Many case reports support a causal link between cannabis and cerebrovascular events. This accords well with epidemiological and mechanistic research on the cerebrovascular effects of cannabis.

There were 34 case reports on 64 patients. Most cases (81%) exhibited a temporal relationship between cannabis exposure and the index event. In 70%, the evaluation was sufficiently comprehensive to exclude other sources for stroke. About a quarter (22%) of patients had another stroke after subsequent re-exposure to cannabis. Finally, half of patients (50%) had concomitant stroke risk factors, most commonly tobacco (34%) and alcohol (11%) consumption.

All case reports on cannabis and cerebrovascular events were retrieved. Four causality criteria were addressed: temporality, adequacy of stroke work-up, effects of rechallenge, and concomitant risk factors that could account for the cerebrovascular event.

An increasing number of case reports link cannabis consumption to cerebrovascular events. Yet these case reports have not been scrutinized using criteria for causal inference.

Introduction

Cannabis sativa is the most popular illicit drug consumed in Western societies. This is, in part, because of an assumption among users that cannabis is a safe recreational drug. Conversely, several experts think that cannabis is a risk factor for stroke and its use should be minimized.1 This perspective is largely premised on case reports linking cannabis exposure to stroke.

One concern is that these case reports have not been formally rated using causality criteria. In particular, the following questions have not been synthesized across the case reports: (1) Was there a temporal relationship between cannabis exposure and the stroke or transient ischemic attack? (2) Were other potential stroke causes excluded through a detailed stroke work-up? (3) Were additional risk factors present that could have explained the stroke (eg, coingested illicit substances)? (4) Was rechallenge with cannabis associated with recurrent stroke? These criteria are based on the Naranjo probability scale for inferring drug-associated causality for adverse events.2

Methods

This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The search combined keywords for cannabis and cerebrovascular disease and was executed in Medline and EMBASE from inception until November 30, 2014 (see Appendix in the online-only Data Supplement for the detailed search strategy). Conference abstracts were permitted. To be included, cases had to undergo parenchymal imaging.

A temporal relationship was defined as a stroke or transient ischemic attack ensuing within 24 hours of consumption of cannabis. A detailed stroke work-up entailed computed tomographic angiography, magnetic resonance angiography, or catheter angiography with parenchymal imaging; blood testing for thrombophilia and vasculitis; and cardiac work-up involving prolonged electrocardiographic monitoring and transthoracic or transesophageal echocardiography. All information for this review was collected from the published case reports themselves.

Results

A total of 989 citations were identified; after relevance screening, the full text of 56 articles were retrieved (Figure). Of these, 34 published case reports or case series were eligible, representing a total of 64 patients (Table; Table I in the online-only Data Supplement).3–36 Most cases were men (80%); the median age was 32 (range 15–64) years. The majority of infarctions occurred in the anterior circulation (56%); 3 cases involved both anterior and posterior circulations (5%); and the remainder either occurred in the posterior circulation (36%) or were not classified (3%).

