---
title: "OP-BRAI210411 1..16"
url: https://stacklist.com/card/5fda1e2f-4f62-4d92-a58f-54320bfa5875
stack: https://stacklist.com/c/wellness/stack/3ec64f10-f7d6-4a20-a3c9-499572b61636
summary: "This paper presents three circuit-level models explaining how psychedelic drugs like psilocybin and LSD affect the brain through serotonin 2A receptor activation, introducing a novel cortico-claustro-cortical model involving the claustrum's role in disrupting canonical cortical networks. The research synthesizes existing models (CSTC and REBUS) while proposing new mechanisms to explain psychedelic drug effects and their potential therapeutic applications for psychiatric disorders."
tags: "psychedelics, neuroscience, serotonin-receptors, brain-circuits, psilocybin, lsd, claustrum"
key_entities: "Manoj K. Doss (person), Roland R. Griffiths (person), Frederick S. Barrett (person), Brian N. Mathur (person), Johns Hopkins University School of Medicine (organization), University of Maryland School of Medicine (organization), serotonin 2A receptor (technology), cortico-claustro-cortical model (concept), CSTC model (concept), REBUS model (concept), claustrum (concept), psilocybin (technology), lysergic acid diethylamide (technology), Baltimore (location)"
classification: "reference"
content_hash: "sha256:ab9b079be01820b0fc95b2bd73fdffe283b923e551eecf001c3f5cc86ed56e5a"
acp_version: "0.2"
token_counts_approximate: 24739
visibility: public
agent_accessible: true
status: "final"
---

# OP-BRAI210411 1..16

Models of psychedelic drug action:
modulation of cortical-subcortical circuits
Manoj K. Doss, 1,2 Maxwell B. Madden, 3 Andrew Gaddis, 1,2 Mary Beth Nebel, 4,5
Roland R. Griffiths, 1,2,6 Brian N. Mathur 3,† and Frederick S. Barrett 1,2,6,7†
† These authors contributed equally to this work. 
Classic psychedelic drugs such as psilocybin and lysergic acid diethylamide (LSD) have recaptured the imagination
of both science and popular culture, and may have efficacy in treating a wide range of psychiatric disorders.
Human and animal studies of psychedelic drug action in the brain have demonstrated the involvement of the
serotonin 2A (5-HT 2A ) receptor and the cerebral cortex in acute psychedelic drug action, but different models have
evolved to try to explain the impact of 5-HT 2A activation on neural systems.
Two prominent models of psychedelic drug action (the cortico-striatal thalamo-cortical, or CSTC, model and
relaxed beliefs under psychedelics, or REBUS, model) have emphasized the role of different subcortical structures
as crucial in mediating psychedelic drug effects. We describe these models and discuss gaps in knowledge, incon-
sistencies in the literature and extensions of both models. We then introduce a third circuit-level model involving
the claustrum, a thin strip of grey matter between the insula and the external capsule that densely expresses
5-HT 2A receptors (the cortico-claustro-cortical, or CCC, model).
In this model, we propose that the claustrum entrains canonical cortical network states, and that psychedelic
drugs disrupt 5-HT 2A -mediated network coupling between the claustrum and the cortex, leading to attenuation of
canonical cortical networks during psychedelic drug effects.
Together, these three models may explain many phenomena of the psychedelic experience, and using this frame-
work, future research may help to delineate the functional specificity of each circuit to the action of both seroto-
nergic and non-serotonergic hallucinogens.
1 Center for Psychedelic and Consciousness Research, Johns Hopkins University School of Medicine, Baltimore, MD,
21224, USA
2 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD,
21224, USA
3 Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
4 Center for Neurodevelopmental and Imaging Research, Kennedy Krieger Institute, Baltimore, MD, 21205, USA
5 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
6 Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
7 Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD 21218, USA
Correspondence to: Frederick S. Barrett, PhD
5510 Nathan Shock Drive
Baltimore, MD 21224, USA
E-mail: fbarrett@jhmi.edu
Received April 14, 2021. Revised August 10, 2021. Accepted October 05, 2021. Advance access publication December 13, 2021 
V C The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email:
journals.permissions@oup.com 
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Keywords: claustrum; psilocybin; thalamus; default mode network; circuit models 
Abbreviations: 5-HT 2A = serotonin 2A receptor; CCC = cortico-claustro-cortical model; CSTC = cortico-striatal tha-
lamo-cortical; DMN = default mode network; FPN = frontoparietal network; IOR = inhibition of return; LSD = lysergic
acid diethylamide; MD = mediodorsal nucleus; PPI = pre-pulse inhibition; REBUS = relaxed beliefs under psychedelics
model; SN = salience network 
Introduction 
Psychedelic drugs, which we define as agonists or partial agonists
of the serotonin 2A receptor (5-HT 2A ) 1 such as psilocybin (the main
psychoactive constituent of Psilocybe mushrooms) and lysergic
acid diethylamide (LSD), have recaptured the imagination of both
science and popular culture. Recent studies have provided empir-
ical evidence that psychedelic drugs evoke a unique array of alter-
ations in perception and cognition, 2–5 with subjective experiences
in humans ranging from blissful and profound to anguished and
paranoid. 6–8 Psychedelics may also have efficacy in treating a wide
range of medical indications, including mood, 9–13 substance
use 14,15 and headache-related disorders. 16,17 Understanding the
neural circuit basis of psychedelic drug action has the potential to
inform strategies for maximizing the therapeutic efficacy of these
drugs, as well as minimizing their harm, while potentially eluci-
dating novel functions of these circuits in both health and disease.
