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Out of the box: A psychedelic model to study the creative mind



Our creativity is challenged daily when facing new situations asking for novel solutions. Creativity, a multicomponent 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 disturbed 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 psychedelics 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 volunteers.
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Medical Hypotheses
journal homepage:
Out of the box: A psychedelic model to study the creative mind
K.P.C. Kuypers
Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands
Divergent exible thinking
Brain networks
Psychedelic model
Our creativity is challenged daily when facing new situations asking for novel solutions. Creativity, a multi-
component construct includes exible divergent and rigid convergent thinking. Psychedelic drugs like psilocybin
can enhance creativity and aect state of mind (mood, empathy, openness). Of note, exible thinking is dis-
turbed in psychopathological conditions like anxiety disorders and depression and preliminary ndings have
shown psychedelics to be ecacious in the treatment of those conditions.
The question how psychedelics induce this state of enhanced exible 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 exible 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 (exible) divergent thinking. It is dierent from (rigid) con-
vergent thinking which is about nding 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 [3]. Flexible
thinking is also known to be decreased in certain psychopathological
conditions like depression, anxiety, and post-traumatic stress disorder
(PTSD) [410].
Interestingly, anecdotal evidence, historical examples and (quasi-)
experimental studies suggest that psychedelic drugs like LSD, psilocybin
and ayahuasca enhance creative exible thinking in the neuro-typical
population [1116]. In addition, the therapeutic potential of these
substances is now being investigated in the treatment of aforemen-
tioned mental disorders [1719]. Preliminary ndings in patient sam-
ples are promising showing benecial therapeutic outcomes lasting up
to a few weeks after treatment [2022]. It is hypothesized that these
eects are due to a shift from rigid thinking patterns to more exible
thinking patterns, facilitating psychotherapeutic interventions [15].
The question how psychedelics induce this state of enhanced ex-
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 exible 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
healthy volunteers.
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 [25]. 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 [2528]. The SN consists of the anterior insula (AI)
and the dorsal anterior cingulate cortex (dACC), both implicated in
empathy [25,2931]. 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 [32].Itis
suggested that the shifts between these externally (CEN) and internally
Received 8 February 2018; Accepted 22 March 2018
E-mail address:
Medical Hypotheses 115 (2018) 13–16
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(DMN) oriented cognitive networks, facilitated by SN, are very im-
portant in the process of divergent thinking [24]. Of note, it has been
shown that the SN becomes active shortly before an insightful solution
is reached [33]. Furthermore, the DMN is considered to be involved in
daydreaming and self-reection 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 [27].
In sum, this activity pattern suggests that divergent exible thinking
involves cooperation between brain networks linked to cognitive con-
trol and spontaneous thought, which may reect focused internal at-
tention and top-down control of spontaneous cognition during creative
idea production [32].
Creativity, networks and neurotransmitters
It has been shown that the three core networks interact during di-
vergent thinking via cortico-striatalthalamo-cortical loops [24,3436].
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 [25].
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 ow, which might lead to en-
hanced performance on divergent thinking tests [36]. The role of do-
pamine (DA) in creative thinking has been suggested by multiple stu-
dies [3739] with too high levels being linked with impaired divergent
thinking and medium levels to high levels of exible thinking [3739].
Of note, the activity of DA neurons in the SN, more specic 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 eects [17].
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 eect being enhanced cognitive exibility and
creative thinking [43]. 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
[13]. It is known that psychedelics have secondary eects 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 eects in healthy participants
[12,46] which lead to openness to novel experiences [47,48], and in-
creases in empathy [49]. The facilitatory theoryproposes that positive
mood states tend to result in activation of a rich and complex set of
positive memories and thoughts, which promotes exibility and in-
novation [5052]. Furthermore two personality traits, openness to ex-
perience and empathy have been linked with enhanced divergent
thinking [48,53].
Psychedelics, personal factors, creativity and brain networks
The induction of positive mood has been associated with increased
activity in the left dlPFC [52], a brain regions which has been
associated with enhanced divergent thinking and the goal-directed
planning of novel solutions [5456]. 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 [28]. Apparently both openness and creativity are associated
with increased functional connectivity in the DMN [28]. With respect to
empathy a positive relation between levels of empathy and creativity
has been shown [58]. Both divergent thinking and empathizing have
been associated with the DMN [25] 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 ones own and
othersemotions and is related to empathy [28]. Research has shown
that empathy [61,62] and openness to experience [63] are positively
related to oxytocin levels; intranasal administration of oxytocin led to
higher levels of empathy in response to positive and negative valence
stimuli [61] and to higher self-ratings of openness [63]. Interestingly,
De Dreu and colleagues (2014) showed that intranasal application of
oxytocin can also lead to enhanced divergent thinking and creative
performance [64].
