnetic resonance imaging (fMRI)
Positron emission tomography (PET),
15–25 mg p.o. increased metabolism in both the lateral
and medial prefrontal cortex (mPFC) including the anterior
cingulum (ACC), temporomedial cortex and basal ganglia.
psychotic positive symptoms (especially ego disintegration)
and mirrored the metabolic pattern typical for acute
psychotic episodes (Vollenweider et al., 1997). Analogously,
other PET studies have demonstrated increased metabolism
in the frontotemporal cortex and ACC, and a reduction of
18FDG uptake in thalamus. In addition, the same study
documented a blunted metabolic increase during cognitive
activation in the left frontal cortex (Gouzoulis-Mayfrank
et al., 1999a).
On the contrary, a recent fMRI study with psilocybin (2 mg
i.v.) documented only a decrease of both BOLD (blood-
oxygen-level-dependent) and perfusion (arterial spin labeling)
in a variety of subcortical regions, high-level association
between fronto-temporo-parietal regions and in the impor-
tant connectivity hubs of thalamus and midline cortex (ante-
rior and posterior cingulum and precuneus). The intensity of
18fluorodeoxyglucose (18FDG) PET study psilocybin
18FDG uptake positively correlated with
the subjective effects was predicted by decreased activity in
the anterior cingulate and mPFC. The subsequent mPFC seed
connectivity analysis revealed that psilocybin induced reduc-
tion of connectivity between the posterior cingulate and
mPFC, indicating that subjective effects of psilocybin could
be caused by decreased activity and connectivity in the
brain's key hubs of functional connectivity (Carhart-Harris
et al., 2012a).
There are several explanations for the substantial dis-
crepancy between PET and fMRI findings in a resting state.
Firstly, the individuals in the PET study were at the peak of
the effect (90 min after p.o.), whilst the fMRI study may
have captured the onset of effect, thus the findings may
correlate with anxiety rather than the psychedelic experi-
ence (King, 2012). Secondly, psilocybin as a 5-HT1B/Dagonist
induces the vasoconstriction (like triptans, anti-migraine
drugs). This vasoactive reaction could directly influence the
fMRI signal but not the resting18FDG uptake. Finally, the
above-mentioned reduced power and desynchronization in
MEG may be congruent with the fMRI as well as PET results
(Muthukumaraswamy et al., 2013). The MEG study describes
an increased excitability of deep-layer pyramidal neurons
rich in 5-HT2Areceptors. These glutamatergic neurons could
rhythms (a decrease in resting connectivity and fMRI signal)
and an increase in glutamate turnover which leads to an
increase in glial metabolism reflected by an increase in
18FDG uptake (Pfund et al., 2000).
Recent fMRI activation studies verifying the psychothera-
peutic effectiveness of psilocybin revealed a robust increase in
the BOLD signal in the early phases of autobiographical
memory recollection (within 8 s) in the striatum and limbic
areas, and in the later phases also in the medial prefrontal
cortex and sensory areas of the cortex (Carhart-Harris et al.,
2012b). The most recent fMRI studies by the same group
documented the increased functional connectivity after 2 mg
i.v. of psilocybin between the two specific neuronal networks.
The first, DMN, is typically activated during a resting state and
introspection, whilst the second, task-positive network, is
activated during focused attention. These two networks
reciprocally alternate in their activity under physiological
circumstances but under meditation, psychosis, propofol
sedation or under the influence of psilocybin they closely
interact. However, unlike propofol, thalamo-cortical connec-
tivity was preserved after the administration of psilocybin and
it would discriminate in a substantial way the psychedelic
experience from sedation (Carhart-Harris et al., 2012b).
