Chapter 73

Neurobiology of the Effects of Psilocybin

in Relation to Its Potential Therapeutic
Targets
Filip Tyls1,2, Tomas Palenicek1,2, Jiri Horacek1,2
1National Institute of Mental Health (NIMH), Klecany, Czech Republic; 23rd Medical Faculty, Charles University in Prague, Prague, Czech Republic

INTRODUCTION (Hasler, Grimberg, Benz, Huber, & Vollenweider, 2004; Tyls et al.,
2014). The most notable sign of psilocybin intoxication are marked
Characteristics of Psilocybin and Its Position psychological changes—the so-called altered state of consciousness
Among Other Hallucinogens (ASC). The degree of psychological alteration is dose-dependent
(for dose–symptoms correlation see (Stebelska, 2013; Tyls et al.,
Psilocybin is the main psychoactive substance contained in many 2014)). It is characterized by changes of perception (both of the self
species of hallucinogenic mushrooms (Figure 1) (genera Psilocybe, and of the external world), thought, and mood (increased range of
Conocybe, Copelandia, Panaeolus, Indocybe, etc.) (Tyls, ­Palenicek, & intense emotions). An intermediate dose of psilocybin (0.2 mg/kg)
Horacek, 2014). Due to the wide distribution of psilocybin- also induced increases in the experience of unity, spiritual experi-
containing mushrooms around the world, it is probably the most ence, blissful state, insightfulness, disembodiment, elementary and
widely used natural hallucinogen in the world (Stafford, 1992). complex imagery, audio-visual synesthesia, and changed meaning
Ritual use of teonanácatl (indigenous name for psilocybin of percepts (Halberstadt, 2015).
mushrooms) by some indigenous tribes of Latin America is a con- Psilocybin itself has a very low toxicity; complications associ-
ventional practice even today (Metzner, 2005). The main purposes ated with its use have been reported only rarely. One recent review
for using sacred mushrooms in these cultures have been to gain showed psilocybin-induced cardiovascular and cerebral damage
knowledge (spiritual development) and to heal (Stafford, 1992). (Stebelska, 2013); however, all cited case reports in this review
Ancient shamans used divine mushrooms for the induction of were linked to the use of mushrooms, where commutation with
visions and trance states, which enabled individuals to transform other fungi containing possibly more toxic substances might be
their thoughts and to get a new view of the disease (Metzner, 2005). a confounding factor. In a commentary to this article, dos ­Santos
The ceremonies are examples of a long tradition of using so-called (2014) concluded that the adverse effects of psilocybin were
altered state of consciousness in therapy and can be inspirational
for modern approaches. Trance states induced during shamanistic
rituals resemble dream states or acute psychosis.
The increasing number of research papers on psilocybin pub-
lished within the last decade (Figure 2) (Tyls et al., 2014) reflects
the interest of the scientific community in understanding the neu-
robiology of psychedelic effects as well as the therapeutic value of
psilocybin (Halberstadt, 2015). The methodology of psychedelic
research has improved greatly, including the drafting of guide-
lines for hallucinogen use in human studies (Johnson, Richards,
& Griffiths, 2008). New double-blind controlled studies have
emerged, suggesting long-term positive subjective effects of psilo-
cybin and thus proving earlier, methodically weaker, observations
(Tyls et al., 2014).
Chemically, psilocybin is one of the indolalkylamine halluci-
nogens with high affinity to serotonin 5-hydroxytryptamine (5-HT)
receptors (Halberstadt, 2015). When administered to humans, psilo- FIGURE 1  Psilocybe cubensis—Thai. The figure shows hallucinogenic
cybin has moderate effects on physiological functions (mild sympa- mushrooms Psilocybe cubensis (Thai type) artificially cultivated indoors.
thomimetic effect, alterations in blood hormone levels, hyperreflexia) Photograph from author’s collection.

Neuropathology of Drug Addictions and Substance Misuse, Volume 2. http://dx.doi.org/10.1016/B978-0-12-800212-4.00073-X

782 Copyright © 2016 Elsevier Inc. All rights reserved.
 Psilocybin–Neurobiology and Therapy Chapter | 73  783

FIGURE 2  Publications dealing with psilocybin. The graph shows the number of publications dealing with psilocybin/psilocin (y axis) in 5-year inter-
vals (x axis) from the year of its synthesis. Human studies are indicated in black, and other studies in gray. Data obtained from PubMed dated 06/02/2013;
advanced search criteria were “psilocybin” [Title/Abstract] OR “psilocin” [Title/Abstract] and Date “YYYY–YYYY” [Date—Publication]; for human
studies, the relevant selection box was checked). Diagram reproduced from Tyls et al. (2014) with the permission of European Neuropsychopharmacology.

overrated. In addition, psilocybin reportedly does not induce long-

term memory impairment, delirium, or addiction (Halberstadt,
2015; Tyls et al., 2014)—on the contrary, it has actually been
reported to have beneficial effects on human well-being (Griffiths,
Richards, McCann, & Jesse, 2006). Finally, the ratio of lethal dose
to psychoactive dose for psilocybin was estimated to be 1000:1
(Gable, 2006).
Detailed chemical, structural, pharmacokinetic, and pharmaco-
dynamic characteristics were reviewed elsewhere (Stebelska, 2013).
Phenomenology of intoxication is similar for all serotonergic hal-
lucinogens; however, it is clearly distinguishable from intoxication
with other psychedelics, e.g., dissociative anesthetics (ketamine),
entactogens (MDMA), or phytocanabinoids (­Halberstadt, 2015).
During the 1960s, most of the clinical studies with psilocybin were
performed using synthetic Indocybin® manufactured by Sandoz
(Passie, Seifert, Schneider, & Emrich, 2002) (Figure 3).

