Cannabidiol enhancement of exposure therapy in treatment refractory patients with phobias: study protocol of a randomized controlled trial

Phobic disorders (e.g. social anxiety disorder, panic disorder with agoraphobia) are among the most prevalent disorders according to the World Health Organization’s World Mental Health Survey Initiative [1]. These and other anxiety disorders have major impact on health, individual suffering and societal costs [2]. The estimated societal costs in Europe as a result of anxiety disorders were 74.4 billion Euros in 2010, affecting more than 69 million Europeans [3]. Anxiety disorders often co-occur with other mental health disorders [4, 5], and are associated with an increased risk of suicide [6]. Spontaneous recovery from these disorders is uncommon; if left untreated, phobias typically follow a chronic course, with low remission and high relapse rates [7].

The current evidence-based treatment entails exposure with response prevention therapy, either alone or in combination with serotonin reuptake inhibitors (SSRIs). Exposure therapy is relatively successful, with improvement in up to 60% of patients. However, only 30 to 50% of phobic patients achieves full remission [8]. Likewise, treatment with SSRIs is relatively effective, however, many patients experience relapse after discontinuing SSRI treatment [9, 10], while the effects of successful exposure treatment seem to be more sustainable [11]. Considering the high prevalence of anxiety disorders and the large number of patients for whom the anxiety symptoms remain refractory after (repeated) gold-standard treatments, new approaches to the treatment of anxiety are urgently needed [12, 13]. Preclinical as well as clinical studies have pointed to the relevance of utilizing fear learning paradigms for a deeper understanding of the neurocircuitry and neurochemistry of the fear system involved in anxiety disorders [14]. Specifically, patients with anxiety disorders show stronger fear responses during extinction than comparison subjects [15], and poor fear extinction is predictive of poor outcome in exposure therapy [16].

A potential novel target for the facilitation of fear extinction has been derived from preclinical research. The crucial involvement of the cannabinoid system in fear extinction was first shown by Marsicano et al. [17]. The results show that (genetic or pharmacological) blockage of transmission at the cannabinoid receptor 1 (CB1) inhibits extinction of fear in mice. This is not surprising given the fact the CB1 receptors are richly expressed in memory-related brain areas such as hippocampus and prefrontal cortex, and as such can modulate (fear) memory [18]. In the last 15 years many studies have extended this finding using both animal and human subjects (for reviews see [12] or [19]). Animal research has shown that facilitation of the endocannabinoid system (ECS) enhances extinction, whereas blocking or deletion of CB1 receptors impairs extinction. In healthy human subjects we have demonstrated that genetic variation in a CB1 polymorphism significantly affected extinction learning [20]. Furthermore, the administration of cannabinoids in humans has shown to strengthen extinction and protect against reinstatement of fear [21‐23]. In summary, previous research clearly points to the ECS as a promising candidate for extinction enhancement. Until now, studies in humans have mainly investigated the effects of delta-9-tetrahydrocannabinol (THC), which has been shown to decrease physiological measures of fear during extinction [24] and recall [21]. However, THC is not suitable for phobic patients given the diversity of psychoactive effects caused by THC, among which the high that recreational users of cannabis seek.

In the meantime, studies have demonstrated the potential benefit of another important ingredient of cannabis: cannabidiol (CBD, for a review see [25]). CBD interacts with several receptors in the brain including cannabinoid receptors 1 and 2, transient receptor potential vanilloid type 1 (TRVP1) and serotonin 1A (5-HT1A) receptor, and inhibits or in other ways negatively affects the function of the enzyme that degrades endogenously released cannabinoid neurotransmitters (fatty acid amine hydrolase; FAAH [26]). In line with FAAH’s function in degrading anandamide [27], inhibition of FAAH has been shown to increase levels of anandamide. Preclinical research indicates that CBD enhances fear extinction and reconsolidation, and co-administrating CB1 antagonists block such effects suggesting that they are exerted via modulation of the ECS [28, 29]. Extinction of conditioned fear is proposed to underlie the effect of exposure therapy [14]. Hence, the finding that CBD specifically affects (the consolidation of) extinction suggests a potential use of CBD in augmenting the effect of exposure therapy. This leads to the hypothesis that administration of CBD during sessions of exposure therapy is expected to specifically enhance the extinction of pathological fears. The advantage of this application is that CBD needs to be administered occasionally, i.e. preceding exposure sessions only.

