Psilocybin for Treating Psychiatric Disorders: A Psychonaut Legend or a Promising Therapeutic Perspective?

Abstract

Psychedelics extracted from plants have been used in religious, spiritual, and mystic practices for millennia. In 1957, Dr. Hofmann identified and synthesized the prodrug psilocybin, a substance present in more than 200 species of psychedelic mushrooms. Although there were limitations related to the scientific design of many studies, clinical observations performed during the 1950s and 1960s showed a potential therapeutic effect of psilocybin for patients affected by depressive symptoms, anxiety, and conversion disorder. Psilocybin was classed as a schedule I substance in 1970, but the fascination with psychedelics has remained almost unchanged over time, promoting a new scientific interest starting in the 1990s. Recent studies have provided further evidence supporting the suggestive hypothesis of the therapeutic use of psilocybin for treating various psychiatric disorders, including pathological anxiety, mood depressive disorder, and addiction.

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Citation: Coppola, M.; Bevione, F.;
Mondola, R. Psilocybin for Treating
Psychiatric Disorders: A Psychonaut
Legend or a Promising Therapeutic
Perspective? J. Xenobiot. 2022,12,
41–52. https://doi.org/10.3390/
jox12010004
Academic Editor: Wen-Tsong Hsieh
Received: 25 June 2021
Accepted: 24 November 2021
Published: 7 February 2022
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Review
Psilocybin for Treating Psychiatric Disorders: A Psychonaut
Legend or a Promising Therapeutic Perspective?
Maurizio Coppola 1, * , Francesco Bevione 1and Raffaella Mondola 2
1
Department of Addiction, ASL CN2, Corso Coppino 46, 12051 Alba, CN, Italy; francescobevione@gmail.com
2Department of Mental Health, ASL CN1, Via Torino 70/B, 12037 Saluzzo, CN, Italy;
raffaellamondola@virgilio.it
*Correspondence: mauriziocoppola1974@gmail.com; Tel.: +39-017-331-6210; Fax: +39-017-335-067
Abstract:
Psychedelics extracted from plants have been used in religious, spiritual, and mystic
practices for millennia. In 1957, Dr. Hofmann identified and synthesized the prodrug psilocybin,
a substance present in more than 200 species of psychedelic mushrooms. Although there were
limitations related to the scientific design of many studies, clinical observations performed during the
1950s and 1960s showed a potential therapeutic effect of psilocybin for patients affected by depressive
symptoms, anxiety, and conversion disorder. Psilocybin was classed as a schedule I substance in 1970,
but the fascination with psychedelics has remained almost unchanged over time, promoting a new
scientific interest starting in the 1990s. Recent studies have provided further evidence supporting the
suggestive hypothesis of the therapeutic use of psilocybin for treating various psychiatric disorders,
including pathological anxiety, mood depressive disorder, and addiction.
Keywords: psilocybin; psilocin; psychedelics; magic mushrooms
1. Introduction
Psychedelics extracted from plants have been used in religious, spiritual, and mystic
practices for millennia [
1
]. The use of peyote cactus buttons and red beans containing
mescaline by humans has been documented for 5700 years in the northeastern region of
Mexico [
2
]. The analysis of archaeological artifacts has confirmed that the use of psilocybin-
containing mushrooms has been ubiquitous since prehistory [
3
]. The first report of the
use of psychedelic mushrooms in Western medicine was made by Prentiss and Morgan in
1895. The authors described the ceremonial use of peyote cactus buttons by indigenous
people in Central America [
4
]. Mescaline, an active alkaloid contained in peyote, was
isolated by Arthur Heffter in 1897 and synthesized by Ernest Spath in 1919. Subsequently,
it was made available as a research chemical by the Merck & Co. pharmaceutical com-
pany [
5
]. In 1938, at the Sandoz laboratories in Switzerland, Albert Hofmann synthesized
lysergic acid diethylamide, best known as LSD. This substance was synthesized during a
systematic study investigation of ergot alkaloids in which LSD was the 25th compound
produced. In 1947, LSD was marketed under the trade name “Delysid” and was made
freely available to researchers interested in investigating its pharmacological properties [
6
].