It is suggested that the link between creativity and oxytocin is
mediated by DA [64]. 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 [67]. Latent in-
hibition is a ltering 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 ltering has been associated with elevated
creativity [2,68].
Psychedelic model to study the creative mind
Psilocybin has been shown to produce a well-controllable altered
state of consciousness marked by stimulation of aect, 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, 5-HT
R and oxytocin receptors blockers when assessing
exible thinking, mood states, openness and empathy, will shed light on
the neurotransmitters involved in the facilitation of psychedelic-in-
duced exible thinking. Proton magnetic resonance spectroscopy (
MRS), a non-invasive neuroimaging technique that allows in vivo
quantication of glutamate-related metabolites in localized brain re-
gions [72], will help determining the role of glutamate in this process.
Functional connectivity analysis will allow determining the network
underlying psychedelic-induced exible thinking.
It is hypothesized that blockade of 5-HT
receptors will lead to an
absence of eects 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
benecial in the treatment of psychopathologies in which exible
thinking is disturbed.
K.P.C. Kuypers Medical Hypotheses 115 (2018) 13–16
Conict of interest statement
The author has no conict of interest to declare.
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K.P.C. Kuypers Medical Hypotheses 115 (2018) 13–16
... (ibid., p. 324) This results in the disorganised activity that becomes visible in the heightened brain activities' entropy and in the subject's entrance to the primary states of consciousness. The affected DMN thereby consists of two important key nodes, the ventromedial prefrontal cortex (vmPFC), implicated in self-referential processing, and the posterior cingulate cortex (PCC) that is assumed to be a critical connector hub to all of the regions of the DMN (Kuypers, 2018). In accordance with the depicted DMN's collapse of organised activity during the entrance into those primary states of consciousness, the primary states for their part seemingly resist on more metastable neural dynamics i.e. on brain sub-states that are less stable or organised (Carhart-Harris et al., 2014). ...
... This clearly seems to enable cognitive flexibility that is visible in learning and plasticity and even the suppression of unsuited action as a kind of behavioural inhibition (ibid. Accordingly, the DMN's core area responsible for self-referential thought or self-consciousness/ego in particular -the ventromedial prefrontal cortex (vMPFC) (Kuypers, 2018) or just the MPFC (medial prefrontal cortex) ) -is from special interest. It seemingly withholds high-level prior beliefs like the experience of self or ego and the experience of its reduction in response to the administration of psychedelic drugs is presumably associated with the MPFC's decreased activity. ...
... Whereas rigid or convergent thinking is understood as the search for the best solution to a problem (Kuypers, 2018;Kuypers et al., 2016), the divergent thinking's mechanism is characterised as the ability to come up with alternative solutions to a problem when there is more than one solution correct, e.g. in brainstorming (ibid.). Hence, divergent thinking facilitates the creation of novel task solutions and psychedelic drugs seem to alter associations and activations of representations, as Baggott (2015) admits. ...
