Israel: Medical cannabis research for combating PTSD

November 22, 2023

Targeting the endocannabinoid system may have a role in the treatment of post-traumatic stress disorder (PTSD). However, few studies have examined the effectiveness of cannabis on symptoms of PTSD, and more research is needed to ascertain cannabis’ effectiveness. In this retrospective naturalistic study, we followed 14 relatively mature (32-68 years of age), treatment-resistant, chronic combat post-traumatic patients who remained severely symptomatic despite treatment with many lines of conventional treatment prior to receiving medicinal cannabis. Our findings show that total sleep score, subjective sleep quality, and sleep duration significantly improved (p < 0.01). Total PTSD symptom score and its subdomains (intrusiveness, avoidance, and alertness) showed improvement (p < 0.05). However, there was no improvement in the frequency of nightmares (p = 0.27). The mean follow-up time was 1.1 ± 0.8 years (range of 0.5 to 3 years).

1. Introduction

Post-traumatic stress disorder (PTSD) is a mental disorder that can develop after a person is exposed to a traumatic event, such as threatened or actual death, serious injury, or sexual violence. Exposure can be direct, as a witness, as learning a traumatic event happened to a close person, or as repeated or extreme exposure to details of a traumatic event, such as during a line of work. The clinical presentation varies, and symptoms may include: Fear-based reexperiencing (such as in intrusive recollections, nightmares, or dissociative states); Intense physiological or psychological distress when exposed to triggering cues that remind of the traumatic events and persistent avoidance of such cues (internally or externally); Negative alterations in cognition or mood including difficulty in remembering important parts of the event, negative expectations about oneself, others or the future. Persistent negative mood states with decreased ability to feel positive feelings. Diminished interest in previously enjoyed activities and feelings of detachment or estrangement from others; Alterations in arousal and reactivity, including irritable behavior, hypervigilance, exaggerated startle response, and more (1). According to different guidelines for the treatment of post-traumatic stress disorder (PTSD), including the American Veterans Affairs (VA) and American Department of Defense (DoD) guidelines (2), and the International Society for Traumatic Stress Studies (ISTSS) (3), the first line treatment of PTSD includes psychotherapy and/or SSRIs or SNRIs. The most evidence-based and effective treatments are cognitive behavioral therapy (CBT), specifically prolonged exposure (PE), as well as eye-movement desensitization and reprocessing (EMDR) (4, 5). However, a large proportion of patients avoid psychological treatment, and the dropout rate among veterans is high (6). Remission rates with medication are only around 20 to 30%, and their side effects cause low compliance resulting in poor efficacy (7, 8). Considering the limitations of these treatments and the need for effective treatment for patients diagnosed with PTSD, an interest in medical cannabis for PTSD has risen in recent years.

In the past two decades, there has been growing literature implicating the involvement of the endocannabinoid system (eCS) in the etiology of PTSD (9, 10). The endocannabinoid system is a system of cannabinoids produced in our body and includes endogenous cannabinoids, such as N-arachidonoyl ethanolamine (anandamide) and 2-arachidonoyl glycerol (2-AG) and CB1 and CB2 receptors. CB1 receptors are located primarily in the brain and are widely located in the same areas in the brain that are involved in PTSD - the amygdala, hippocampus, and prefrontal cortex (11). CB2 receptors are located primarily in peripheral immunological tissue, although their presence in the central nervous system has also recently been documented. In fact, activating circuits and mechanisms involving CB receptors are similar to pathways involved in PTSD (12).

By activating CB1 receptors in the amygdala, cannabis can potentially reduce fear, anxiety, and aversive memories (13–18). By stimulating CB1 receptors in the prefrontal cortex, cannabis may increase serotonin levels, thus reducing depression, and improving mood, memory, and neurogenesis (17). Cannabis may also decrease hyperarousal and intrusive memories by activating CB1 receptors in the hippocampus and thus might help to reduce PTSD symptoms (13). Furthermore, studies demonstrate a lower concentration of endocannabinoids in patients with PTSD. For example, in a study by Hill et al., endocannabinoid levels were measured in 46 people (24 with PTSD and 22 without PTSD) who were exposed to the 9/11 terror attack. They found that 2-arachidonoylglycerol (2-AG) levels were significantly lower among those who developed PTSD (19).

Cannabinoids are a group of active compounds found in the cannabis plants. The most well-known cannabinoids are Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which bind to the endocannabinoid receptors mentioned above. Both THC and CBD act on cannabinoid receptors CB1.CBD acts on CB2 too as well as other targets such as Fatty acid amide hydrolase (FAAH), serotonin 5-HT1A receptor and more (20). THC is the primary psychoactive ingredient in cannabis. It reduces anxiety (but can also increase anxiety), improves sleep, reduces nightmares, increases hunger, and helps in the extinction of fear memory (15, 21, 22). Cannabidiol (CBD) is a non-psychotomimetic cannabinoid that causes the least side effects while reducing the anxiety and psychoactive symptoms caused by THC (23). CBD significantly reduces the consolidation of aversive memories and has an anti-inflammatory effect with neuroprotective, analgesic, sedative, antiemetic, antispasmodic, anti-inflammatory, and anxiolytic properties (24). Cannabis use is not without its dangers. Cannabis use disorder afflicts about 22% of cannabis users, and 13% develop cannabis dependence (25). Cannabis use may increase the risk of psychosis and hinder its treatment (26, 27).