In 1957, Dr. Hofmann also identified and synthesized the prodrug psilocybin, a substance
present in more than 200 species of psychedelic mushroom. In 1958, psilocybin was made
available by Sandoz under the brand name “Indocybin”. During the 1950s and 1960s,
psilocybin, LSD, and mescaline were largely used for treating non-psychotic disorders. In
more than 1000 scientific reports, authors described the results obtained from the treatment
of about 40,000 patients [
7
]. Although there were limitations related to the scientific design
of many studies, clinical observations performed during the pre-prohibition era showed
a potential therapeutic effect of psilocybin for patients affected by depressive symptoms,
anxiety, and conversion disorder [
8
–
12
]. Contrariwise, there is very limited information
about the therapeutic effects of psilocybin in psychotic patients [
13
,
14
]. On the whole,
J. Xenobiot. 2022,12, 41–52. https://doi.org/10.3390/jox12010004 https://www.mdpi.com/journal/jox

J. Xenobiot. 2022,12 42
patients treated with psycholytic or psychedelic doses of psilocybin reported no significant
side effects [
15
]. In the 1960s, psychedelics became widely used as recreational drugs, as
well as a symbol of the counterculture. Most human studies reported low toxicity; however,
some severe psychiatric reactions and occasional tragic events reported in the scientific
literature produced socio-political alarm in many countries [
16
,
17
]. Consequently, the
interest in medical research for studying the potential therapeutic activity of psychedelics
was reduced, and these substances became considered unethical for medical use [
17
]. Psilo-
cybin was classed as a schedule I substance in 1970, but the fascination with psychedelics
remained almost unchanged over time, promoting a new scientific interest starting from
the 1990s [
17
,
18
]. Recent studies have provided further evidence supporting the suggestive
hypothesis of the therapeutic use of psilocybin for treating various psychiatric disorders,
including pathological anxiety, mood depressive disorder, and addiction [
17
,
18
]. In our re-
view, we summarize the clinical, pharmacological, and toxicological information currently
available about psilocybin, focusing our attention on evaluating the therapeutic effects
in humans.
2. Chemistry
Psilocybin (Figure 1) and psilocin (Figure 2) are tryptophan indole-based compounds
present in mushrooms of the genus Psilocybe, Panaeolina, Pluteus, Panaeolus, Stropharia,
Conocybe, and Gymnopilus. These mushrooms are known and distributed worldwide
[19–21]
.
Their indole ring structure derives from a fusion between a pyrrole ring and a benzene
ring, joined to an amino group by a two-carbon side chain [
22
]. Psilocybin, IUPAC name
[3-[2-(dimethylamino)ethyl]-1H-indol-4-yl] dihydrogen phosphate, is a tertiary amino
compound belonging to the tryptamine alkaloid group. This substance, with a molecular
weight of 284.25 g/mol, has a phosphoryloxy substituent attached at position four of the
N,N-dimethyltryptamine structure. Psilocin, IUPAC name 3-[2-(dimethylamino)ethyl]-1H-
indol-4-ol, is the dephosphorylated psilocybin derivative representing the active compound
of psilocybin. Psilocin, molecular weight 204.27 g/mol, is a tryptamine alkaloid in which an
additional hydroxy group is attached to the N,N-dimethyltryptamine skeleton. Psilocybin
has a water solubility of 2.7 g/L and a melting point of 224
◦
C. Psilocin has a water solubility
of 4.08 g/L and a melting point of 174.5
◦
C [
23
]. Psilocybin is a zwitterion alkaloid with a
highly polar phosphate group; consequently, it is more soluble in water than psilocin [24].
Contrariwise, psilocin is more lipid soluble than psilocybin. Both substances are soluble in
methanol and ethanol but almost insoluble in ether, chloroform, and petroleum. In pure
form, psilocybin and psilocin are white crystalline powders, unstable in light but relatively
stable under an inert atmosphere, in the dark, and at low temperatures [23,24].
J. Xenobiot. 2022, 12, FOR PEER REVIEW 3
Figure 1. Psilocybin. PubChem: https://pubchem.ncbi.nlm.nih.gov/compound/10624#section=2D-
Structure (accessed on 10 June 2021).
Figure 2. Psilocin. PubChem: https://pubchem.ncbi.nlm.nih.gov/compound/4980#section=2D-
Structure (accessed on 10 June 2021).
3. Pharmacokinetics
Magic mushrooms are usually taken orally or, less frequently, smoked. The concen-
trations of psilocybin and psilocin in psychedelic mushrooms are 2% and 0.5%, respec-
tively [25]. However, the concentrations of active principles may vary in relation to the
species, origin, size, age, growing, and drying conditions [26]. In animal studies, it was
found that after oral administration, 50% of the 14C-labelled psilocin was absorbed and
almost evenly distributed throughout the body, including the brain [27]. In pregnant rat
studies, after intravenous administration, the 14C-psilocin crossed the placental barrier
reaching fetal tissue concentrations lower than maternal tissue, but with a slower elimi-
nation half-life [28]. In adult men, following oral administration, psilocybin is
dephosphorylated to psilocin from the hydrochloric acid made by the stomach [29,30].