The cerebral cortex is thought to be central to the neural mech-
anisms underlying the psychedelic experience due to its high ex-
pression of these receptors. 5-HT 2A receptor activation via the
psychedelic 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane
(DOI) induces a substantial increase in the frequency and ampli-
tude of excitatory postsynaptic current events in rodent prefrontal
layer V pyramidal neurons, which are the major projectors and
integrators in the cortex. 18 DOI also increases c-fos expression in
prefrontal and somatosensory GABA-releasing interneurons,
which are important neuromodulators. 19 Additional findings in
rodents show that LSD induces gene expression changes in the
cortex, 20 and DOI increases extracellular GABA 21 and glutamate in
the cortex. 22 Complementary work in humans has shown that psy-
chedelic drugs acutely increase glutamate concentrations in the
medial prefrontal cortex. 23 Recent evidence from rodent studies
suggests that a subset of 5-HT 2A receptor-containing ‘trigger neu-
rons’ in the medial prefrontal cortex and somatosensory cortex
are responsible for the initial neural response to psychedelics. 19
These neurons appear to recruit other neuronal populations, lead-
ing to cascading disruption of cortical and subcortical pathways in
the development of psychedelic drug effects. In line with these
observations, psychedelics generally attenuate the functional seg-
regation of human cortical networks. 24,25 Finally, 5-HT 2A -mediated
signalling pathways in the cortex are required for stereotyped ani-
mal behaviours produced by psychedelics such as the head-twitch
response, 26–28 and 5-HT 2A receptor antagonism in humans blocks
the subjective, cognitive and neural system effects of psilocybin, 29–
34 LSD 35–37 and N , N -dimethyltryptamine (DMT). 38
Although the role of cortical 5-HT 2A receptors in psychedelic
drug action is evident (primarily in prefrontal regions), the down-
stream effects of cortical psychedelic drug activation on subcor-
tical targets and the activation of subcortical 5-HT 2A receptors 1
may also be crucial to psychedelic effects. Two leading models of
the neural basis of psychedelic drug action differ on their views
regarding the importance of different subcortical structures and
extracortical 5-HT 2A receptors. One model, the cortico-striatal
thalamo-cortical loop model (CSTC; Fig. 1), proposes that psyche-
delic drugs modulate both the cortex and subcortical structures
including the striatum and thalamus, resulting in aberrant thala-
mocortical coupling. 39–41 This is thought to increase the flow of
sensory information to the cortex, leading to perceptual altera-
tions and effects on cognition, including diminished attention and
sensorimotor gating. Another model, referred to as relaxed beliefs
under psychedelics (REBUS; Fig. 2), asserts that cortical modulation
by psychedelic drugs reduces the ability of higher-level cortical
networks (i.e. the default mode network) to control lower-levels in
the brain (e.g. ‘lower’ relative to the default mode network), specif-
ically the hippocampus and parahippocampal gyrus (but also sen-
sory cortices). 42 This hypothesized reduction in top-down control
is proposed to disrupt typical predictive coding processes and is
expressed as increased entropy in measures of cortical function
and network topology.
Here, we briefly review evidence for the CSTC and REBUS mod-
els, while describing potential gaps and extensions of each. Then,
we introduce a third circuit-level model centering on the claus-
trum, a subcortical telencephalic nucleus that contains a sub-
population of 5-HT 2A -containing neurons. These neurons appear
to be responsible for the initial neural response to psychedelics 19
and have widespread, largely bidirectional cortical connections. 43–
49 This model, termed the cortico-claustro-cortical model (CCC;
Fig. 3), emphasizes the function of the claustrum in the control of
cortical network states, which arise from the synchronization of
stereotyped sets of cortical regions across time. In the context of
this new model, we highlight the potential role of psychedelic dis-
ruption of cortico-claustro-cortical circuits that may contribute to
our understanding of the neural and subjective effects of psyche-
delic drugs. 
Cortico-striatial thalamo-cortical model
and the disruption of thalamocortical
gating 
The thalamus is, in part, a collection of subcortical nuclei that ‘re-
lay’ sensory information from sensory organs to the cortex. In this
role of relaying sensory information, the thalamus acts as a ‘gate’,
restricting the flow of information to permit only a subset of sen-
sory information at any given time. All thalamic relay nuclei re-
ceive cortical inputs that control this gating function to support
cognition and action, and the thalamic reticular nucleus may espe-
cially be important to gating via local inhibition of other thalamic
nuclei. 50 Apart from the reticular nucleus, all thalamic nuclei pro-
vide direct glutamatergic input to the cortex. 51 CSTC loops have a
rich history in the study of both neural development and the
pathophysiology of a number of disorders, 52 including psychotic
disorders. In the context of psychedelic drugs as psychotomimetic
substances, disruption of the gating of sensory information
through thalamocortical circuits was hypothesized to underlie the
acute alterations in perception and cognition that accompany 
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psychedelic experiences. 39–41 Here, we will review the basic con-
ceptualization of the CSTC model as it pertains to psychedelics,
discuss thalamic nuclei that are most likely to be involved, sum-
marize the behavioural and neuroimaging evidence that supports
this model and consider potential limitations and extensions of
the model. 
Cortico-striatal-thalamo-cortical loops 
In the original conception of psychedelic disruption of CSTC
loops, 39 psychedelics are understood to activate medial prefrontal
layer V 5-HT 2A -containing pyramidal neurons projecting to
GABAergic neurons of the ventral striatum, which in turn inhibit
GABAergic pallido-thalamic neurons within these CSTC circuits
(Fig. 1). Disruption of these GABAergic pallido-thalamic neurons
results in disinhibition of the thalamus and inundation of the cor-
tex with sensory information. Accordingly, independent groups
have found that LSD administration in humans increases func-
tional connectivity (i.e. the temporal coupling between the activity
of two regions) between the thalamus and much of the cortex
under task-free conditions. 53–55 Moreover, directional modelling of
human neuroimaging data has found evidence that LSD increases
thalamic influence on posterior cingulate activity in a 5-HT 2A -de-
pendent fashion, but an accompanying decrease in striatal input
to the thalamus was found to be independent of 5-HT 2A activa-
tion. 56 Although the CSTC model describes 5-HT 2A receptors in
regions within CSTC loops other than the thalamus and empha-
sizes specific thalamic nuclei such as the mediodorsal (MD) and
reticular nuclei of the thalamus, 39,40 it remains unclear how the
model may account for the contribution of other subnuclei and
extracortical 5-HT 2A receptors to the effects of psychedelics. 
