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Out of the box: A psychedelic model to study the creative mind
Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands
Divergent ﬂexible thinking
Our creativity is challenged daily when facing new situations asking for novel solutions. Creativity, a multi-
component construct includes ﬂexible divergent and rigid convergent thinking. Psychedelic drugs like psilocybin
can enhance creativity and aﬀect state of mind (mood, empathy, openness). Of note, ﬂexible thinking is dis-
turbed in psychopathological conditions like anxiety disorders and depression and preliminary ﬁndings have
shown psychedelics to be eﬃcacious in the treatment of those conditions.
The question how psychedelics induce this state of enhanced ﬂexible thinking remains to be answered and
investigating the neurobiology underlying this phenomenon will not only help in understanding why psyche-
delics are of use in the therapeutic setting but also in other settings where ﬂexible thinking is challenged. A
model including neuronal networks, neurotransmitters and personal factors playing a role in this process will be
proposed which can be put to the test by means of placebo-controlled pharmaco-imaging studies in healthy
In daily life people are challenged by situations of all kinds asking
for creative problems solving skills [1,2]. Being able to come up with
alternative solutions to a problem is one aspect of creativity which is
called (ﬂexible) divergent thinking. It is diﬀerent from (rigid) con-
vergent thinking which is about ﬁnding the best solution to a problem.
Divergent thinking has been shown to be a more useful estimate of
creative thoughts in daily life than convergent thinking . Flexible
thinking is also known to be decreased in certain psychopathological
conditions like depression, anxiety, and post-traumatic stress disorder
Interestingly, anecdotal evidence, historical examples and (quasi-)
experimental studies suggest that psychedelic drugs like LSD, psilocybin
and ayahuasca enhance creative ﬂexible thinking in the neuro-typical
population [11–16]. In addition, the therapeutic potential of these
substances is now being investigated in the treatment of aforemen-
tioned mental disorders [17–19]. Preliminary ﬁndings in patient sam-
ples are promising showing beneﬁcial therapeutic outcomes lasting up
to a few weeks after treatment [20–22]. It is hypothesized that these
eﬀects are due to a shift from rigid thinking patterns to more ﬂexible
thinking patterns, facilitating psychotherapeutic interventions .
The question how psychedelics induce this state of enhanced ﬂex-
ible thinking remains to be answered and investigating the neuro-
biology underlying this phenomenon will not only help in under-
standing why psychedelics are of use in the therapeutic setting but also
in other settings where ﬂexible thinking is challenged. A model in-
cluding neuronal networks, neurotransmitters and personal factors
playing a role in this process will be proposed which can be put to the
test by means of placebo-controlled pharmaco-imaging studies in
Creativity and brain networks
The biological base underlying creativity has been suggested to
consist of a dynamic interplay between several brain regions including
the three core brain networks, the central executive network (CEN), the
default mode network (DMN) and the salience network (SN) [23,24].
The CEN links the dorsolateral prefrontal cortex (dlPFC) and pos-
terior parietal cortices (PPC) and is engaged in higher-order cognitive
and attentional control . The DMN has 2 important key nodes, the
ventromedial (vm) PFC, implicated in self-referential processing, and
the posterior cingulate cortex (PCC), a critical connector hub to all
regions of the DMN [25–28]. The SN consists of the anterior insula (AI)
and the dorsal anterior cingulate cortex (dACC), both implicated in
empathy [25,29–31]. It monitors events occurring outside of the body
as well as internal consciousness, and is able to direct attention to
whatever is more important at a certain moment in time.
Increased coupling between DMN and SN regions was demonstrated
at the beginning of a divergent thinking task, followed by increased
coupling between DMN and CEN regions at later stages .Itis
suggested that the shifts between these externally (CEN) and internally
Received 8 February 2018; Accepted 22 March 2018
E-mail address: firstname.lastname@example.org.
Medical Hypotheses 115 (2018) 13–16
0306-9877/ © 2018 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
(DMN) oriented cognitive networks, facilitated by SN, are very im-
portant in the process of divergent thinking . Of note, it has been
shown that the SN becomes active shortly before an insightful solution
is reached . Furthermore, the DMN is considered to be involved in
daydreaming and self-reﬂection and responsible for the capacity to
imagine past, future, or hypothetical scenarios [25,27,28]. A positive
association between divergent thinking and resting state functional
connectivity in the vmPFC and the PCC was demonstrated .
In sum, this activity pattern suggests that divergent ﬂexible thinking
involves cooperation between brain networks linked to cognitive con-
trol and spontaneous thought, which may reﬂect focused internal at-
tention and top-down control of spontaneous cognition during creative
idea production .
Creativity, networks and neurotransmitters
It has been shown that the three core networks interact during di-
vergent thinking via cortico-striatal–thalamo-cortical loops [24,34–36].
The extensive connectivity between the SN and CEN, and subcortical
structures like the dorsomedial thalamus and the putamen on the one
hand and the anterior thalamus and the dorsal caudate nucleus on the
other hand being important in this light .