Furthermore, psilocybin is dephosphorylated to psilocin in the intestine, kidney, and
blood by the alkaline phosphatase and nonspecific esterases [29,30]. In rat studies, it was
found that psilocybin was more easily absorbed from the jejunum and colon than psilocin
[31]. Moreover, many other rodent tissues can convert psilocybin to psilocin before the
transit into the systemic circulation [31]. In rat studies performed with the 14C-labelled
Figure 1.
Psilocybin. PubChem: https://pubchem.ncbi.nlm.nih.gov/compound/10624#section=2D-
Structure (accessed on 10 June 2021).

J. Xenobiot. 2022,12 43
J. Xenobiot. 2022, 12, FOR PEER REVIEW 3
Figure 1. Psilocybin. PubChem: https://pubchem.ncbi.nlm.nih.gov/compound/10624#section=2D-
Structure (accessed on 10 June 2021).
Figure 2. Psilocin. PubChem: https://pubchem.ncbi.nlm.nih.gov/compound/4980#section=2D-
Structure (accessed on 10 June 2021).
3. Pharmacokinetics
Magic mushrooms are usually taken orally or, less frequently, smoked. The concen-
trations of psilocybin and psilocin in psychedelic mushrooms are 2% and 0.5%, respec-
tively [25]. However, the concentrations of active principles may vary in relation to the
species, origin, size, age, growing, and drying conditions [26]. In animal studies, it was
found that after oral administration, 50% of the 14C-labelled psilocin was absorbed and
almost evenly distributed throughout the body, including the brain [27]. In pregnant rat
studies, after intravenous administration, the 14C-psilocin crossed the placental barrier
reaching fetal tissue concentrations lower than maternal tissue, but with a slower elimi-
nation half-life [28]. In adult men, following oral administration, psilocybin is
dephosphorylated to psilocin from the hydrochloric acid made by the stomach [29,30].
Furthermore, psilocybin is dephosphorylated to psilocin in the intestine, kidney, and
blood by the alkaline phosphatase and nonspecific esterases [29,30]. In rat studies, it was
found that psilocybin was more easily absorbed from the jejunum and colon than psilocin
[31]. Moreover, many other rodent tissues can convert psilocybin to psilocin before the
transit into the systemic circulation [31]. In rat studies performed with the 14C-labelled
Figure 2.
Psilocin. PubChem: https://pubchem.ncbi.nlm.nih.gov/compound/4980#section=2D-
Structure (accessed on 10 June 2021).
3. Pharmacokinetics
Magic mushrooms are usually taken orally or, less frequently, smoked. The concen-
trations of psilocybin and psilocin in psychedelic mushrooms are 2% and 0.5%, respec-
tively [
25
]. However, the concentrations of active principles may vary in relation to the
species, origin, size, age, growing, and drying conditions [
26
]. In animal studies, it was
found that after oral administration, 50% of the 14C-labelled psilocin was absorbed and al-
most evenly distributed throughout the body, including the brain [
27
]. In pregnant rat stud-
ies, after intravenous administration, the 14C-psilocin crossed the placental barrier reaching
fetal tissue concentrations lower than maternal tissue, but with a slower elimination half-
life [
28
]. In adult men, following oral administration, psilocybin is dephosphorylated to
psilocin from the hydrochloric acid made by the stomach [
29
,
30
]. Furthermore, psilocybin is
dephosphorylated to psilocin in the intestine, kidney, and blood by the alkaline phosphatase
and nonspecific esterases [
29
,
30
]. In rat studies, it was found that psilocybin was more eas-
ily absorbed from the jejunum and colon than psilocin [
31
]. Moreover, many other rodent
tissues can convert psilocybin to psilocin before the transit into the systemic circulation [
31
].
In rat studies performed with the 14C-labelled psilocybin, psilocin crossed the blood–brain
barrier and entered the central nervous system, where it exerted its psychotropic effect [
32
].
In humans, if administered in the empty stomach, psilocybin is rapidly converted to
psilocin, which is detectable in the plasma within 20–40 min [
29
]. Maximum psilocin
plasma concentrations are reached within 80–100 min [
29
]. Since psilocin is structurally
related to the neurotransmitter serotonin, it follows a comparable human metabolism [
33
].