Literature reviews from the past two years that have examined the effectiveness of cannabis on PTSD symptoms count a small number of heterogeneous studies (open-label, longitudinal, and retrospective studies) with methodological problems and many limitations (28, 29). To date, there were only two randomized, controlled clinical trials for PTSD patients. The first used the synthetic cannabinoid nabilone (30), and the second used smoked cannabis but for only three weeks and was underpowered to detect significant differentiation from placebo (31). The conclusions of the few systematic reviews examining the effectiveness of cannabis on PTSD symptoms are that cannabis and synthetic cannabinoids may have a role in the treatment of PTSD, but there is currently limited evidence regarding their safety and efficacy (28, 29). Therefore, additional research is needed to better understand the effectiveness and safety of cannabis in the treatment of PTSD.

Israel has one of the longest-running medical cannabis programs in the world, starting in the 1990s (32). However, the use of medical cannabis for PTSD in Israel began only in 2014 (33). The use of cannabis for PTSD increased to almost 10% of total licenses by 2018, although Israel has a lower prevalence of PTSD than the USA (1.5% vs. 6.8%, respectively) (32). Medical cannabis is available as dried buds for inhalation or smoking and as an oil for sublingual ingestion. License for the medicinal use of cannabis for PTSD requires an application sent to the Medical Cannabis Unit at the Ministry of Health on behalf of a patient by the treating psychiatrist. Licenses are valid for a year and require that the psychiatrist request extending the permit annually (34). The initial dose is 20 grams per month, with possible increments of 10 grams at the treating physician’s request. We advised patients to start with a low-THC concentration strain. The cannabis is dispensed at specialized pharmacies given special permit by the Ministry of Health. According to the Ministry of Health guidelines at the time, medical cannabis may be prescribed to patients who are diagnosed with moderate PTSD and above, lasting at least three years, and characterized by great distress. Cannabis will only be given after at least two trials with different drugs and two psychological interventions have been attempted. Contraindications to treatment include a history of psychosis or drug abuse (33). In this study, we examined the effectiveness of medical cannabis among patients suffering from chronic combat-PTSD in a clinical setting in Israel.

2. Materials and methods

The study is a retrospective naturalistic study that used data meticulously gathered in a real-life clinical setting during routine follow-up unrelated to the study. It was approved by the institutional review boards and was conducted following the International Conference on Harmonization guidelines and ethical principles of the Declaration of Helsinki (approval# 0118-19-COM1). Patients consented verbally for their anonymized data to be examined with no patient declining.

Since 2015, our specialized psychiatric trauma unit has offered medical cannabis to treatment-resistant combat-PTSD veterans who fit the MOH criteria. Patients complete questionnaires every six months as part of their treatment follow-up and before applying for a medical cannabis license. The two questionnaires used are the Hebrew versions of the PSQI (35) and PDS (36).

The Pittsburgh Sleep Quality Index Hebrew version (PSQI-H) is a self-administered ten-question questionnaire (Cronbach’s alpha = 0.72). A previous study had the original English questionnaire translated, back-translated, refined, and later validated by fluent speakers of both English and Hebrew. We used the following questions: (A) subjective quality of sleep rated between 0 (very good) to 3 (very bad), (B) duration of sleep in hours, (C) Inability to fall asleep within 30 minutes rated between 0 (not in the past month) to 3 (three or more times a week), and (D) total score calculated from all ten questions (higher scores indicate worse sleep quality). The Posttraumatic Diagnostic Scale (PDS) is a 49-item measure that assesses all the DSM-IV criteria for PTSD and measures symptom severity. For this study, we only used part three of the questionnaire, which includes 17 questions that measure the severity/frequency of PTSD symptoms in the past month, as the diagnosis was already well established. Questions range between 0 (never or once in the past two weeks) to 3 (at least five times a week). Symptoms can be separated into reexperiencing, avoidance, and arousal clusters. Although a formal validation of the Hebrew translation of the PDS has not been published, several theses have implemented similar translations. Weisblum (37) reported that her translation had a satisfactory internal consistency level (Cronbach’s Alpha = 0.90) in a study of parents whose children underwent heart catheterization or cardiac surgery. We used Weisblum’s translation as we found it most accurate and faithful to the original English questionnaire.

We extracted data from the questionnaires given to patients diagnosed with combat-PTSD who started treatment with cannabis at the trauma unit at the Brüll Mental Health Center, Tel Aviv, between 2015 and 2018. The questionnaires were completed as part of the patients’ standard assessment just before receiving medical cannabis and every six months afterward.

This study included all patients who were treated with cannabis for combat-PTSD and who completed PDS and PSQI questionnaires both before starting treatment with cannabis and at least once afterward (no less than six months after starting cannabis treatment). In addition, these patients had to fit the criteria for medical cannabis treatment laid out by the Ministry of Health: (1) PTSD lasting at least three years (2) Moderate or severe severity of PTSD (3) At least two previous medications were used for at least two months, including SSRIs or SNRIs (4) Two psychotherapeutic treatments. Excluded for treatment by the MOH criteria: any history of psychosis or current psychosis or any substance abuse (specifically, patients in our sample stated they had no previous cannabis use).

Source: NHI GOV