Oh, we can get a good title out of this if we blame cannabis for the stroke rather than the much more likely reason of smoking and unstable plaque.
Shattering the Carotids
A 22-year-old right-handed gentleman, previously healthy, worker for a company involved in cutting trees, presented to our hospital with a transient episode of word finding difficulty lasting for 10 to 15 minutes, in March 2019. He had a background history of multiple episodes of right-sided numbness lasting for 15 to 20 minutes for 1 to 2 years before this presentation. These episodes were not associated with involuntary jerking of limbs, facial twitching, or headaches. He considered these episodes as benign and had never sought any medical help. There was a significant history of smoking along with a family history of stroke in mother at the age of 19 years. He denied any history of trauma or recent chiropractic neck manipulation.
His general physical and systemic examination at presentation was unremarkable. Computerized tomography (CT) brain was negative for acute ischemia, CT angiogram of the head and neck showed evidence of left internal carotid artery occlusion and a significantly narrowed right internal carotid artery with near total occlusion (Figure 1A and 1B). His magnetic resonance imaging showed left middle cerebral artery territory infarcts (Figure 1C and 1D). The magnetic resonance angiogram for carotid arteries done subsequently showed evidence of a completely occluded left internal carotid artery at the level of high carotid bulb with irregular right internal carotid artery with focal narrowing most pronounced proximal to the skull base. The findings appeared to have evolved in comparison to the CT angiogram with the clinical possibility of a dissection.
Figure 1. Computed tomography angiogram and magnetic resonance imaging (MRI) demonstrating the site of occlusion and infarcts.A, Left internal carotid artery (ICA) occlusion. B, Significantly narrowed right ICA with near total occlusion at its cephalad end. C, MRI-diffusion weighted imaging showing left middle cerebral artery infarcts. D, MRI-apparent diffusion coefficient showing left middle cerebral artery infarcts.
He was started on dual antiplatelets and was thoroughly investigated. His blood investigations and transthoracic echocardiogram were unremarkable except for a mildly increased fasting blood glucose of 6.7 mmol/L. Secondary workup for vasculopathy and young stroke including thrombophilia profile, C-reactive protein, screening for sickle cell anemia, anticardiolipin and beta-2 glycoprotein antibodies, lupus anticoagulant, anti-dsDNA, ANA, complement levels, p-ANCA, c-ANCA, Anti-SA/SSB, and anti-HIV antibodies was negative. He was seen by the department of genetics in regard to ruling out the possibility of any genetic causes for collagen vascular disease or Marfan syndrome but no abnormality was detected.
On follow-up visits, he gave the history of smoking 15 to 20 joints of marijuana per day in the form of shatter, for the last several years and had quit smoking recently. He promised to decrease the use of shatter after the episode in March 2019. After 6 months of this event, he was again seen in the clinic. The patient had a repeat CT angiogram of the head and neck, previously documented left internal carotid artery occlusion had completely recanalized, focal or high-grade stenosis seen in the right internal carotid artery at the skull base could not be appreciated (Figure 2A and 2B). There was no evidence of an acute intracranial abnormality.
Figure 2. Repeat imaging findings for the patient. Computed tomography (CT) angiogram (A and B) showing complete recanalization of the left internal carotid artery (ICA) occlusion and absence of focal or high-grade stenosis seen in the right ICA, (C and D) CT angiogram showing complete occlusion of the left internal carotid artery starting several centimeters rostral to the bifurcation.
He returned to the hospital in February 2020 with repeat symptoms of right-sided weakness and numbness in the right arm along with word finding difficulties. Symptoms gradually resolved during the hospital stay and neurological examination was unremarkable. He confessed reusing shatter again since September, 2019. A CT scan of the brain did not indicate any new pathology. CT angiogram indicated complete occlusion of the left internal carotid artery starting several centimeters rostral to the bifurcation, which was new from the previous imaging (Figure 2C and 2D).
Discussion
Shatter is one of the newer forms of cannabis extracts, which in itself is brittle and glass-like, snaps easily, and is hence easier to use while dabbing or inhaling. Cannabis or marijuana is one of the most prevalent recreational substances used globally and more so in the developed nations. Clinical implications and the knowledge of the cannabinoid system along with its associations with stroke should be kept in mind while evaluating patients in day-to-day practice.
