Probing the antidepressant potential of psilocybin: integrating insight from human research and animal models towards an understanding of neural circuit mechanisms

14 Pages·2022·0.741 MB·English

by  Juliet Meccia Joëlle Lopez Rosemary C. Bagot

Psychopharmacology
https://doi.org/10.1007/s00213-022-06297-0
REVIEW
Probing the antidepressant potential of psilocybin: integrating insight
from human research and animal models towards an understanding
of neural circuit mechanisms
Juliet Meccia1 · Joëlle Lopez1 · Rosemary C. Bagot1,2
Received: 25 May 2022 / Accepted: 12 December 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022
Abstract
Interest in the therapeutic potential of serotonergic psychedelic compounds including psilocybin has surged in recent years.
While human clinical research suggests psilocybin holds promise as a rapid and long-lasting antidepressant, little is known
about how its acute mechanisms of action mediate enduring alterations in cognition and behavior. Human neuroimaging
studies point to both acute and sustained modulation of functional connectivity in key cortically dependent brain networks.
Emerging evidence in preclinical models highlights the importance of psilocybin-induced neuroplasticity and alterations in
the prefrontal cortex (PFC). Overviewing research in both humans and preclinical models suggests avenues to increase cross-
talk between fields. We review how acute modulation of PFC circuits may contribute to long-term structural and functional
alterations to mediate antidepressant effects. We highlight the potential for preclinical circuit and behavioral neuroscience
approaches to provide basic mechanistic insight into how psilocybin modulates cognitive and affective neural circuits to
support further development of psilocybin as a promising new treatment for depression.
Keywords Psilocybin · Psychedelics · Depression · Medial prefrontal cortex · Preclinical models · Affect · Cognition
Introduction
of these enduring effects is not well understood (Ross et al.
2016; Carhart-Harris et al. 2017; Griffiths et al. 2016;
Mushrooms containing psilocybin have been used in North, Gukasyan et al. 2022; Davis et al. 2021).
Central, and South America for millennia (Furst 1972; Given its potential rapid therapeutic efficacy, understand-
Schultes et al. 1992; Metzner 1998), and scientific explora- ing how psilocybin regulates neural circuits in depression is
tion of their psychedelic and psychoactive properties and important. There is a scarcity of research investigating spe-
effects has recently intensified. Like other classical psych- cific behavioral effects of psilocybin and limited preclinical
edelics, psilocybin’s primary mechanism of action is sero- research examining how psilocybin modulates neural circuit
tonergic, signaling through serotonin receptors (5-HTRs), function, cognition, and behavior. To understand antidepres-
and specifically, the 5-HT2A receptor, to produce changes sant actions, it is critical to distinguish between acute and
in the nature of consciousness, sensation, and perception delayed, sustained effects. Acute effects will reflect a mix
(Corne et al. 1963; Corne and Pickering 1967; Aghajanian of processes, some of which will be causal to the delayed
and Marek 1999). In recent studies, psilocybin rapidly and effects that ultimately mediate sustained antidepressant effi-
enduringly reduced depression symptoms in patients with cacy. To support continued evidence-based advancement in
major depressive disorder (MDD); however, the mechanism this rapidly growing field, greater integration of clinical and
preclinical research is needed. Preclinical investigations can
reveal how psilocybin acutely induces molecular changes to
*
Rosemary C. Bagot enduringly alter circuit function, cognition, and behavior.
[email protected]
Preclinical research is also not subject to placebo effects,
1 Department of Psychology, McGill University, 1205 Ave Dr. and can provide uniquely objective evidence, which is par-
Penfield, Montréal, QC H3A 1B1, Canada ticularly relevant for psychedelic drugs where the conscious-
2 Ludmer Centre for Neuroinformatics and Mental Health, ness-altering effects make fully blinded trials challenging
Montréal, QC, Canada (Burke and Blumberger 2021). In this review, we provide
Vol.:(0112 33456789)
Psychopharmacology
an overview of current knowledge of psilocybin’s antide- The behavioral pharmacology of psilocybin has been
pressant effect, bridging human and preclinical research to extensively investigated in rodents. In mice, 5-HT1A, but not
highlight potential neural circuit mechanisms, outstanding 5-HT2A or 5-HT2C, receptors mediate psilocybin-induced
questions, and considerations for preclinical research. We suppression of locomotion and exploration (Halberstadt et al.
emphasize linking neural circuits to behavior and the need 2011). In contrast, 5-HT2ARs mediate psilocybin-induced head
for research using robust preclinical models for depression twitches, a benchmark measure of acute psychedelic activity
coupled with behavioral measures of clear translational rele- induced by all serotonergic psychedelics (Corne et al. 1963;
vance to solidify the foundation of this rapidly growing field. Corne and Pickering 1967; González-Maeso et al. 2007; Hal-
berstadt et al. 2011, 2020). The role of 5-HT2ARs in effects of
acute psilocybin is also well established in humans, with acute
Pharmacology of psilocybin
psilocybin dose-dependently impairing sustained attention in
an acoustic pre-pulse inhibition (PPI) task, effects blocked by
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), an ketanserin (Vollenweider et al. 2007). Serotonergic psychedelic
indoleamine pro-drug, is dephosphorylated into the active drugs may also mediate biased signaling. For example, behav-
metabolite psilocin (4-hydroxy-dimethyltryptamine) upon ioral effects of LSD (0.3 mg/kg) are blunted in β-arrestin 2, but
ingestion. Psilocin shares a similar chemical structure to ser- not β-arrestin 1 knockout mice (Rodriguiz et al. 2021) although
otonin (5-hydroxytryptamine; 5-HT) (Hofmann et al. 1958; this remains to be investigated with psilocybin.