In fact, about 4% of psilocin is metabolized by demethylation and oxidative deamina-
tion, catalyzed by the liver monoamine oxidase (MAO) or aldehyde dehydrogenase, via a
presumed intermediate metabolite, 4-hydroxyindole-3-acetaldehyde, to yield 4-hydroxy-
indole-3-acetic acid, 4-hydroxy-indole-3-acetaldehyde, and 4-hydroxytryptophole [
34
,
35
].
After oral administration, the plasma elimination half-lives estimated for psilocybin and
psilocin are 160 and 50 min, respectively [
29
,
36
]. In rat studies, after oral administration,
it was found that psilocin was excreted in the urine at 65%, and in the bile and feces at
approximately 15–20% within 8 h [
34
–
38
]. In rat studies, about 25% of the whole psilocybin
dose was excreted unaltered, whereas about 10–20% remained in the body, with its metabo-
lites detected in the urine for 6–7 days [
34
]. In a study performed on male volunteers,
around 3.5% of the oral psilocybin dose was excreted in the urine as free psilocybin within
24 h [
29
,
36
]. As emerged in pharmacokinetic and forensic studies, approximately 80% of
psilocin is eliminated as psilocin-O-glucuronide [
37
,
38
]. In the small intestine, glucuronida-
tion is mediated by the glucuronosyltransferase UGT1A10 [
39
]. Instead, when psilocin is
administered intravenously, glucuronidation is mediated by the glucuronosyltransferase

J. Xenobiot. 2022,12 44
UGT1A9 [
39
]. Conversely, N-glucuronidation was not observed in cell studies [
39
]. Finally,
the third metabolic pathway might be the oxidation of psilocin by the hydroxyindole
oxidases to produce compounds with an o-quinone or iminoquinone structure [40].
4. Pharmacodynamic
Psilocybin and psilocin exert a predominant agonist activity at serotonin receptors,
particularly the 5HT2A receptor. Agonist activity at the 5HT2A receptor is generally
considered a key pharmacological mechanism for inducing hallucinogenic effects. The
role of other receptors is documented, but less investigated [
41
]. In all studies, psilocin
displayed high 5HT2A receptor affinity (ki = 6 nM). In addition, psilocin binds many other
serotonin and non-serotonin receptors including: 5HT2B; 5HT1D; D1; 5HT1E; 5HT1A;
5HT5A; 5HT7; 5HT6; D3; 5HT2C; 5HT1B. A weak imidazoline 1, alpha 2A, alpha 2B,
alpha 2C receptors, and 5HT transporter affinity was also demonstrated [
42
]. Unlike
LSD, there was no information showing the pharmacodynamic activity of psilocin at the
D2 receptor [
43
]. In human studies, pre-treatment with the 5HT2A receptor antagonist
ketanserin blocked the psychotomimetic effects of psilocybin in a dose-dependent man-
ner [
44
]. Furthermore, psychotomimetic effects were also blocked using a pre-treatment
with the atypical antipsychotic risperidone [44]. On the contrary, psychotomimetic effects
were increased by the dopamine antagonist and typical antipsychotic haloperidol. In
line with this result, psilocybin could exert its psychotropic effect with a mechanism of
action independent/partially independent from dopamine stimulation [
44
]. However, in a
positron emission tomography (PET) study performed on male volunteers using the D2
dopamine receptor antagonist [11C]-raclopride, psilocybin decreased the [11C]-raclopride
receptor-binding bilaterally in the caudate nucleus (19%) and putamen (20%). These results
suggest an increase in endogenous dopamine in response to psilocybin administration.
In humans, changes in the [11C]-raclopride receptor-binding in the ventral striatum have
been correlated with depersonalization and euphoria; consequently, 5-HT1A and 5-HT2A
receptor stimulation could be important for striatal dopamine release. Psychotropic effects
induced by psilocybin could be related to both striatal dopamine release and serotonin
transmission [
45
]. In human studies, equimolar amounts of psilocybin and psilocin induced
the same psychotropic effects [
46
]. However, the inhibition of dephosphorylation using the
alkaline phosphatase competitive antagonist beta-glycerophosphate prevented all symp-
toms induced by psilocybin. This clinical information has strongly confirmed that psilocin
is the main active metabolite, and responsible for the psychedelic effects experienced [47].