Applications to Other Addictions and

Substance Misuse
Psychedelic mushrooms became a popular recreational drug dur-
ing the hippie cultural revolution of the late 1960s, due to their
“natural” origin (unlike the synthetic LSD). As the abundant distri-
bution of psilocybin-containing mushrooms was largely unknown
at this time, users as well as researchers made successful attempts
to cultivate them artificially (e.g., (Oss & Oeric, 1991), Figure 1).
Even though psychedelic mushroom harvesting is popular in many
FIGURE 3  Synthetic psilocybin Indocybin®. The figure shows an
countries worldwide these days, cultivation is still popular as well. original phial with psilocybin pills from Sandoz, which was used during
Today it is also easy to obtain many kinds of hallucinogenic mush- the initial psilocybin experiments. Source: http://www.herbmuseum.ca/
room spores over the Internet. Psilocybin and psilocin belong to content/sandoz-indocybin-psilocybin.
a group of Schedule I drugs in most countries around the world.
They were classified as such during the hippie era despite the
fact that psilocybin does not induce any signs of severe toxicity “Therapeutic targets”). The relative risks associated with the use
and addiction (either in animals or in humans). On the contrary, of psilocybin as well as with other hallucinogens can be divided
promising results from recent studies show that psilocybin could into two subgroups. First, the drug induces profound changes in
be beneficial in the treatment of addiction (detailed information in perception, including hallucinations, and affects normal cognitive
784  PART | IV Hallucinogens

processing, thereby increasing the risk of injury/accidents linked Horáček, 2008). The most recent theory reports protein kinase
to inappropriate/inadequate behaviors. Even though cases of death C (PKC)–dependent phosphorylation of serin on position 280
or severe injuries have been described, these are extremely rare. of the intracellular loop of the 5HT2A receptor activated specifi-
Another risk is a toxic psychotic reaction (for the risk of persist- cally by hallucinogens (Karaki et al., 2014). The authors sug-
ing psychosis, see “Pro-psychotic potential of psilocybin”), and, gest that this phosphorylation decreases desensitation/facilitates
finally, flashbacks or hallucinogen persisting perception disorder re-sensitization of the 5-HT2A receptor and therefore strongly
(HPPD). Again, these symptoms were reported only rarely and potentiates the effect of the agonist.
can be easily managed by psychotherapeutic and pharmacological Psilocybin and other hallucinogenic tryptamines as well as
(anxiolytics, atypical antipsychotics) interventions. LSD directly inhibit the dorsal raphe nucleus (DRN) by bind-
ing to presynaptic inhibitory 5-HT1A receptors. Neurons of this
nucleus send serotonergic projections to all forebrain structures,
Pro-Psychotic Potential of Psilocybin particularly to the frontal cortex. DRN is also inhibited indirectly
Extensive exploration has been conducted in order to estimate by the stimulation of 5-HT2A receptors on GABAergic interneu-
the potential of 5-HT hallucinogens to induce persisting psy- rons in the periaqueductal gray (Liu, Jolas, & Aghajanian, 2000;
chotic symptoms. In thousands of individuals, the prevalence was Nichols, 2004; Páleníček & Horáček, 2008). Both mechanisms
­estimated to be 0.1–0.2% (Tyls et al., 2014). The risk after a single cause a decrease in overall serotonergic tone, thereby leading to a
dose of psilocybin is very low and is usually associated with a prevalence of the effects of hallucinogens on 5HT2A receptors at
personal predisposition (Johnson et al., 2008). The main psycho- the level of the cortex (due to lower competition with serotonin)
logical side effects of psilocybin are anxiety, paranoia, derealiza- (Nichols, 2004). In addition, 5-HT2A-mediated disinhibition of
tion and depersonalization, psychotic reaction (toxic psychosis), the noradrenergic nucleus locus coeruleus (LC) and of the dopa-
and HPPD (Tyls et al., 2014). The causality between HPPD and minergic neurons in the ventral tegmental area (VTA) (Horacek
the use of hallucinogens is criticized (Johansen & Krebs, 2015). et al., 2006) results in an increased release of norepinephrine and
It is essential to realize that the risk of all of these side effects can dopamine to the neocortex. It is assumed that although a suppres-
be decreased by subject education (the “set”) and administration sion of activity of the DRN could theoretically be responsible for
in a safe, comfortable environment (the “setting”) (Johnson et al., the relaxing (anxiolytic) and intoxicating effects of psychedelics,
2008). Two Norwegian population studies (n = 130,000) did not the increased activity of the LC accounts for the experience of
find an increased risk of psychological disorders in hallucinogen novelty and surprise (King, 2012). Further on, electrophysiologi-
users (lifetime use of LSD/psilocybin/mescaline was reported by cal studies have shown that hallucinogens enhance the response
13.4% or 13.6% of respondents). Psilocybin use was actually asso- of LC to sensory stimuli (phasic activation) but simultaneously
ciated with a lower rate of mental health problems (Johansen & depress the spontaneous firing of LC neurons (tonic activation)
Krebs, 2015; Krebs & Johansen, 2013). (Halberstadt, 2015). The activity of hallucinogens at other recep-
tors (5-HT1A, 5-HT2C, D1, D2) most likely modulates the effects
and can be responsible for the small specific differences within the
NEUROBIOLOGY OF PSILOCYBIN’S class of 5-HT hallucinogens (Tyls et al., 2014).
ACTION On the functional level, psilocybin and other hallucinogens
are thought to disrupt the cortico-striato-thalamo-cortical (CSTC)
The Mechanism of Action of Psilocybin in circuits (Figure 4), most likely via 5-HT2A agonism. On one hand,
they attenuate the function of thalamus as a sensory filter, which
the Brain
in turn leads to an information overload in the cortex; on the other
Psilocybin is an agonist at several serotonin receptors, espe- hand, they induce the hyperexcitability of the cortex. These two
cially 5-HT1A and 5-H2A/C; however, some other activities have mechanisms in turn yield a reduction of the signal/noise ratio
been also reported (Table 1) (Tyls et al., 2014). It has been also which is thought to be a characteristic underlying mechanism for
shown to induce the release of dopamine in the human striatum the psychedelic/hallucinogenic effects (Geyer & Vollenweider,
(­Vollenweider, Vontobel, Hell, & Leenders, 1999) and recently 2008; Nichols, 2004). The disruption of thalamic filtering is most
in the rat nucleus accumbens (Sakashita et al., 2015), an effect likely caused by 5-HT2A-mediated activation of GABAergic inter-
most likely mediated indirectly via activity at serotonin recep- neurons in the reticular nucleus and subsequent inhibition of other
tors. 5-HT2A agonist activity has been postulated to be crucial thalamic nuclei (Nichols, 2004). Increased cortical excitability is
for the hallucinogenic effects of classical hallucinogens. The mediated via 5-HT2A receptors on glutamatergic pyramidal neu-
similar phenomenology of intoxication in comparison with rons of the layer V (Artaloytia et al., 2006). These neurons are
other serotonergic hallucinogens and the occurrence of cross- normally activated by axons from the mediodorsal nucleus of the
tolerance between these compounds (Halberstadt, 2015) sug- thalamus in response to stimuli from the external environment.
gest a common mechanism of action linked predominantly to The excitability of pyramidal neurons in the cortex also increases
5HT2A receptor agonism (Glennon, Titeler, & McKenney, 1984; due to the inhibition of the thalamic filter and the joint action of
­Halberstadt, 2015). Because some 5-HT2A agonists, e.g., lisuride, the activated dopaminergic (VTA) and noradrenergic systems
do not exert hallucinogenic effects, several recent hypoth- (LC) (Nichols, 2004) and deactivated serotonergic systems (DRN)
eses trying to explain this discrepancy related to the 5-HT2A (King, 2012). Disrupted function of the thalamus in the limbic
receptor–mediated intracellular signaling have emerged (e.g., CSTC circuit with subsequent hyperfrontality can be the poten-
activation of specific protein kinase, agonist trafficking of recep- tial mechanism of the production of hallucinations (Behrendt &
tor signaling) (Gonzalez-Maeso et al., 2003, 2007; Páleníček & Young, 2004; Halberstadt, 2015).
TABLE 1  Affinity of Psilocin to Serotonin Receptors