Nichols 2004). Both psilocybin and psilocin are used in Recent findings raise the possibility that 5-HT2AR activ-
preclinical and clinical research and differ in bioavailability ity may not mediate all of psilocybin’s antidepressant-like
and stability. Orally ingested and intravenously administered effects (Hesselgrave et al. 2021; Shao et al. 2021). Psilocy-
psilocybin is rapidly converted to psilocin, with administra- bin may also inhibit monoamine oxidase to increase levels
tion route determining kinetics. In human plasma, signifi- of 5-HT in brain, an effect not shared by LSD, suggesting
cant psilocin levels following oral ingestion of psilocybin the potential for drug-specific effects in addition to shared
are variously detectable between 70 and 90 min, while intra- mechanisms (Freedman et al. 1970). Dopamine D2 receptor
venous administration of psilocybin results in similar levels antagonists can also partially block some effects of psilo-
of psilocin at around just 2 min (Hasler et al. 1997; Passie cybin, and psilocybin can regulate D2 receptor occupancy,
et al. 2002). Psilocin crosses the blood–brain barrier and suggesting effects on dopaminergic transmission (Vollen-
directly binds with 5-HT receptors (5-HTRs) (Dinis-Oliveira weider et al. 1999). Psilocin signaling beyond 5-HTRs is
2017). Both psilocybin and psilocin are used in preclinical possible (with some evidence suggesting binding to hista-
and clinical research with varying dose and administration mine receptor 1 (H1), dopamine receptor 3 (D3), and alpha-
routes, as such we note specifics throughout. 2A/2B adrenergic receptors), although more research is
Psilocybin signaling through 5-HTRs has been confirmed needed (National Institute of Mental Health—Psychoactive
via radioligand binding assays, in vitro electrophysiology, Drug Screening Program; Nichols 2004; Ray 2010; Roth
and human and rodent pharmacological studies (Halber- et al. 2000).
stadt et al. 2020; Halberstadt and Geyer 2011; Halber- Whether acute 5-HT2AR-mediated hallucinogenic effects
stadt and Nichols 2010; Inserra et al. 2021; Nichols 2004). are required for subsequent long-term therapeutic and anti-
5-HTRs comprised 14 receptor subtypes, 13 of which are depressant effects is debated. Limiting acute hallucinogenic
G-protein coupled receptors (GPCRs) (Nichols and Nichols effects while maintaining long-term antidepressant benefits
2008; McCorvy and Roth 2015), and are widely expressed could increase the acceptance and utility of psilocybin as a
throughout the brain. Serotonergic psychedelics bind to treatment and recent preclinical research reports some antide-
both 5-HT1ARs and 5-HT2ARs to exert opposing effects pressant-like effects that may be independent of 5-HT2ARs,
of inhibition or excitation, respectively. Psilocybin binding positioning non-hallucinogenic analogues as a goal for drug
is enriched at cortical 5-HT2ARs (Barrett et al. 2022) and development (Cameron et al. 2021; Hesselgrave et al. 2021;
signaling at these receptors primarily mediates its psychoac- Dong et al. 2021). However, human clinical work continues
tive hallucinogenic effects (Quednow et al. 2012), identify- to emphasize a potential link between the acute mystical
ing the cortex as an important locus of action (Aghajanian and spiritually transformative aspects of psychedelics and
and Haigler 1975; Mckenna et al. 1990; Blair et al. 2000; the enduring changes in mood (Barrett and Griffiths 2018;
Sard et al. 2005; Halberstadt and Geyer 2011; Halberstadt Roseman et al. 2018; Yaden and Griffiths 2021). Preclinical
et al. 2011). Recent crystallography work identified a spe- research may help to disentangle the various of effects of psil-
cific extended binding pocket on 5-HT2ARs that psilocin ocybin by further linking psilocybin effects to specific metrics
occupies to stimulate β-arrestin2 signaling, which may be of change in depression-relevant behaviors and uncovering the
critical to inducing antidepressant effects (Cao et al. 2022). precise molecular mechanisms of these effects.