5. Functional Studies
Electroencephalographic alterations induced by psilocybin in humans and animal
models have been studied since the 1960s [48–52]. The first electroencephalographic stud-
ies performed in primates and humans under psilocybin intoxication showed numerous
electroencephalographic tracing alterations, such as a decrease in alpha and theta activity,
an increase in fast activity, and desynchronization [
48
–
52
]. Changes in visually evoked
potentials were described in humans [
51
,
52
]. In a visual-evoked potentials study performed
on 26 healthy male volunteers, psilocybin decreased prestimulus parieto-occipital
α
-power
values, precluding a subsequent stimulus-induced
α
-power decrease. Moreover, psilocybin
decreased N170 potentials that were associated with visual perceptual alterations, including
visual hallucinations. All effects were blocked by pre-treatment with the 5-HT2A antago-
nist ketanserin [53]. In a magnetoencephalography study performed on a group of fifteen
healthy male volunteers, after the intravenous infusion of psilocybin, a spontaneous cortical
oscillatory power reduction from 1 to 50 Hz in the posterior association cortex was found,
and from 8 to 100 Hz in the frontal association cortex. Conversely, no effect was found on
low-level visually induced or motor-induced gamma-band oscillations. Dynamic causal
modelling showed a correlation between posterior cingulate cortex desynchronization and
increased excitability of the deep-layer pyramidal neurons. This correlation appeared to
be triggered by the 5-HT2A receptor-mediated excitation of deep pyramidal cells [
54
]. In

J. Xenobiot. 2022,12 45
a PET and [F-18]-fluorodeoxyglucose (FDG) study performed on 10 healthy volunteers,
prior to and following a 15 or 20 mg dose of psilocybin, authors found a global increase in
the cerebral metabolic rate of glucose with a predominant localization in the frontomedial
and frontolateral cortex, anterior cingulate, and temporomedial cortex. Instead, a smaller
increase in the metabolic rate of glucose was found in the basal ganglia, sensorimotor
area, and occipital cortex [
55
]. In a double-blind, placebo-controlled study performed on
healthy volunteers using the [F-18]-fluorodeoxyglucose FDG PET, psilocybin increased
the metabolic rate of glucose in the right anterior cingulate, right frontal operculum, and
right inferior temporal region. Conversely, a significant decrease in the metabolic rate of
glucose was found in the right thalamus, left precentral region, and left thalamus. Authors
have further observed a trend decrease in the metabolic rate of glucose in the compos-
ite right hemisphere and bilateral subcortical regions, as well as a trend increase in the
cortical/subcortical ratio of the right hemisphere [
56
]. Carhart-Harris et al. designed a
functional MRI study to capture the transition from normal waking consciousness to the
state induced by the intravenous infusion of 2 mg of psilocybin. Arterial spin labelling
perfusion and a blood–oxygen level-dependent functional MRI were used to map cerebral
blood flow and changes in venous oxygenation before and after the placebo and psilocybin
infusion. Results showed a significant cerebral blood flow (CBF) decrease in the subcortical
(bilateral thalamus, putamen, and hypothalamus) and cortical regions (posterior cingulate
cortex (PCC), retrosplenial cortex, precuneus, bilateral angular gyrus, supramarginal gyrus,
rostral and dorsal anterior cingulate cortex (ACC), paracingulate gyrus, medial prefrontal
cortex (mPFC), frontoinsular cortex, lateral orbitofrontal cortex, frontal opercu-lum, pre-
central gyrus, and superior, middle and inferior frontalgyrus). Subjective effects were
strongly related to the decreased activity and connectivity in the brain’s key connector
hubs including thalamus, mPFC, and ACC [
57
]. In their placebo-controlled, double-blind
study—performed to measure perfusion changes, with and without adjustment for global
brain perfusion, after two doses of oral psilocybin (low dose: 0.160 mg/kg; high dose:
0.215 mg/kg)—in two groups of healthy volunteers, Lewis et al. showed a reduction in ab-
solute perfusion in the frontal, temporal, parietal, and occipital lobes, bilateral amygdalae,
anterior cingulate, insula, striatal regions, and hippocampi. The data that emerged from
the study suggest that relative changes in brain perfusion should be interpreted in relation
to the absolute signal variations and analysis method [
58
]. In a psilocybin vs. placebo
cross-over functional MRI study, psilocybin enhanced the autobiographical recollection
facilitating the underlying neural processes. Significant activation was found in the limbic
and striatal region in the early phase. Otherwise, significant activation in the late phase
was found in the medial prefrontal cortex. Additional visual and sensory cortical activation
in the late phase was found under psilocybin only. Rating of memory vividness and visual
imagery was significantly higher after psilocybin than placebo. Furthermore, authors
found a significant positive correlation between vividness and subjective well-being at
follow-up [
59
]. In a PET study performed on eight healthy volunteers using the 5-HT2A
receptor agonist radioligand [11C]-Cimbi-36, oral intake of 3–30 mg of psilocybin produced
a dose-related 5-HT2A receptor occupancy. Moreover, the study highlighted a correlation
between subjective effects induced by psilocybin, 5-HT2A receptor occupancy, and plasma
psilocin levels [
60
]. In two PET studies performed on healthy volunteers using the 5-HT2A
receptor agonist radioligand [11C]-Cimbi-36, after psilocybin administration, individual
brain 5-HT2A receptor-binding predicted subjective mystical effects [
61
], mindfulness, and
openness [62].