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Master's Thesis by Tomko Settgast, supervised by Mathias Hegele and Dominik Endres: The text at hand investigates the possibilities to capture the so-called flow-experience without the reliance on subjective reports, i.e. it follows the intention to explore reliably and objectively measurable markers. This search especially regards neural correlates of the experience in question that have not been found yet. The text is thereby subsumed under the umbrella of enactivism since it gives similar credit to phenomenology and neuroscience, uses the description of the dynamical system’s theory and bridges the phenomenal and natural scientific aspects of cognition via an ecologically psychological sense-making. The introduction of the neurophenomenological method at the beginning of the text offers the possibility to suggest objective markers of subjective experience based on correlation. A central position within thisobjectification is given to the entropic brain hypothesis, as it is prominently represented by Carhart-Harris (2018). Its claim to connect subjective experience to the brain’s dynamically working mechanism enables its linkage to a dynamical system’s account for cognition. The dynamical attractors that the systems theory suggest for guiding behaviour is thereby easily integrated within the notions of predictive coding (i.a. Kilner, Friston, Frith, 2007; Clark, 2015) that assumes predictions to be the foundation of perception. Under the assumption of enactivism and its notion of a unity of perception and action, one gets the opportunity to translate the dynamical system’s attractors with Gibson’s (1986) idea of affordances. Thus, the brain’s dynamical working mechanism is the reflection of the phenomenal experience of affordances that guide perception and action. Especially, skilled action will be explored as the consequence of simultaneously attracting affordances which allow for the use of different strategies in pursuing a goal. This dynamically metastable attunement to different affordances (Bruineberg & Rietveld, 2014) constitutes exactly the entirety of the introduced dynamical attractors and is reflected in the brain activities’ entropy. This hypothesis is completed with the introduction of the serotonin’s and dopamine’s neuromodulation on these attractor-based affordances where those neuromodulator’s influences in perceptual guidance and behavioural selection as well as execution are emphasised. The exploration of these neurophysiological measurements enables the linkage of subjective and objective markers of flow-experience after a flow-experience’s phenomenal characterisation is given. Therefore, the outlined objective measurements are followed by an introduction of flow-experience within the notion of Csíkszentmihályi (1975). Its phenomenal characterisation and the introduced theories are used to suggest an objective measurement of flow-experience. The text uses the similarity between the flow-experience’sphenomenology and the experience of (musical) improvisation to infer a way to investigate ojectively measurable markers of flow. As it will be revealed later, this is based on the fact that the cognitive neuroscience of improvisation leads to a phenomenological experience that is summarised as the creator-witness phenomenon a fter Berkowitz (2010) what will be made fruitful as a way to investigate the state of flow. Taken together, professional musical improvisation as a specific example of skilled action shows a phenomenal proximity to flow-experience wherefore its underlying neural mechanism isinferred as the underlying mechanism of flow-experience. Hence, an objectively measurable marker of theflow’s state of mind will be explored in the increase of the brain activities’ entropy that reflects an increase in themetastable attunement to different but simultaneously visible affordances.
... Importantly, if psychedelics can mediate changes in particular dimensions of the creative process, they could be used as a potentially novel tool to investigate these processes 1 , as well as the underlying neural mechanisms 24 . In regards to creative cognition, previous research has consistently implicated the coordination of three resting-state networks (RSNs); the default mode network (DMN), suggested to support idea generation, the frontoparietal control network (FPN), supporting idea evaluation, and areas of the salience network (SN), suggested to facilitate the shift between the internally (DMN) and externally (FPN) oriented cognitive networks [25][26][27] . ...
... In conclusion, this study found that psilocybin induces a time-and construct-related differentiation of effects on creative thinking, suggesting that psychedelics could be a novel tool to investigate underlying neural mechanisms of the creative process 1,24 . In addition, these findings add some support to the historical claims that psychedelics can influence aspects of the creative process, reducing conventional, logical thinking, and giving rise to novel thoughts, but emphasizes the distinction between spontaneous and deliberate creative cognition, as well as acute and persisting effects of the drug. ...
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Creativity is an essential cognitive ability linked to all areas of our everyday functioning. Thus, finding a way to enhance it is of broad interest. A large number of anecdotal reports suggest that the consumption of psychedelic drugs can enhance creative thinking; however, scientific evidence is lacking. Following a double-blind, placebo-controlled, parallel-group design, we demonstrated that psilocybin (0.17 mg/kg) induced a time- and construct-related differentiation of effects on creative thinking. Acutely, psilocybin increased ratings of (spontaneous) creative insights, while decreasing (deliberate) task-based creativity. Seven days after psilocybin, number of novel ideas increased. Furthermore, we utilized an ultrahigh field multimodal brain imaging approach, and found that acute and persisting effects were predicted by within- and between-network connectivity of the default mode network. Findings add some support to historical claims that psychedelics can influence aspects of the creative process, potentially indicating them as a tool to investigate creativity and subsequent underlying neural mechanisms. Trial NL6007; psilocybin as a tool for enhanced cognitive flexibility;
... Similarly to the study of Pokorny and colleagues (2017), the present findings show medium increases in participants' ratings of arousal (implicit EE) towards positive emotions 1 week after the ceremony. Overall, there is growing evidence supporting the claim of acute enhancements in EE after administration of psychedelics and other serotonergic compounds, like MDMA and psilocybin Schmid et al., 2014;Preller et al., 2015;Kuypers et al., 2017;Pokorny et al., 2017;Kuypers, 2018). The current study adds to this body of literature by pointing out the possible long-term enhancements of emotion recognition/ awareness, which might bring interesting therapeutic applications of psychedelics' use for stress-related psychopathologies like depression, anxiety disorders, and posttraumatic stress disorder, which are characterized by low levels of empathy (Donges et al., 2005;Chamberlain et al., 2006;Nietlisbach and Maercker 2009;Cusi et al., 2011;Palm and Follette 2011;Lee and Orsillo 2014;Parlar et al., 2014;Morrison et al., 2016). ...
