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The Link Between Marijuana Use and Higher Risk of Cardiovascular Disease

Abstract

Cannabis, or marijuana, has potential therapeutic and medicinal properties related to multiple compounds, particularly Δ-9-tetrahydrocannabinol and cannabidiol. Over the past 25 years, attitudes toward cannabis have evolved rapidly, with expanding legalization of medical and recreational use at the state level in the United States and recreational use nationally in Canada and Uruguay. As a result, the consumption of cannabis products is increasing considerably, particularly among youth. Our understanding of the safety and efficacy of cannabis has been limited by decades of worldwide illegality and continues to be limited in the United States by the ongoing classification of cannabis as a Schedule 1 controlled substance. These shifts in cannabis use require clinicians to understand conflicting laws, health implications, and therapeutic possibilities. Cannabis may have therapeutic benefits, but few are cardiovascular in na

ture. Conversely, many of the concerning health implications of cannabis include cardiovascular diseases, although they may be mediated by mechanisms of delivery. This statement critically reviews the use of medicinal and recreational cannabis from a clinical but also a policy and public health perspective by evaluating its safety and efficacy profile, particularly in relationship to cardiovascular health.


Table 2. Known, Purported, and Possible Medical Benefits Associated With Cannabis Use


Known (conclusive or substantial evidence)

 Pain

Improvements in neuropathic pain with smoked cannabis, dronabinol, and cannabis-based medicine vs placebo.

Improvements in fibromyalgia pain with nabilone vs placebo.

The limited available clinical evidence with certain cannabinoids (dronabinol) suggests a modest analgesic effect of dronabinol on cancer pain.

 Cachexia

The anorexia/cachexia syndrome is the result of weight loss (caused by changes in taste, lack of hunger) and increased energy metabolism; cannabis use has been associated with an increase in appetite and weight gain, leading to examination of its therapeutic effect on cancer and HIV-associated anorexia/cachexia.

Results from systematic review indicate low efficacy for the use of cannabis for enhancing appetite and weight gain in HIV and cancer.

 Nausea and vomiting

Results from a systematic review indicate that in the setting of chemotherapy-induced nausea and vomiting, oral cannabinoids (nabilone and dronabinol) are effective antiemetics.

Long-term (≈6–7 y) daily and weekly cannabis use has been associated with hyperemesis (ie, cannabis hyperemesis syndrome). Mechanisms may include downregulation of CB1 receptors and a decrease in gastric emptying.

 Multiple sclerosis spasticity

Improvements in central pain with cannabis-based medicine and dronabinol vs placebo.

Reductions in spasticity with cannabis-based medicines vs placebo.

 Epilepsy (Dravet syndrome and Lennox-Gastaut syndrome

Improvements in monthly motor seizures in an open-label, multicenter expanded-access program in subjects with severe childhood-onset, drug-resistant epilepsy.

Double-blind, placebo-controlled RCT showed significant reduction in the frequency of convulsive seizures in the CBD group vs placebo in pediatric and young adult subjects with treatment-resistant Dravet syndrome.

Double-blind, placebo-controlled RCT showed a significant reduction in the frequency of drop seizures in pediatric and adult subjects with treatment-resistant Lennox-Gastaut syndrome randomized to CBD as add-on therapy vs placebo.

Meta-analysis of observational clinical studies on the treatment of refractory epilepsy with reported improvement in the frequency of seizures in subjects treated with CBD-rich extracts and purified CBD.

Possible (moderate evidence)

 Reduction in long-term use of opioids and opiate withdrawal

Although preclinical and case studies suggest an opioid-sparing effect of certain cannabinoids, epidemiological and clinical studies with oral THC are mixed.

Observational studies suggest an association between US states with laws permitting access to cannabis (for medical and nonmedical purposes) and lowered rates of prescribed opioids and opioid-associated mortality.

Evidence from observational studies suggests that cannabis use could help alleviate opioid withdrawal symptoms, but there is insufficient clinical evidence from which to draw any reliable conclusions.

 Dystonia

Evidence from limited preclinical studies suggests that a synthetic CB1 and CB2 receptor agonist may alleviate dystonia-like symptoms and that CBD delays dystonia progression.

Evidence from a limited number of case studies and small placebo-controlled or open-label clinical trials suggests improvement in symptoms of dystonia with inhaled cannabis, mixed effects of oral THC, improvement in symptoms of dystonia with oral CBD, and lack of effect of nabilone on symptoms of dystonia.

 Glaucoma

Limited evidence from small clinical studies suggests that oral administration of THC reduces intraocular pressure and that oral administration of CBD may, in contrast, cause an increase in intraocular pressure.

The American Glaucoma Society does not recommend.

Inconclusive evidence (no RCTs)

 Alzheimer disease

Preclinical studies suggest that THC and CBD may protect against excitotoxicity, oxidative stress, and inflammation in animal models of Alzheimer disease.