Table. Case Reports With Causality Appraisal Report Year Published Age, y/Sex Territory of Infarct Temporality Other Causes of Stroke Excluded Concomitant Stroke Risk Factors Subsequent Re-exposure and Effect Alvaro et al3 2002 33/M Right PCA Yes Yes Acute coital cephalgia … Baharnoori et al4 2014 22/M Right lentiform nucleus and corona radiata Yes Yes None … Bal et al5 2009 22/M Bilateral cerebellum and left temporal lobe Yes Yes None … Barnes et al6 1992 30/M Left cerebellar hemisphere; left striatocapsular area Yes Yes Tobacco Stroke Drumm et al (1)7 2012 34/F Multiple arterial territories Yes Yes Unclear Stroke Drumm et al (2)7 2012 29/F Multiple arterial territories Yes Yes Unclear Stroke Drumm et al (3)7 2012 64/M Right MCA Yes Yes Unclear Stroke El Scheich et al8 2013 16/M Adjacent to the internal capsule at the lateral portion of the left thalamus Yes No Anabolic steroid … Finsterer et al9 2004 37/M Right occipital subcortex Yes Yes Tobacco, mild dyslipidemia … Giray et al10 2011 35/M Left MCA No No None … Haubrich et al11 2005 50/M Left parietal subcortex Yes Yes Hypertension, tobacco … Ibrir et al12 2014 34/M Left sylvian fissure No Yes Tobacco, alcohol … Inal et al13 2014 23/M Left temporal lobe No Yes Tobacco, alcohol … Lawson and Rees14 1996 22/M Right posterior external capsule, upper part of the internal capsule and corona radiata Yes No Tobacco, alcohol, LSD … Maguire et al15 2011 40/M Left dorsolateral frontal cortex No No Amphetamine, alcohol, diazepam, tobacco … Marinella16 2001 18/M Right occipital lobe Yes No Factor V Leiden … Mateo et al17 2005 36/M Left temporal and right parietal, left/right frontal, right posterior-temporal and lower parietal Yes Yes Alcohol Stroke x 2 McCarron and Thomas18 1997 29/M Right MCA No No Tobacco, alcohol … Mesec et al19 2001 23/M Left cerebral hemisphere Yes No Tobacco, alcohol … Mouzak et al (1)20 2000 18/M Leukoariosis Yes Yes Tobacco … Mouzak et al (2)20 2000 26/M Leukoariosis Yes Yes Tobacco … Mouzak et al(3)20 2000 30/M Leukoariosis Yes Yes None … Nouh et al21 2014 32/F Bilateral occipital infarcts Yes Yes Migraines … Oyinloye et al22 2014 26/M Left corpus striatum and insula cortex Yes Yes None … Pazderska et al23 2009 35/F Multiple arterial territories (especially right frontal lobe) No No Tobacco, cocaine Stroke x 2 Reece24 2009 56/M Parieto-occipital cortex No No Mild hypertension, tobacco … Renard and Gaillard25 2008 34/F Right temporal lobe hemorrhage Yes Yes Tobacco, buprenorphine … Renard et al26 2012 33/M Right MCA and bilateral ACA-MCA watershed zones No Yes Tobacco … Russmann et al27 2002 27/M Left MCA Yes No Chemotherapy, tobacco … Santos et al28 2014 27/M Left basal ganglia; right lenticulostriate area; right frontal and parietal (ACA and MCA) No Yes None Stroke x 2 Singh (1)29 2012 15/M Right cerebellum Yes Yes None specified … Singh et al (2)29 2012 16/M Bilateral cerebellum No Yes None specified … Singh et al (3)29 2012 17/M Left cerebellum Yes Yes None specified … Singh et al (4)29 2012 22/M Right cerebellum Yes Yes None specified Stroke Singh et al (5)29 2012 27/F Left MCA branch Yes Yes Tobacco … Singh et al (6)29 2012 28/F Right cerebellum Yes Yes None specified … Singh et al (7)29 2012 37/M Left MCA branch Yes Yes None specified … Singh et al (8)29 2012 44/M Bilateral cerebellum Yes No None specified Stroke Singh et al (9)29 2012 44/F Left MCA branch Yes No None specified … Singh et al (10)29 2012 49/M Right MCA branch Yes Yes None specified … Singh et al (11)29 2012 52/F Right MCA/ACA Yes No Hypertension, tobacco … Singh et al (12)29 2012 50/M Bilateral cerebellum Yes Yes Hypertension Stroke Singh et al (13)29 2012 56/M Right PCA and cerebellum Yes No PFO Stroke Singh et al (14)29 2012 58/M Left MCA branch Yes No Tobacco … Singh et al (15)29 2012 59/M Pons Yes No Hypertension, previous stroke … Singh et al (16)29 2012 61/M Left PCA Yes No Previous stroke Stroke Singh et al (17)29 2012 63/M Left MCA branch Yes No Hypertension, previous stroke … Smaoui et al30 2014 42/M Left frontal lobe Yes No None specified … Terceno et al31 2013 37/M Bilateral MCA and PCA infarctions No Yes Unclear … Termote et al32 2007 27/M Left mesencephalon Unclear Yes Alcohol, tobacco … Trojak et al33 2011 24/M Insular mantle, lenticular and caudate nuclear structures Yes Yes None … Tsivgoulis et al34 2014 42/M Left putamen Yes Yes None … Wolff et al (1)35 2011 21/M Vertebrobasilar Yes Yes Unclear … Wolff et al (2)35 2011 19/M Vertebrobasilar Yes Yes Unclear … Wolff et al (3)35 2011 24/F Vertebrobasilar Yes Yes Unclear … Wolff et al (4)35 2011 31/F Anterior circulation Yes Yes Unclear … Wolff et al (5)35 2011 37/M Vertebrobasilar Yes Yes Unclear … Wolff et al (6)35 2011 26/F Vertebrobasilar Yes Yes Unclear … Wolff et al (7)35 2011 31/M Anterior circulation Yes Yes Unclear … Wolff et al (8)35 2011 44/M Anterior circulation Yes Yes Unclear Stroke Wolff et al (9)35 2011 29/M Vertebrobasilar Yes Yes Unclear … Wolff et al (10)35 2011 21/F Vertebrobasilar Yes Yes Unclear … Zachariah (1)36 1991 34/M Right basal ganglia and frontoparietal Yes Yes Tobacco Worsened deficit Zachariah (2)36 1991 32/M Left basal ganglia and parietal lobe Yes Yes Tobacco …

