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Cannabis Use Is Associated with Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

Article In Brief

A retrospective, single-center study identified an association between cannabis use and cerebral ischemia in patients who have experienced a subarachnoid hemorrhage. While the pathophysiology of this association is still unknown, researchers agree that more studies are warranted as the popularity of cannabis increases in the US.

Cannabis use appears to be associated with cerebral ischemia in patients who have experienced a subarachnoid hemorrhage, according to a research letter published online on January 5 in Stroke.

The letter reported the findings of a retrospective single-site study of more than 1,000 patients hospitalized for ruptured aneurysm.

“This study identified a significant relationship between cannabis use and the development of strokes after aneurysm rupture,” said lead author Michael Lawton, MD, president and CEO of Barrow Neurological Institute and the chair of the department of neurosurgery. “It is one of the first, and the largest study to report this finding.”

The finding confirms an earlier, smaller study published in Stroke in 2016 by Reza Behrouz, MD, and colleagues that also found an association between delayed cerebral ischemia (DCI) after subarachnoid aneurysm among cannabis users.

In the new Stroke report, the authors reviewed records for all patients who underwent endovascular or microsurgical treatment at Barrow Neurological Institute for aneurysmal subarachnoid hemorrhage (aSAH) from August 1, 2007, to July 31, 2019.

The primary exposure of interest was cannabis use. All patients underwent urine toxicology screening for the major metabolite of THC, tetrahydrocannabinol carboxylic acid, which indicates exposure within three days after a single use to approximately 30 days for chronic, heavy users. All patients were also screened for other vasoactive substances (cocaine, amphetamines, tobacco), which were adjusted for in the statistical analysis.

The primary outcomes that were analyzed included delayed cerebral ischemia (DCI), poor functional outcome as defined by a score of 2 or greater on the modified Rankin Scale, and mortality.

During the 12-year study period, 1,014 patients were hospitalized and treated for aSAH; 419 of them received an endovascular intervention and 595 were treated with microsurgery. The average age was 55.6 years; 703 (69.3 percent) of the 1,014 patients were female.

Forty-six patients (4.5 percent) were positive for cannabis exposure as determined by a urine toxicology report. The rate of DCI, poor functional outcome, and mortality among the 1,014 patients was 36.2 percent (n=367), 50.2 percent (n=509), and 13.5 percent (n=137), respectively.

The rate of DCI was significantly higher in patients with a urine drug screen positive for cannabis (52.2 percent versus 35.4 percent for those with no exposure). Cocaine, methamphetamine, and tobacco use were not associated with DCI. However, Hunt and Hess and Fisher grades, both well-known predictors of DCI, were significantly associated with DCI.

In a statistical analysis controlling for use of other substances, patients exposed to cannabis had a 2.7 times greater likelihood of DCI than those who were not exposed. In separate analyses of secondary outcomes, DCI was independently associated with poor functional outcomes and with mortality.

The pathophysiology of this association is unknown, but Dr. Lawton and colleagues said research suggests that multifocal intracranial stenosis, oxidative stress, and cerebral mitochondrial dysfunction are contributors. “The exact mechanism by which THC increases vulnerability to stroke may involve the mitochondrial respiratory functions, reactive oxygen species, and free radical metabolism,” he told Neurology Today. “THC may increase the amounts of these potentially harmful agents. In addition, THC may have a direct action on the arteries that stimulates vasospasm. These mechanisms warrant further research.”

The Stroke report found a higher rate of angiographic spasm in cannabis users—88.9 percent among users compared with 70.5 percent in nonusers—which supports vasospasm as a potential reason for increased DCI. “However, we cannot exclude the possibility that cannabis users have a lower threshold for DCI,” Dr. Lawton and colleagues wrote.

Dr. Lawton said the take-home message for neurologists is that there is a doubling of the risk of stroke after aneurysm rupture for patients using cannabis. “We have identified a previously unrecognized danger associated with cannabis use that users should consider when deciding whether to continue.”

