Assessment of clinical outcomes in patients with post-traumatic stress disorder: analysis from the UK Medical Cannabis Registry

Manaswini Pillai, Simon Erridge, Lara Bapir, Martha Nicholas, Nishaanth Dalavaye, Carl Holvey, Ross Coomber, Daniela Barros, Urmila Bhoskar, Gracia Mwimba, Kavita Praveen, Chris Symeon, Simmi Sachdeva-Mohan, James J Rucker and Mikael H Sodergren

Expert Review of Neurotherapeutics, 2022, 22, 11–12, 1009–1018.

Doi : 10.1080/14737175.2022.2155139

1. Introduction

Post-traumatic stress disorder (PTSD) is a debilitating condition defined by over 1 month of symptoms following trauma exposure, causing significant distress or functional impairment [1]. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM- 5), symptoms are categorized into four subgroups of intrusions, avoidance, altered mood, and altered reactivity [1]. These may manifest as flashbacks, trigger avoidance, hyperarousal, depressive symptoms, and nightmares. PTSD affects between 5% and 10% of the population during their lifetimes [2] and is associated with other psychiatric disorders and physical health conditions [3–5]. Hence, there is a high socio-economic cost owing to increased reliance on health and social care, loss of productivity and impaired leisure activities [6].

Management of PTSD involves a biopsychosocial approach, with psychotherapy being the mainstay at present, although long- term effectiveness remains unclear [7,8]. The data on pharma- cotherapy suggest that selective serotonin reuptake inhibitors (SSRIs) are not appropriate first-line agents if sustained long-term symptom improvement is intended [7]. Side-effects such as

agitation may explain why SSRIs are poorly tolerated, since hyper- arousal is a common symptom of PTSD [9]. Other pharmacological options that have also been evaluated for the treatment of PTSD include prazosin, an alpha-1 adrenoceptor antagonist [10], trazo- done, a serotonin receptor antagonist and reuptake inhibitor [11], and agomelatine, a melatonin antagonist [12]. However, these have demonstrated variable efficacy. As such, there is a need for continued research into novel PTSD therapies that offer long-term symptom relief and minimal side-effects.

Cannabis-based medicinal products (CBMPs) have been sug- gested as a potential pharmacotherapeutic option to address this need. Cannabis plants, such as Cannabis sativa, contain two major phytocannabinoids: cannabidiol (CBD) and (−)-trans -Δ9-tetrahydrocannabinol (Δ9-THC), among other potentially active pharmaceutical ingredients [13]. Δ9-THC is a partial agonist of G-protein coupled receptors of the endocannabinoid system, cannabinoid receptors 1 and 2 (CB1/CB2), whilst CBD is a noncompetitive negative modulator of CB1 via allosteric binding [14]. CBD also acts by inhibiting fatty acid binding proteins required for cellular uptake of anandamide; this prevents the breakdown of the endocannabinoid by fatty acid amino hydrolase[15]. CB1 receptors are concentrated in the central nervous system, particularly the presynaptic terminals in the cerebellum, basal ganglia, and hippocampus [16]. Agonism leads to the inhibition of gamma-aminobutyric acid (GABA) and glutamate neurotrans- mitter release [16]. This is one mechanism that mediates the cognitive, emotional, memory, and psychoactive effects of Δ9-THC [17].

Further effects of cannabinoids are mediated by non-CB1/2 targets such as peroxisome proliferator-activated receptors, transient receptor potential vanilloid type 1 (TRPV1), and ser- otonin (5-HT) receptors [18]. In vitro studies have shown that CBD is a 5-HT3 negative allosteric modulator and indirectly activates 5-HT1a receptors [19,20]. This may explain the anxio- lytic effects of CBD, since 5-HT1a receptors from the median raphe nucleus can mediate fear extinction, whilst 5-HT3 recep- tors have anxiogenic effects [21]. As a result, CBD can counter the anxiogenic effects of the psychotomimetic component Δ9-THC [22]. TRPV1 receptors are found in relevant brain areas such as the dorsal periaqueductal gray matter, to facil- itate anxiogenic responses via glutamate release [23]. CBD activates and desensitizes these receptors, whilst indirectly increasing levels of anandamide, which is also a TRPV1 agonist [23]. These mechanisms have been demonstrated to reduce learned fear expression and anxiety within in vivo models given CBD [22,23].

The key neurobiological changes witnessed in PTSD include structural synaptic enhancement in the amygdala during fear consolidation, leading to hypothalamic–pituitary–adrenal axis (HPA) stimulation via the paraventricular nucleus, and decreased connectivity to the ventromedial prefrontal cortex (vmPFC) [18,24]. This leads to greater emotional memory expression and reduced fear extinction to both threatening and non-threatening stimuli in PTSD [25]. CBMPs may counter these changes as demonstrated by preclinical evidence of enhanced amygdala-vmPFC connectivity [26,27], increased fear extinction retention [28], and alleviated PTSD sleep disturbances within in vitro and in vivo assessments of their effects [18,29].

At present, available evidence on CBMPs and PTSD is con- flicting and difficult to synthesize owing to the use of selective cohorts, methodological heterogeneity, and underpowered studies. Whilst certain studies have reported significantly reduced PTSD symptom severity, improved sleep, and minimal adverse events (AEs), these were often limited due to small cohorts, short-term follow-up, and potential confounding from other psychotropic drug use [29–31]. Conversely, a longitudinal observational study of 2,276 veterans being treated in specialized PTSD programs found medical cannabis worsened violent behavior and substance use disorders [32]. Since excessive recreational cannabis consumption is shown to be associated with impaired fear extinction and downregu- lation of CB1 receptors, there is a need for long-term investi- gation [33].

The UK Medical Cannabis Registry (UKMCR) collects pro- spective data regarding outcome measures for patients receiv- ing CBMP prescriptions in the UK. This paper analyzes the patient-reported outcome measures (PROMs) and AE data of PTSD patients prescribed CBMPs within the UKMCR, with the aim of identifying effects on health-related quality of life (HRQoL) and safety of use.

2. Methods

2.1. Study design

This study reports a case-series of patients diagnosed with PTSD, enrolled in the UKMCR. Patients provided written con- sent upon registration into the UKMCR, prior to baseline data collection. Formal ethical approval was not required for this study following guidance from the Health Research Authority. This paper is reported in line with strengthening the reporting of observational studies in epidemiology guidelines for obser- vational studies [34].

2.2. Setting and participants

The UKMCR is the first UK patient registry to prospectively collect anonymized data regarding CBMP prescription formulations, patient demographics, PROMs, and AEs [35]. It was created in 2019 and is privately managed by the Sapphire Medical Clinics [35]. Participants are enrolled consecutively and asked to provide informed consent. The only screening criterion is whether partici- pants have been prescribed CBMPs. Patients from the UKMCR were included in the analysis if PTSD was the primary indication for CBMP treatment. Exclusion criteria extended to those with incom- plete baseline PROMs data and those who had started treatment less than 1-month prior to the date of data extraction and therefore had not reached the first follow-up milestone. There were no further exclusion criteria. The date of data extract from the UKMCR was 15 February 2022.

(…)