Blogging Stroke

ISC 2022 Session: Effect of Marijuana on Brain Health

Fransisca Indraswari, MD

International Stroke Conference 2022
February 9–11, 2022
Session: Effect of Marijuana on Brain Health

Marijuana is perceived as a harmless drug, and its recreational use has gained popularity among young individuals. The concentration of active ingredients in recreational formulations has gradually increased over time, and high-potency illicit cannabinomimetics have become available. Marijuana use in the United States is increasing, particularly among adolescents and young adults, with about one-third of 12th graders and nearly half of college students reporting marijuana use in 2018. In addition, the use of marijuana medicinally and/or recreationally has been legalized or decriminalized in many states across the U.S. in the past 2 decades, and the concentration of tetrahydrocannabinol (THC, the psychoactive component in marijuana) in cannabis products has increased significantly, from about 4% in 1995 to 15% in 2018.¹

The most studied chemicals in cannabis are THC and CBD. THC is the compound in marijuana that gives the sensation of being high. CBD (cannabidiol) has antioxidant and anti-inflammatory properties but does not have psychoactive effects. The potential therapeutic benefits of CBD continue to be investigated in clinical trials. The U.S. Drug Enforcement Agency (DEA) and the Food and Drug Administration (FDA) classify cannabis as a Schedule I controlled substance, on par with heroin and LSD, for having a “high potential for abuse and little to no medical benefit.” In contrast, CBD is legal when derived from hemp, which is the same species of plant as cannabis and contains less than 0.3% THC.¹

Cannabis use may be linked to an increased risk of heart attacks, atrial fibrillation and heart failure.² Some studies have found that within an hour after cannabis is smoked, THC may induce heart rhythm abnormalities, such as tachycardia, premature ventricular contractions, atrial fibrillation and ventricular arrythmias. Acutely, THC also appears to stimulate the sympathetic nervous system, which is responsible for the “fight or flight” response, resulting in a higher heart rate, a greater demand for oxygen by the heart, higher blood pressure while laying down, and dysfunction within the walls of the arteries. In contrast, studies on CBD, which does not produce a “high” or intoxication, have found associations with reduced heart rate, lower blood pressure, increased vasodilation (ability of the arteries to open), and potentially reduced inflammation.²

As for the association of marijuana with stroke or TIA, per Dr. Hugo Aparicio, there are mixed results, and most of the studies were observational, cross-sectional, case reports and case series. Adverse effects of marijuana in cerebrovascular disease include sympathetic nervous system activation, blood pressure changes, platelet activation, and electrophysiological effects. CBD, though in the first hour of usage leads to lowering of blood pressure, can also lead to higher blood pressure among heavy users. However, this association has not shown statistical significance upon adjustment with other substance abuse, such as tobacco and binge alcohol use. Findings from case-control or population-based studies on association of marijuana and cerebrovascular disease have been equivocal, mainly due to different variables being considered and other confounding factors causing strokes or TIA among marijuana users vs. non-users, which are difficult to control within human studies. In contrast, it is more feasible to control the exact timing and amount of marijuana exposure, as well as the social and environmental condition, in animal studies. Because of theoretical vasoactive effects of cannabis, its use has been implicated in reversible cerebral vasoconstriction syndrome, as well as delayed cerebral ischemia in subarachnoid hemorrhage (SAH), per Dr. Aparicio. Both vasoconstrictive and vasodilatory properties of cannabis were exerted through CB1 receptor, by promoting inflammation, upregulating the production of reactive oxygen species, and activating proapoptotic pathways in endothelial cells and cardiomyocytes.³

To fully understand the potential impact of marijuana, it is important to know that the human body naturally produces compounds called endocannabinoids that are similar to those in marijuana. Endocannabinoids are involved in learning, memory, pain control, and sleep. The action of endocannabinoids is essential to prenatal brain development and to brain maturation during adolescence. Endocannabinoids, as well as THC, can attach to neurons in the brain through molecules called cannabinoid receptors. When THC activates cannabinoid receptors in the brain, it can disrupt the normal actions of endocannabinoids. Prolonged exposure to THC disrupts memory and learning, and impacts brain development and maturation in specific ways if exposed at certain stages of life. Active substances in marijuana, such as THC, affect many areas in the brain, such as the hypothalamus, basal ganglia, ventral striatum, amygdala, neocortex, hippocampus, cerebellum, brainstem, and spinal cord. It also affects parts of the brain that regulate movement, coordination, learning and memory, judgement, and pleasure, per Dr. Francesca Filbey.

Data obtained in animal studies demonstrate that disruption of endocannabinoid pathways leads to behavioral and cognitive abnormalities, such as poorer memory and learning ability and a heightened sensitivity to stress. Also, there may be vital life periods — gestation and adolescence — when the brain may be particularly vulnerable to the impact of THC. Based on a recent meta-analysis, global neurocognition was worse among the marijuana users, which includes decision making, verbal learning and retention. Two large longitudinal twin studies showed deficits in terms of learning, abstraction, processing speed, delayed memory, inhibition, working memory, and attention.

Findings from sMRI (structural MRI) studies showed that smaller hippocampal and orbitofrontal cortex volume was associated with cannabis use. However, two large twin studies from the U.S. and Australia did not show association between cannabis use and volume of thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and nucleus accumbens. This is to show that the effect of cannabis on cognition may be domain-specific. Neuroimaging studies have shown structural changes in cannabis users; however, the results are inconsistent. Effects of marijuana on cognition are complicated since it depends on several factors. For example, a prospective study on medical marijuana patients showed that it improved executive function and stable verbal learning and memory over time; however, the study was also confounded by improvements in mood, anxiety, and sleep.

In the last segment of the discussion, Dr. Miriam Melis talked about the physiologic and molecular mechanisms linking marijuana use to cognitive impairment. She described both the acute and chronic effect of cannabis, which can decrease both working and episodic memory, as well as reduce plasticity in the prefrontal cortex and hippocampus. Chronic cannabis exposure induces a profound decrease in the number of CB1 receptors used in cognitive and memory function, hence causing long-term depression and depolarization-induced excitation contributing to cognitive impairment.

In summary, our understanding of the ramifications of cannabis on brain health is limited but rapidly evolving; hence, research trials on humans in this area are still “a work in progress.” However, the results of recent animal studies have shown harmful effects of marijuana on developing brains, which was further supported by molecular studies. The challenges that need to be addressed in translating the animal studies to human studies in this area include addressing the other lifestyle and/or vascular risk factors affecting brain health, heterogeneous effects of compounds within marijuana, and diverse pharmacodynamic and pharmacokinetics of marijuana in human bodies. Lastly, controlling human subjects with the same strict parameters as animal models is just impossible.

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