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Background: Naturalistic and placebo-controlled studies have suggested that ayahuasca, a traditional Amazonian beverage, could be helpful in the treatment of psychopathologies like depression and anxiety disorders by changing otherwise disturbed cognitive and emotional processes. To better understand its full therapeutic potential, one way is to study the effects on processes like flexible thinking, empathy, and well-being, which are normally compromised in stress-related psychopathologies. Materials and Methods: Volunteers attending ayahuasca ceremonies were asked to complete a test battery at three separate occasions: baseline, the morning after, and 1 week after the ceremony. We included the constructs of creative thinking (measured by Picture Concept Test), empathy (Multifaceted Empathy Test), satisfaction with life (Satisfaction with Life Scale), decentering (Experiences Questionnaire), and personality (Big Five Inventory) into the test battery. Additionally, the psychedelic experience was quantified with the Persisting Effects Questionnaire, the Ego Dissolution Scale, and Visual Analogue Scales. Results: In total, 43 attendees (males = 22; females = 21) completed parts of the baseline assessment, 20 (males = 12; females = 8) completed assessments in the morning after the ceremony, and 19 (males = 14; females = 5) completed assessments at the 1-week follow-up. At one and 7 days post-ceremony, cognitive empathy, satisfaction with life, and decentering increased, while divergent thinking ( Fluency corrected for Originality ) decreased, when compared to baseline. Implicit emotional empathy increased at 1-week follow-up, whereas ratings of the trait neuroticism decreased. Conclusion: The study suggests that a single ingestion of ayahuasca in a social setting is associated with enhancement of subjective well-being, an enhanced ability to take an objective and non-judging stance towards the self (decentering), and the ability to correctly recognize emotions in others, compared to baseline, lasting up to 1 week post-ceremony. To understand the therapeutic potential related to these effects, further research with clinical populations is needed in which these effects can be assessed, including its link with therapeutic outcomes. Together, this will increase our understanding of the effectiveness and breadth of future therapeutic options.
... Acutely, psilocybin increases spirituality [7,8,[26][27][28], emotional empathy [29,30], creative thinking [30,31], optimism, happiness, mindfulness [32], insightfulness [33], motivation [34], memory recovery [35], acceptance of, and connectedness to, others [35,36], and induces ego dissolution/personality change (i.e. collapse of rigidified identity) [37] and emotional breakthrough experiences [38]. ...
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Anorexia Nervosa (AN) is a major health problem with one of the highest mortalities and treatment costs of any psychiatric condition. Cognitive behavioural therapy (CBT) is currently the most widely used treatment for AN in adults but provides remission rates ≤ 50%. Treatment drop-out is exceedingly high and those that persevere with treatment often relapse, causing increased risk of morbidity and mortality. There is an urgent need to find new interventions, especially as there are no approved pharmacological treatments for AN. Ideally, new treatments would target treatment-resistance and to decrease the chronicity associated with the disorder. Over the past two decades, emerging research into classic psychedelic substances (lysergic diethylamide acid (LSD), 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT), N,N-Dimethyltryptamine (DMT) and psilocybin), indicates that marked reductions in anxiety and depression-like symptoms, and lasting improvement in mental health, can follow from one or two exposures to these psychedelic substances. Anxiety and depression are the most prevalent co-morbid psychiatric symptoms in AN. Here we suggest that classic psychedelics, particularly psilocybin, have the potential to normalise dysfunctional neurobiological systems in AN and provide a novel treatment intervention that is worthy of consideration, particularly for treatment-resistant patients.
... EBT also explains why fMRI studies reported decrements in BOLD activity in frontal, temporal, and parietal cortex after psychedelics, since the activity within these networks becomes less centralized. Previous research suggested that shifts and interactions between internally (DMN) and externally (TPN) oriented functional networks are vital in divergent thinking (Beaty et al., 2018;Jung, Mead, Carrasco, & Flores, 2013;Kuypers, 2018). It is a simplified visualization that depicts the strength of connectivity pattern between and within brain functional networks, which are presented in different colors. ...
