Introduction

The most common cause of a non-traumatic subarachnoid hemorrhage (SAH) is the rupture of a cerebral aneurysm [1]. The fatality rate of SAH patients within the first 28 days can be as high as 42%, while 10–20% of patients die before reaching the hospital [2, 3]. In aneurysmal subarachnoid hemorrhage (aSAH), the cardinal symptom is a severe, sudden headache [4], and the most common risk factors are hypertension, smoking, and extensive alcohol consumption [5]. Females in specific populations and first-degree relatives with SAH are also associated risk factors [6, 7]. Patients that survive the initial bleed have outcomes that range from minor cognitive deficits to severe neurological disability.

Delayed cerebral ischemia (DCI) is a potentially fatal condition that occurs in the subacute phase of SAH episodes. DCI affects approximately 30% of patients and is the leading cause of morbidity and mortality after surviving the initial aneurysm rupture [8]. Characterized by an acute reduction of arterial blood supply to the brain, DCI is dependent on the severity of the initial aneurysm, early brain pathologies, and the development of cerebral vasospasm (CV), though other factors such as microvascular spasm and micro-thrombosis have been considered contributary [9, 10]. CV, the constriction of intracranial arteries that usually begins 3 days after SAH and can last up to 2–3 weeks, was once considered the singular cause of DCI, though this has since been challenged after incongruencies between the presence of CV and evidence of DCI were observed [11, 12]. It is, however, still identified as a major contributor to DCI. An increase in intracellular calcium is thought to play an important role in CV due to its characteristic vasoconstriction effects in smooth-muscle cells; however, many other conducive mechanisms have been described, including the nitric oxide pathway, endothelin-induced vasoconstriction, pro-inflammatory cascades, hypoxia-inducible factor-1 (HIF-1) transcriptional modulation, oxidative stress, and apoptosis from early brain injury (EBI), among others [13,14,15]. Nimodipine, a calcium channel blocker, is one of the few current standard therapies following SAH as it has shown efficacy in reducing neurologic deficits from DCI, an effect believed to be due to the prevention of CV, though evidence of this mechanism via angiography visualization has been variable [16]. Other treatments consist of blood pressure maintenance, including induced hypertension when the CV is present, and neurovascular intervention (intra-arterial administration of spasmolytics and balloon angioplasty) if needed [17, 18]. Pain management includes acetaminophen/caffeine/butalbital cocktail and opioids [19]. Despite these treatment protocols, poor patient outcomes persist. Given there are many pathological mechanisms at play following SAH that significantly impact morbidity and mortality, research has focused on determining which pathways may have a key role in the pathophysiology behind CV and DCI in order to evaluate new treatment options.

Cannabidiol (CBD) is the dominant phytocannabinoid that accumulates in hemp, a plant closely related to marijuana that contains a much lower amount (< 0.3% dry weight) of the psychoactive cannabinoid tetrahydrocannabinol (THC). Unlike THC, CBD does not cause euphoria or intoxication, making it an attractive drug for daily therapeutic use [20]. First used for the treatment of pain, preclinical reports now demonstrate tissue-protective and anti-inflammatory effects in models of colitis, kidney injury, cardiovascular disease, arthritis, and cancer [20,21,22,23,24]. It has also been FDA-approved for the treatment of specific types of pediatric epilepsy after clinical trials found it to be more effective than conventional agents as well as therapeutically additive when used as an adjunctive agent [25,26,27]. The most common side effects include diarrhea, weight loss, transaminase elevations, and sleep disturbance, while showing little evidence of any severe adverse side effects [28]. However, many of CBD’s pharmacologic mechanisms and targets are still undetermined, so further research into its long-term side effects and therapeutic potential needs evaluation before definitive conclusions are drawn. This literature review will evaluate the potential use of CBD as a treatment option for post-SAH critically ill patients based on the correlations between the known pharmacology and physiological effects of CBD and the pathologies associated with SAH, most notably CV and DCI.

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