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Psilocybin in human studies The medial PFC (mPFC) mediates diverse cognitive and
affective processes (Miller 2000; Miller and Cohen 2001;
Clinical evidence of antidepressant efficacy Euston et al. 2012) and is a key region of interest in psyche-
delic human neuroimaging work. In a within-subjects trial
Clinical trials and human experimental investigations into of healthy participants, psilocybin infusion (2 mg) induced
the therapeutic potential of psilocybin support the use of decreased mPFC activity, suggesting acute local inhibitory
the drug for treatment of psychiatric disorders, includ- effects; however, longer term changes, including potential
ing MDD. In foundational research, healthy participants rebound of activity, were not investigated (Carhart-Harris
who ingested 30 mg/70 kg of psilocybin during two or et al. 2012). In a cohort of 16 patients with treatment-resist-
three experimental sessions reported feelings of intense ant depression, imaging 1 day post-psilocybin (10 or 25 mg)
joy, peace, and harmony during sessions, as well as last- treatment showed circuit-specific effects, with decreased
ing positive mood changes and contentedness 2 months activity in the temporal lobes and amygdala correlating with
post-ingestion (Griffiths et al. 2006). This seminal finding decreases in depression symptomatology (Carhart-Harris
of psilocybin-induced positive mood has paved the way et al. 2017). These task-free scans also revealed increased
for research investigating potential benefits for patients functional connectivity of the ventromedial PFC–inferior
with depression and various other psychiatric illnesses. In lateral parietal cortex network as well as decreased func-
patients with advanced-stage cancer, psilocybin adminis- tional connectivity of the parahippocampal-mPFC network,
tration decreased anxiety and lowered scores on the Beck both of which predicted greater MDD symptom reduction
Depression Index, with effects lasting 6 months post-drug 5 weeks post-treatment. While these findings suggest that
(Grob et al. 2011; Griffiths et al. 2016; Ross et al. 2016). psilocybin treatment in MDD patients may enduringly mod-
A two-part trial testing 10 mg and 25 mg of psilocybin in ulate mPFC and its cortico-limbic functional networks, the
treatment-resistant depression reported symptom reduc- lack of a placebo control group necessitates caution. This
tions at 5 weeks, 3 months, and 6 months post-treatment limitation is endemic in human imaging studies with psilo-
(Carhart-Harris et al. 2018). These findings were recently cybin and more research is needed to establish effects rela-
replicated in cohorts of patients with MDD, with antide- tive to appropriate placebo controls in larger sample sizes.
pressant effects enduring as long as 12 months after psilo- Disrupted affective processing is frequently observed in
cybin therapy sessions (Carhart-Harris et al. 2021; Davis MDD for example in affective biases wherein social and
et al. 2021; Gukasyan et al. 2022). The lasting ameliora- emotional cues are interpreted less positively and more neg-
tion of depression symptoms established in these studies atively (Elliott et al. 2011). Effects of psilocybin on emo-
suggests that psilocybin exerts sustained antidepressant tional and social processing have been explored in functional
effects, yet the mechanism remains to be determined. imaging tasks in both healthy participants and patients with
MDD. In emotional recognition and emotional go/no-go
Investigations of neural and behavioral mechanisms tasks, oral psilocybin (0.215 mg/kg) acutely enhanced posi-
of psilocybin in humans tive mood, decreased recognition of negative facial expres-
sions, and enhanced responding to positive versus negative
The efficacy of psilocybin in treating depression and anxiety salient cues in healthy participants, suggesting that modula-
in terminally ill patients spurred an uptick of neuroimaging tion of affective bias (Preller et al. 2016). fMRI studies found
studies investigating the neural correlates of its antidepres- that oral psilocybin alters PFC, amygdala, and striatal con-
sant effects. A recent human imaging study found varying nectivity acutely and 24 h post-treatment during emotional
degrees of acute 5-HT2AR occupancy across the cortex facial discrimination in healthy participants and depressed
in participants with acute psilocybin (10 mg/70 kg), with patients (Grimm et al. 2018; Mertens et al. 2020). Emotional
high receptor occupancy in several key regions implicated processing and empathy are key to adaptive social behavior
in the default mode network (DMN) (Barrett et al. 2022). and psilocybin may promote adaptive social and affective
The DMN consists of the medial PFC, posterior cingulate processing; psilocybin (0.215 mg/kg) increased implicit and
cortex, and angular gyrus (Raichle et al. 2001; Raichle and explicit emotional empathy in a randomized, double-blind,
Snyder 2007; Uddin et al. 2008; Barnett et al. 2019). DMN within-subjects cohort of healthy participants 160 min fol-
alterations have been implicated in MDD, although not with- lowing oral ingestion (Pokorny et al. 2017). In a cohort of
out controversy and it remains unclear whether disease state healthy participants on a psychedelic nature retreat, inges-
and symptoms associate with DMN hyperconnectivity or tion of a mix of psilocybin (1.9 mg) and psilocin (10.5 mg)
hypoconnectivity (Kaiser et al. 2015; Yan et al. 2019). The altered baseline empathy 24 h and 7 days post-drug (Mason
importance of the DMN in acute and sustained serotonergic et al. 2019). The day after drug consumption, participants
psychedelic drug effects is also debated (Doss et al. 2021a). exhibited increased arousal and responsivity to both positive
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Psychopharmacology
and negative emotional stimuli in a multifaceted empathy measured by correct answers in the picture concept task, was
test, with enhanced responsivity to negative stimuli main- increased. Given mood and cognitive impairments in depres-
tained at a 7-day retest. This could suggest a window of sion, the pro-cognitive effects of psilocybin may contribute
heightened sensitivity to therapeutic intervention but also to long-term therapeutic benefits.
raises a caution as to potentially undesirable effects. Moreo- In summary, human clinical studies establish that psilocy-
ver, the focus on healthy individuals and lack of a control bin induces both acute and long-term changes in cognition,
group limits conclusions. A randomized, double-blind, affect, and behavior with correlated alterations in regional
placebo-controlled, within-subjects fMRI study tracking activity and connectivity in MDD-associated networks.
