Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Toxicity/Substance Abuse
Introduction
Stroke is the second leading cause of mortality and most common cause of disability worldwide. About 30% of stroke survivors are permanently disabled, and 20% require institutionalized care. In 2002, the cost of stroke was estimated at $49.4 billion . Although stroke in adults younger than 55 years comprises only 10% of stroke, it remains a significant source of morbidity and mortality . At a younger age, stroke is also associated with higher societal costs compared to older age groups . In 2009, a national health survey reported an estimated 2.2 million people in the United States used illicit drugs. About 17,000 deaths were related to drug use in 2000, and over 1 million emergency department visits were attributed to drugs in 2007 . The major causes of death related to drug use are acquired immune deficiency syndrome (AIDS), overdose, suicide, and accidents. However, cerebrovascular complications also pose a threat and remain a significant source of morbidity and mortality. Illicit drug use remains the most common predisposing factor for stroke in patients under 35 years, and those of age 15–44 years are 6.5 times more likely to suffer a stroke as compared to nondrug users . Epidemiological data remain scarce with a need for more population-based studies assessing the link between drug use and ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) .
Sloan and colleagues reported that 12.1% of 422 patients aged 15–44 years had recent drug use in the setting of acute ischemic stroke, and in 4.7%, drug use was the most likely cause of stroke . In 2007, Westover et al. reported that drug use was associated with 14.4% of ICH and 14.4% of ischemic stroke in 1935 patients . The most commonly associated drugs with stroke are cocaine, amphetamines, ecstasy, heroin, phencyclidine (PCP), lysergic acid diethylamide (LSD), cannabis, tobacco, and ethanol.
Cannabis
Marijuana is the most widely used illicit drug in the United States. Cannabis is consumed by about 181 million people worldwide, with 13.1 million dependent on it. About 7 million people in the United States use cannabis weekly . Its use in older adults (50+ years) is expected to rise , but is greatest among adults aged 18–25 years . In the United States, young adults aged 18–25 years who used cannabis rose from an incidence of 5.8% in 1965 to 50% in 2002.
The desired nonpermanent effects of cannabis are euphoria, self-confidence, and relaxation which start within minutes of use and last 2–3 h . Adverse effects of cannabis include red eyes, possible weight loss, thunderclap headache, psychiatric symptoms, memory alterations, motor incoordination, poor executive functioning, sedation, and cardio- and cerebrovascular effects. Because of the widespread use of cannabis, it is difficult to establish a causal relationship .
Cannabinoids (CBs) consist of a wide group of compounds with various affinities to G-protein-coupled membrane-bound receptors classified according to their source. CB receptors are located in the brain, spleen, blood vessels, cells of the immune system, and heart . Three of the major classes include the endogenous form, the phytocannabinoids derived from cannabis and include delta-9-tetrahydrocannabinol (delta-9-THC), cannabidiol (CBD), and cannabinol (CBN), and the synthetic CBs manufactured artificially in the laboratory .
Benefits of Cannabis
The CBs hold much promise in not only improving stroke but also traumatic and anoxic brain injury outcome. There is a rise in evidence that the endocannabinoids and botanical nonpsychoactive cannabidiol derivatives from the cannabis plant have a multitude of beneficial effects, particularly with ischemic stroke. Animal models of stroke have shown cannabidiol increases cerebral blood flow (CBF) mediated by 5-hydroxytryptamine (serotonin) receptor 1A (5HT1A) receptors and induces vasorelaxation .
A major goal of acute stroke care entails salvaging the penumbra and extra-penumbral regions of brain by preventing further growth of the infarct zone. Necrosis and apoptosis within the stroke core lead to free radical formation, glutamate release, and an inflammatory cascade leading to accumulation of intracellular calcium and cell death . Endocannabinoids accumulate in ischemic tissue with CB 1 receptor (CB1 receptor) activation resulting in neuroprotective mechanisms including inhibition of glutamate release, decrease in intracellular calcium, hypothermia, decreased reactive oxygen species, and expression of brain-derived neurotrophic factor (BDNF). CB 2 receptor (CB2 receptor) activation leads to a decrease of leukocyte adhesion and cytokine release .