Study Method Constant Subtypes of Serotonin Receptors

5HT1A 5HT1B 5HT1D 5HT1E 5HT1F 5HT2A 5HT2B 5HT2C 5HT3 5HT4 5HT5A 5HT5B 5HT6 5HT7
Blair Radioligand Ki (nM) 49nM, [3H] x x x x 25nM, x 10nM, x x x x x x
et al. competition, 8-OH-DPAT [1251] [1251]
(2000) rat brain DOI DOI
McKenna, Radioligand Ki (nM) 190nM, [3H] x x x x 6nM, 410 nM, [3H] x x x x x x x
Repke, competition, 8-OH-DPAT [1251] ketanserin
Lo, and rat/bovine DOI
Peroutka brain
(1990)
Ray (2010) http://pdsp. npKi* 2,88 2,19 3,4 3,03 x 2,14 4 2,52 x x 2,83 x 2,82 2,82
med.unc.
edu/pdspw/
binding.
php

x, missing data.
*npKi is the logarithm of the normalized value of Ki. It is calculated as follows: npKi= 4 + pKi − pKimax, where pKi = −log10(Ki).
Table reproduced from Tyls et al. (2014) with the permission of European Neuropsychopharmacology.
786  PART | IV Hallucinogens

FIGURE 4  The mechanism of hallucinogenic action. Brain structures are depicted in orange, serotonin receptors as gray rectangles, and receptor
agonists in rose (serotonin) and violet (hallucinogen). The main neurotransmission pathways are depicted in red (5-HT, serotonin), blue (GABA, γ-amino-
butyric acid), green (GLUT, glutamate). Modified, according to Baumeister et al. (2014).

Psilocybin as a Model of Psychosis In accordance with that, it was hypothesized that the persisting
effects (that is, the effects that outlast the acute pharmacological
Models of psychosis are crucial for understanding the neurobiol- effects) of hallucinogens are related to the acute psychological
ogy, neuropathology, and etiology of psychosis as well as for the effects during the intoxication (Bogenschutz, 2013). These biolog-
development of novel treatment strategies. Various approaches ical and psychological aspects will be discussed in the subchapters
have different levels of constructive, face, and predictive validity. focusing on the treatment of specific disorders.
Intoxication by serotonergic hallucinogens, which shows high face
validity with positive symptoms of psychosis, resulted in a postu-
lation of the serotonergic hypothesis of schizophrenia. Psilocybin Anxiolytic and Antidepressant Potential
is currently one of the main serotonergic models used in animal as
A potential future use of psilocybin in the treatment of anxiety-
well as human experiments (Tyls et al., 2014). The main animal
depressive disorder is emerging (Carhart-Harris, Leech, et al.,
behavioral models evaluate parameters such as startle habitua-
2012; Vollenweider & Kometer, 2010). Baumeister et al. con-
tion, prepulse inhibition, head twitch response, and interval tim-
cluded their review of antidepressant potential of hallucinogens as
ing (Halberstadt, Powell, & Geyer, 2013). In contrast to animals,
follows: “Depression causes a profound burden on society. These
human models give us the possibility of exploring the higher brain
drugs [hallucinogens] offer at least the potential of better under-
functions and unconscious processes. Furthermore, as mentioned
standing the neurobiology of depression, and of providing novel
above, the experience with hallucinogen intoxication can be a
therapeutic agents.” (Baumeister, Barnes, Giaroli, & Tracy, 2014).
valuable tool for psychiatrists, providing insight into the mental
The idea of using a psychedelic drug to alleviate the suffering
states and experiences of their patients (Halberstadt et al., 2013).
of patients with terminal illness first surfaced in 1963 in the work
of Dr. Eric Kast (Phifer, 1977). This early research focused on
the pain-relieving effects of LSD, but later Dr. Kast recognized
THERAPEUTIC TARGETS and described the transcendental experience that can help patients
The main advantageous properties of psilocybin for human clinical overcome the fear of death (Dutta, 2012). Dr. Walter Phanke
research and treatment are its intermediate duration of action (3 h) explained this phenomenon as follows: “Once the patient is able to
and good oral absorption (Hasler et al., 2004). The four promis- release all the psychic energy which he has tied to the fear of death
ing targets for psilocybin treatment seem to be anxiety/depression, and worry about the future, he seems able to live more meaning-
addiction, obsessive-compulsive disorder, and cluster headache. fully in the present.” (Phifer, 1977). Dr. Stanislav Grof went further
From a neurobiological point of view, psilocybin directly acts and performed a psychedelic peak therapy with high doses of LSD
on receptors, neurotransmitters, and structures that are involved (350–400 μg) at the Maryland Psychiatric Research Center. Sixty
in the pathophysiology of the disorder. Another point of view is terminal cancer patients received LSD as an adjunct for psycho-
well represented by Abraham Maslow, who presented a psycho- therapy, with each patient receiving at least 20 h of psychotherapy
logical perspective on psilocybin action, stating that “ASCs are prior to LSD administration. LSD-induced psychedelic experience
key to realizing one’s psychological well-being” (Dutta, 2012). increased the sense of unity, insight, and positive mood, and it
 Psilocybin–Neurobiology and Therapy Chapter | 73  787