Thalamic nuclei of interest 
It is worth noting that human studies with acute psychedelic
manipulations that report on changes in thalamic connectivity
have not parcellated the thalamus into its constituent nuclei, des-
pite differential 5-HT 2A expression, functional specificity and ana-
tomical connectivity of thalamic nuclei. One would expect those
thalamic nuclei expressing 5-HT 2A mRNA or receptor protein to be
more important to consider when determining the basis of psyche-
delic drug action within the brain. However, only a subset of thal-
amic nuclei exhibits such receptor expression. For instance, the
reticular nucleus expresses 5-HT 2A 57 receptors and was one of the
thalamic nuclei originally proposed to be of importance to psyche-
delic effects in CSTC loops. 39,40 Indeed, LSD increases burst firing
in some reticular nucleus neurons, while suppressing burst firing
in others. 58 The reticular nucleus is thought to function as a ‘neur-
onal oscillator’, 59 regulating the frequency of cortical rhythms, es-
pecially gamma waves. 60–64 Oscillations of this kind are thought to
support synchronization between brain regions and enable com-
munication and information transfer. 65,66 Some evidence indicates
that presynaptic 5-HT 2A receptors in the reticular nucleus are
involved in GABA release, 67 providing a potential mechanism by
which psychedelics desynchronize low frequency bands in a
5-HT 2A -dependent manner. 34,38,68–74 The reticular nucleus also 
Figure 1 Summary of the cortico-thalamo-cortical and CSTC loops. Disruption of this circuit by 5-HT 2A activation is hypothesized to inundate the cor-
tex with sensory information, contributing to the alterations of cognition and perception during psychedelic experiences. 39–41 Glu = glutamate; TRN
= thalamic reticular nucleus.
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supports selective visual attention by controlling the gain of the
lateral geniculate nucleus, 75 the main target of the retina. Finally,
neurons of the reticular nucleus are dependent on prefrontal inter-
actions via the basal ganglia, 76 suggesting a potential role for stri-
atal nodes of CSTC circuitry in psychedelic-induced impairments
of attention. 30,77,78
The MD is a higher-order nucleus (i.e. not directly receiving
sensory information), receiving inputs from the cortex, medial
temporal lobe, pallidum and other thalamic nuclei 79 that was ori-
ginally proposed to be important to psychedelic action in CSTC
loops 39,40 (Fig. 1). Of relevance to psychedelics, the MD projects to
the medial prefrontal cortex, thus completing a CSTC loop with a
cortical region containing neurons that may be particularly sensi-
tive to 5-HT 2A -mediated activation by psychedelic drugs. 19
Moreover, the MD expresses 5-HT 2A receptors both within the thal-
amus, at the somatic level and on presynaptic projections in med-
ial prefrontal cortex, 80,81 suggesting multiple points within an MD
to medial prefrontal cortex loop that could be targeted by 5-HT 2A
receptor activation. One study found DOI activation of the pre-
synaptic 5-HT 2A receptors of this circuit to increase excitatory
postsynaptic currents in medial prefrontal cortex, and deletion of
these receptors impaired episodic-like memory in mice. 82 In an-
other study, LSD increased action potential firing frequency,
including burst firing, of neurons in a subregion of MD known to
receive GABAergic input from the reticular nucleus and to project
out to medial prefrontal cortex. 58 This LSD-induced increase in
MD firing, which was also met with increases in spontaneous
firing activity in medial prefrontal cortex pyramidal neurons, 58
lends further support to the notion that psychedelics increase
thalamic activation of cortex. Interestingly, although psyche-
delics impair most aspects of cognition in humans, episodic
memory encoding is relatively less impaired, even at high doses
of psilocybin. 5
Somatic and perceptual distortions often accompany the sub-
jective effects of psychedelics. 3 Thus, 5-HT 2A receptor-containing
sensory nuclei of the thalamus, such as the ventrobasal thalamus
and pulvinar, may also play a role in psychedelic drug action. The
ventrobasal thalamus is a first-order relay (i.e. a nucleus receiving
direct sensory projections) that carries ascending tactile informa-
tion to somatosensory cortex. Glutamatergic projections from the
ventrobasal thalamus are activated by DOI and induce immediate
early gene c-fos expression in layer V somatosensory neurons. 22
Consistent with these findings, LSD increases functional connect-
ivity between the thalamus and somatosensory cortex in
humans, 53–55 although it is unclear whether these effects play a
role in specific psychedelic effects such as loss of perceptual boun-
daries between one’s body and the world.
Compared with somatosensation, psychedelics appear to have
more reliable and complex effects on vision, perhaps in part due to
modulation of the pulvinar, a nucleus that receives higher-order
visual inputs from visual cortex. The pulvinar contains 5-HT 2A pro-
tein without expressing 5-HT 2A mRNA. 83 This indicates that the
pulvinar receives inputs that express the 5-HT 2A receptor on axon
terminals, and thus, psychedelics may alter pulvinar output to the 
Figure 2 Summary of the hippocampal-cortical processing loop implicated in the REBUS model. Psychedelic action is hypothesized to preferentially
enhance bottom-up prediction error signalling to higher-level structures compared with top-down reciprocal signalling. This manifests as decreases
in cortical synchrony in addition to relaxed priors. The REBUS model specifies hippocampus and the parahippocampal gyrus as originators of this
bottom-up signalling, in concert with other unspecified structures. 42 Glu = glutamate. 
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cortex in a polysynaptic manner. Consistent with the pulvinar’s
role in visual attention and object motion, 84,85 psychedelics impair
visual attention 77,78 and motion perception, 86 increase thalamic
connectivity with visual cortex 53–55 and increase activity in pri-
mary visual cortex during an attention task. 78 However, pretreat-
ment with ketanserin (a 5-HT 2A /5-HT 2C antagonist) did not block
psilocybin effects on visual attention 30 or binocular rivalry, 31 sug-
gesting other potential receptor targets of psilocybin [e.g. the sero-
tonin 1B receptor (5-HT 1B )] in mediating these effects. 
Behavioural evidence, limitations and
extensions 
Behavioural models relevant to thalamocortical gating include
pre-pulse inhibition (PPI) and inhibition of return (IOR), and some
evidence from animal and human models suggests that psyche-
delics impact these behaviours. PPI is a phenomenon that occurs
when a startle response is reduced by a preceding weaker, non-
startling stimulus, and IOR refers to suppressed processing of a
stimulus to which one has recently attended. PPI and IOR are
thought to reflect pre-attentive sensory gating processes.