Synthetic CB1/CB2 receptor agonists are associated with a reduction of infarct size and hypothermia in animal models. CB1 receptor antagonists, however, have also shown a reduction of infarct size. The conflicting results prove the complexity of the ECS; others hypothesize that the CB receptor inhibitors may be targeting nonCB receptors but still producing neuroprotective effects. Studies are also investigating modulation of CB1/CB2 receptor activation with promising results on reducing infarct size with stimulation of CB2 and inhibition of CB1 . CB may also play a beneficial role in post-stroke rehabilitation with studies reporting CB1 and CB2 receptor expression in neural stem and progenitor cells .
Cons of Cannabis
Delta-9-THC is the main active ingredient in cannabis and most often implicated in depression, psychosis, and anxiety . Delta-9-THC is a psychoactive substance with vasoconstrictor effects. It has been associated with arteriopathies of small muscular arteries of the legs, coronary arteries, and cerebral circulation based on angiographic studies. A study by Ntholang and collaborators was the first study demonstrating histological evidence of hyperplastic tunica intima with associated luminal stenosis of cerebral arteries in young cannabis users .
Despite the known underreporting, the rate of cannabis-related cardiovascular complications, including peripheral, cerebral, and cardiac, has steadily risen over the past 5 years, with acute coronary syndromes and peripheral arteriopathies comprising the majority of complications . Cannabis is associated with arterial disease resulting in stroke with a high rate of occurrence in the posterior circulation, myocardial infarction (MI), and limb arteritis. An incidence of 2–39% of cannabis-associated stroke has been reported . The temporal relationship between symptom onset and resolution with starting and stopping cannabis, respectively, suggests cannabis is a trigger of these arterial disorders (Matteo).
Cannabis-related ischemic strokes are limited to case reports and population-based studies. Cannabis-related hemorrhagic stroke is also limited to few case reports. Pathogenesis of hemorrhagic stroke may be related to transient cannabis-induced hypertension with altered autoregulation. Most reported cases of cannabis-related ischemic stroke are seen in patients younger than 50 years of age without traditional vascular risk factors . Concomitant alcohol use and tobacco use have been suggested as risk factors. The pathogenesis of cannabis-related ischemic stroke is thought to be due to altered cerebral autoregulation and regional hypoperfusion, or an acute inflammatory cascade with thrombosis. It remains uncertain if platelet activation is involved in the pathogenesis of THC-triggered procoagulant properties. In vivo studies are necessary to evaluate the role on THC-platelet activation leading to a procoagulant effect .
Other mechanisms include arterial hypotension, cardioembolism, vasospasm, vasculitis, or reversible cerebral vasoconstriction syndrome (RCVS) . Chronic cannabis is associated with increased cerebrovascular resistance . Because delta-9-THC increases CBF, transcranial Doppler (TCD) was studied in marijuana users assessing blood flow velocity in the anterior and middle cerebral arteries (ACAs and MCAs, respectively) in control groups and participants using marijuana in different intensities. Blood flow velocity was also measured for 30 days of marijuana abstinence . The pulsatile index, which is a measure of cerebrovascular resistance, and systolic velocity were elevated in marijuana users compared to control groups and persisted despite abstinence. This increase in cerebrovascular resistance may account for strokes as well as cognitive deficits seen in chronic marijuana users .
Laced marijuana poses a serious danger, increasing risk of stroke in users. Marijuana can be laced with cocaine, crack (also called bazooka), PCP, heroin, and even embalming fluid . Although reports are infrequent, unregulated marijuana can easily be adulterated by dealers but most often occurs at the user level. Powdered cocaine or crack is sprinkled into a joint or blunt in order to combine the stimulant effects of cocaine with the depressant effects of marijuana. A joint can also be immersed in formaldehyde (a known carcinogen), mimicking the effects of PCP in which the user develops hallucinations, euphoria, panic, or rage. Laced marijuana undoubtedly poses cardio- and cerebrovascular complications and should be avoided .