Limited case, clinical, and observational studies suggest that oral THC and nabilone are associated with improvement in a number of symptoms associated with Alzheimer disease (eg, nocturnal motor activity, disturbed behavior, sleep, agitation, and restiveness).

 Anxiety and depression

A systematic review and meta-analysis of patient-reported medical cannabis use indicated that ≈50% of patients report anxiety as a reason for using medical cannabis and 35% report depression as the reason.

Small studies with adjunct functional neuroimaging in healthy individuals have demonstrated that CBD and dronabinol reduce anxiety related to its effects on activity in limbic and paralimbic brain areas.

In data from a nationally representative sample of US adults (age ≥18 y), cannabis use (ie, some use but less than once per month over the last 12 mo) was not significantly associated with the new occurrence of social anxiety disorder. However, more frequent use (≥1 times per month) was associated with significantly increased odds of incident social anxiety disorder.

 Antitumor effect

Preclinical studies suggest that certain cannabinoids (THC, CBD, CBG, CBC) often, but not always, block the growth of cancer cells in vitro and display a variety of antineoplastic effects in vivo, but typically at very high doses that would not be seen clinically.

Although limited evidence from 1 observational study suggests that patients with cancer use cannabis to alleviate symptoms associated with cancer (eg, chemosensory alterations, weight loss, depression, pain), there has been only 1 limited clinical study in patients with glioblastoma multiforme, which reported that intratumor injection of high doses of THC did not improve patient survival beyond that seen with conventional chemotherapeutic agents.

 Inflammatory bowel diseases (Crohn disease, ulcerative colitis)

Preclinical studies in animal models of inflammatory bowel disease suggest that certain cannabinoids (synthetic CB1 and CB2 receptor agonists, THC, CBD, CBG, CBC, whole-plant cannabis extract) may limit intestinal inflammation and disease severity to varying degrees.

A very limited number of small clinical studies of patients with inflammatory bowel disease who failed conventional treatments reported improvement in a number of inflammatory bowel disease–associated symptoms with smoked cannabis.

 Heart failure

In retrospective propensity-matched analysis of 161 000 patients with heart failure, cannabis use was associated with a lower risk for death while the patient was hospitalized with acute heart failure (OR, 0.197 [95% CI, 0.046–0.833]), shorter mean hospital stay (4.2 vs 4.8 d, respectively; P=0.004), and lower mean hospital costs ($43,800 vs $50,900, respectively; P=0.039) compared with nonusers. However, these data are retrospective and observational and have not been peer reviewed.

 Hepatitis C

Preclinical studies suggest that CB1 receptor activation is detrimental in liver diseases (eg, promotes steatosis, fibrosis), whereas CB2 receptor activation appears to have some beneficial effects.

In patients with ongoing chronic hepatitis C, daily cannabis use has been shown to be a predictor of steatosis severity.

Survey and case reports suggest improvement in symptoms of nausea and reduced weight loss.

 Ischemia/reperfusion injury

Preclinical studies suggest that CBD, THCV, and ultralow doses of THC may have some protective effects against ischemia/reperfusion injury related to the anti-inflammatory properties mediated by the CB2 receptor.

 Huntington disease

Preclinical studies report mixed results with THC on Huntington disease–like symptoms.

Limited evidence from case studies and small clinical trials is mixed and suggests a lack of effect with CBD and a limited improvement in Huntington disease symptoms with smoked cannabis.

 Metabolic syndrome, obesity, diabetes mellitus

Preclinical studies suggest that acute CB1 receptor activation results in increased fat synthesis and storage, whereas chronic CB1 receptor activation (or CB1 receptor antagonism) results in weight loss and improvement in a variety of metabolic indicators.

Observational studies suggest an association between long-term cannabis use and an improved metabolic profile, and preclinical and very limited clinical evidence suggests a potential beneficial effect of THCV on glycemic control (in patients with type 2 diabetes mellitus).

 Parkinson disease

Limited preclinical, case, clinical, and observational studies of certain cannabinoids for symptoms of Parkinson disease are mixed.

One observational study suggests improvement in symptoms with smoked cannabis; another clinical study of an oral cannabis extract (THC/CBD) and a clinical study of CBD suggest no improvement in symptoms.

 Sleep

Human experimental data suggest that cannabis and THC have a dose-dependent effect on sleep: Low doses appear to decrease sleep-onset latency and increase slow-wave sleep and total sleep time, whereas high doses appear to cause sleep disturbances.

Clinical studies suggest that cannabis, nabilone, and dronabinol may improve sleep in patients with disturbances in sleep associated with certain chronic disease states.

CB indicates cannabinoid; CB1, cannabinoid receptor subtype 1; CB2, cannabinoid receptor subtype 2; CBC, cannabichromene; CBD, cannabidiol; CBG, cannabigerol; OR, odds ratio; RCT, randomized controlled trial; THC, Δ-9-tetrahydrocannabinol; and THCV, tetrahydrocannabivarin.

Data derived from Health Canada,5 National Academies of Sciences, Engineering, and Medicine,12 Volko et al,13 Segura et al,17 and Wu et al.18

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