Use of Medicinal Cannabis and Synthetic Cannabinoids in Post-Traumatic Stress Disorder (PTSD) : A Systematic Review
Laura Orsolini, Stefania Chiappini, Umberto Volpe, Domenico De Berardis, Roberto Latini, Gabriele Duccio Papanti and John Martin Corkery
Medicina, 2019, 55, 525, 1-14
doi : 10.3390/medicina55090525
Background and Objectives : Post-traumatic stress disorder (PTSD) is a common psychiatric disorder resulting from a traumatic event, is manifested through hyperarousal, anxiety, depressive symptoms, and sleep disturbances. Despite several therapeutic approaches being available, both pharmacological and psychological, recently a growing interest has developed in using cannabis and synthetic cannabinoids stems from their consideration as more efficient and better tolerated alternatives for the treatment of this condition. The present paper aims to evaluate the clinical and therapeutic potentials of medical cannabis and synthetic cannabinoids in treating PTSD patients.
Methods : A systematic electronic search was performed, including all papers published up to May 2019, using the following keywords (((cannabis [Title/Abstract]) OR (synthetic cannabinoids [Title/ Abstract])) AND ((PTSD [Title/Abstract]) OR (Posttraumatic stress disorder [Title/Abstract]))) for the topics ‘Cannabis’, ‘Synthetic Cannabinoids’, ‘PTSD’, and MESH terms, on the PubMed, Cochrane Library, and Web of Science online databases. For data gathering purposes, PRISMA guidelines were followed. Results were organized into two groups, considering cannabis and synthetic cannabinoids as different therapeutic approaches for PTSD.
Results : Present data show that cannabis and synthetic cannabinoids, both acting on the endocannabinoids system, may have a potential therapeutic use for improving PTSD symptoms, e.g., reducing anxiety, modulating memory-related processes, and improving sleep.
Conclusions : Even though the current literature suggests that cannabis and synthetic cannabinoids may have a role in the treatment of PTSD, there is currently limited evidence regarding their safety and efficacy. Therefore, additional research is needed in order to better understand the effectiveness and therapeutic usage of these drug classes and monitor their safety.
Keywords : PTSD; trauma; CBD; cannabis; endocannabinoid system; cannabinoids; synthetic cannabinoids
1.1. Post Traumatic Stress Disorder (PTSD)
Post-traumatic stress disorder (PTSD) is a psychiatric condition that develops as an aberrant adaptation to a traumatic event. The disorder may manifest itself through a broad range of symptoms, involving cognition (e.g., repeated recall of the event, through intrusive thoughts, flashbacks, nightmares), mood (e.g., depression, anxiety), and emotion (e.g., psychological instability, impulsivity, and hyperarousal), and impaired social abilities [1,2], that can cause a significant alteration in personal and interpersonal functioning. Thus, the conceptual model of PTSD as a disorder of fear conditioning and extinction can assist our understanding of how the underlying neurobiological dysfunction observed in subjects suffering from PTSD. Symptoms arise in response to an acutely traumatic event, that is an incident that may cause serious injury or is life-threatening and is perceived as uncontrollable and dangerous. The effect is an activation of the hypothalamic–pituitary axis as well as of the locus coeruleus and the noradrenergic system, regionswhich are connected to the amygdala and hippocampus,mediating, respectively, fear conditioning and memory consolidation . As a result, the experience, associated sensory stimuli, and emotional response (fear) become encoded, such that later exposure to a related cue triggers reactivation of the traumatic memories as well as anxiety and increased arousal . Thus, the pathophysiology of PTSD involves several neurotransmitters, including the noradrenergic, serotonergic, endogenous cannabinoid, and opioid systems, as well as the hypothalamic–pituitary adrenal axis and the release of the corticotropin-releasing factor, which are systems involved in other psychiatric conditions, such as mood or anxiety disorders . Structural changes and central neurotransmitter imbalances involve the following mechanisms : (1) increased responsivity in the amygdala and decreased volume in the prefrontal cortex and in the hippocampus, triggering hyperarousal and anxiety; (2) dysfunction in the hypothalamic–pituitary axis coordinating the neuroendocrine stress response systems; and (3) dysregulation of neurotransmitters, e.g., increase in norepinephrine and glutamate, and decrease in serotonin [3–5].