6. Toxicity
Psilocybin is generally considered to be well tolerated and low in toxicity. Some
cases of fatal intoxication have been reported; however, the majority of them were not
directly linked to the toxic effects induced by psilocybin. They were related to mixed drug
intoxication, suicide, and jumping out of the window during hallucinations [
26
,
63
]. In 1996,
Gerault and Picart described a case in which a massive dose of psilocybe semilanceata was

J. Xenobiot. 2022,12 46
considered as the cause of death. Toxicological examination evidenced a psilocin plasma
level of 4
µ
g/mL [
64
]. The human lethal dose is not known; however, the LD50 for a rat,
mouse and rabbit, after the intravenous administration of psilocybin, were 280 mg/kg,
275 mg/kg, and 13 mg/kg, respectively [
65
]. In comparison, the LD50 for a rat, mouse
and rabbit, after intravenous administration of psilocin, were 75 mg/kg, 74 mg/kg, and
7 mg/kg, respectively [
66
]. The human toxic dose low (TDLo) for oral psilocybin adminis-
tration was 0.04–0.06 mg/kg, whereas TDLo for intravenous psilocybin administration was
1–2 mg, corresponding to a psilocin plasma level of 4–6 ng/mL. At these dosages, patients
reported visual field changes, muscle weakness, nausea, and vomiting. In dose-effect
studies, psilocybin was found to be 66 times more potent than mescaline and 45 times
less potent than LSD [
67
] In two cross-over studies performed at the end of the 1950s,
authors found cross tolerance between psilocybin and LSD [
68
]. Psilocybin is principally
used for its psychedelic effects, including altered self-perception, impaired perception
of time and space, alteration in thought contents, derealization, depersonalization, body
image distortion, and alterations in mood and emotions [
69
–
71
]. As previously reported,
symptoms induced by psilocybin can be reverted using the 5HT2A/C antagonist ketanserin
or 5HT2A/C and D2 antagonist risperidone. Haloperidol, a D2 antagonist, can normalize
euphoria, derealization and depersonalization [
44
]. On the other hand, MAO inhibitors
can intensify psychedelic effects induced by psilocybin [
72
]. Alcohol can enhance the
psychedelic effects induced by psilocybin, since its metabolite acetaldehyde reacts with the
endogenous biogenic amines producing the MAO inhibitors tetrahydroisoquinoline and
β
-carbolines [
73
]. Psilocybin effects can be prolonged by tobacco, because it may reduce the
central nervous system and peripheral tissue MAO B levels [
74
]. In addition to the central
nervous system, psilocybin can affect other organs and systems, including the renal [
75
],
cardiovascular, respiratory, gastrointestinal, visual, and musculoskeletal systems [
76
], as
reported in Table 1. Overall, psychotropic and neuropsychological effects appear to be
influenced by personal expectations, setting, and brain structure metrics [
41
,
77
]. Pro-
longed hallucinations or psychotic experiences are rarely reported in healthy persons,
when compared with people affected by psychotic or personality disorders [
78
] However,
long-lasting unpleasant experiences, best known as “bad trips” or hallucinogen-persisting
perception disorder (HPPD), have been reported [
79
]. Psilocybin does not directly affect
the mesolimbic dopaminergic pathway involved in the reward system; consequently, it
does not induce craving, addiction or withdrawal [
41
,
76
]. Finally, there is not enough
information to confirm or exclude genotoxicity or teratogenicity [80].
Table 1. Psilocybin effects [69–71].
Central Nervous System
Dream-like state, illusions, hallucinations, synesthesiae,
paraesthesia altered state of consciousness, altered self-perception,
derealization, depersonalization, altered perception of time and
space, altered mood, altered concentration, delusions or unusual
ideas, altered emoziona state, euphoria, panic attacks,
convulsions, headache, verigo, flushing.