decreased fear of death, anxiety, and depression. One-third of the The second mechanism is related to the activity on 5-HT2A recep-
patients reported no significant improvement, one-third reported tors. Hallucinogens including psilocybin induce rapid 5-HT2A
a certain extent of improvement, and one-third noticed dramatic downregulation after a single dose (Roth, Berry, Kroeze, Wil-
improvement (Phifer, 1977). lins, & Kristiansen, 1998; Tyls et al., 2014), whereas increased
The need to develop new strategies for depression treatment cortical expression of 5-HT2A receptors has been observed in
has gained importance in light of a recent metaanalysis that depressed patients post mortem and in “learned helplessness,” an
showed low efficacy of standard antidepressant drugs (Andrews, animal model of depression (Baumeister et al., 2014). Therefore,
Thomson, Amstadter, & Neale, 2012). A recent paper reviewed 5-HT2A downregulation is likely to be one of the key mechanisms
the results of studies with a single application of the psychedel- (Baumeister et al. 2014; Roth et al., 1998; Tyls et al., 2014). Hal-
ics ketamine and psilocybin (Young, 2013), showing high efficacy lucinogens also increase neuroplasticity in a way similar to anti-
after a single dose. Further evidence comes from double-blind depressants, because the activation of 5-HT2A receptors leads to
controlled studies with healthy volunteers, which showed long- increased expression of cellular brain-derived neurotropic factor
term positive subjective effects of psilocybin, proving earlier, (BDNF) (Baumeister et al., 2014; Vollenweider & Kometer, 2010)
methodically weaker, observations (Tyls et al., 2014). Similarly, in and it was also shown to reduce the inflammatory cytokines tumor
animal models of depression, a reduction of anxiety-like behavior necrosis factor-α and interleukin-6 (Baumeister et al., 2014).
was observed after psilocybin treatment (Catlow, Song, Paredes, Some activity can be also related to psilocybin’s activity at 5-HT2C
Kirstein, & Sanchez-Ramos, 2013). receptors: (1) opposite changes in expression have been associ-
The first recent placebo-controlled study (n = 12) in patients ated with anxiety (increase) and depression (decrease); and (2) in
with low-dose psilocybin (0.2  mg/kg) was performed by Dr. animal models, 5-HT2C antagonist showed an antidepressant effect
Charlres Grob at the Harbor-UCLA Medical Center; it confirmed (Baumeister et al., 2014). Finally, psilocybin also affects hippo-
anxiolytic and antidepressant effects of this drug while discovering campal neurogenesis; at a low dose (0.1 mg/kg i.p.), it tends to
no side effects (Grob et al., 2011). During the intoxication, patients increase neurogenesis, whereas at high doses (1 mg/kg i.p.) it tends
underwent an autobiographic reevaluation that allowed them to to be suppressed (Baumeister et al., 2014; Catlow et al., 2013).
gain new insights into the meaning of their lives (Macready, 2012). Although the mechanism of acute psilocybin action has been
The cancer study is currently being replicated by Dr. Stephan Ross well investigated, the prolonged duration of changes is still to
at New York University with a similar design (n = 32), except that it be elucidated. Some investigators propose that these effects are
uses a medium dose of psilocybin (0.3 mg/kg). Although the study secondary to the spiritual epiphany during ASC resulting in com-
has not yet been completed, the initial data (n = 12) indicate a rapid plex psychological changes (Macready, 2012; Young, 2013). It
clinical improvement (decreased anxiety and depression). Patients was shown that a structural correlate of psychologically induced
reported that psilocybin transformed their perspective on life ASC, namely mindfulness meditation, increased the volume of the
and death (Macready, 2012). Another study with cancer patients gray matter of the brain (Holzel et al., 2011). Therefore psilocybin
focused on the anxiolytic/antidepressant effect of psilocybin is cur- could induce similar structural changes due to the psychological
rently ongoing at Johns Hopkins University since 2008 (­Nichols, effects during acute intoxication (ASC), which can be considered
2014). Psychedelic therapy of dying patients undermines the mod- correlates of the long-term changes in the subjects’ well-being
ern cultural paradigm of repressing the issue of death (Dutta, 2012). (Young, 2013). Furthermore, psilocybin alters the brain’s neural
Psilocybin treatment of terminal cancer can thus be viewed as a networks in a manner similar to selective serotonin reuptake inhib-
shift in treatment strategy from delaying death to improving the itors (SSRIs) and the form of psychotherapy known as cognitive-
quality of the remaining days of life. The celebration of death rather behavioral therapy (both of which reduce medial PFC activity)
than repression (preparing for the death, planning the death, accept- and meditation (which causes a decrease in default mode network
ing the idea of assisted death) is something that we can learn a lot [DMN] activity) (Baumeister et al., 2014).
about from the indigenous nonwestern cultures (Sessa, 2008). It is
very likely that the psychedelic experience itself is important for
Dependence Treatment
the antidepressant effects of psilocybin, similar to LSD and ket-
amine: it has been reported that the stronger the psychedelic/psy- Psilocybin and possibly other hallucinogens are now studied as a
chotic experience after LSD/ketamine, the better the antidepressant potential adjunct in the treatment of addiction. In fact, substance
effect (Phifer, 1977; Sos et al., 2013). dependence was the first indication for psychedelic therapy, a con-
The serotonergic system, which has a crucial role in the neuro- cept that pointed toward religion and mysticism (Carhart-Harris,
biology of affective states, is a target for conventional antidepres- Leech, et al., 2012). Most of the available evidence supports the
sants as well as psilocybin. The most striking difference between high-dose, single-session model (Bogenschutz, 2013).
them is that psilocybin is effective after a single dose (Baumeister From the 1950s until the early 1970s, LSD was used in alco-
et al., 2014). The long-term effect of classical antidepressants is hol dependence treatment (Bogenschutz, 2013). The promising
related to receptor upregulation/downregulation and induction of results initiated the use of psilocybin in studies on the treatment
neuroplasticity. Contrary to classical antidepressants, the primary of substance dependence (Young, 2013). Dr. Bogenschutz at the
action of psilocybin is related to its activity on 5-HT receptors and University of New Mexico, Albuquerque, used psilocybin for alco-
not on the 5-HT transporter (SERT). The role of 5-HT1A activity is hol dependence treatment in a small pilot study (n = 10), showing
supported by the facts that: (1) depressed patients have lower post- some promising outcomes in the recent follow-up (Nichols, 2014).
synaptic 5-HT1A binding potential in the amygdala, hippocam- Dr. Johnson at Johns Hopkins University examined the effect of
pus, and medial PFC; and (2) 5-HT1A agonists show anxiolytic/ three psilocybin sessions (20 or 30 mg) on tobacco smoking cessa-
antidepressant effects (e.g., buspirone) (Baumeister et al., 2014). tion using self-report measures and smoking-related biomarkers.
788  PART | IV Hallucinogens