1.2. Therapeutic Approaches for PTSD
Pharmacotherapy approved for PTSD includes traditional antidepressant and anxiolytic medications, e.g., selective serotonin reuptake inhibitors (SSRIs), such as sertraline, paroxetine, fluoxetine; and serotonin and norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine,which are considered as first-line treatments [5,6]. However, both SSRIs and SNRIs have only partial efficacy, with remission rates reported to range from20% to 30%, as well as the onset of potential side-effects, mainly responsible for their early discontinuation and consequent poor efficacy . Furthermore, second-generation antipsychotics (SGAs)—such as risperidone, quetiapine, and olanzapine—are suggested for managing symptoms for adults with a diagnosis of PTSD in a secondary care setting . According to current guidelines, a trauma-focused psychotherapy (TFP), acting on cognitive restructuring is primarily recommended . Finally, cognitive behavioral therapy (CBT) and eye movement desensitization and reprocessing (EMDR) have been shown to be effective in the treatment of PTSD and trauma-related disorders, by acting on the dysregulation of the learning process of aversive memories .
Other promising approaches for PTSD treatment are represented by molecules acting on dierent neurotransmitter circuits, e.g., (1) prazosin, which is an alpha 1 adrenergic antagonist, found to be
effective in reducing symptoms of anxiety, hyperarousal and sleep disorders, which are typical of PTSD; (2) gamma amino butyric acid (GABA) agonists, such as pregabalin or gabapentin, which may be used in addition to an antidepressant therapy; (3) N-methyl d-aspartate (NMDA) receptor partial agonists
such as D-cycloserine (DCS), which has been associated with a reduction in symptoms of anxiety,
avoidance, and numbing, and has also demonstrated an ability to augment the learning process for
extinction of conditioned fear responses in both animal and human models [3,9].
1.3. Cannabis use in PTSD : A Coping Strategy ?
Research has demonstrated a strong link between trauma, PTSD, and substance use disorders (SUDs) in general, and particularly between cannabis use disorders and PTSD [10–13]. In fact, the pathophysiology of PTSD involves many of the structures and neurocircuitry identified as key components in the development and/or perpetuation of addictive processes, such as amygdala hyperactivity, chronic activation of brain stress systems, and increased corticotropin-releasing factor (CRF) during acute drug-withdrawal; and the medial prefrontal cortex and its connections to the nucleus accumbens and ventral pallidum involved in animal models of craving and drug-induced reinstatement . It has been estimated that individuals with PTSD are 2–4 times more likely to have a SUD compared to individuals without PTSD . An association between PTSD and SUD has been documented amongst US veterans [13,15,16], possibly due to shared etiological factors, but also in an attempt to act as a copying strategy for PTSD symptoms using substances, and specifically cannabis, as a self-medication [3,10,11,13,17]. In fact, cannabis has been consumed for to its calming and relaxing eects, in order to cope with symptoms of intrusions (like repeated and disturbing thoughts or dreams) and hyperarousal (anxiety, trouble sleeping, irritability) [1,7,18–22]. Between 2002 and 2009, the diagnosis of a cannabis use disorder increased more than 50% (from 0.66% to 1.05%) amongst veterans , facilitated by users’ perception of safeness compared to psychopharmacological compounds and/or alcohol, both of which are reported to have undesired side-eects, ranging from loss of cognitive acuity and social withdrawal to anhedonia and decreased sex drive/libido, which cannabis usually did not cause .