Amphetamines
Amphetamines have been used medically since the early 20th century and long been used to treat children and adolescents for attention deficit hyperactivity disorder (ADHD). Amphetamines are now increasingly prescribed to adults for maintenance therapy of ADHD and narcolepsy but remain the most commonly abused prescription drugs. In 2000, prescription amphetamines exceeded 8 million. The pharmacokinetics of amphetamines differ among children and adults, posing a cardiovascular risk in adults with prolonged amphetamine use .
Amphetamines produce their effect by increasing the synaptic levels of dopamine, biogenic amines, norepinephrine, and serotonin. They also disrupt vesicular storage of dopamine and inhibit its degradative enzymes (monoamine oxidases, MAO-A and MAO-B), promoting dopamine accumulation within the cytoplasm. The behavioral effects are mediated through dopamine modulation . Amphetamines exist as two stereoisomers, the l -enantiomer (levoamphetamine) that produces more cardiovascular and peripheral effects as compared to the d -enantiomer (dextroamphetamine). Pharmaceutical amphetamines are either d -amphetamine or a mixture of the d - and l -amphetamine salts . The most potent and most often abused amphetamine is methamphetamine (meth) which undergoes hepatic metabolism and has an active metabolite that functions as a hallucinogen. Users experience euphoria, increased motor movements, decreased appetite, and increased libido. Adverse effects include bad halitosis, nervousness, convulsions, irritability, paranoia, hypertension, coma, and death. Addiction and tolerance with chronic use are inevitable .
The effects of prolonged amphetamine use have not been explored and warrant further research. They are generally considered to have a safe drug profile, but studies reported during late 2010s and early 2010s have raised concern of their safety with reports of associated sudden death, MI, SAH, and ischemic and hemorrhagic stroke, especially in a younger population . Amphetamines have also been associated with multiorgan injury including cardiomyopathy, renal and liver failure, respiratory compromise, memory changes, and psychiatric manifestations .
Amphetamines and ICH/SAH
ICH is a more common adverse effect than ischemic stroke after sympathomimetic use . The association between amphetamines and ischemic or hemorrhagic stroke is based solely on case series . Most epidemiological studies assessing this association have been conducted in underserved settings or largely based on the minority population, but small case–control studies have demonstrated a strong risk factor of stroke in the insured, urban populations with amphetamine use . Most case series report that the risk of hemorrhagic stroke due to amphetamines is twice that of cocaine use . Amphetamines and other related sympathomimetic drugs can result in ICH within minutes to hours after exposure. The acute rise of blood pressure leading to ICH has been observed even after first time use of amphetamines. Transient arterial hypertension after drug exposure is thought to cause ICH in locations typical of a hypertensive hemorrhage including the basal ganglia, thalamus, pons, and subcortical white matter. Hypertension induced by amphetamine use is also thought to contribute to aneurysm formation with resulting SAH . Some studies have refuted this demonstrating that in patients presenting with amphetamine-related SAH, autopsy failed to show aneurysm or arteriovenous malformations . Although rare, methamphetamines and synthetic cannabis have also been associated with spinal SAH due to ruptured thoracic radicular artery pseudoaneurysm rupture in a single case report .
Other mechanisms of ICH include altered cerebrovascular autoregulation, coagulopathy, vasculitis, and hemorrhagic transformation of ischemic stroke . Cerebral vasoconstriction has been reported with cocaine, amphetamine, ephedrine, phenylephrine, LSD, and heroin, but it is difficult to distinguish between vasospasm and vasculitis. It is suspected that as vasospasm resolves and perfusion is restored, arterial rupture can occur .
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here