10. Psilocybin as a model of psychosis
Hallucinogens including psilocybin induce complex changes at
various levels of the brain which lead to altered states of
consciousness. The neurobiology of the hallucinogenic effect
was described elsewhere (Gonzalez-Maeso and Sealfon, 2009;
Nichols, 2004; Palenicek and Horacek, 2008; Vollenweider,
Psilocybin is used as one of the major acute serotonergic
models of psychosis/schizophrenia (Geyer and Vollenweider,
2008; Hanks and Gonzalez-Maeso, 2013) due to its phenom-
enological and construct validity characterized by: induc-
tion ofpositivepsychoticsymptoms(alterations in
5Ayahuasca, a hallucinogenic beverage used by indigenous tribes
in Amazonia, contains the hallucinogen N,N-Dimethyltryptamine
(DMT; structurally and pharmacologically very close to psilocybin)
and harmine and harmaline with monoaminooxidase inhibiting
F. Tylš et al.350
perception, thinking and emotivity), changes in information
processing, changes of brain metabolism and/or activity
and induction of a hyperdopaminergic state in the striatum
(Gouzoulis-Mayfrank et al., 1998; Vollenweider et al., 1998).
Further support follows from the mechanism of action of
atypical antipsychotics, of which most of them show antago-
nist properties at 5-HT2A/C receptors and congruently also
restored changes induced by psilocybin (Horacek et al., 2006;
Vollenweider et al., 1998). More evidence of the role of these
receptors in psychosis is given by the fact that an increased
amount of 5-HT2Areceptors was described in the cortex of
young untreated subjects with schizophrenia postmortem
(Gonzalez-Maeso et al., 2008; Muguruza et al., 2013).
The validity of serotonin models of psychosis, however, is
hampered by the fact that antagonism at dopamine D2
receptors but not 5-HT2Aantagonism is essential to treat
psychotic symptoms in patients, whereas 5-HT2Aantagonism
might be important for amelioration of negative symptoms
(Horacek et al., 2006). Further on, unlike auditory halluci-
nations typical in schizophrenia, hallucinations after psilo-
cybin intoxication are primarily visual (Gonzalez-Maeso and
Sealfon, 2009; Hasler et al., 2004) and there is an absence
of negative symptoms and cognitive deficits, otherwise
typical for schizophrenia. However, psilocybin intoxication
may be phenomenologically more similar to the early stages
of the psychotic process in which the serotonin system may
be crucial (Geyer and Vollenweider, 2008). The lack of
negative symptoms can be attributed to the chronification
of the disease related to the adaptation of the brain to
information overload (Geyer and Vollenweider, 2008). In
relation to this, however, theoretical modeling of psychosis
using the chronic administration of psilocybin is not possible
due to the rapid development of shortly lasting tolerance to
the drug and to ethical issues. On the other hand, a chronic
animal model with LSD has already been created (Marona-
Lewicka et al., 2011).
Therapeutic uses and recent clinical
Most clinical studies with psilocybin were performed in the
1960s, often using synthetic Sandoz's Indocybins(Passie
et al., 2002). Hallucinogens were considered as key tools for
understanding the etiopathogenesis of some mental ill-
nesses and to have some therapeutic potential. In spite of
often being considered as methodologically inaccurate from
a current perspective, thousands of scientific papers pub-
lished by 1965 described positive results in more than
40,000 patients who had taken psychedelics with minimal
side effects and a high level of safety (Grinspoon and
Bakalar, 1981; Masters and Houston, 1970).
By 2005, approximately 2000 subjects had undergone
psycholytic and psychedelic psychotherapy6in clinical stu-
dies with psilocybin (Metzner, 2005). Use of psychedelic
psychotherapy encountered varying degrees of success in
neurotic disorders, alcohol dependence and psychothera-
peutic adjunct to the dying (Grinspoon and Bakalar, 1981).