Thalamic nuclei within thalamocortical circuits, including MD and
sensory nuclei, facilitate these processes, and prefrontal cortical
nodes are thought to control these processes. 77,87,88 Animal mod-
els demonstrate that LSD and DOI reduce PPI of the acoustic startle
response, 89 but evidence for the presence or direction of an effect
of psychedelics on PPI in humans is mixed. Some have reported
that psilocybin dose-dependently reduces PPI when there are short
intervals between pulses (30 ms) but has either no effect or
increases PPI at intermediate and longer intervals ( 5 120 ms). 90,91
Another study that used intermediate and longer intervals (100
and 240 ms) failed to show any effect of DMT on PPI. 92 Although
DMT has been found to attenuate IOR, 93 DMT was also found to
blunt neural responses in primary sensory cortices during sus-
tained attention tasks in auditory and visual modalities. 78 This is
seemingly inconsistent with an attenuation of suppressed sensory
processing and a general prediction of the CSTC model that cor-
tical regions are inundated with sensory information under psy-
chedelics. Alternatively, decreased activation of primary sensory
cortices during the acute effects of psychedelics could represent
increased noise and decreased sensitivity to experimentally con-
trolled stimuli.
Other mixed evidence for the CSTC model comes from its pre-
diction that psychedelics should produce increased activity within
the prefrontal cortex. Activity within the prefrontal cortex might
reasonably follow from disinhibition of the MD in CSTC loops 58
and subsequent attempts by the prefrontal cortex to exert control
over ungated sensory thalamic information. 39–41 Diminished thal-
amic gating might also presume an accompanying increase in
thalamic activity. However, both decreases 24,94,95 and increases 54–
56,96,97 have been reported in overall prefrontal and thalamic activ-
ity in humans. This inconsistency could be a product of the uncon-
strained nature of task-free scans in which small samples of
participants might not necessarily perform the same range of
mental functions during relatively short scans. Such work could be
improved through the use of task-based sensory paradigms and
parcellation of the thalamus into its subnuclei.
Although the CSTC model focuses on psychedelics disrupting
thalamo-cortical striatal-thalamic circuits, a recently revised
view of thalamic anatomy suggests a potential role for other bi-
directional thalamocortical projections in psychedelic drug ac-
tion (Fig. 1; for reviews, see Sherman 98,99 ). Layer V pyramidal
neurons receiving first-order thalamic relays (e.g. lateral 
Figure 3 Summary of the CCC model circuitry. In this model, disruption of prefronto-claustro-cortical circuitry by 5-HT 2A activation dysregulates cor-
tical network initiation, which contributes to the disruption of cortical network states (yellow circles). Turquoise and yellow circles depict two net-
work states that arise from the dynamic synchronization of cortical regions across time. The first (turquoise circles) is a network state in which
frontal, associative and sensory cortices are synchronized (represented by a similar wave form in each of the turquoise circles), and the second (yel-
low circles) is a state in which the network is disrupted across various cortical regions (represented by different waveforms in each of the yellow
circles). Glu = glutamate.
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geniculate nucleus to primary visual cortex) project to higher-
order thalamic nuclei (e.g. primary visual cortex to the inferior
pulvinar). Interestingly, these projections back to the thalamus
also branch to synapses on subcortical motor centres. 100–103
Because of these branches, such corticothalamic projections
have been proposed to carry ‘efference copies’, or motor mes-
sages sent to sensory areas that allow for prediction of the sen-
sory consequences of self-generated movements. 104 This
bidirectional connectivity is not limited to early sensory process-
ing. Thalamic nuclei receiving these putative efference copies
also project back to higher levels of cortex (e.g. parietal associ-
ation cortex), which in turn continue this pattern of branched
projections to subcortical motor centres and subsequently
higher-order thalamic nuclei (e.g. medial pulvinar). This neural
scaffolding suggests that as information is processed through a
sensory hierarchy, efference copies allow higher levels to predict
the sensation of possible lower-level motor commands. Because
5-HT 2A receptors are widely expressed both in thalamic nuclei
and on layer V pyramidal neurons within these circuits, psyche-
delics may drive aberrant predictions via such efference copies,
potentially explaining sensory distortions and a sense of surprise
that is often encountered during psychedelic experiences.
Interestingly, efference copies are also thought to be sent to the
striatum from the cortex in CSTC circuits, suggesting that aber-
rant predictions from the cortex could also be involved in disin-
hibition of the thalamus. 105 In the next section, we discuss a
model that describes how psychedelics might break down func-
tional hierarchies in the brain, resulting in predictions from
lower levels exerting greater influence on processing at higher
levels. 
Relaxed beliefs under psychedelics and
the disruption of cortico-medial
temporal constraints 
The REBUS model proposes that psychedelics disrupt the hierarch-
ical nature of the brain by reducing the typical constraints that
higher levels place on lower levels. This reduction in top-down
control results in the increased influence of low-level prediction
errors on higher levels of processing that encode or maintain prior
beliefs. By allowing greater influence of incoming stimuli in predic-
tion circuits, a greater number of cortical brain states may be
expressed, thereby increasing cortical ‘entropy’ and putatively
allowing updates or changes to prior beliefs. Although the hierar-
chies described in this model are stated to encompass sensory-
centric circuit relationships (e.g. association to sensory cortices or
secondary visual to primary visual cortex), the ‘lower levels’ are
stated to include evolutionarily older subcortical structures,
including the hippocampus, amygdala and thalamus. The REBUS
model specifies the hippocampus (but also evolutionarily more re-
cent cortical regions of the parahippocampal gyrus) as a structure
involved in this psychedelic-mediated prediction error
signalling. 42
Whereas the CSTC model is less specific in terms of which
cortical regions are of primary importance to psychedelic drug
action (e.g. medial prefrontal cortex and sensory cortices, 39 pos-
terior cingulate and the superior temporal gyrus 56 ), the major
cortical focus of the REBUS model has been on higher-level cor-
tical networks composed primarily of prefrontal and parietal as-
sociation cortices such as the default mode, frontoparietal and
salience networks (DMN, FPN and SN, respectively). Specifically,
the DMN is the crux of this model and posited to be at the top of
the brain’s hierarchy. In contrast to the CSTC model, and as
described below, the REBUS model is rather vague regarding the
subcortical structures of greatest importance to psychedelic drug
effects or what constitutes a ‘lower’ level. Here we will review the
basic conceptualization of REBUS, neuroimaging and behavioural
evidence that supports this model and potential limitations and
extensions of the model. 