In this small pilot study (n = 15), he found that 80% of participants the activation of 5-HT2C receptors by psilocybin, which results in
showed 7-day point prevalence abstinence in the 6-month follow- inhibition of dopaminergic neurons in the ventral tegmental area
up. Such a smoking cessation rate is much higher compared to (VTA) (Baumeister et al., 2014).
other behavioral/pharmacological approaches (<35%) (Johnson, The antiaddictive effects of 5-HT hallucinogens can be also
Garcia-Romeu, Cosimano, & Griffiths, 2014). The relevance of mediated by an increase in neurotrophic factor levels, leading
the study is limited by the absence of a control group. Dr. Ross to synaptic remodeling. Activation of BDNF signaling in the
(2012) at New York University is going to start a controlled trial medial prefrontal cortex and dorsal striatum has antiaddictive
of psilocybin-assisted psychotherapy in the treatment of alcohol effects; however, it has opposite effects in the nucleus accumbens
dependence. Burdick et al. proposed a design of opioid depen- (Ross, 2012). 2,5-Dimethoxy-4 iodoamphetamine (DOI) induced
dence treatment study with psilocybin controlled by a nonphar- 5-HT2A-mediated increase in BDNF mRNA in the neocortex but a
macological ASC induction (holotropic breathwork) and active decrease in the hippocampus (­Bogenschutz, 2013; Vaidya, Marek,
placebo (niacin) (Burdick & Adinoff, 2013). Aghajanian, & Duman, 1997) and an increase of dendritic spine
Dr. Johnson postulated that hallucinogen-mediated treatment remodeling in rat pyramidal cells (Bogenschutz, 2013; Jones et al.,
of addiction involves higher psychological and/or biological 2009).
mechanisms. This contrasts with conventional pharmacotherapy On the level of brain networks, 5-HT hallucinogens increase
of dependence, in which the treatment aims at the same phar- activity in the prefrontal–limbic circuitry through an increase in
macological system as the drug of abuse (Johnson et al., 2014). glutamate levels. The normalization of functional connectivity in
There are two main psychological components of the antiaddictive this network is associated with antiaddictive effects (Ross, 2012).
effect: psychological insight and mystical experience (Burdick &
Adinoff, 2013). Similarly to the situation with depression, psilocy-
Obsessive-Compulsive Disorder (OCD)
bin-induced deepening of spirituality can have a significant posi-
tive impact, just like religiosity (Burdick & Adinoff, 2013; Cook, OCD is a severe psychiatric disease with pathological changes
2004). The sacramental use of hallucinogens in native commu- in the 5-HT system. Specific treatment is yet to be developed.
nities, together with low rates of alcohol and drug consumption, The most effective treatment for OCD, namely, SSRIs and clo-
suggests antiaddictive effects. This was shown in two religious mipramine, reduces OCD symptoms only by 30–50% (Moreno,
groups in the United States that are allowed to use hallucinogens ­Wiegand, Taitano, & Delgado, 2006). Identifying new approaches
by the government: the Native American Church, with mescaline, in affecting the 5-HT system of OCD patients is therefore of high
and Uniao do Vegetal, with ayahuasca. There are considerable importance.
confounding factors such as social, spiritual, or communal aspects The first observations indicating the effectiveness of psilocy-
of religion (Ross, 2012); however, all of these can be potentially bin in OCD treatment were made by OCD patients self-medicating
linked to or even directly potentiated by hallucinogens. with psychedelic mushrooms. One case report showed that obses-
The biological components of psilocybin’s antiaddictive sive thoughts completely disappeared after ingestion of psilocybin-
effects remain unclear. Although the acute effects of psilocybin on containing mushrooms (Leonard & Rapoport, 1987). Based on these
the brain are relatively well understood, the long-lasting changes, early observations, Dr. Moreno designed a double-blind study explor-
which are more relevant for addiction treatment (Bogenschutz, ing the effects of up to four psilocybin sessions (doses of 25–300 μg/
2013), are yet unexplored. It is a common feature of substances kg) in patients with OCD. This study found an acute alleviation of
with dependence potential that they increase extracellular dopa- OCD symptoms in all (n = 9) subjects (23–100% decrease in Yale–
mine in the mesolimbic pathway (Ross, 2012). Although psilocy- Brown Obsessive Compulsive Scale [YBOCS]) during the session.
bin lacks affinity for dopamine receptors, it can increase dopamine The 25% and 50% reduction of OCD symptoms persisted after 24 h
levels indirectly through 5-HT receptors. In humans, psilocybin after psilocybin administration in 89% and 67% of subjects, respec-
increased dopamine in the striatum (in correlation with euphoria tively. Moreover, one patient achieved a complete 5-month remis-
and depersonalization) (Vollenweider et al., 1999) but failed to sion (Moreno et al., 2006). Although these results are promising, the
activate the nucleus accumbens to any significant extent (Ross, limitations of the study are the absence of a placebo group, small
2012). Dr. Ross et al. suggested that a low-grade increase in dopa- sample size, and no long-term follow-up (Baumeister et al., 2014).
minergic transmission caused by 5-HT hallucinogens can lead to Especially the placebo effect should be taken into account, because
regeneration of D2 receptors (i.e., normalization of their function), Hallucinogen Rating Scale (HRS) scores after such a low dose of
similarly to a substitution therapy of addiction (Ross, 2012). psilocybin were higher than the authors expected.
Classical hallucinogens are associated with tachyphylaxis The study by Dr. Moreno et al. also explored the relation-
(rapid induction of tolerance following repeated administration) ship between psychedelic effects (measured by the HRS) and
that is hypothesized to be a result of 5-HT2A receptor downregu- the severity of obsessive and compulsive symptoms (measured
lation (Tyls et al., 2014). Dr. Bogenschutz (2013) pointed out by the YBOCS and visual analog scale [VAS]); however, he did
that this can be relevant, because 5-HT2A receptors are upregu- not find any significant interaction (Moreno et al., 2006). This
lated with chronic alcohol exposure in rats (Akash, Balarama, & is supported by a case report that showed the reduction of OCD
­Paulose, 2008). 5-HT2A downregulation can also result in the pre- symptoms after repeated doses of psychedelic mushrooms
vention of stress-induced relapse of abuse, since higher 5-HT2A despite the absence of psychedelic effects due to a development
density in the human brain correlates with an increase in anxi- of tolerance (Moreno & Delgado, 1997). The observation that
ety and stress response activation (Ross, 2012). Another possible psilocybin is useful in OCD treatment irrespective of the depth
mechanism can be a decrease in dopamine activity precipitated by of the psychedelic experience and of the dose administered
 Psilocybin–Neurobiology and Therapy Chapter | 73  789