Cannabinoid System
Chemical derived from cannabis plants (Cannabis sativa, Cannabis ruderalis, and Cannabis indica) are called cannabinoids and mainly belong to 3 classes—phytocannabinoids, synthetic cannabinoids, and endocannabinoids. Δ9 Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the 2 most extensively studied phytocannabinoids. The discovery of these phytocannabinoids further paved the way for research on cannabinoid receptors—CB1-present mostly in the central nervous system and CB2-found in peripheral nervous and immune systems.1 These are primarily G-protein coupled and act by inhibiting cAMP (CAMP) through intracellular signaling.2 THC acts through CB1 receptors affecting mood, cognition, and psychomotor performance whereas CBD exerts its anti-inflammatory analgesic effects via the CB2 receptors.3
THC and CBD share a similar chemical structure, but they have differing effects on the blood vessels. Whereas THC acts by increasing the expression of GpIIb/IIIa and P selectin leading to increased platelet aggregation and ischemic stroke, CBD on the other hand mitigates the effect of THC via its action on serotonergic pathway.4 As mentioned previously, THC acts by binding to CB1 receptor producing vasoconstriction or relaxation, which varies according to the vascular bed involved (central versus peripheral vasculature) and its inherent properties. Furthermore, the literature about the differing vascular effects of cannabinoids is still evolving with the possible existence of uncloned receptors in the blood vessels and hence it is hard to characterize their vascular effects individually. Limited human and animal studies continue to highlight several gaps in our knowledge about the understanding of the cannabinoid compounds.
Synthetic derivatives of THC often contain its active ingredient, Dronabinol, and are used for managing anorexia and chemotherapy associated hyperemesis. Also, Epidiolex, a purified CBD has found its application in management of epilepsy.5
Cannabis and Stroke
There is evidence to suggest increasing cannabis use and its association with the risk of stroke, more so since its use has been legalized in several nations across the globe. Recent review by Wolff et al described several characteristics of stroke related to cannabinoid use. They pointed out that cannabis associated stroke was mostly ischemic, more common in young males and had a predilection for the anterior circulation.5
Reversible cerebral vasoconstriction remains an important mechanism of stroke in these patients, along with labile blood pressure, cardio embolism, vasculopathy, and increased oxidative stress (Figure 3).5,6 However, only a handful of studies have looked at the effects of cannabis on the extracranial vessels especially the carotid and vertebral circulation. These vessels are prone to dissections, which is a common cause of young stroke and at times it is difficult to differentiate this from cannabis associated vasospasm. Lately, there have been few reports similar to our case presenting with vasospasm of extracranial carotid arteries, which is unique and important to recognize in the clinical setting.7,8 Although the mechanism for the latter still remains unclear, potential clues to its identification are bilateral causation, temporal association with cannabis use, lack of history of trauma or neck pain and reversibility of imaging findings. It is of utmost importance to have a high index of suspicion and repeatedly ask for illicit drug abuse in all patients presenting with young stroke. Impaired cerebral autoregulation, coronary artery and intracranial vasospasm along with sympathomimetic effects are some of the key features associated with long-term marijuana use. Furthermore, a prospective cohort study of 48 patients has also highlighted the association of multifocal angiopathy with cannabis consumption in young patients.9
Figure 3. Mechanisms of cannabis-associated stroke.
Another aspect of stroke associated with cannabis abuse would be the underlying genetic predisposition in certain individuals, which make them prone to the harmful effects of the latter. This was further potentiated by Freeman et al10 who reported ischemic strokes in 2 young siblings after marijuana use. This might be one of the reasons for under reported neurovascular complications of marijuana use in spite of its widespread use.
To strength the diagnosis of stroke in association with cannabis use, a urine screen for metabolites might be helpful; however, it should be kept in mind that urine screening for synthetic cannabinoids is not routinely performed with the toxicology screen and it would be worthwhile to order screening for synthetic variants of cannabis in young patients presenting with acute stroke with a normal routine workup.
It is also important to keep in mind that an important limitation of studying cannabis associated stroke is the lack of large case series or clinical trials. Most of the available information comes from animal studies or small case studies and the association could be mediated by unmeasured confounders like recreational substances including cocaine, amphetamines, nicotine (tobacco), and alcohol.
Take-Home Points
Cannabis concentrates like shatter and synthetic cannabinoids are associated with strokes and a high index of suspicion should be present when evaluating young patients presenting with ischemic strokes.
Extracranial reversible vasospasm may be associated with cannabis abuse and should be kept in differential diagnosis of arterial dissections.
Bilateral occurrence, temporal association with cannabis use, lack of history suggesting trauma, and reversibility of imaging findings are the key features favoring cannabis abuse over dissections.
Urine screen with special screening of synthetic cannabinoids must be ordered when the conventional workup for young stroke is unremarkable.
Sources of Funding
None.
Disclosures None.
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