Default mode network centricity,
egocentricity and medial temporal
entropy release 
The DMN is one of the most studied networks in the brain and its
major hubs, the medial prefrontal and posterior cingulate cortices,
densely express 5-HT 2A receptors. 106 The DMN is implicated in a
number of high-level cognitive functions, including episodic mem-
ory, theory of mind, semantic processing and self-referential proc-
essing. 107,108 The DMN’s role in self-referential processing has
situated it at the top of the brain’s hierarchy in the REBUS model,
with the DMN proposed to be the neurobiological substrate of the
‘ego’ (in the Freudian sense) 109 and attenuations of DMN function
have been interpreted as reflecting the ‘ego dissolution’ some-
times reported to be produced by psychedelics (but see Millie ` re et
al . 110 for inconsistencies regarding post hoc neural correlates of psy-
chedelic-mediated ego dissolution). Psychedelics have been shown
to impact the activity or functional connectivity of regions belong-
ing to the DMN, but whether such effects are increases or
decreases, or even selective to the DMN, has varied by study. Some
studies in humans found relatively selective decreases in activity
in regions of the DMN under psychedelics compared with drug-
free conditions, 24,111 but most other studies have found both
increases and decreases in regions within and outside the
DMN. 74,94–97,112 Although psychedelics consistently decrease func-
tional connectivity within the DMN, 23,24,74,111,113 equal or stronger
decreases within other brain networks, including the FPN, SN and
sensory networks, 23,74,113 have also been reported during acute
psychedelic effects. Rodent studies have failed to find selective
decreases in activity or functional connectivity of the DMN during
acute psychedelic drug effects, however this may be confounded
by the isoflurane anaesthesia that was concurrent with drug ad-
ministration and imaging procedures. 114,115
One explicit hypothesis of the REBUS model is that psyche-
delics increase bottom-up, over reciprocal top-down, information
flow from the hippocampus and paraphippocampal gyrus to
higher-level cortical areas, especially the DMN 42 (Fig. 2). The hippo-
campus and parahippocampal gyrus both express 5-HT 2A recep-
tors, 106,116 and the entorhinal cortex of the parahippocampal gyrus
is a particularly important site for serotonergic transmission. 117
The entorhinal cortex is the principal input to the hippocampus
and has been referred to as a ‘wall of inhibition’, due to its intrin-
sically inhibitory circuitry that appears to gate selective inputs to
the hippocampus. 118 In addition to episodic memory, the hippo-
campus has been shown to be involved in prediction that can de-
termine the fate of episodic memories. 119–121 Although
speculative, psychedelics could attenuate entorhinal gating of in-
formation to the hippocampus and drive erroneous predictions
that could subsequently flood higher-level cortical areas with ab-
errant mnemonic representations (analogous to disrupting thal-
amic gating). Empirical evidence, however, is contrary to this view.
Psilocybin and LSD decrease functional connectivity of the hippo-
campus and parahippocampal gyrus with DMN regions. 74,122
Moreover, perirhinal and parahippocampal cortices of the parahip-
pocampal gyrus are considered higher levels of the ventral and
dorsal visual processing streams, respectively, yet contrary to the
REBUS model, directional modelling has found evidence for psy-
chedelics to increase top-down information flow from the 
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parahippocampal gyrus to visual cortex. 123 These analyses suffer
from a similar problem as analyses of thalamic connectivity,
namely, treating the hippocampus and the parahippocampal
gyrus as unitary structures when they are understood to have a
more segregated functional anatomy. Future work may benefit
from parsing the parahippocampal gyrus (i.e. entorhinal, perirhi-
nal and parahippocampal cortices) and hippocampus (e.g. anterior
and posterior or hippocampal subfields) into their subregions to
hone in on potential increases in bottom-up modulation of higher-
level cortices under psychedelics.
According to the REBUS model, psychedelic release of low-level
information manifests as an increase in cortical entropy or com-
plexity (in the information theoretic sense). 42,122,124 Several studies
have shown that psychedelics desynchronize scalp electrophysio-
logical oscillations, especially in lower frequencies, 34,38,68–74 while
simultaneously increasing the complexity (i.e. decreasing the in-
formation compressibility) of these signals. 125,126 Moreover, psy-
chedelics increase various measures of entropy and variability
within the DMN or between the hippocampus and cortex. 122,127,128
However, these increases appear to be more widespread 129 and
greater in magnitude in the SN, FPN and even sensory and motor
networks than in the DMN. 122,127 Together, these findings have
been interpreted as an expansion of ‘brain states’; although as
described below, behavioural evidence for this assertion is lacking. 
Behavioural evidence, limitations and
extensions 
A broad behavioural prediction put forth by the REBUS model is
that ‘higher-level’ cognitive functions (i.e. processes later than ini-
tial sensory information processing such as attention and mem-
ory) should be more impaired than lower-level functions (e.g.
perception). 42 Consistent with this prediction, one study found
psilocybin to impair motion perception but not contrast sensitiv-
ity. 86 Moreover, due to a relaxation of top-down priors in favor of
bottom-up signalling, some lower-level cognitive functions may
even be enhanced. For example, noticing a unique stimulus with a
salient feature in a visual array of otherwise similar objects (i.e.
the ‘pop-out’ effect) 130 appeared to be enhanced under the effects
of the R -enantiomer of 3,4-methylenedioxyethylamphetamine
(MDEA), 131 a hallucinogenic 5-HT 2A agonist like the R -enantiomer
of its more commonly known analog 3,4-methylenedioxymethy-
lamphetamine (MDMA; in contrast, the S -enantiomers of these
drugs have entactogenic, stimulant and monoaminergic effects).