Increasing evidence suggests that altered states of consciousness (ASC) are associated with both positive and negative effects on components of creative performance, and convergent and divergent thinking in particular. We provide a metacontrol framework that allows characterizing factors that induce ASC in terms of their general impact on the information processing style of problem solvers. We discuss behavioral and neuronal findings from three areas that reflect strong connections between ASC and the underlying effects on metacontrol on the one hand and components of creativity on the other hand: drug-induced ASC, meditation-induced ASC, and hallucinations. While more, and especially more systematic research is needed, we identify a general trend, suggesting that factors that induce ASC are likely to alter the metacontrol state by biasing it toward either persistence, which is beneficial for convergent thinking and other persistence-heavy operations, or flexibility, which is beneficial for divergent thinking and other flexibility-heavy operations.
... The concept that LSD induces its subjective effects mainly via increases in functional connectivity between brain regions is tempting. For example, this concept provides a straightforward idea as to how LSD might induce effects like synaesthesia (e.g., the phenomenon of tasting music) or increased abilities for divergent thinking [32]. ...
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Lysergic acid diethylamide (LSD) is a potent hallucino-genic substance that was extensively investigated by psychiatrists during the 1950s and 1960s. Researchers were interested in the unique effects induced by this substance, some of which resemble symptoms seen in schizophrenia. Moreover, during that period LSD was studied and used for the treatment of several mental disorders such as depression , anxiety, addiction and personality disorders. Despite this long history of research, how LSD induces its specific effects on a neuronal level has been relatively unclear. In recent years there has been a revival of research in hallucinogenic drugs and their possible clinical applications. These contemporary studies in the UK and Switzer-land include neuroimaging studies using functional magnetic resonance imaging (fMRI). In this review, we collect and interpret these recent neuroimaging findings. Overall, previous results across studies indicate that LSD administration is associated with extensive alterations in functional brain connectivity, measuring the correlated activities between different brain regions. The studies mostly reported increases in connectivity between regions and, more specifically, consistently found increased connectiv-ity within the thalamocortical system. These latter observations are in agreement with models proposing that hal-lucinogenic drugs exert their effects by inhibiting cerebral filtering of external and internal data. However, studies also face several limitations, including potential biases of neuroimaging measurements.
... Anecdotal evidence and (quasi-)experimental studies suggest that a single administration of a psychedelic drug like ayahuasca, LSD, or psilocybin can enhance creative, flexible thinking and emotional empathy in the neuro-typical population (Dolder et al. 2016;Harman et al. 1966;Krippner 1964;Kuypers 2018;Kuypers et al. 2016;Pokorny et al. 2017;Preller et al. 2015;Sessa 2008;Uthaug et al. 2018). Furthermore, clinical studies have found that administration of psilocybin can induce long-lasting positive psychological changes, such as symptom remission and enhancement of well-being, in clinical populations (Carhart-Harris et al. 2016;Griffiths et al. 2016;Johnson, Garcia-Romeu, and Griffiths 2017). ...
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Creative thinking and empathy are crucial for everyday interactions and subjective well-being. This is emphasized by studies showing a reduction in these skills in populations where social interaction and subjective well-being are significantly compromised (e.g., depression). Anecdotal reports and recent studies suggest that a single administration of psilocybin can enhance such processes and could therefore be a potential treatment. However, it has yet to be assessed whether effects outlast acute intoxication. The present study aimed to assess the sub-acute effects of psilocybin on creative thinking, empathy, and well-being. Participants attending a psilocybin retreat completed tests of creative (convergent and divergent) thinking and empathy, and the satisfaction with life scale on three occasions: before ingesting psilocybin (N = 55), the morning after (N = 50), and seven days after (N = 22). Results indicated that psilocybin enhanced divergent thinking and emotional empathy the morning after use. Enhancements in convergent thinking, valence-specific emotional empathy, and well-being persisted seven days after use. Sub-acute changes in empathy correlated with changes in well-being. The study demonstrates that a single administration of psilocybin in a social setting may be associated with sub-acute enhancement of creative thinking, empathy, and subjective well-being. Future research should test whether these effects contribute to the therapeutic effects in clinical populations.
