Psilocybin as a tool for enhanced divergent thinking and positive learning mechanisms

Psychological disorders as a result of exposure to a traumatic event are common
and occur in up to 50% of survivors by the end of the first year. Among these
disorders includes posttraumatic stress disorder (PTSD), an anxiety disorder in
which an individual*s ability to function is impaired by emotional responses to
memories of a traumatic event (Shin & Liberzon, 2010). PTSD is typically a
chronic illness associated with high rates of psychiatric and medical
comorbidity, disability, suffering, drug abuse, and suicide (Breslau, 2001;
Perkonigg, Kessler, Storz, & Wittchen, 2000). However, despite the high
incidence and lifetime prevalence rates of PTSD, current treatments such as
cognitive behavioural therapy or selective serotonin reuptake inhibitors
provide limited effectiveness in treating the disorder, with many people being
unresponsive to treatment (Hamner, Robert, & Frueh, 2004; Mithoefer, Wagner,
Mithoefer, Jerome, & Doblin, 2011). Thus, there is an urgent need for the
development of new, effective treatments.
Suggestions for effective treatments for PTSD include a hypothetical
drug that would be capable of enhancing divergent thinking (Sessa, 2011), a
cognitive process used to generate as many innovative ideas as possible. Three
core networks have been specifically implicated in this process, namely the
central executive network, the default mode network, and the salience network
(Buckner et al., 2008; Jung et al., 2013; Beaty et al., 2016). These neural
networks have all been found to be impaired in patients suffering from PTSD as
well as other disorders similarly characterized by maladaptive, habitual
behaviours or thought patterns (Chen et al., 2016; Dutta, McKie, & Deakin,
2014; Lanius, Frewen, Tursich, Jetly, & McKinnon, 2015; Posner et al., 2016),
suggesting that they underlie these symptoms. Thus, it is suggested that by
enhancing divergent thinking, a shift from habitual to goal directed behaviour
could be facilitated, and patients would be able to explore alternative
solutions for tackling their ingrained problems (Sessa, 2011). However, the
mechanisms underlying enhanced divergent thinking are unknown.
A recent study from our lab showed that psychedelics significantly
increased divergent thinking after drug intake (Kuypers et al, 2016).
Furthermore, imaging studies have shown that the classic psychedelic,
psilocybin, promotes a de-synchronization in the default mode network via
agonism of the 5-HT2A receptor that is suggested to result in cognitive
flexibility and enhanced creative thinking (Carhart-Harris et al., 2012;
Carhart-Harris et al., 2014). Additionally, rodent research has shown that low
doses of psilocybin facilitate extinction of a conditioned (fear) response
(Catlow et al., 2013). Taken together these studies suggest that psilocybin can
enhance divergent thinking, which may provide therapeutic potential in
facilitating goal directed over habitual behaviour. Principal demonstrations
showing that psilocybin facilitates cognitive flexibility would be very
relevant for future support of clinical applications of psilocybin assisted
therapy in PTSD patients. As such, psilocybin-assisted psychotherapy may offer
a promising option for PTSD patients for whom current options are not
effective.

Primary Objective: to use psilocybin as a research tool in order to enhance
divergent thinking, and facilitate relative goal-directed versus habitual
behaviour during and after drug intoxication, and to assess whether psilocybin
will deter a stress induced shift from goal directed to habitual behaviour.

Secondary Objective(s): to assess whether enhancement in divergent thinking is
mediated by activation at the 5-HT2A receptor (by pretreating individuals with
ketanserin), and to assess cortical-subcortical functional connectivity
alterations, as well as the relationship between metabolic activity and
behavioural outcomes. Furthermore, subjective experience and drug
concentration levels will be assessed in relation to the aforementioned
variables

The study consists of two parts, both of which are a double-blind, randomized,
placebo controlled, parallel-group design. Part one is a 2 (psilocybin vs
placebo) x 2 (Maastricht Acute Stress Test vs. control) design. Participants
will receive either a single dose of psilocybin (.17 mg/kg), or placebo, and
will experience an incidence of stress induction or a no-stress control
manipulation. Part two is a 2 (psilocybin & ketanserin vs placebo &
ketanserin) x 2 (Maastricht Acute Stress Test vs. control) design.
Participants will receive either ketanserin (60 mg) & placebo or a dose of
ketanserin (60mg) & placebo.
For both parts, task performance, brain activity, subjective experience, and
blood concentration will be assessed repeatedly throughout a 6 hour time window
following drug administration. Participants will then be asked to return one
week following administration in order to undergo an incidence of induced
stress or a no-stress control manipulation, and to repeat task performance and
subjective questionnaires. As it is hypothesized that psilocybin will induce
long term changes in behaviour, matched participants will be used.

Administration of treatments (see objective of the study and study design), the
Maastricht Acute Stress Test, and collection of blood samples each test day to
determine treatment concentrations,cortisol, and oxytocin concentrations in
blood.

Participants will visit our lab four times. The first visit includes a full
medical screening by a licensed physician ensuring their safety, which will
include a medical history review, a blood sample (12 ml), and an
electrocardiogram recording. The second includes a short training session to
familiarize them with the testing procedures and the MRI scanner. The third
visit will consist of taking the study treatment (psilocybin or placebo if they
are in Part 1; or psilocybin & ketanserin or ketanserin & placebo if they are
in Part 2), taking 4 blood samples (=75ml in total throughout the entire 7 hour
testing day), giving an earwax sample, completing computer tasks inside and
outside the magnetic resonance scanner (time in MRI scanner is 60 minutes), and
filling out questionnaires. Participants will then return a week later for a
follow up visit in which they will undergo a stress or control manipulation,
give blood on 4 different occasions (=30 ml in total), and repeat the computer
tasks and questionnaires. Over the course of the medical examination and the
two test days, participants will give a total of 117 ml of blood. In case they
experience complaints, the medical supervisor will be contacted. The total
discomfort experienced by the volunteer is minimal when all precautions are
taken into account.