Extinction learning in mice, a form of memory evolutionarily older
relative to other types of memory such as episodic, has also been
found to be enhanced by psilocybin and the psychedelic
TCB-2. 132,133 However, as previously described, psychedelics im-
pair PPI and IOR, pre-attentive processes that are arguably even
lower levels of sensory memory than extinction. 89,90,93 Moreover,
inconsistent with the neuroanatomy highlighted by the REBUS
model, various forms of hippocampally-dependent learning are
unaffected or even impaired by psychedelics. Specifically, in
rodents, psilocybin does not enhance trace fear conditioning, 132
DOI impairs the learning of a novel spatial location 134 and TCB-2
impairs the encoding of hippocampal place fields. 135 Similarly in
humans, encoding of recollection memory, which is a form of epi-
sodic memory dependent on the hippocampus, is impaired by
psilocybin 5 and the entactogen-stimulant-psychedelic hybrid
MDMA 136 (the amnestic effects of the latter stemming from 5-HT 2A
activation). 137
Although it has been claimed by proponents of the REBUS
model that cognitive impairments under psychedelics are simply
due to ‘generalized disengagement’, 42 psilocybin has been found
to more selectively impair working memory compared with epi-
sodic memory, while the opposite pattern was found with the hal-
lucinogenic NMDA antagonist dextromethorphan 5 (see also
Lofwall et al . 138 and Braun et al . 139
). Such double dissociations ob-
fuscate claims of generalized disengagement (see also Doss et al . 136
for disproportionate effects of MDMA on emotional compared to
neutral memory). One interesting finding from these studies of
episodic memory is that the encoding of familiarity, a mnemonic
process dependent on the perirhinal cortex of the parahippocam-
pal gyrus, 140 was unaffected or even enhanced under psyche-
delics. 5,136 Similarly in mice, post-encoding (i.e. during
consolidation) administration of TCB-2 enhanced novel object rec-
ognition, 132 a perirhinal-dependent analogue to familiarity. 141
Together, these findings suggest that psychedelics could have a
unique profile of effects on cognition via episodic memory hubs
that the REBUS model proposes to drive cortical entropy. These
findings also highlight the nuances of specific episodic memory
processes and medial temporal subregions (for review see
Ranganath and Ritchey 142
) compared with more generalized
effects within the brain that may be elucidated by careful com-
parative pharmacology.
The functional outcomes of increased entropy and diversity of
brain states under psychedelics remain unclear. Successful mem-
ory retrieval, arguably greater information content than the failure
to retrieve a memory, is associated with less entropy in scalp elec-
trophysiological signals, 143 and GABAergic sedatives increase en-
tropy during episodic memory retrieval 143 but reduce resting state
measures of complexity. 144,145 Greater neural diversity has been
suggested to be of relevance to cognitive flexibility, 42,146,147 and 5-
HT 2A antagonism can attenuate models of cognitive flexibil-
ity 148,149 in rats. However, in mice, psychedelics impair or have no
effect on cognitive flexibility, 150,151 and in humans, LSD was found
to acutely impair cognitive flexibility. 37 Furthermore, studies sup-
porting psychedelic-induced increases in the number of brain
states are based on task-free conditions and thus are under am-
biguous control of cognitive operations. Increased cycling between
brain states under task-free psychedelic conditions may simply be
produced by participants inadvertently ‘performing cognitive
tasks’ (e.g. related to visualization, memory retrieval, shifts in at-
tention and theory of mind operations) instead of ‘resting.’ That is,
under drug-free conditions, participants possess the capacity to
cycle through multiple cognitive states despite not typically doing
so, but under psychedelics, cognitive control is impaired, resulting
in more cycling between cognitive states and less rest-like neural
activity. In the next section, we discuss a model that describes
how psychedelics might disrupt cognitive control and an associ-
ated neural interface that permits switching between cortical net-
works for complex cognition. 
Cortico-claustro-cortical model and
disruption of canonical cortical networks 
The claustrum is a thin, ribbon-like telencephalic nucleus located
lateral to the putamen, medial to the insula and in between the ex-
ternal and extreme capsules. The claustrum densely expresses 5-
HT 2A receptors and possesses bidirectional glutamatergic connec-
tions with the majority of the cortex, 47,152 suggesting a role for the
claustrum in psychedelic drug effects. 1,153 This structure was fam-
ously proposed to mediate sensory binding and, therefore, gener-
ation of conscious percepts. 152 However, functional assessments
of the claustrum have pointed to a role for the claustrum in cogni-
tive control functions rather than in sensory binding or the gener-
ation of consciousness (see also Bickel and Parvizi 154
). A synthesis
of recent evidence points to a specific role of the claustrum as a
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brain structure of central importance in supporting cortical net-
work states. Additional evidence supports a role of psychedelic
drugs in disrupting higher-level cortical networks through claus-
tro-cortical circuits, which may subsequently contribute to the
neural and subjective effects observed during psychedelic experi-
ences (Fig. 3). The claustrum also densely expresses j -opioid
receptors, 153,155 the primary target of the atypical dissociative hal-
lucinogen salvinorin A. Interestingly, some of the effects of salvi-
norin A on task-free brain function (e.g. reductions of DMN
functional connectivity) resemble those of psychedelics (i.e. 5-
HT2A activating hallucinogens), 156 suggesting that the CCC model
may also explain some effects of j -opioid activating
hallucinogens. 
The cortico-claustro-cortical model 
In rodents, the claustrum receives dense projections from primar-
ily contralateral areas of association cortices 157–164 such as pre-
frontal (including regions of the DMN and FPN) and cingulate
cortex (including the anterior cingulate cortex, a hub of the SN),
while receiving comparatively sparser input from sensory and
motor regions. 163–166 Similarly, the human claustrum is functional-
ly connected to much of the DMN, FPN and anterior cingulate cor-
tex. 48,49 Accordingly, claustrum neuron firing is primarily driven
by input from prefrontal cortex. 163,167 In contrast, the claustrum
provides expansive ipsilateral projections back to prefrontal cor-
tex, as well as to sensory and parietal association cortices. 157–164
Claustrum input to the cortex powerfully and transiently sup-
presses cortical activity, followed by rebound excitation. 168,169
Optogenetic activation of the claustrum results in widespread cor-
tical synchronization. 169 In the process of frontal regions initiating
synchronous network activity, 170–173 the CCC model proposes that
a prefrontal cortico-claustro-cortical circuit configuration allows
for prefrontal cortex-mediated instantiation of higher-level cor-
tical networks that include prefrontal and posterior association
cortices (Fig. 3). Thus, the CCC model proposes that the prefrontal
cortex entrains canonical cortical network states through the acti-
vation of the claustrum, which in turn coordinates the recruitment
of cortical networks in response to changing task demands.