Figure. Literature search and selection.

Most cases (81%) exhibited a temporal relationship between cannabis exposure and the index cardiovascular event. In 70% of cases, the evaluation was sufficiently comprehensive to exclude other sources of stroke. About a quarter of patients (22%) had recurrent stroke from subsequent re-exposure to cannabis. Half of patients (50%) had concomitant risk factors for stroke, most commonly tobacco (34%) and alcohol (11%). Three quarters of patients (48 of 64) underwent toxicological analysis for common street drugs; results were positive for drugs other than cannabis in only 2 cases (Table II in the online-only Data Supplement).

Discussion

This review suggests that the case reports linking cannabis with acute stroke are relatively robust, with high rates of temporality, exclusion of other causes of stroke, and substantial stroke recurrence in patients who resumed cannabis consumption during follow-up. In half, there were concomitant risk factors, such as tobacco and alcohol consumption. However, even if all criteria were met, only a prospective epidemiological study could prove a causal association.

Two epidemiological studies have studied this association. In a large study of hospital admissions in Texas, cannabis exposure was associated with ischemic stroke even after adjusting for alcohol and tobacco (adjusted odds ratio, 1.76; 95% confidence interval, 1.15–2.71).37 Second, in a prospective case–control study with adjustment for age, sex, and ethnicity, cannabis was associated with the composite of cerebrovascular events (odds ratio, 2.30; 95% confidence interval, 1.08–5.08).38 Yet after further adjustment for tobacco, the association was weakened (odds ratio, 1.59; 95% confidence interval, 0.71–3.70).

A recent French pharmacovigilance study of cannabis complications detected 3 cerebral complications among a pool of 35 cardiovascular-related cases of cannabis toxicity reported to a central network.39 The 3 cerebral complications were acute cerebral angiopathy, transient cortical blindness, and spasm of the cerebral artery. Although these 3 cases recovered, there was an overall mortality rate of 25.6% for cardiovascular complications related to cannabis.

Given broad exposure to cannabis in the general population, it is striking that more strokes do not occur among cannabis users. There may be modulation by dose, frequency, strength (% tetrahydrocannabinol), genetic susceptibility, and coingestants. It is possible that exposure is not mentioned by patients with stroke in emergency departments, or that such exposure is overlooked. Overall, however, it seems clear that physiological, clinical, and epidemiological data converge on an increased stroke risk from cannabis exposure. Heightened clinician awareness of this association, particularly in the treatment of young adults, is necessary for preventing recurrent events from future re-exposure to cannabis.

Disclosures None.

Footnotes