suggests that the contribution of psychological effects to the receptors, shared by both psilocybin and triptans (Tyls et al., 2014).
long-term clinical effects is only small. The involvement of 5-HT2C receptor is likely because many pro-
Psilocybin-induced increase in extracellular 5-HT levels may phylactic anti-migraine drugs exhibit 5-HT2C affinity. Other 5-HT
underlie the acute alleviation of obsessions and compulsions in a receptors are also involved in the regulation of vascular lumen
way similar to SSRIs. On the other hand, Dr. Moreno et al. sug- (Johnson et al., 2012).
gested that the long-lasting effect of psilocybin can be partially Psilocybin can induce headache through many different
mediated by 5-HT2A downregulation or early gene expression mechanisms including NO release, increase in glutamate levels,
(Moreno et al., 2006). This means that repeated low doses and inhibition of the DRN with consequent activation of LC, 5-HT2B
induction of tolerance are more beneficial for OCD patients than agonism, and induction of gene transcription. Acute administra-
the psychedelic experience. tion of some 5-HT-releasing drugs (e.g., fenfluramine) can pro-
voke migraine, but their repeated administration can also prevent
Cluster Headache migraine attacks. It is possible that related mechanisms can be
involved in psilocybin-mediated induction and treatment of head-
A promising effect was observed in patients with so-called cluster aches due to the many rebound mechanisms at play (Johnson
headaches—strong, disabling, periodically occurring headaches, et al., 2012).
which are often resistant to medication. One of the possible phar-
macological treatments of these headaches are indole derivatives
and antimigraine drugs, triptans, to which psilocybin is also struc-
NEW INSIGHTS
turally related (Johnson, Sewell, & Griffiths, 2012). New approaches such as functional magnetic resonance imag-
Based on a case report of a complete remission of clus- ing (fMRI), positron emission tomography (PET), quantitative
ter headache attacks after psychedelic mushroom ingestion, Dr. electroencephalography (QEEG), and magnetoencephalography
Sewell et al. performed an online survey in a group of individuals (MEG) have been used to explore the neurobiology underlying the
diagnosed with cluster headache, assessing psilocybin mushroom– psychedelic state. The study of the phenomenology of psilocybin
induced alleviation of the symptoms of both episodic and chronic intoxication in combination with neuroimaging methods will help
(i.e., no remission period) forms of the disease. They found that us to understand the ties between subjective consciousness and
psilocybin is effective in aborting cluster headache attacks (85%) brain function (Nichols, 2014). The results of modern imaging
as well as in preventing future attacks (52% completely, 37% studies with psychedelics can be interpreted in light of the theo-
partially). Psilocybin is thus more effective than conventional retical framework of psychoanalysis but also the theory of chaos
medication in both acute and prophylactic treatment. Furthermore, and complexity.
psilocybin was the only treatment that was able to extend the
remission period. The psychedelic effects seem not to be neces-
Brain Imaging Data from Recent Studies
sary for the reduction of cluster headache symptoms, considering
the fact that the users reported only relatively low doses (Sewell, Both animal and human studies have described nonspecific desyn-
Halpern, & Pope, 2006). One cannot exclude the confounding fac- chronization of EEG activity after psilocybin administration.
tor of other substances contained in psychoactive mushrooms, but Recent animal data from our laboratory confirmed these initial
the superior effect of psilocybin is supported by the similar effi- findings. Psilocin induced a decrement of absolute spectral power
cacy of LSD, which was also assessed in the survey (Sempere, (which can be explained by local network desynchronization) and
Berenguer-Ruiz, & Almazan, 2006). A placebo-controlled clinical a decrement of EEG coherences (a measure of functional connec-
trial is needed to confirm these promising results. tivity of the long projections in the brain). Similar QEEG pattern
However, recent human studies with psilocybin also showed was found with other serotonergic hallucinogens and the decre-
an opposite effect, namely, that psilocybin can induce transient ment of EEG coherences was shared with dissociative anesthetics,
mild to moderate headaches. The incidence and duration of the as reviewed elsewhere (Tyls et al., 2014). These findings are in
headaches was dose-dependent (Johnson et al., 2012). accordance with the first MEG study in human volunteers intoxi-
The potential of psilocybin to both induce and treat headaches cated with psilocybin. It found decreased broadband spontaneous
can be better understood with a deeper insight into the complex cortical oscillatory power during resting state with the most pro-
role of the 5-HT system in the pathogenesis of headaches. One nounced changes in the default mode network (DMN). Psilocybin
of the possible mechanisms of headache triggering is serotonin- reduced cortical synchrony by increasing the excitability of deep
mediated vasoconstriction. During the headache attacks, patients layer pyramidal neurons (Muthukumaraswamy et al., 2013).
with migraines showed a strong increase in brain serotonin con- PET studies using psilocybin (15–25 mg p.o.) documented
centrations, with lower serotonin levels observed between attacks increased metabolism in the prefrontal cortex (lateral, medial,
(Johnson et al., 2012). Psilocybin induced a decrease in 5-HT tone and anterior cingulate cortex [ACC]), temporal cortex, and basal
through DRN inhibition via 5HT1A autoreceptors. Hypothetically, ganglia, and decreased metabolism in the thalamus (Gouzoulis-
the agonist activity on these receptors can be responsible for the Mayfrank et al., 1999; Vollenweider et al., 1997), as reviewed else-
prevention of cluster headache episodes. Furthermore, animal where (Tyls et al., 2014). However, an fMRI study with psilocybin
studies showed that the activation of the 5-HT1A receptor may (2 mg i.v.) showed both blood-oxygen-level-dependent (BOLD)
have analgesic effects in relation to nociceptive pain (Colpaert, and arterial spin labeling (ASL) decrements in the frontal, tempo-
Deseure, Stinus, & Adriaensen, 2006). Another possible mecha- ral, and parietal cortical midline structures (ACC, PCC, precuneus)
nism of headache reduction can be agonist activity on 5-HT1B/1D and the thalamus. This study also found decreased connectivity
790  PART | IV Hallucinogens