psilocybin-induced changes in participants at a mindful- There is compelling evidence that psilocybin acutely targets
ness retreat found a single oral dose of psilocybin (315 μg/ PFC and other cortical loci and enduringly alters cortical
kg) down-regulated mPFC–posterior cingulate cortex (PCC) networks. However, more research is needed to fully under-
activity during an open-awareness meditation 2 days after stand effects on cortically dependent cognitive and affective
drug (Smigielski et al. 2019). Four months later, participants processes as well as other cognitive and behavioral processes
who had received psilocybin scored higher on question- such as reward processing, motivation, learning, memory,
naire measures of positive changes in mood, attitude, social and attention that are disrupted in MDD. Precise, systematic
behaviors, and self-perception, and this was predicted by interrogation of the sustained behavioral alterations induced
post-drug resting-state mPFC–PCC connectivity (Smigielski by psilocybin may help clarify the basis of its antidepressant
et al. 2019). Taken together, these findings suggest a post- efficacy. Beyond research examining psilocybin in human
acute “therapeutic window” that could provide an oppor- cognition and behavior, preclinical rodent models offer the
tunity for evidence-based psychotherapeutic interventions potential to probe the precise neural circuit mechanisms of
to reshape emotional processes and may relate to effects on long-term antidepressant effects.
neuroplasticity (Schenberg 2018; Reiff et al. 2020). More
research examining neural correlates of emotional process-
Psilocybin in animal studies
ing in task-based fMRI studies with MDD patients with inte-
gration of changes in symptom profiles will be important to
determine the broader relevance of existing neuroimaging While the scientific pipeline for novel therapeutics com-
findings. monly begins with preclinical rodent research, psilocybin
Promising new work reports that psilocybin therapy pro- has been more widely studied in human research. This is
motes post-treatment pro-cognitive effects in patients with in part due to ease of access to other unscheduled psyche-
MDD, which may be linked to the drug’s modulation of delic drugs for preclinical investigations has resulted in
ACC and PCC activity (Doss et al. 2021b). In this open-label fewer studies using psilocybin. The recent surge of interest
study, non-medicated MDD patients underwent baseline in psilocybin’s therapeutic potential stimulated important
testing followed by two psilocybin-assisted (20 mg/70 kg advances examining antidepressant effects in rodent mod-
and 30 mg/70 kg) therapy sessions over 2 weeks. To control els, bolstering classic discoveries and aligning with clinical
for non-specific symptom changes, a second group received findings in identifying cortical alterations as central to the
treatment only 2 months after baseline screening. Follow- sustained drug effects.
ing psilocybin therapy, patients reported fewer depression
Preclinical pharmacological and behavioral
symptoms, and this was accompanied by increased cognitive
paradigms
flexibility and decreased perseverative errors in a set-shifting
task (Doss et al. 2021b). Longitudinal fMRI scans 4 weeks
prior and 1 week post-drug showed a general increase in Preclinical studies have begun to examine acute brain-wide
dynamic functional connectivity between the anterior cin- effects of psilocybin in mice. fMRI in mice during intra-
gulate cortex and posterior cingulate cortex. Post-psilocybin venous psilocybin (1 mg/kg or 2 mg/kg) found changes in
connectivity increases were highest in patients with lowest resting state functional connectivity in networks associ-
baseline connectivity (Doss et al. 2021b), suggesting that ated with 5-HT and dopamine activity (Grandjean et al.
the drug may be especially beneficial for certain patient 2021). Psilocybin increased functional connectivity in
populations. Cognitive behavioral data from the previously HTR2A-expressing regions while decreasing functional
discussed study of retreat participants suggest that psilo- connectivity in the ventral striatum and other dopamine
cybin post-acutely promotes cognitive creativity (Mason receptor Drd2-expressing regions, suggesting that psilo-
et al. 2019). One day after psilocybin, participants exhib- cybin may modulate both serotonergic and extra-seroton-
ited increased divergent thinking in a picture concept task, ergic circuits. A recent study profiled expression of the
generating a greater number of associations with more origi- immediate early gene c-Fos after psilocybin injection at
nality than at baseline, and at 7 days, convergent thinking, a dose previously shown to induce antidepressant-like
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Psychopharmacology
effects in mice (1.0 mg/kg) to map brain-wide activity and not made, potentially suggesting altered cognitive engage-
potential neuroplasticity (Davoudian et al. 2022, bioRxiv). ment and attention (Popik et al. 2022). Lower doses did not
Psilocybin induced robust c-Fos expression across a wide disrupt performance and a recent study even reported mod-
number of cortical, subcortical, and brainstem areas at 2 est pro-cognitive effects of acute ultra-low-dose psilocybin
and 3.5 h post-injection, emphasizing the breadth of acute in the 5CSRTT (Higgins et al. 2021). Sub-psychomimetic
effects. Comparing psilocybin-induced c-Fos expression “micro-doses” (0.05–0.1 mg/kg, i.p.) increased correct
to another rapid acting antidepressant, ketamine, revealed responses in the 5CSRTT in a sub-group of rats defined as
regions of both overlapping and distinct regulation with “low-performers” based on a pre-test baseline period. In
similar modulation in regions including the anterior cin- the same study, micro-doses of psilocybin also increased
gulate cortex, claustrum, amygdala, and locus coeruleus, lever pressing in low-performers on a progressive ratio test
and psilocybin-specific induction in regions including the probing motivation/anhedonia. However, the same treatment
lateral habenula and insular cortex. Correlating regional also increased impulsive responding, suggesting any micro-
psilocybin-induced c-Fos to publicly available gene expres- dose effects may not be uniformly beneficial. While intrigu-
sion atlases for a number of receptors identified enrichment ing, these findings should be interpreted with caution; even
of glutamate receptors (e.g., Grin2b, Gria2) and dopamine restricting analyses to a small sub-group of low-performing
receptors (e.g., Drd1, Drd2) in addition to serotonin recep- rats, effects were modest. Despite their limited consideration
tors (e.g., Htr2a, Htr1a) in regions highly activated by of acute drug effects, both studies demonstrate a potentially
psilocybin, which may point to extra-serotonergic mecha- powerful approach of probing precise behavioral metrics that
nisms. Together, these studies support psilocybin’s acute align with specific symptom domains of depression using
neuromodulatory potential in broadly distributed neural well-validated rodent behavioral paradigms. Future research
circuits. Potential enduring changes in network activity or applying a similar approach to examine delayed effects of
connectivity remain unknown, and future studies integrat- psilocybin can help to understand psilocybin’s antidepres-
ing measures of behavioral effects with sustained brain- sant actions.