Claustrocortical neurons thereby provide a cortical network syn-
chronization broadcast signal necessary for appropriate goal-
directed or internally directed mental activity. We refer to these
context-appropriate instantiations of cortical region synchrony as
network states.
Supporting this role of the claustrum in instantiating network
states, during performance of an attention task that elicits FPN
responses in humans, the claustrum is activated along with the
deactivation of the DMN. 48 Moreover, in mice, the claustrum
receives a preparatory signal from the anterior cingulate cortex,
and this input, along with activation of the claustrum itself, are
both required for accurate performance on the cognitively
demanding five-choice serial reaction time task. 167 Consistent
with these findings, the mouse claustrum is also required for re-
silience to distraction. 164 
Psychedelic disruption of the
cortico-claustro-cortical system 
Interestingly, the claustrum expresses both 5-HT 2A receptor mRNA
and the 5-HT 2A receptor protein, suggesting that it both contains
5-HT 2A projection neurons and receives 5-HT 2A -expressing projec-
tions. 43,46,83,174 A large proportion of 5-HT 2A receptor-containing
psychedelic ‘trigger neurons’ were also found to be claustrum neu-
rons, in addition to prefrontal cortical neurons. 19 This finding led
to the proposal that disruption of claustrum function by psyche-
delic drugs could amplify neuronal avalanches that eventually re-
sult in the destabilization of network states. 175 We propose that,
during psychedelic drug action, 5-HT 2A activation causes a mis-
alignment between the claustrum and cortex by driving prefrontal
inputs to the claustrum and also by independently activating the
claustrum. Thus, according to the CCC model, broad disruption of
canonical network states may be effected by 5-HT 2A -mediated
decoupling of prefrontal activity from claustral activity, leading to
aberrant cognitive control. 176 This decoupling may ultimately lead
to attenuation of cortical network (e.g. FPN and DMN) states
(Fig. 3). While such states typically fluctuate depending on the
goals, cues, cognitive load, prior cognitive state and upcoming
states required for ongoing goal-directed behaviour, this natural
fluctuation is altered during psychedelic drug action.
Supporting the CCC model account of psychedelic drug action,
in humans, psilocybin decreases resting state claustrum activity,
which was found to correlate with a sense of ineffability, 49 a facet
of ‘mystical experiences’ that closely aligns with a decrease in cog-
nitive control. Moreover, psilocybin was found to decrease func-
tional connectivity between the claustrum and cortical
networks. 49 Specifically, psilocybin decreased right claustrum con-
nectivity with the DMN and auditory network and left claustrum
connectivity with the FPN. Unexpectedly, psilocybin increased
connectivity between the right claustrum and FPN. Although the
CCC model might predict widespread decreases in connectivity of
the claustrum with cortical networks, the laterality effects
observed during acute effects of psilocybin may be a function of
the claustrum’s laterality bias in structural connectivity. 163,165,166
Considering the potential lateralization inherent in cognitive con-
trol processes, 177 a task-based study may help to contextualize
such idiosyncratic network states. Finally, some evidence supports
the hypothesis that 5-HT 2A -mediated disruption of prefrontal-
claustrum coupling attenuates cortical network instantiation.
During the acute effects of psilocybin, within-network connectivity
of the DMN and FPN (which can be interpreted as ‘network integ-
rity’) is correlated with their functional connectivity with the right
and left claustrum, respectively. 49
Together, these data provide support for the hypothesis that
coordination between the claustrum and cortex is critical to estab-
lishing cortical network states necessary for cognitive control. In
the context of prior evidence of psilocybin effects on prefrontal
cortex, 95,96,178 psilocybin may induce a ‘two-hit’ dysregulation of
this system by disrupting both the prefrontal cortex and claus-
trum. In humans, claustrum activity was found to be prominently
coupled with activity in the thalamus, striatum and the parahippo-
campal gyrus. 48 Thus, while speculative, the claustrum may be
positioned as a hub connecting key components inherent in all
three circuit models of psychedelic drug action. While the human
evidence of direct impingement of psychedelics on claustrum
function is currently limited, new methods are allowing for this
structure to be studied in humans. 48,49 Given the integral involve-
ment of the claustrum and prefrontal cortex with dynamic
changes in goal-directed behaviour, psychedelic-induced disrup-
tion of this prefrontal cortico-claustro-cortical system may con-
tribute to cognitive control dysfunction induced by psychedelic
drugs. 