The drugs of abuse market has been steadily increasing, and new classes of psychoactive substances appear every year, with potential addictive properties and side effects. Healthcare providers need to be aware of the toxicodynamic and toxicokinetic properties of these drugs for prevention, diagnosis and treatment of emergency cases. Serotonergic hallucinogens or psychedelics are strong psychoactive substances that act on the psychological state and influence the mood and several other processes in the brain. Among these, the use of the psychoactive natural substances has a long history in many cultures in sacred and religious rituals. Starting from the 1960s and 1970s, their popularity increased also as drugs of abuse. Serotoninergic hallucinogens include the classical psychedelic natural products containing N,N-dimethyltryptamine, psilocybin and psilocin, bufotenine, mescaline, lysergic acid amide, the synthetic hallucinogens as lysergic acid diethylamide, and the new hallucinogenic substances as tryptamine and phenethylamines derivatives, for which little is known regarding the toxicological properties and acute and chronic effects. This chapter provides a comprehensive update on serotoninergic hallucinogens, starting from their history and focusing on their classification, toxicokinetics, toxicodynamics, acute and chronic effects. Preface Toxicology is a multidisciplinary science where a vast interdisciplinary field of applications is continuously evolving and developing, aiming to maintain and enhance the safety of global health and to assist and strengthen ongoing policy regulatory frameworks. Thinking outside the box, the concept of toxicology has successfully evolved throughout the years, as new research techniques have been developed on preexisting methods and new data became available, resulting in a continuous update of our current knowledge on many different toxicological aspects. The development, improvement, and validation of such steps significantly improve our ability to further understand the hazards and risks posed by chemicals and toxic stimuli that are detrimental to human health. In modern life today, simultaneously or sequentially, we are all exposed to chemicals from diverse sources where a toxicological risk assessment has played a pivotal role in clarifying the mechanistic reasons and resulting outcomes. This book focuses on crucial modern toxicology issues highlighting aspects such as toxicity methods and models, testing tools and concepts, risk-assessment insights, pharmaceuticals and nutraceuticals, biomaterials and nanomaterials, special topics in toxicology, epidemiology, and public health, and clinical biomarkers, among others, providing an “in-depth” review of today’s scientific stance, equally benefiting toxicological scientific communities and respective regulatory bodies. Written by renowned and leading experts in these scientific fields with whom I have been closely collaborating over the past decade, this resource is dedicated to all toxicological risk assessments and multihealth impacts from different exposures. I am immensely proud of this collection of excellent studies and strongly believe that it will be a valuable asset to all scientists working on risk assessment and a substantial contribution to modern toxicology. The book’s success belongs to the authors of the chapters. The design of the book is based on the expertise and knowledge of many collaborations and partners in research. Of course, there will always be room for improvement, but the book provides an attempt at a holistic approach. The central philosophy is, “we know less than we think we know” (Socrates).
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Here, we briefly overview the various aspects of classic serotonergic hallucinogens reported by a number of studies. One of the key hypotheses of our paper is that the visual effects of psychedelics might play a key role in resetting fears. Namely, we especially focus on visual processes, since they are among the most prominent features of hallucinogen-induced hallucinations. We hypothesize that our brain has an ancient visual-based (preverbal) intrinsic cognitive process that, during the transient inhibition of top-down convergent and abstract thinking (mediated by the prefrontal cortex) by psychedelics, can neutralize emotional fears of unconscious and conscious life experiences from the past. In these processes, the decreased functional integrity of the self-referencing processes of the default mode network, the modified multisensory integration (linked to bodily self-consciousness and self-awareness), and the modified amygdala activity may also play key roles. Moreover, the emotional reset (elimination of stress-related emotions) by psychedelics may induce psychological changes and overwrite the stress-related neuroepigenetic information of past unconscious and conscious emotional fears.
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Rationale: Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. Objectives: Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression. Methods: Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure. Results: Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen's d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience. Conclusions: Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.
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Plant-based psychedelics such as psilocybin have an ancient history of medicinal use. After the first English-language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aides to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programmes. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and 3 separate clinical trials of psilocybin for depressive symptoms. In this Circumspective piece, Robin Carhart-Harris and Guy Goodwin share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.Neuropsychopharmacology accepted article preview online, 26 April 2017. doi:10.1038/npp.2017.84.