wide alterations may help to resolve which of the many Delayed effects of psilocybin have recently been exam-
regions acutely activated by psilocybin mediate antidepres- ined in several animal models for depression. In a learned-
sant effects. helplessness test (a paradigm resulting in stress-susceptible
The benchmark behavioral measure of hallucinatory and stress-resilient behavioral phenotypes), susceptible mice
potential and psychedelic compound’s affinity for 5-HTRs, pretreated with psilocybin (1.0 mg/kg, i.p.) 1 day before test-
the rodent head-twitch response, provides a reliable dose- ing showed a reduction in failed escapes from an aversive
dependent measure of acute 5-HT2AR binding (Corne et al. foot-shock (Shao et al. 2021). Chronic multimodal stress
1963; Corne and Pickering 1967; Nabeshima et al. 1987; decreased sucrose preference and female urine preference in
Halberstadt et al. 2011). This easily observable behavior, male mice, effects that were restored 24–48 h after psilocy-
in which a rodent exhibits rapid bursts of head shakes, is bin (1.0 mg/kg, i.p.) (Hesselgrave et al. 2021). Longer term
blocked by 5-HT2AR antagonists and absent in mice lacking effects of psilocybin have also been observed. For example,
the Htr2a gene (Halberstadt et al. 2011). The head twitch in a battery of tests measuring anxiety- and depression-like
provides a dose-dependent metric of drug action but is not behaviors, male rats given a single injection of psilocybin
informative of antidepressant efficacy nor is there a clear (1.0 mg/kg, i.p.) maintained reduced immobility in a forced
human analogue, and more nuanced exploration of psilo- swim test for up to 5 weeks, suggesting sustained increases
cybin’s behavioral effects is needed. Paired-pulse inhibition in active coping (Hibicke et al. 2020). These enduring effects
(PPI) measures adaptation of the startle reflex across spe- are not limited to rodents. In a Drosophila depression model,
cies (Geyer et al. 2001; Kohl et al. 2013) and is sensitive male, but not female, flies treated once with low- or high-
to acute psychedelics in both humans and animals (Vollen- dose psilocybin (0.03 or 3.5 mM of psilocybin in food) were
weider et al. 2007); however, although a useful translational significantly less immobile during a forced-swim test 4 days
biomarker in schizophrenia, there is no compelling evidence later (Hibicke and Nichols 2022). Five days of treatment
of PPI deficits in MDD (Perry et al. 2004; Kohl et al. 2013). with the conventional antidepressant citalopram induced
Recent research has begun to examine effects of psilo- similar outcomes, supporting psilocybin’s rapid antide-
cybin and psilocin in more refined, depression-relevant pressant effect. Preliminary preclinical investigations sug-
rodent behavioral paradigms developed to assess specific gest that psilocybin administered 24 h before fear learning
symptom domains. The five-choice serial-reaction time (0.1–1.5 mg/kg, i.p.) may facilitate later extinction of a fear
task (5CSRTT) probes attention and impulsivity (Bari et al. memory without altering the initial fear association (Catlow
2008). In rats, systemic psilocybin (1.0 mg/kg) or psilocin et al. 2013). Together, these studies suggest psilocybin can
(0.72 mg/kg) acutely disrupted 5CSRTT performance largely rapidly and enduringly reduce depression-relevant stress-
by increasing the number of trials on which a response was related behavioral impairments in preclinical models.