It has been shown that the thalamus, one of the aforementioned
subcortical structures, together with the dopamine 2 (D2) receptor
system, play an important role in divergent thinking. Decreased D
receptor densities are suggested to lower thalamic gating thresholds,
increasing thalamo-cortical information ﬂow, which might lead to en-
hanced performance on divergent thinking tests . The role of do-
pamine (DA) in creative thinking has been suggested by multiple stu-
dies [37–39] with too high levels being linked with impaired divergent
thinking and medium levels to high levels of ﬂexible thinking [37–39].
Of note, the activity of DA neurons in the SN, more speciﬁc the
ventral tegmental area (VTA), is under the excitatory control of ser-
otonin (5-HT) 2A receptors in the PFC [25,40]; the 5-HT
being the principle site via which psychedelics exert their eﬀects .
Psychedelics and creativity networks
A decrement in the functional connectivity in parts of the DMN was
demonstrated after administration psychedelics [41,42]. A hypothe-
sized consequence of this eﬀect being enhanced cognitive ﬂexibility and
creative thinking . Furthermore, the increased frontal activation
and divergent prefrontal-subcortical activation pattern induced by
psychedelics might be attributed to a disruption of thalamic gating of
sensory and cognitive information. Thalamic gating is under the control
of glutamatergic cortico-striatal pathways projecting to thalamic nuclei
. It is known that psychedelics have secondary eﬀects on gluta-
matergic, dopaminergic, and noradrenergic pathways [13,14] and that
stimulation of the 5-HT
receptors, can lead to an alteration of tha-
lamo-cortical transmission [13,44,45].
Psychedelics, personal factors and creativity
Psychedelics generate positive mood eﬀects in healthy participants
[12,46] which lead to openness to novel experiences [47,48], and in-
creases in empathy . The ‘facilitatory theory’proposes that positive
mood states tend to result in activation of a rich and complex set of
positive memories and thoughts, which promotes ﬂexibility and in-
novation [50–52]. Furthermore two personality traits, openness to ex-
perience and empathy have been linked with enhanced divergent
Psychedelics, personal factors, creativity and brain networks
The induction of positive mood has been associated with increased
activity in the left dlPFC , a brain regions which has been
associated with enhanced divergent thinking and the goal-directed
planning of novel solutions [54–56]. Numerous studies have reported a
positive relationship between creativity and openness [27,48,57] and
the trait has been studied in relation to the neurobiological basis of
creativity . Apparently both openness and creativity are associated
with increased functional connectivity in the DMN . With respect to
empathy a positive relation between levels of empathy and creativity
has been shown . Both divergent thinking and empathizing have
been associated with the DMN  and activity in this network has
shown to be increased during high-level social cognitive tasks
Psychedelics, personal factors, creativity and neurotransmitters
Openness seems to facilitate awareness of both one’s own and
others’emotions and is related to empathy . Research has shown
that empathy [61,62] and openness to experience  are positively
related to oxytocin levels; intranasal administration of oxytocin led to
higher levels of empathy in response to positive and negative valence
stimuli  and to higher self-ratings of openness . Interestingly,
De Dreu and colleagues (2014) showed that intranasal application of
oxytocin can also lead to enhanced divergent thinking and creative
It is suggested that the link between creativity and oxytocin is
mediated by DA . The interaction between oxytocin and DA sys-
tems is supported by animal research where co-located oxytocin and D
receptors in the striatum played an important role in social and emo-
tional behavior [65,66]. Elevated striatal DA is often associated with
reduced DA in the PFC and reduced latent inhibition . Latent in-
hibition is a ﬁltering mechanism which tags novel information as re-
levant. When this mechanism is reduced, known stimuli or information
is treated as novel, independently of the number of times we have seen
it before. This reduced ﬁltering has been associated with elevated
Psychedelic model to study the creative mind
Psilocybin has been shown to produce a well-controllable altered
state of consciousness marked by stimulation of aﬀect, enhanced ability
for introspection, increased empathy [69,70]. It has been widely used in
psychopharmacological research without reports of severe adverse
events [46,70,71]. Placebo-controlled mechanistic experimental studies
in healthy volunteers being administered psilocybin in combination
with a D
R and oxytocin receptors blockers when assessing
ﬂexible thinking, mood states, openness and empathy, will shed light on
the neurotransmitters involved in the facilitation of psychedelic-in-
duced ﬂexible thinking. Proton magnetic resonance spectroscopy (
MRS), a non-invasive neuroimaging technique that allows in vivo
quantiﬁcation of glutamate-related metabolites in localized brain re-
gions , will help determining the role of glutamate in this process.
Functional connectivity analysis will allow determining the network
underlying psychedelic-induced ﬂexible thinking.
It is hypothesized that blockade of 5-HT
receptors will lead to an
absence of eﬀects on glutamatergic levels and divergent thinking.
Furthermore it is hypothesized that heightened empathy and openness
will lead to enhanced divergent thinking and that D
R blockade and/or
oxytocin receptor blockade in combination with psilocybin will lead to
the absence of an oxytocin response, and no enhancement in divergent
Psilocybin as tool to investigate the neurobiology underlying the
creative mind will help to answer the question why psychedelics can be
beneﬁcial in the treatment of psychopathologies in which ﬂexible
thinking is disturbed.
K.P.C. Kuypers Medical Hypotheses 115 (2018) 13–16
Conﬂict of interest statement
The author has no conﬂict of interest to declare.
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