There are also records of the successful application of
psycholytic therapy with repeated administration of psilo-
cybin in treatment resistant autistic and schizophrenic
children (Fisher, 1970). For decades, due to law restrictions,
the use of psychedelics including psilocybin in the treat-
ment was considered a closed chapter, however the idea
has been recently revived (Sessa, 2005; Vollenweider and
In a recent pilot study psilocybin at low doses (0.2 mg/kg)
acted as an anxiolytic and antidepressant in terminally ill
cancer patients without clinically significant side effects
(Grob et al., 2011). This study follows on from another three
where effects on psychosocial distress/inner psychological
well-being, anxiety and depression, attitudes to the disease
and towards death, quality of life and spiritual/mystical
states of consciousness, secondarily changes in the percep-
tion of pain and plasma markers of stress and immune
system function are evaluated (Griffiths, 2007; Kumar, 2009;
Case reports and clinical trials have also reported
improvement of obsessive-compulsive disorder (OCD) symp-
toms after psilocybin. In one patient the effect persisted for
five months (Leonard and Rapoport, 1987; Moreno et al.,
2006). In studies devoted to the treatment of alcohol
dependence (Bogenschutz, 2012) and smoking cessation
(Johnson and Cosimano, 2012) it is suggested that psilocybin
deepens spirituality (Griffiths et al., 2006) and stimulates
motivation to overcome the addiction. Further on, a
potential future use of psilocybin in the treatment of
anxiety depressive disorder is also emerging (Carhart-
Harris et al., 2012b; Vollenweider and Kometer, 2010).
The last reported effect of psilocybin is in the treatment
of cluster headaches: mushrooms containing psilocybin
improved individual attacks but also stopped the cycle of
otherwise intractable cluster headache attacks (Sempere
et al., 2006; Sewell et al., 2006). A possible explanation is a
reduction in blood flow to the hypothalamus induced by the
psilocybin (Carhart-Harris et al., 2012a) or the activity of
psilocybin at 5-HT1B/D receptors (Ray, 2010), similar to
triptans (Cologno et al., 2012). Further research, however,
will be necessary in the future in order to clarify the above.
In summary, psilocybin has a strong research and therapeu-
tic potential. Due to the good knowledge of its pharmaco-
dynamics and pharmacokinetics, beneficial safety profile
and zero potential to cause addiction it is frequently used
both in animal and human research. It brings a number of
key findings regarding the functioning of the human brain,
in particular the role of the serotonergic system in complex
functions such as perception and emotions. It also serves as
a useful tool for the study of the neurobiology of psychoses.
Due to its considerable degree of translational validity of
animal and human studies, a psilocybin model of psychosis
plays a key role in the development of new treatments for
psychotic disorders. Finally, the most recent human studies
also suggest its potential therapeutic use in the treatment
of several psychiatric and neurological disorders.
6In psycholytic therapy a low dose is given and analysis and
interpretation are performed during the course of its effects,
psychedelic therapy uses high doses of psilocybin and the processing
of experiences and their interpretation takes place after the effects
have worn off.
351 Psilocybin – Knowledge and perspectives
Role of funding source
Funding for this study was provided by IGA MHCR no. NT/13897; the
IGA MHCR had no further role in study design; in the collection,
analysis and interpretation of data; in the writing of the report; and
in the decision to submit the paper for publication.
Author Filip Tylš designed the layout of the article and collected the
relevant literature. He contributed to all parts of the text.
Author Tomáš Páleníček supervised the layout and wrote the
abstract. He also greatly contributed to the pharmacokinetic and
pharmacodynamic parts of the text.
Author Jiří Horáček supervised the whole article and contribute
mainly to the discussion about imaging studies with psilocybin.
Conflict of interest
We wish to confirm that there are no known conflicts of interest
associated with this publication and there has been no significant
financial support for this work that could have influenced its
outcome. We confirm that we have given due consideration to the
protection of intellectual properly associated with this work and
that there are no impediments to publication, including the timing
of publication, with respect to intellectual property. In so doing we
confirm that we have followed the regulations of our institutions
concerning intellectual property.
This work was supported by the research Grant IGA MHCR no.
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