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Psychopharmacology
Moving towards translatable preclinical paradigms Mechanistic insight from preclinical models: role
of neuroplasticity
While promising, findings using preclinical paradigms
with simple behavioral metrics can be difficult to trans- Psilocybin’s sustained antidepressant effects in patient
late to a clinical framework and more work is needed to populations and preclinical models suggest a role for
explore effects on depression-relevant behaviors with drug-induced changes in neuroplasticity. Promising find-
clearer translational correlates. Animal models for depres- ings from recent work exploring synaptogenic effects of
sion have long relied on simple behavioral metrics such as psilocybin support the hypothesis that psilocybin is a
time immobile in a forced-swim test and reduced sucrose psychoplastogen, promoting neural plasticity to alter neu-
preference to model depression-like behavioral states ral connectivity and, ultimately, behavior. In cultured rat
which have some utility in testing candidate antidepres- embryonic cortical neurons, psilocin dose-dependently
sant drugs (Slattery and Cryan 2012; Liu et al. 2018). increased dendritic branching and neurite formation and
However, recent debate has questioned the validity and these effects were blocked by pre-treatment with ketan-
accepted interpretations of these tests, for example, sug- serin (Ly et al. 2018). In vivo, in male and female mice,
gesting that immobility can be adaptive (Molendijk and a single dose of psilocybin (1.0 mg/kg, i.p.) increased
de Kloet 2015) and that sucrose preference tests do not both the number of dendritic spines and spine head width
adequately encapsulate the complex cognitive processes in medial PFC layer V pyramidal neurons, with effects
contributing to anhedonia (Hales et al. 2014). There is a persisting for more than 30 days (Shao et al. 2021). This
push towards paradigms with stronger external validity structural plasticity was accompanied by increased excit-
with clearly defined behavioral metrics that are translat- atory neurotransmission. Administration of 5-HT2AR
able across species. In addition to 5CSRTT and progres- antagonist ketanserin blocked head-twitch response but
sive ratio tests, reward processing and motivation can be not dendritic spine increases, suggesting that 5-HT2ARs
assessed in probabilistic and effort-based decision-making may not be the sole mediator of psilocybin’s effects or,
tasks, which can be computationally modeled to meas- alternatively, the incomplete occupancy of 5-HT2ARs by
ure formally defined metrics of anhedonia and apathy to ketanserin. These findings align with another recent study
probe similar underlying neural computations across spe- showing that ketanserin pre-treatment blocked head-twitch
cies (Adams et al. 2016; Salamone et al. 2016; Robbins response but did not reduce either reversal of anhedonia
and Cardinal 2019; Liao and Kwan 2021). In parallel, measured by sucrose preference 24 h after psilocybin
there is a rapidly growing interest in probing naturalistic (1.0 mg/kg, i.p.) or the associated strengthening of hip-
behaviors, such as social interaction or facial expressions, pocampal synapses measured 3 days post-drug (Hessel-
using automated machine learning analyses to comprehen- grave et al. 2021). The lasting increases in spinogenesis
sively characterize behavioral variation (Hong et al. 2015; suggest that psilocybin-induced plasticity is a plausible
Forkosh et al. 2019; Mathis and Mathis 2020; Dolensek mechanism of long-term changes in behavior. The direc-
et al. 2020). While these approaches are powerful in cap- tion of the relationship between plasticity and behavior is
turing a larger, dynamic range of behavioral repertoires, important to consider—if indeed synaptic and behavio-
how such findings can be translated across species is less ral modifications are independent of 5-HT2AR activity,
evident. It is largely unknown how psilocybin enduringly as these studies suggest, the psychoplastogenic effects of
alters depression-relevant processes of reward-process- psilocybin may be driving the long-lasting antidepressant
ing, motivation, emotion, memory, or naturalistic social effects independent of hallucinogenic activity.
behavior. In addition to leveraging robust, translationally Psilocybin also mediates transcriptional alterations
relevant behavioral paradigms, aligning rodent pharma- through molecular signaling downstream of 5-HT2AR
cological and imaging studies with clinical research to activation to mediate short- and long-term structural, func-
consider anatomical homology and analogous brain cir- tional, and behavioral changes (Aleksandrova and Phillips
cuits will help establish the precise neural circuits targeted 2021; Slocum et al. 2021; Kwan et al. 2022). For example,
by psilocybin to induce antidepressant effects. Moreover, investigations into alcohol-induced mGluR2 down-regu-
more research is needed to study psilocybin within pre- lation in rats found that 1.0 mg/kg of systemic psilocybin
clinical depression models (e.g., chronic stress, genetically restored NAc Grm2 expression, and ketanserin blocked this
susceptible rodents) in order to understand therapeutic upregulation (Meinhardt et al. 2021), indicating transcrip-
effects in the context of disease-relevant behavioral and tional regulation by psilocybin signaling at 5-HT2ARs.
neural disruptions, just as in human studies it is essential More research is needed to comprehensively profile psilo-
to understand variable drug effects in both healthy and cybin’s effects on transcription and potential contributions
depressed individuals. to acute and sustained neural and behavioral alterations.
1 3
Psychopharmacology
Psilocybin and cortical circuits: links in both PFC pyramidal neurons (PNs) and interneurons
to depression symptomatology (INs) (Morilak et al. 1994; Aznar et al. 2003; Santana
and Artigas 2017). Almost 60% of cells in the PFC con-
The PFC governs executive function and cognitive control tain mRNA for 5-HT1/2ARs, with co-localization in up
via extensive interconnections with cortical and subcorti- to 80% (Amargós-Bosch et al. 2004; Santana 2004). The
cal brain regions, and aberrant PFC function in depres- six layers of the PFC form a matrix of INs and PNs, both
sion is implicated in a variety of cognitive, emotional, locally routing in microcircuits and projecting to other cor-
affective, and motivational impairments, as well as in tical and sub-cortical brain regions (Radnikow and Feld-
learning and memory deficits (George et al. 1994; Nes- meyer 2018). PFC layer I contains IN soma and, although
tler et al. 2002; Price and Drevets 2010; Pizzagalli and limited, data suggests that these INs may express both
Roberts 2021). The human PFC can be subdivided into 5-HT1/2ARs (Weber and Andrade 2010). Layer I also
dorsolateral, ventrolateral, medial, and ventral subsections serves as an initial landing point for thalamo-cortical sig-
(Petrides 2005; Euston et al. 2012; Hiser and Koenigs nals, receiving axons from thalamic projection neurons
2018; Haber et al. 2022). PFC homology in non-human (Cruikshank et al. 2012; Collins et al. 2018). PFC lay-
primates and rodents remains a topic of debate (Uylings ers II and III contain PNs that project to other cortical
et al. 2003; Laubach et al. 2018), but broadly, the rodent regions, the striatum, and the amygdala (McGarry and
mPFC encapsulates infralimbic, prelimbic, and anterior Carter 2017). Reciprocal amygdalo-cortical projections
cingulate cortex (ACC) regions (Chudasama and Robbins also target these superficial layers and influence affec-
2003). Cortico-limbic and cortico-thalamic 5-HTR sign- tive cognition (Little and Carter 2012; Cho et al. 2013).