between the medial PFC and PCC. The intensity of subjective 5-HT1A, 5-HT2A, and 5-HT2C receptors, which precipitates com-
effects correlated with decreased activity in the medial PFC and plex changes in the cortico-striato-thalamo-cortical circuitry and
ACC. Another important finding is that two important brain net- in different activations of neural networks. These changes result
works, the DMN and task positive network (TPN), are both acti- in aberrant processing of information (mostly visual hallucina-
vated simultaneously under psilocybin intoxication, although tions) and loss of ego boundaries, connected with positive as well
under normal conditions they are always activated in mutual as negative experiences. The complex effects of psilocybin, on the
exclusion (Carhart-Harris, Erritzoe, et al., 2012; Carhart-Harris, psychological as well as biological level, may yield promising
Leech, et al., 2012). The discrepancy between these studies can results in the therapy of hyperstable pathological states such as
be explained by several mechanisms, as recently reviewed (Tyls depression, OCD, and addiction. There is also growing evidence
et al., 2014), but in light of the MEG study, both findings from for the efficacy of psilocybin in the therapy of cluster headaches.
fMRI and PET can be congruent. Psilocybin-induced increase in Contemporary scientific use of psilocybin can be seen as an
glutamatergic pyramidal neuron excitability can lead to desychro- extension of ancient rituals with psilocybin mushrooms. Clini-
nization, reflected by a decrease of fMRI signal, and to an increase cians have converted healing rituals into therapeutic sessions, and
in glutamate turnover and consequently increased glial metabo- scientists have transformed the induction of trance states into the
lism, reflected by an increase in PET signal (Tyls et al., 2014). modeling of psychosis. The scientific community is divided in its
view on psilocybin: some researchers remain extremely critical
Psilocybin and Brain Entropy (Stebelska, 2013), especially with regard to the psychotomimetic
effects of psilocybin. However, in light of a recent theoretical view
Looking at the findings from neuroimaging studies, we can on brain states, it seems that the psychotomimetic action and ther-
hypothesize that disconnection might be one of the main mecha- apeutic value of psilocybin are two sides of the same coin, at least
nisms underlying the “psychedelic state.” The coactivation of in the treatment of anxiety, depression, and addiction (Carhart-
brain networks (DMN and TPN) may result from their disconnec- Harris et al., 2014). The impossibility of separating the psyche-
tion from each other and may thus contribute to altered processing delic and therapeutic properties of psilocybin contributes to the
of information. aura of divinity surrounding teonanácatl and its unique position in
According to Dr. Carhart-Harris, the brain changes induced by society, which lasts to this day.
psilocybin are characterized by an increase in entropy. He pos-
tulated the theory of the “entropic brain” (Carhart-Harris et al., Psychedelics free people from their usual thinking patterns
2014), which distinguishes a continuum of brain states based and show that thoughts and behaviour can be changed.
on the rate of entropy with two extreme states at each end of the Dr. Carhart-Harris
spectrum. High-entropy states (called “primary consciousness”)
are unstable and characterized by creative thinking; they include
altered states of consciousness such as drug-induced psychedelic DEFINITION OF TERMS
state, moments of insight, dreaming during rapid eye movement
(REM) sleep, near-death experiences, or sensory deprivation. ASC  Altered states of consciousness. ASC is any mental state induced
Hypothetically, the disconnection of central connectivity hubs by physiological, psychological, or pharmacological maneu-
from the other brain areas can contribute to the increased entropy. vers or agents which deviates from the normal waking state of
There is, therefore, a link between the concept of acute psychosis consciousness.
as a state of pathologically increased entropy and the disconnec- QEEG  Quantitative electroencephalography. QEEG is a numerical
tion hypothesis (Friston & Frith, 1995). The main output of this analysis of electroencephalography data. Fourier analysis is often
link is lower regularity of the instrumentally measured biosignal. used for digital data processing to recognize shared activity between
The observed coactivation of brain networks under psilocybin rhythms based on phase (phase lag, coherence) and magnitude syn-
intoxication can be seen as a collapse of dualities, which is char- chrony (comodulation, asymmetry).
acteristic for primary consciousness (Carhart-Harris et al., 2014). MEG  Magnetoencephalography. MEG is a functional neuroimaging
On the other hand, low-entropy states (called “secondary con- technique for mapping brain activity by recording magnetic fields
sciousness”) are hyperstable and are characterized by rigid think- produced by electrical currents occurring naturally in the brain,
ing with a low level of creativity (e.g., novelty of the worldview). using very sensitive magnetometers.
These include sedation or deep sleep but also pathological con- fMRI  Functional magnetic resonance imaging. fMRI is a functional
ditions such as depression, OCD, and addiction (Carhart-Harris neuroimaging procedure using MRI technology that measures brain
et al., 2014). The potential treatment of these states may include a activity by detecting associated changes in blood flow. This tech-
transient increase in entropy. This explains the efficacy of psilocy- nique relies on the fact that cerebral blood flow and neuronal activa-
bin in clinical studies and implies that the induction of the psyche- tion are coupled. When an area of the brain is in use, blood flow to
delic state is not a side effect but an integral part of the treatment. that region also increases.
PET  Positron emission tomography. PET is a functional imaging tech-
nique from the field of nuclear medicine that produces a three-dimen-
CONCLUSIONS sional image of functional processes in the body. The system detects
Psilocybin is a substance that causes an altered state of conscious- pairs of gamma rays emitted indirectly by a positron-emitting radio-
ness, which is phenomenologically similar to acute psychosis, even nuclide (tracer), which is introduced into the body on a biologically
though its potential for triggering acute psychosis is low. This state active molecule. Three-dimensional images of tracer concentration
is induced by its effects of the 5-HT system, mostly by agonism of within the body are then constructed by computer analysis.
 Psilocybin–Neurobiology and Therapy Chapter | 73  791