1.4. Cannabis, Cannabinoids, and Their Role in PTSD
Marijuana is derived from the Sativa and Indica species of the Cannabis plants. It contains cannabinoids and several other classes of chemical compounds acting on the cannabinoid receptors. Specifically, D-9-tetrahydrocannabinol (THC) is a highly lipophilic alkaloid and is the primary psychoactive ingredient in marijuana, varying from 0.2% to 30% potency per plant and strain; whilst cannabidiol (CBD) is a non-psychotomimetic cannabinoid, with neuroprotective, analgesic, sedative antiemetic, antispasmodic, anti-inflammatory, and anxiolytic properties . Both THC and CBD act on cannabinoid receptors, but, compared with THC, CBD shows a lower CB1 and CB2 receptor anity and, being an inverse agonist at the human CB2 receptor, it shows anti-inflammatory effects as well . The cannabinoid receptors are part of the endocannabinoid system (eCS) together with vendogenous cannabinoids, such as N-arachidonoyl ethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG) [4,7]. CB1 receptors are mainly located in the brain and widely expressed in the prefrontal-limbic system, including areas such as the amygdala, hippocampus, and prefrontal cortex, while CB2 receptors are mainly expressed in peripheral immunological tissue, although their presence in the central nervous system has been also recently documented in regions such as the amygdala, hippocampus, striatum, substantia nigra and cortex. Both cannabinoid receptors cause dierent molecular events, resulting in a general inhibition of neurotransmitters release, such as glutamate, serotonin, noradrenaline, and dopamine, from pre-synaptic terminals of neurons where cannabinoid receptors are expressed [7,25]. In fact, the activation of circuitries and mechanisms involving CB receptors may intervene in some PTSD neurobiological pathways and symptoms, influencing its etiology and maintenance, e.g.:
(1) CB1 receptors are found in moderate to high levels throughout brain limbic structures, and have been shown to possess modulating properties on behaviors, including mood, stress, learning, and memory : in fact, by activating the CB1 receptors in the amygdala, cannabis can potentially block the consolidation of aversive memories, fear, and anxiety; moreover, through stimulating CB1 receptors in the prefrontal cortex, cannabis may increase serotonin and, therefore, display antidepressant properties; finally, cannabis agonism on CB1 receptors in the hippocampus seems to improve neurogenesis, mood, and memory as well as causing decreases in hypervigilance, hyperarousal, and intrusive memories, eects which may contribute to the anxiolytic and antidepressant eects of cannabinoids [1,4,5,7]; conversely, animal studies have shown that a reduction in the number of CB1 receptors may be associated with heightened indices of anxiety and depression, especially if the disorder persists .
(2) Stimulation of the limbic and paralimbic areas might decrease amygdala and hypothalamus activity, regulating the hypothalamic–pituitary axis and cortisol response, and, therefore, decreasing hypervigilance and hyperarousal [1,5]. Conversely, a low eCB tone contributes to amygdala hyperactivation as well as anxiety and hyperarousal symptoms characteristic of PTSD, including sleep disturbances, memory and cognitive impairments, depression, and suicidality . Interestingly, a dierence in gender has been evidenced, with males showing a higher degree of endocannabinoids released in response to a stressor and stronger physiological effects to cannabis compared to women [4,26,27];
(3) Within the eCB system, reduced peripheral levels of anandamide, abnormalCB1 receptor-mediated anandamide signaling and compensatory increase of CB1 receptor availability are implicated in PTSD etiology and degree of intrusive symptoms [1,4,7,11,27,28];
(4) Cannabinoid modulation exerts eects on memory processes through alteration of the brain-derived neurotrophic factor (BDNF) concentrations in the hippocampus and the basolateral amygdala, as well as altering long-term potentiation in hippocampal neurons .
1.5. Therapeutic use of Synthetic Cannabinoids in PTSD
Several cannabinoid-acting compounds already approved to treat low appetite, nausea, vomiting, pain, and spasticity in cancer, AIDS, and multiple-sclerosis, have been furtherly developed due to the increasing interest in the role of the eCB system in fear, anxiety and stress, and in specific psychiatric conditions, such as PTSD . Thus, a growing interest around the therapeutic use of cannabis and cannabinoids for the treatment of the PTSD symptoms  has emerged in recent years, with animal studies showing CBD may facilitate the disruption of fear memory consolidation, decrease the salience of ordinarily significant stimuli, or facilitate the extinction of fear memories , processes that are relevant to PTSD’s psychopathology [2,29,30]. The beneficial effects on anxiety depend on the cannabinoids’ agonism on the CB1 receptors, showing in animal models a biphasic dose-dependent effect, producing anxiolytic-like eects at low doses and producing an anxiogenic response at higher doses, possibly related to dierences in sensitivities of CB1 receptors in neuronal systems . Among all, Nabilone appeared to be the most explored synthetic cannabinoid in the treatment of PTSD. It is a synthetic cannabinoid agonist already approved by the Food and Drug Administration (FDA) for the treatment of chemotherapy-induced nausea and vomiting , but it has been also shown as promising for the treatment of PTSD-related insomnia and nightmares with increased sleep time and reduction of daytime flashbacks. Interestingly, it has also been proposed for harm reduction in cannabis dependence , with little evidence of development of tolerance and abuse recorded .