aling has been implicated in the treatment of MDD since Layer II/III PNs express 5-HT1ARs, and patients with
the advent of the monoamine hypothesis of depression MDD exhibit lower 5-HT1AR binding than healthy indi-
postulated a primary role for deficient levels of serotonin, viduals. In rats, early life stress and adult social isolation
norepinephrine, and dopamine (Schildkraut 1965; Bun- both regulate 5-HT1AR expression and function in these
ney and Davis 1965; Hillhouse and Porter 2015). Both neurons (Drevets et al. 1999; Goodfellow et al. 2009).
clinical and preclinical research suggests that psilocybin 5-HT1A/2ARs are expressed in the majority of layer V
acutely targets cortical 5-HTRs to exert neuromodulatory PNs (Araneda and Andrade 1991; Celada et al. 2013)
effects on cortical circuits, with potential long-term conse- which are well studied for their excitatory projections to
quences. Indeed, psilocybin acutely and enduringly mod- the striatum (specifically, nucleus accumbens) and thala-
ulates mPFC-cortical connectivity, reducing depression mus (Britt et al. 2012; Collins et al. 2018), and also receive
symptoms and altering affective and cognitive processes input from the hippocampus, thalamus, and other cortical
(Carhart-Harris et al. 2012, 2017; Barrett et al. 2020; Doss regions (Parent et al. 2010; Anastasiades and Carter 2021).
et al. 2021b). Acutely, the drug occupies 5-HT2ARs in In the striatum, signals from these PFC neurons are inte-
various cortical regions, including the PFC (Barrett et al. grated with converging inputs from hippocampus, amyg-
2022). In mice, a single injection of psilocybin sufficient dala, and thalamus to orchestrate motivated behavior, and
in reversing depression-like behavior 24 h later rapidly this is susceptible to stress-induced alterations (Goto and
and enduringly increased layer V pyramidal neuron spino- Grace 2005, 2008; Vialou et al. 2014; Heshmati and Russo
genesis and synaptic transmission in cingulate/premotor 2015; Bagot et al. 2015). Thalamic inputs to PFC layer
cortex (Shao et al. 2021). Taken together, evidence that the II/III also make connections with layer V PNs, which in
PFC is disrupted in depression, along with recent findings turn project back to thalamic nuclei (Collins et al. 2018).
demonstrating that psilocybin modulates cortical activity, These cortico-thalamo-cortical and cortico-striatal circuits
suggest the PFC may be a primary locus of psilocybin’s are theorized mediate psychedelic effects of drugs such as
antidepressant effects. Understanding 5-HTR dynamics in psilocybin (Vollenweider and Geyer 2001; Vollenweider
this region, along with potential 5-HT-independent mech- and Preller 2020). Preclinical circuit dissections can elu-
anisms, can help inform how acute local drug-induced cidate how psilocybin acutely modulates neural activity
changes can exert enduring circuit-wide alterations. in these complex circuits as well as how acute effects may
induce enduring changes in circuit function.
Given the functional significance of PFC layer V/VI
Serotonergic modulation of the PFC: dynamic neurons and their expression of 5-HT1/2ARs, understand-
implications for psilocybin ing effects of serotonergic signaling within this circuit may
inform hypotheses as to how psilocybin modulates local
Inhibitory 5-HT1A and excitatory 5-HT2A receptor and downstream effects. Both PNs and INs in layers V/VI
subtypes are highly expressed, and often co-expressed, are subject to complex serotonergic modulation. 5-HT1AR
1 3
Psychopharmacology
signaling reduces membrane excitability and induces hyper- 2021). Current models of psychedelic activity all consider
polarization (Araneda and Andrade 1991; Pehrson and modifications of cortical control a key contributing factor
Sanchez 2014). Conversely, 5-HT2AR activation increases in acute drug-induced perceptual, affective, and experien-
membrane excitability to induce depolarization (Araneda tial changes. A framework integrating clinical knowledge
and Andrade 1991). Where both receptors are co-expressed, with preclinical interrogation of psilocybin-induced changes
the cellular response is determined by the summation of in circuit activity as well as sustained modulation through
5-HT1AR-induced inhibition and 5-HT2AR-induced excita- neuroplasticity informed by known neural circuit bases of
tion (Celada et al. 2013). PFC GABAergic INs provide local behavior could significantly advance efforts to uncover psil-
inhibition to PNs via dendritic, somatic, and axonal syn- ocybin’s mechanisms of action (see Fig. 1).
apses (Santana 2004; Lladó-Pelfort et al. 2012). 5-HT1AR
signaling at INs may inhibit this inhibitory control of PNs,
Sex differences in psilocybin research
ultimately leading to disinhibition of the PNs. Conversely,
5-HT2AR agonism at INs may amplify inhibitory control
in PFC (Amargos-Bosch 2004). Through modulating cel- Gender and sex differences in depression and stress suscep-
lular excitability, 5-HTR-binding drugs such as psilocybin tibility in humans and rodents make it essential to consider
may alter PFC microcircuit dynamics, and ultimately impact the role of sex in psilocybin’s antidepressant effects. MDD
distributed brain circuits via layer V/VI projections to the is globally more prevalent in women (Ferrari et al. 2013;
thalamus, amygdala, striatum as well as shaping integra- Albert 2015). In women, MDD presents earlier and co-
tion of inputs from the thalamus, amygdala, and extended occurs with anxiety more frequently than in men (Piccinelli
cortical regions (Anastasiades and Carter 2021). In addi- and Wilkinson 2000). There are also sex differences in treat-
tion, psilocybin may also directly modulate these PFC target ment response to pharmacological interventions—evidence
regions via local signaling at 5-HTRs throughout the brain. points to women showing greater responsivity to selective
More research is needed to determine precisely how psilo- serotonin reuptake inhibitors (Kornstein et al. 2000; Khan
cybin shapes both local PFC circuit function and extended et al. 2005; Sramek et al. 2016). Gender differences in MDD
connectivity to mediate antidepressant effects. incidence and treatment response are mirrored in preclinical
animal models to the extent that females have been con-
Extended cortical circuits
sidered, although more research is needed (LeGates et al.
