Pamela Cheng, DO
Stroke remains one of the leading causes of death and disability in the United States. Currently, the main therapeutic approach includes thrombolysis and mechanical thrombectomy. However, immediate reperfusion therapy does not tell the whole story. Following a stroke, there are complex biochemical events that occur that lead to excitotoxicity and oxidative stress, which may contribute to long-term functional outcomes. As such, there has been great interest and research in the field of neuroprotection. While there are currently no approved neuroprotective treatment options for stroke, there have been some promising yet conflicting results on the endocannabinoid system (ECS).
The ECS is composed of endogenous, lipid-based neurotransmitters that bind to the cannabinoid receptors. The ECS has shown promise in a wide range of pathological conditions and neurological disorders. In stroke, there is evidence that the ECS is altered in both animals and humans, and may contribute to the consequences of ischemic stroke. While studies have been conflicting in either supporting or refuting the use of cannabinoids, they remain a prominent research focus.
Cannabis (Cannabis sativa), also known as marijuana, has been used for centuries for various medicinal and recreational purposes. It contains several different cannabinoids, the most notable being tetrahydrocannabinol (THC) and cannabidiol (CBD). THC and its well-known psychoactive effects are due to interaction with the cannabinoid receptor type 1 (CB1R). However, in addition to its psychoactive effects, THC has been shown to promote hippocampal neurogenesis and memory restoration, and to limit the development of atherosclerosis in animal models.
CBD, which lacks a psychoactive effect, has also shown anti-inflammatory, immunosuppressive, analgesic, and anxiolytic effects. In fact, on June 25, 2018, the FDA approved a CBD derived oral solution for the treatment of two rare forms of genetic epilepsy. Other forms of CBD have also been approved for cancer-related symptoms. The use of cannabis in stroke is less clear, but there are some preclinical studies that suggest some benefit. In fact, in a recent systematic review and meta-analysis, all subclasses of cannabinoids, cannabis-derived, synthetic, specific CB1R and CB2R agonists showed reduced infarct volume and improvement in both early and late functional outcome in experimental stroke. CBD showed a trend towards reduced infarct size when given < 6 hours from stroke. Repeated treatment with CBD from day 1 or day 3 to day 14 showed improved functional outcome and survival rates, suggesting that CBD may have a promising neuroprotective effect. Furthermore, in animal models, CBD significantly increased cerebral blood flow and reduced brain edema and barrier permeability associated with ischemic conditions. Despite a large number of preclinical studies, there are currently no clinical trials involving cannabis and stroke.
Cannabis is the most common illicit substance in the world. However, the current strains of cannabis have significantly higher THC content than even a decade ago. The trend towards higher THC carries significant health risks. Recent studies show that cannabis use can significantly affect physical and mental health and lead to substance dependence. In fact, a study in patients aged 18 to 55 found that cannabis use was independently associated with a 26% increase in obesity, hypertension, smoking, and alcohol use. Another study showed that in people aged 25 to 34 years old, there was a 2.25-fold increase in the risk of acute ischemic stroke. On the contrary, other studies have failed to show an association between cannabis use in young adults and stroke. What can be said is that there does appear to be a temporal correlation with the increase in strokes in young adults and the use of cannabis. This, in part, could be related to cannabis-related angiopathy and the procoagulant effects of THC on platelets, though the exact relationship and pathogenesis of cannabis and stroke is not entirely clear.
There has been some research on the endogenous cannabinoid 2-arachidonoylglycerol (2-AG), which is a full agonist at cannabinoid receptors. Although the role of 2-AG is unclear, the neuroprotection that is seen by exogenous 2-AG suggests that it is involved in reducing neuronal excitotoxicity and limiting cerebral vasoconstriction. 2-AG is inactivated by MAGL (monoacylglycerol lipase), and targets for MAGL inhibitors have shown some benefit in experimental stroke and other neurodegenerative diseases. Recently, a potent MAGL inhibitor ABX-1431 (Abide Therapeutics) has completed a phase I safety trial and is currently in phase II trials for treatment of Tourette syndrome and neuropathic pain.
In conclusion, despite the controversy of cannabis in medicine, the FDA approved the first cannabis-derived medication for two rare forms of genetic epilepsy. This will undoubtedly open up a door for further cannabis research. Whether cannabis helps to reduce stroke size and improve functional outcomes in humans remains to be elucidated.