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Introduction: Ayahuasca is a South American psychotropic plant tea traditionally used in Amazonian shamanism. The tea contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT), plus β-carboline alkaloids with monoamine oxidase-inhibiting properties. Increasing evidence from anecdotal reports and open-label studies indicates that ayahuasca may have therapeutic effects in treatment of substance use disorders and depression. A recent study on the psychological effects of ayahuasca found that the tea reduces judgmental processing and inner reactivity, classic goals of mindfulness psychotherapy. Another psychological facet that could potentially be targeted by ayahuasca is creative divergent thinking. This mode of thinking can enhance and strengthen psychological flexibility by allowing individuals to generate new and effective cognitive, emotional, and behavioral strategies. The present study aimed to assess the potential effects of ayahuasca on creative thinking. Methods: We visited two spiritual ayahuasca workshops and invited participants to conduct creativity tests before and during the acute effects of ayahuasca. In total, 26 participants consented. Creativity tests included the "pattern/line meanings test" (PLMT) and the "picture concept test" (PCT), both assessing divergent thinking and the latter also assessing convergent thinking. Results: While no significant effects were found for the PLMT, ayahuasca intake significantly modified divergent and convergent thinking as measured by the PCT. While convergent thinking decreased after intake, divergent thinking increased. Conclusions: The present data indicate that ayahuasca enhances creative divergent thinking. They suggest that ayahuasca increases psychological flexibility, which may facilitate psychotherapeutic interventions and support clinical trial initiatives.
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Neuroimaging studies of internally generated behaviors have shown seemingly paradoxical results regarding the dorsolateral prefrontal cortex (DLPFC), which has been found to activate, not activate or even deactivate relative to control conditions. On the one hand, the DLPFC has been argued to exert top-down control over generative thought by inhibiting habitual responses; on the other hand, a deactivation and concomitant decrease in monitoring and focused attention has been suggested to facilitate spontaneous associations and novel insights. Here, we demonstrate that prefrontal engagement in creative cognition depends dramatically on experimental conditions, that is, the goal of the task. We instructed professional pianists to perform improvisations on a piano keyboard during fMRI and play, either with a certain emotional content (happy/fearful), or using certain keys (tonal/atonal pitch-sets). We found lower activity in primarily the right DLPFC, dorsal premotor cortex and inferior parietal cortex during emotional conditions compared with pitch-set conditions. Furthermore, the DLPFC was functionally connected to the default mode network during emotional conditions and to the premotor network during pitch-set conditions. The results thus support the notion of two broad cognitive strategies for creative problem solving, relying on extrospective and introspective neural circuits, respectively. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
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The role of attention in creative cognition remains controversial. Neuroimaging studies have reported activation of brain regions linked to both cognitive control and spontaneous imaginative processes, raising questions about how these regions interact to support creative thought. Using functional magnetic resonance imaging (fMRI), we explored this question by examining dynamic interactions between brain regions during a divergent thinking task. Multivariate pattern analysis revealed a distributed network associated with divergent thinking, including several core hubs of the default (posterior cingulate) and executive (dorsolateral prefrontal cortex) networks. The resting-state network affiliation of these regions was confirmed using data from an independent sample of participants. Graph theory analysis assessed global efficiency of the divergent thinking network, and network efficiency was found to increase as a function of individual differences in divergent thinking ability. Moreover, temporal connectivity analysis revealed increased coupling between default and salience network regions (bilateral insula) at the beginning of the task, followed by increased coupling between default and executive network regions at later stages. Such dynamic coupling suggests that divergent thinking involves cooperation between brain networks linked to cognitive control and spontaneous thought, which may reflect focused internal attention and the top-down control of spontaneous cognition during creative idea production.
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The experiences induced by psychedelics share a wide variety of subjective features, related to the complex changes in perception and cognition induced by this class of drugs. A remarkable increase in introspection is at the core of these altered states of consciousness. Self-oriented mental activity has been consistently linked to the Default Mode Network (DMN), a set of brain regions more active during rest than during the execution of a goal-directed task. Here we used fMRI technique to inspect the DMN during the psychedelic state induced by Ayahuasca in ten experienced subjects. Ayahuasca is a potion traditionally used by Amazonian Amerindians composed by a mixture of compounds that increase monoaminergic transmission. In particular, we examined whether Ayahuasca changes the activity and connectivity of the DMN and the connection between the DMN and the task-positive network (TPN). Ayahuasca caused a significant decrease in activity through most parts of the DMN, including its most consistent hubs: the Posterior Cingulate Cortex (PCC)/Precuneus and the medial Prefrontal Cortex (mPFC). Functional connectivity within the PCC/Precuneus decreased after Ayahuasca intake. No significant change was observed in the DMN-TPN orthogonality. Altogether, our results support the notion that the altered state of consciousness induced by Ayahuasca, like those induced by psilocybin (another serotonergic psychedelic), meditation and sleep, is linked to the modulation of the activity and the connectivity of the DMN.