2019; Lopez and Bagot 2021). Sex differences in endog-
Disruptions of extended cortical circuits and associated cog- enous and exogenous 5-HTR signaling, and in the pharma-
nitive and behavioral symptoms are implicated in depression cokinetics and pharmacodynamics of 5-HTR agonist drugs
(George et al. 1994; Nestler et al. 2002; Nestler and Carle- are understudied; however, significant sex differences have
zon 2006; Heshmati and Russo 2015; Pizzagalli and Roberts been described. Healthy males synthesize 5-HT at faster
Fig. 1 5-HT1/2AR agonists such as prodrug psilocybin’s active metabo- ventral tegmental area as well as in extended interconnected sub-cortical
lite psilocin modulate local PFC microcircuit dynamics. 5-HT1ARs and circuits. 5-HT1AR, serotonin receptor subtype 1A; 5-HT2AR, serotonin
5-HT2ARs exert opposing effects on cellular excitability in both interneu- receptor subtype 2A; AMY, amygdala; DStr, dorsal striatum; GABA,
rons (IN) and principal neurons (PN) leading to altered micro-circuit gamma aminobutyric acid; GLUT, glutamate; PFC, prefrontal cortex;
dynamics that feed forward to induce changes in downstream activation VStr, ventral striatum; VTA, ventral tegmental area
of mono-synaptic projection targets that include the dorsal striatum, ven-
tral striatum (including the nucleus accumbens), amygdala, thalamus, and
1 3
Psychopharmacology
rates than females (Nishizawa et al. 1997), and females may neuroscience, we can begin to understand how psilocybin
benefit from hormonal interactions with selective serotonin acutely modulates neural signaling, uncover its lasting
reuptake inhibitors, leading to increased efficacy of such effects on circuit dynamics and depression-relevant behav-
drugs in the treatment of MDD (Dalla et al. 2010; Eid et al. iors, and map the specific cell-types and circuits in which
2019). Sex differences in expression of 5-HTR subtypes and these changes occur. The continued development of biosen-
transcriptional regulation likely exist in both healthy indi- sors provides much opportunity for psychedelic research.
viduals and MDD patients (Eastwood et al. 2001; Jans et al. For example, a novel biosensor that fluoresces upon ligand-
2007; Szewczyk et al. 2009). Understanding the intersection induced 5-HT2AR conformational changes can be combined
of sex with serotonergic mechanisms in stress and depres- with in vivo imaging to measure psilocybin-induced modu-
sion is important in optimizing the therapeutic potential of lation of neural activity (Dong et al. 2021). Using animal
psilocybin. models to probe psilocybin’s acute and sustained effects can
Few clinical or preclinical studies with psilocybin have provide critical mechanistic insight into the mechanisms of
investigated sex differences. Psilocybin (1.0 mg/kg, i.p.) antidepressant efficacy.
induced greater increases in dendritic spine density in
females suggesting potential enhanced female sensitivity to
the psychoplastogenic effects (Shao et al. 2021). In contrast,
Conclusions
in male rats, acute psilocin (0.25, 1.0, or 4.0 mg/kg) induced
greater dose-dependent impairments in PPI and locomotor
Psilocybin shows considerable promise for treatment of
activity than in females, although females were more sensi-
mood disorders and psychiatric illness in human clinical
tive to psilocin-induced head twitch, suggesting complex
research. Evidence in humans and rodents points to the
sex differences (Tylš et al. 2016). A recent investigation into
PFC as a primary locus of the drug’s antidepressant actions.
the acute subjective effects of weight-adjusted (20 mg/70 kg
Preclinical research examining psilocybin effects on cir-
or 30 mg/70 kg) or fixed-dose (25 mg) psilocybin across
cuit function is scarce, and a greater understanding of how
healthy male and female participants did not find significant
psilocybin modulates local PFC microcircuits and longer-
sex differences (Garcia-Romeu et al. 2021). Already, these
range projections may reveal new insight into the drug’s
limited findings demonstrate the need to fully consider sex
effects. Leveraging neuroscience techniques in robust rodent
and gender to understand mechanisms of psilocybin’s anti-
behavioral models in males and females has great potential
depressant efficacy.
to reveal mechanisms of psilocybin’s therapeutic effects.
Ultimately, this may lead to development of more effective
Future directions and specific protocols for clinical use.
Establishing psilocybin’s neuromodulatory effects
Declarations
in cortical circuits
Conflict of interest JM reports receiving consulting fees from Knowde
Understanding how psilocybin modulates neural activity and Group Inc.
interconnected circuits to alter behavior and ultimately exert
antidepressant effects is limited. The human literature sug-
gests that psilocybin’s enduring antidepressant effects are References
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