We aim to take this previous research to the next level by conducting the first randomized controlled trial with CBD versus 7, administered in a double-blind fashion, for the augmentation of exposure treatment in patients with social phobia or panic disorder with agoraphobia. Also, we aim to specifically target patients who have already received one of the gold-standard treatments without responding sufficiently or having relapsed, because this group needs additional approaches most.

The main study aim is to test whether administration of CBD as an augmentation step in exposure therapy can strengthen treatment outcome in patients with phobic disorders who have previously failed to respond satisfactorily to evidence-based treatment. Clinical measurements are used to investigate whether the effect of CBD on exposure is quicker, stronger, or longer-lasting than regular exposure therapy only. Additionally, there are various exploratory subsidiary aims in this study. First, a fear conditioning and extinction task is applied at baseline. This task has shown enhanced fear responses in patients with anxiety disorders as opposed to healthy comparison subjects [30]. This task also revealed different extinction trajectories, with patients being overrepresented in a poor extinction profile [16]. These profiles have also shown to be sensitive to differences between patients who will benefit from exposure treatment and those who will not. A re-extinction assessment is done after the first medication administration. The aim of this task is to explore a) whether patients with a specific profile can particularly benefit from CBD augmentation during exposure, and b) the acute effects of CBD intake on fear extinction. Second, we aim to explore the interactions between specific genetic variation and CBD administration on treatment effect. We are particularly interested in studying whether variants within the cannabinoid receptor 1 gene are involved in a differential response to CBD augmented exposure therapy, including rs2180619 identified in our previous study in healthy individuals associated with impaired spontaneous extinction of conditioned fear [20]. Additionally, impact of genetic polymorphisms within the FAAH gene [31] and genetic polymorphisms identified as being related to treatment response in anxiety disorders [32] will be explored. Similarly, clinical predictors of treatment response will be assessed to determine which sort of patients might benefit most from this augmented treatment. Lastly, we aim to assess cost-effectiveness of CBD enhancement of exposure treatment.

Phobic disorders are among the most prevalent disorders and have a major impact on the life of patients and society as a whole resulting in suffering and associated costs. Evidence-based treatments of these disorders, while effective for a large number of patients, are not adequate for a substantial group who are not sufficiently relieved from their anxiety symptoms. One strategy may be to boost the effectiveness of current treatments. Enhancing exposure therapy with pharmacological agents that affect the neurological processes involved in the extinction of fear is an avenue that has been explored with augmentation using d-cycloserine, with mixed success [68]. Since an enhancer of exposure therapy is needed but the compounds so far have not proven to be sufficiently effective, we have opted to use a new strategy using the modulation of the endocannabinoid system. This study will be the first clinical trial in which cannabidiol is used to augment exposure therapy for phobic patients.

It is important to note that this study is investigator initiated, and independent from pharmaceutical or other industry interests. Findings will be submitted to a peer reviewed scientific journal for publication.

This study is based on the preclinical evidence that ECS manipulations can be used to enhance (the retention of) fear extinction. However, acute anxiolytic effects of cannabidiol have also been reported. One study reported anxiolysis during a public speaking challenge, which resembles the type of challenges that patients with phobia are faced with during exposure therapy [69]. Hence, an additional possible outcome of the study is that cannabidiol reduces fear and anxiety acutely during the treatment sessions, making the treatments easier to tolerate. Despite the conviction based on other anxiolytic treatments that anxiolysis during exposure reduces effectiveness [70], the expectation is that cannabidiol may combine acute anxiolysis with enhanced retention of treatment effects.

A strong feature of this study is the exploratory assessment of genetic, experimental and clinical differences between patients related to extinction and subsequent treatment response. The results of this study might give rise to new insights into the possibility of personalized treatment, by exploring whether this strategy is best, specifically for patients with certain characteristics.