KEY FACTS around the eye. There are often accompanying autonomic
symptoms (eye watering, nasal congestion, and swelling
Altered States of Consciousness around the eye).
l A typical characteristic is grouping of headache attacks occur-
l 
ASCs are a diverse group of physiological and pathological
ring in succession (cluster). Individuals typically experience
brain states with some common features that can be induced in
repeated attacks of excruciatingly severe unilateral headache.
a variety of very different ways.
l Cluster headache attacks often occur periodically, and active
l Examples are drug-induced psychedelic states, acute psycho-
periods of pain may be interrupted by spontaneous remissions,
sis, meditation, moments of insight, dreaming during REM
although about 10–15% of chronic cluster headaches never
sleep, holotropic breathing, near-death experiences, or sensory
remit. The cause of cluster headache has not been identified.
deprivation.
l Although there is no known cure, cluster headaches can
l All of these states have a dream-like phenomenology and other
sometimes be prevented and acute attacks can be treated.
similarities such as certain patterns of brain activation.
Recommended treatments for acute attacks include oxygen or
fast-acting triptans. Primary recommended prevention is vera-
Model of Psychosis pamil. Steroids may be used as a transitional treatment and
may prevent attack recurrence until preventive therapy takes
l Acute psychosis can be modeled in humans and, to a certain
effect.
degree, in animals by using pharmacological agents such as
amphetamines, serotonergic hallucinogens, dissociative anes-
thetics, and cannabinoids. SUMMARY POINTS
l The phenomenological validity of the models rests on the sim-
ilarity of the phenomena induced by the model and symptoms l Psilocybin is a serotonergic hallucinogen that is convenient for
of mental disorders (e.g., hallucinations, thought disorder, human research due to its relative safety and optimal pharma-
altered informational processing, self-awareness, empathy). cokinetic profile.
l The predictive validity of the models allows us to test new l Psilocybin induces altered state of consciousness by agonist
antipsychotics in animals. This makes them one of the most action at 5-HT1A, 5-HT2A, and 5-HT2C receptors, precipitat-
important tools in the research of psychosis. ing complex changes in the cortico-striato-thalamo-cortical
l Construct validity is a degree to which a model actually mim- circuitry and in the activation of neural networks.
ics the pathophysiology of the disorder that is modeled. l These changes result in aberrant processing of information
l With modern imaging techniques, we can also study the role of (mostly visual hallucinations) and loss of ego boundaries, con-
brain structures and the networks affected or involved. nected with positive as well as negative experiences. This state
is phenomenologically similar to acute psychosis.
l The complex effects of psilocybin (on the psychological as
Terminal Depression well as biological level) may yield promising results in the
l Depression triggered by a serious somatic condition that cannot therapy of hyperstable pathological states such as depression,
be cured and that is reasonably expected to result in the death of OCD, and addiction. There is also growing evidence for the
the patient within a short period of time (very often cancer). effectiveness of psilocybin in the therapy of cluster headaches.
l Contemporary scientific use of psilocybin can be seen as an
extension of ancient rituals with psilocybin mushrooms; clini-
Obsessive-Compulsive Disorder cians have converted healing rituals into therapeutic sessions,
l OCD is an anxiety disorder with intrusive thoughts and repeti- and scientists have transformed the induction of trance states
tive behaviors. into the modeling of psychosis.
l The psychotomimetic action and therapeutic value of psilocy-
l Individuals with OCD experience uneasiness, apprehension,
and worry (obsessions) that can be temporarily relieved by bin are two sides of the same coin.
certain behaviors (compulsions).
l Symptoms of the disorder include excessive washing or clean-
ACKNOWLEDGMENT
ing, repeated checking, extreme hoarding, preoccupation with
sexual, violent, or religious thoughts, relationship-related We would like to thank Jakub Korcak and Michaela Viktorinova for
obsessions, aversion to particular numbers, and nervous rituals valuable feedback and Jan Tichy for language corrections. This study
such as opening and closing a door a certain number of times was supported by the projects IGA MHCR NT/13897, “National Insti-
before entering or leaving a room. tute of Mental Health (NIMH–CZ),” grant number ED2.1.00/03.0078,
l These symptoms are time-consuming, may result in loss of and by the European Regional Development Fund.
relationships with others, and often cause severe emotional
and financial distress.
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