Potential shared neural circuit
mechanisms of 5-HT 2A and j -opioid
hallucinogen effects 
In addition to the claustrum densely expressing 5-HT 2A receptors,
it also densely expresses j -opioid receptors, 153,155 the primary 
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target of atypical dissociative hallucinogens such as salvinorin A
and enadoline. Compared with psychedelics, atypical dissociative
hallucinogens seem to be more dysphoric, 179 perhaps owing to
their reduction in striatal dopamine transmission 180–182 (but see
Carlezon et al . 180 and Braida et al . 183 for no changes or even
increased dopaminergic transmission at lower doses). Despite the
sale of salvinorin A being unregulated in many states, it appears to
be less commonly used than psychedelics, further suggesting
fewer ‘good’ subjective effects and more frequent or stronger ‘bad’
subjective effects of salvinorin A compared with classic psyche-
delics. Nevertheless, atypical dissociative hallucinogens produce
some subjective effects similar to classic psychedelics (i.e. 5-HT 2A
agonists) such as laughing, visual imagery and mystical-like expe-
riences. 184–187 Moreover, like psychedelics, there is increasing evi-
dence that atypical dissociative hallucinogens may be useful in
the treatment of addiction. 188
Interestingly, some of the effects of salvinorin A on task-free
brain function in humans resemble those of psychedelics. Similar
to psilocybin, LSD and ayahuasca, 70–72,74 salvinorin A was found to
decrease power across frequency bands as measured using EEG. 189
Also, in a recent functional MRI study, 156 the largest effect of salvi-
norin A on human brain functional connectivity was a decrease of
connectivity within the DMN, accompanied by trends for increased
between-network connectivity of the DMN. Some of these effects
were recently associated with changes in claustrum function dur-
ing the acute effects of psilocybin. 49 Finally, entropy was found to
be increased across much of the brain during the acute effects of
salvinorin A. 156 However, despite a high, breakthrough dose of sal-
vinorin A administered in the recent functional MRI study, 156
changes in connectivity of task-positive networks during the
acute effects of salvinorin A were not nearly as substantial as
those observed during the acute effects of classic
psychedelics. 54,55,74,113,178,190
These data interpreted together suggest that claustrum disrup-
tion by both serotonergic psychedelics and j -opioid receptor ago-
nists may represent a polypharmacological mechanism
underlying some ‘psychedelic-like’ effects. This interpretation
must be tempered, though, as salvinorin A functional MRI data are
limited to only one small-sample study, and claustrum functional
MRI data during acute psychedelic effects are limited to only one
separate small-sample study. Also, as noted earlier in this review,
reductions in DMN connectivity and increases in entropy may be
less specific than previously claimed and may be a direct result of
participants cycling through various task-positive-like states,
which has been understood to reduce DMN activation and con-
nectivity for decades. 108,191 
j -opioid receptors are also densely expressed in prefrontal cor-
tex. It is possible that j -opioid receptor-mediated disruption of the
medial prefrontal cortex, or activation of striatal-projecting neu-
rons in the medial prefrontal cortex, could result in disinhibition
of the thalamus and a flooding of the cortex in line with the CSTC
model, though of course this is speculative. Of note, decreases in
DMN connectivity and increases in entropy are explicit features of
psychedelic action in the brain that are proposed by REBUS. In fact,
REBUS may be more applicable to salvinorin A, considering the
largest effects of salvinorin A on human brain function were found
in the DMN. Nevertheless, as described earlier, one has to be cau-
tious when interpreting task-free connectivity. Increases in be-
tween-network connectivity and entropy may simply be an
artefact of comparing a drug-free rest condition to a condition in
which cognitive operations (that are able to be carried out while
sober) are unconstrained (leading to inconsistent increases in spe-
cific between-network increases observed during psychedelic drug
action). 113 
Conclusion 
Here, we discussed three circuit models that may explain various
effects of classic psychedelic drugs and highlight potential revi-
sions to each. With bidirectional glutamatergic projections be-
tween the cortex and thalamus, the CSTC model’s role for the
thalamus in psychedelic drug action is likely incomplete. Not
only might psychedelics cause the thalamus to inundate the cor-
tex with activity, psychedelics may also drive layer V cortical
inputs to the thalamus (i.e. motor predictions or ‘efference cop-
ies’). However, similar to the REBUS model, there may be differ-
ences along the sensory processing hierarchies (e.g. under
psychedelics, the thalamus may have more influence on associ-
ation cortices than vice versa). Moreover, aberrant lower-level
motor predictions that typically inform higher levels of cortex
aligns with the REBUS model’s proposal that psychedelics can re-
lease lower-level predictions (due to less cortical constraints,
however). The REBUS model also must be revised particularly
regarding what constitutes a higher or lower level of the brain or
cognition. Nevertheless, the brain regions specified and effects of
psychedelics on behaviour suggest the possibility for unique
effects of psychedelics on processes dependent on the medial
temporal lobes such as episodic memory. Both the CSTC and
REBUS models could benefit from more precise definitions in
neuroanatomy (e.g. subnuclei of the thalamus and medial tem-
poral lobe). Finally, the CCC model is in its infancy, and with
newer technologies for probing the claustrum, future work will
be needed to test its validity.
Although we discuss how disruption of claustrum function
could contribute to the disruption of network states, 49 cortical
layer V pyramidal neurons 18,19,192 and the thalamus 22,53–55,94–96
could also be directly involved in such disruption. Network state
disruption could take three possible forms: inhibition of sensory
gating resulting in increased sensory information flow to higher
cortical regions, 39–41 a relaxation of predictive codes acquired from
past experience, 42 and disengagement of executive faculties and
control of network states. 49 Each of these cases could be used to
explain why psychedelic drugs can allow new interpretations of
familiar sensory cues, which may, in turn, promote novel behav-
ioural responses. Modulation of maladaptive network states
observed in clinical populations could provide clues to how psy-
chedelics exhibit efficacy for brain disorders in which inelastic
responses to cues foster repetitive behaviour or thoughts (e.g. ad-
diction, depression, obsessive-compulsive disorder). Finally, differ-
ential modulation of one or all of these circuits might explain
similarities among and differences between classic and atypical
hallucinogenic compounds, specifically NMDA receptor antago-
nists (e.g. ketamine or dextromethorphan) and j -opioid receptor
agonists (e.g. salvinorin A) that have been shown to exhibit psy-
chedelic-like effects. 5,156,184,185,193,194 Pharmacological modulation
of these other receptors is also being explored for therapeutic
effects, and the claustrum, specifically, has a high density of both
of these receptors. Mechanistic, hypothesis-driven work based on
circuit models of cortical function coupled with the careful control
of behaviour and cognition is needed to further establish evidence
for and differentiate between the role of each model in explaining
psychedelic drug effects. 
Funding 
This work was supported by grants from the National Institute on
Drug Abuse T32DA007209 (M.K.D), the National Institute on
Alcohol Abuse and Alcoholism R01AA024845 (B.N.M.), the Heffter
Research Institute (R.R.G.) and by the financial support of the
Johns Hopkins Center for Psychedelic and Consciousness Research
Models of psychedelic drug action BRAIN 2022: Page 9 of 16 | 9 
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by Tim Ferriss, Matt Mullenweg, Craig Nerenberg, Blake Mycoskie
and the Stephen and Alexandra Cohen Foundation. 
Competing interests 
M.K.D. is a scientific advisor for Ocean Bio, Ltd. F.S.B. is a scientific
advisor for Wavepaths, LLC. R.R.G. is a board member of the
Heffter Research Institute. The other authors do not declare any
competing interests. 
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