Visual System Mydriasis
Cardiovascular System Achicardia, hypertension, hypotension
Respiratory System Hypoxemia
Gastrointestinal System Nauseas, vomiting, abdominal pain
Renal System Urinary incontinence, renal failure
Musculoskeletal System Muscle weakness
7. Psilocybin and Mood Disorders
In a double-blind, placebo-controlled study performed on 12 patients (11 women
and 1 man), affected by advanced-stage cancer, 0.2 mg/kg of psilocybin administered in a
single dose produced a significant reduction in anxiety at 1 and 3 months, and depressive
symptoms at 6 months, compared with the placebo (niacine 250 mg). Symptoms of anxiety
and depression were assessed using the State-Trait Anxiety Inventory and Beck Depression

J. Xenobiot. 2022,12 47
Inventory [
81
]. In a two-session, double-blind cross-over study, authors compared the effect
of low (1 or 3 mg/70 kg) versus high (22 or 30 mg/70 kg) psilocybin dose on depressive
symptoms, anxiety, and quality of life in 51 patients with life-threatening cancer. High-dose
psilocybin produced a significant decrease in depressive symptoms, anxiety and death
anxiety, along with a significant increase in quality of life and optimism. At the 6-month
follow-up, improvement in mood, anxiety and quality of life were confirmed in about
80% of the patients [
82
]. In a similar double-blind, placebo-controlled, cross-over trial
performed on 29 patients affected by life-threatening cancer, a single-dose psilocybin of
0.3 mg/kg improved depressive symptoms, anxiety and quality of life in the weeks after
administration. At the 6.5-month follow-up, around 80% of patients had kept these clinical
benefits [
83
]. In an open-label study performed on 12 patients (6 men and 6 women),
affected by moderate-to-severe unipolar, treatment-resistant major depression, two oral
doses of psilocybin (10 mg and 25 mg, 7 days apart) in association with psychological
support, before, during, and after each session, produced a marked reduction in depressive
symptoms, as assessed by the 16-item Quick Inventory of Depressive Symptoms (QIDS) at
1 week and 3 months. Patients reported mild adverse effects such as transient headaches,
anxiety, confusion, and nausea [
84
]. In another open-label study performed on 20 patients
(12 males and 6 females), affected by severe unipolar, treatment-resistant major depression,
two oral doses of psilocybin (10 mg and 25 mg, 7 days apart), in association with psycho-
logical support, produced a marked reduction in depressive symptoms, as assessed by the
16-item Quick Inventory of Depressive Symptoms (QIDS) at 1 week, 5 weeks, 3 months,
and 6 months. Depressive symptom reduction at 5 weeks was predicted by the quality
of the acute psychedelic experience [
85
]. Recently, two further clinical studies have con-
firmed the efficacy of psilocybin in patients affected by major depressive disorder. In the
first study, 24 of 27 patients completed a randomized, waiting-list-controlled clinical trial
at the Johns Hopkins Medical Center. Patients received psilocybin at moderately high
(20 mg/70 kg) and high (30 mg/70 kg) doses in two sessions. Statistical analysis showed
a significant decrease in GRID-HAMD scores from baseline to weeks 1 and 4 [
86
]. In
the second study, 59 patients affected by moderate to severe major depressive disorder
were enrolled in a phase 2, double-blind randomized, controlled trial in which the an-
tidepressant effect of psilocybin was compared to escitalopram. The authors showed no
difference between the groups at week 6 in the 16-item Quick Inventory of Depressive
Symptomatology-Self-Report (QIDS-SR-16) score [87].
8. Psilocybin and Obsessive–Compulsive Disorder
Clinical information regarding the potential therapeutic effects of psilocybin in pa-
tients affected by obsessive–compulsive disorder is very limited. In a double-blind study
performed on 9 patients (7 males and 2 females), affected by resistant obsessive–compulsive
disorder, psilocybin showed to be safe and effective in reducing obsessive–compulsive
symptoms for a duration extended beyond the psychedelic effect [
88
]. Psilocybin was
administered in up to four different doses in a modified dose escalation from very low
dose (25
µ
g/kg) to high dose (300
µ
g/kg) [
87
]. In 2014, Wilcox described a case report in
which a patient had used psilocybin for years in order to reduce obsessive–compulsive
symptoms [
89
]. This case report followed the case report of Leonard and Rapoport, in
which authors described the history of a 17 year-old patient who used LSD and psilocybin
to reduce obsessive–compulsive symptoms [90].