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Interest in the therapeutic potential of psychedelic substances has recently resumed. During an early phase of human psychedelic research, their therapeutic application in different pathologies had been suggested, and the first evidence for efficacy was provided. The range of recent clinical applications of psychedelics spans from cluster headaches and obsessive-compulsive disorder to addiction and the treatment of fear and anxiety in patients suffering from terminal illness, indicating potentially different therapeutic mechanisms. A variety of approaches in psychotherapy emphasize subjective experiences, such as so-called peak experiences or afterglow phenomena, as differentially mediating therapeutic action. This review aims to re-evaluate earlier and recent concepts of how psychedelic substances may exert beneficial effects. After a short outline of neurophenomenological aspects, we discuss different approaches to how psychedelics are used in psychotherapy. Finally, we summarize evidence for the relationship between subjective experiences and therapeutic success. While the distinction between pharmacological and psychological action obviously cannot be clear-cut, they do appear to contribute differently from each other when their effects are compared with regard to pathologies.
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People frequently feel anxious. Although prior research has extensively studied how feeling anxious shapes intrapsychic aspects of cognition, much less is known about how anxiety affects interpersonal aspects of cognition. Here, we examine the influence of incidental experiences of anxiety on perceptual and conceptual forms of perspective taking. Compared with participants experiencing other negative, high-arousal emotions (i.e., anger or disgust) or neutral feelings, anxious participants displayed greater egocentrism in their mental-state reasoning: They were more likely to describe an object using their own spatial perspective, had more difficulty resisting egocentric interference when identifying an object from others' spatial perspectives, and relied more heavily on privileged knowledge when inferring others' beliefs. Using both experimental-causal-chain and measurement-of-mediation approaches, we found that these effects were explained, in part, by uncertainty appraisal tendencies. Further supporting the role of uncertainty, a positive emotion associated with uncertainty (i.e., surprise) produced increases in egocentrism that were similar to anxiety. Collectively, the results suggest that incidentally experiencing emotions associated with uncertainty increase reliance on one's own egocentric perspective when reasoning about the mental states of others. (PsycINFO Database Record (c) 2015 APA, all rights reserved).
Background: Impaired empathic abilities lead to severe negative social consequences and influence the development and treatment of several psychiatric disorders. Furthermore, empathy has been shown to play a crucial role in moral and prosocial behaviour. Although the serotonin (5-HT) system has been implicated in modulating empathy and moral behaviour, the relative contribution of the various 5-HT receptor subtypes is still unknown. Methods: We investigated the acute effect of psilocybin (0.215mg/kg p.o.) in healthy human subjects on different facets of empathy and hypothetical moral decision-making using the Multifaceted Empathy Test (MET) (n=32) and the Moral Dilemma Task (MDT) (n=24). Results: Psilocybin significantly increased emotional, but not cognitive empathy compared to placebo, and the increase in implicit emotional empathy was significantly associated with psilocybin-induced changed meaning of percepts. In contrast, moral decision-making remained unaffected by psilocybin. Conclusions: These findings provide first evidence that psilocybin has distinct effects on social cognition by enhancing emotional empathy but not moral behaviour. Furthermore, together with previous findings psilocybin appears to promote emotional empathy presumably via activation of 5-HT2A/1A receptors suggesting that targeting 5-HT2A/1A receptors has implications for potential treatment of dysfunctional social cognition.
Scientific interest in serotonergic psychedelics (e.g., psilocybin and LSD; 5-HT2A receptor agonists) has dramatically increased within the last decade. Clinical studies administering psychedelics with psychotherapy have shown preliminary evidence of robust efficacy in treating anxiety and depression, as well as addiction to tobacco and alcohol. Moreover, recent research has suggested that these compounds have potential efficacy against inflammatory diseases through novel mechanisms, with potential advantages over existing anti-inflammatory agents. We propose that psychedelics exert therapeutic effects for psychiatric disorders by acutely destabilizing local brain network hubs and global network connectivity via amplification of neuronal avalanches, providing the occasion for brain network “resetting” after acute effects have resolved. Anti-inflammatory effects may hold promise for efficacy in treatment of inflammation-related non-psychiatric as well as potentially for psychiatric disorders. Serotonergic psychedelics operate through unique mechanisms that show promising effects for a variety of intractable, debilitating, and lethal disorders, and should be rigorously researched. This article is protected by copyright. All rights reserved.