Cannabidiol enhancement of exposure therapy in treatment refractory patients with phobias.

Phobic disorders (e.g., social anxiety, panic disorder with agoraphobia) have
an estimated lifetime prevalence of 19% (de Graaf et al. 2012), and are among
the most prevalent disorders according to the WHO (2003). The estimated annual
health care costs in the USA due to anxiety disorders are $42 billion, and
these disorders are burdensome in terms of loss of quality of life and loss of
work productivity. Standard treatments (exposure with response prevention
therapy (ERP), and/or serotonin reuptake inhibitors (SSRI)) are relatively
successful, with improvement in up to 60% of patients, but only 30% to 50%
phobic patients achieve full remission (Gloster et al. 2013). Therefore, there
is still substantial room for improvement, especially in treatment resistant
patients. Preclinical research has yielded solid evidence that the cannabinoid
system is involved in the extinction of fear, presumed to underlie the
beneficial effects of exposure therapy with response prevention in anxiety
disorders (Hofmann 2008). A recent study from our experimental psychology group
(Heitland et al. 2012) uncovered a genetic variant in the cannabinoid system
that is associated with little to no spontaneous extinction of fear in a large
group of healthy controls. Together, these findings suggest that: 1) the
endocannabinoid system may form a novel target for the facilitation of
extinction of pathological anxiety in general; 2) those individuals who have a
high risk genetic profile within the endocannabinoid system, with the
consequence of reduced efficacy of fear extinction mechanisms, may be
particularly enhanced by administration of cannabidiol preceding exposure
therapy. Cannabidiol functions through inhibition of the FAAH enzyme that
degrades endogenously released cannabinoid neurotransmitters (Leweke et al.
2012), thereby enhancing endogenous endocannabinoid signalling. As opposed to
tetra hydrocannabinol (THC), the psychoactive compound in cannabis that
produces "high" feelings, cannabidiol does not produce any of these effects,
nor other significant side effects (see Chapter 6 and the Investigational
Brochure, IB), which makes it relatively safe to use.

The aim of this research project is to investigate cannabidiol as a new
medicine to target the cannabinoid system in the reduction of anxiety disorder
symptoms. The research question is whether cannabidiol, as an augmentation
strategy of exposure therapy in patients with phobic disorders (panic disorder
with agoraphobia and social phobia), can speed up and/or increase the magnitude
of change due to treatment. We specifically want to target those subjects in
whom previous treatment as usual (with serotonergic antidepressants and/or
psychotherapy) has not yielded in sufficient response to treatment, since it is
this group that needs treatment enhancement most and therefore may benefit most
from treatment enhancement with cannabidiol.
A subsidiary aim of this project is to explore determinants of the expected
treatment-enhancing effect of cannabidiol; specifically, we are interested in
exploring which combination of clinical, behavioural and genetic profiles of
patients are related to treatment response. Preclinical studies have confirmed
that pharmacological or genetic blockade of the CB1 receptor blocks extinction
of fear (Marsicano et al. 2002). Our study in healthy volunteers translated
these findings by demonstrating that a polymorphism in the cannabinoid receptor
1 (CB1) affects spontaneous extinction of fear (Heitland et al. 2012). Based on
the analogy with the preclinical findings, we expect the group with the profile
associated with markedly reduced spontaneous fear extinction to have relatively
poor endocannabinoid signalling. We will explore whether augmentation of
exposure therapy (which is based on extinction learning) with cannabidiol will
facilitate favourable therapy outcome especially in this particular group.

Seventy-two patients with phobic disorders with incomplete response to earlier
treatment will be included. Incomplete response is defined as insufficient
improvement, i.e. still fulfilling the criteria of a phobic disorder (according
to the SCID) after pharmacotherapy with an serotonergic antidepressant or
golden standard psychotherapy. Patients are randomly assigned to the placebo or
300 mg cannabidiol group. The study medication is administered orally,
preceding 8 sessions of exposure with response prevention. If necessary (which
is to be agreed upon between patient and therapist) regular treatment with ERP
will be given after the research phase. This flexible dosage of ERP will
improve sensitivity to pick up (cost-)effectiveness due to treatment
augmentation. Direct response will be assessed at baseline, at each individual
session throughout treatment, at mid-treatment, post-treament and at 3 and 6
months follow-up. Outcome will be measured using both symptom-specific measures
and quality of life measures. For patient recruitment and inclusion,
departments will collaborate with the anxiety outpatient clinic of GGZinGeest
Amsterdam, the Altrecht Academic Anxiety center Utrecht, and University Center
Psychiatry Groningen.

All patients receive exposure therapy following the treatment protocol. One
group will additional receive 300 mg cannabidiol before ERP, and one group
placebo.

This study can make a contribution to a better understanding of how and with
what kind of treatment phobic anxiety disorders (more specifically social
phobia and panic disorder with agoraphobia) could be treated better. It is
expected that this study brings little harm to the patients. The only burden is
that patients will be requested to invest some time for extra measurements.
Risk for adverse effects of cannabidiol are low. Research to date has reported
no side-effects at this dosage, as no significant side-effects have been
reported to date (Bergamaschi, 2011). However, occurrence of possible
side-effects will be closely monitored.