9. Psilocybin and Addiction
In a proof-of-concept study performed on 10 volunteers (6 men and 4 women), oral ad-
ministration of psilocybin in one or two sessions in combination with motivational enhance-
ment therapy induced a reduction in drinking days during the subsequent
5–12 weeks
.
Drinking-day reduction was correlated to the mystical quality of psychedelic experience.
Patients did not report significant side effects [
91
]. The first pilot study performed on
15 people (10 males and 5 females)—which involved a smoking cessation program, and

J. Xenobiot. 2022,12 48
psilocybin in combination with cognitive behavioural therapy—induced a seven-day point
prevalence abstinence at 6-month follow-up in 12 of the 15 participants [
91
]. In a simi-
lar open-label pilot-study performed on 12 people—which involved smoking cessation
treatment, and psilocybin in combination with cognitive behavioural therapy—6 months
of abstinence was produced in 80% of volunteers, without significant side effects. In the
sample, abstinence was related to the mystical quality of psychedelic experience [
92
]. An
open label study is currently in progress, in which the primary endpoint is the assessment
of the safety of concurrent buprenorphine and naltrexone administration. The estimated
study completion date is November 2021 [93].
10. Discussion
In recent years, there has been a resurgence of scientific interest about the potential
use of psilocybin and other psychedelics for treating psychiatric disorders, in particular
mood disorders, anxiety and addiction [
17
,
18
]. Recent clinical studies have tried to fill
the methodological errors presented by the past studies, including the small size of the
enrolled samples, absence of double-masking design, non-use of validated tools for mea-
suring the life expectancy of patients, and non-use of biomarkers [
94
]. As emerged from
the 1950s and 1960s studies, psilocybin has been shown to be safe and well tolerated,
particularly when used at therapeutic doses. The most commonly reported side effects
were anxiety, headaches, nausea, confusion, vomiting, and slight sympathomimetic symp-
toms [
67
–
69
,
72
,
73
,
81
]. All symptoms were described as transient, and no patients required
any specific pharmacological treatment. In patients affected by mood depressive disorder
and anxiety, psilocybin was displayed to be effective in reducing depressive symptom in
short-, medium- and long-term analysis [
78
–
82
]. Antidepressant activity lasted longer than
psychotropic effects; however, the quality of acute psychedelic experience significantly
influenced the therapeutic results [
82
,
88
]. The most important pharmacological property
showed by psilocybin, in all trials, was the rapid onset of the antidepressant effect. This
effect could allow an improvement if used in conjunction with traditional antidepressants
therapy, which has a long latency of action [
90
]. However, no study compared psilocybin
with other rapid-acting antidepressants such as ketamine. On the other hand, our analysis
of information extracted by clinical studies performed on patients affected by depression
has shown two principal limitations: first, the small size of the enrolled samples; second, the
comorbidity between depressive symptoms and severe diseases (cancer) in many patients.
Overall, the studies have only enrolled a few dozen patients; therefore, results cannot be
generalized for more heterogeneous people in terms of age, social status, and disease dura-
tion. Moreover, depressive symptoms associated with other diseases could have different
expression/evolution compared with primary mood depressive disorder. Consequently,
the pharmacological response to therapeutic dosages of psilocybin could be different in
primary and secondary depression. In addition, no study included personal expectancy
measures as a concomitant variable in the statistical analyses of clinical responses. The
unblinding design, expectancy of participants, and evaluators, could be in part responsible
of the good results found in all clinical studies. Further and more robust trials are needed
to better understand the potential therapeutic properties of this psychedelic. Recently, in a
clinical study performed on patients affected by depression, the antidepressant effect of
psilocybin was comparable to that of citalopram [
87
]. Finally, the effectiveness of psilocybin
for treating other illnesses, such as obsessive–compulsive disorder and addiction, is not
demonstrable, due to the paucity of clinical information currently available. The positive
results reported by the authors can be considered interesting hypotheses to be explored
in future and more robust clinical studies. In conclusion, psilocybin confirms to be safe
and well tolerated when administered at therapeutic doses. Clinical studies currently
available, in particular those performed in patients affected by mood depressive disorder,
show encouraging therapeutic results requiring further and better designed trials.
Author Contributions:
Authors have equally contributed to the manuscript. All authors have read
and agreed to the published version of the manuscript.

J. Xenobiot. 2022,12 49
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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