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“We need to advocate with our senators and congressmen to move cannabis from its current schedule 1 DEA category to schedule 2 DEA category. This will open doors for the randomized controlled trials using cannabis in different disease processes so people can learn more about the ill effects of cannabis. People have a right to know about the benefits and adverse effects of cannabis so that they can make an informed decision before using it.”—DR. MANOJ K. MITTAL

Expert Commentary

Experts who reviewed the report for Neurology Today said the study is an important contribution to understanding the possible risks associated with a substance that has grown increasingly popular. The recreational use of cannabis is legalized in 18 states and the District of Columbia; another 13 states have decriminalized its use.

“This is an excellent study addressing an important and relevant clinical question,” said Manoj K. Mittal, MD, medical director of stroke and neurocritical care at Sutter Medical Center in Sacramento, CA. “The patient level data and inclusion of common predictors of DCI in aSAH patients is a strength. Weaknesses are the retrospective nature of the study, small sample size of cannabis users in the study, lack of data about the timing/dose of cannabis used prior to admission, and effect of other unknown and non-measured confounders.”

He said clinicians should be alerted to the risk of delayed cerebral ischemia in aneurysmal SAH patients admitted to a tertiary care center. “Cannabis use is common in society with a number of states approving it for recreational use,” Dr. Mittal told Neurology Today. “People believe that cannabis use has no adverse effect on our health. We should inform our patients that cannabis use is associated with higher likelihood of admission with subarachnoid hemorrhage and also with higher chance of brain ischemia after SAH.”

John W. Cole, MD, MS, associate professor of neurology at the Maryland Stroke Center, Baltimore VA Medical Center, and University of Maryland School of Medicine, agreed the study supports the risk of stroke in a subset of cannabis users who have had cerebral aneurysm.

Dr. Cole was senior author of a report in October 2021 in Stroke that showed no significant association with stroke among marijuana users. After adjusting for other risk factors, including the amount of current tobacco smoking, Dr. Cole and colleagues found that marijuana use was not associated with ischemic stroke, regardless of the timing of use in relationship to the stroke, including ever use, use within 30 days, and use within 24 hours. There was a nonsignificant trend towards increased stroke risk among those who smoked marijuana at least once a week.

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“It shows there is an increased risk of stroke associated with cannabis in this group of patients with aneurysm, but I suspect there may be underlying factors that increase the risk for certain individuals.”—DR. JOHN W. COLE

Dr. Cole emphasized the small sample size of cannabis users among the patients with aSAH as a weakness of the new study. He also cited the lack of a measured dose-response relationship. He said unmeasured confounders, including reversible cerebral vasoconstriction syndrome, could contribute to the risk for stroke among cannabis users. “It shows there is an increased risk of stroke associated with cannabis in this group of patients with aneurysm, but I suspect there may be underlying factors that increase the risk for certain individuals.”

Dr. Mittal said the results of the study call for advocacy in the face of increasing public perception that cannabis is without risks. “We need to advocate with our senators and congressmen to move cannabis from its current schedule 1 DEA category to schedule 2 DEA category,” he said. “This will open doors for the randomized controlled trials using cannabis in different disease processes so people can learn more about the ill effects of cannabis. People have a right to know about the benefits and adverse effects of cannabis so that they can make an informed decision before using it.”

Disclosures

Drs. Lawton, Mittal, and Cole had no disclosures.

Link Up for More Information

• Catapano JS, Rumalla K, Srinivasan VM, et al. Cannabis use and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage https://www.ahajournals.org/doi/10.1161/STROKEAHA.121.035650. Stroke 2022; Epub 2022 Jan 5.
    • Behrouz R, Birnbaum L, Grandhi R, et al. Cannabis use and outcomes in patients with aneurysmal subarachnoid hemorrhage https://www.ahajournals.org/doi/full/10.1161/STROKEAHA.116.013099. Stroke 2016;47:1371–1373.
    • Dutta T, Ryan KA, Thompson O, et al. Marijuana use and the risk of early ischemic stroke: The Stroke Prevention in Young Adults Study https://www.ahajournals.org/doi/10.1161/STROKEAHA.120.032811. Stroke 2021;52(10):3184–3190.