Illicit Drug Utilize and Stroke Risk: A Growing Concern

A comprehensive analysis of over 100 million participants reveals a significant link between the use of several illicit substances and an increased risk of stroke, with genetic evidence suggesting a causal relationship. This research highlights a critical public health issue as stroke rates continue to rise globally.

The Rising Global Stroke Risk

Stroke is now the third leading cause of death and disability worldwide, and its incidence is increasing.¹ Many stroke risk factors are modifiable, including substance misuse, which is likewise strongly associated with cardiovascular disease. Substance misuse, whether involving legal or illicit drugs, poses a major threat to public health due to its connection with numerous adverse health outcomes.

Meta-Analysis and Genetic Findings

Researchers conducted a systematic review and meta-analysis, examining 32 studies encompassing more than 100 million individuals from administrative, hospital-based, and population-based datasets.² The analysis focused on pooled odds ratios for cannabis, cocaine, amphetamine, and opioid use in relation to ischemic and hemorrhagic stroke subtypes. Mendelian randomization (MR) was then employed, utilizing genome-wide association study (GWAS) summary statistics to investigate potential causal effects of substance dependence on stroke.

MR uses genetic variants linked to specific exposures to assess causality. Because genetic variants precede both exposures and outcomes, associations are more likely to reflect causal relationships. The study examined seven key exposures:

• Substance Use Disorder (SUD)
• Problematic Alcohol Use (PAU)
• Alcohol Use Disorder (AUD)
• Problematic Opioid Use (POU)
• Cannabis Use Disorder (CUD)
• Cocaine Dependence (CD)
• Nicotine Dependence (ND)

Key Findings: Substance-Specific Stroke Risks

The meta-analysis revealed significant associations between several illicit drugs and increased stroke risk:

• Cannabis: Associated with a 37% increase in stroke risk.² A 39% increase in ischemic stroke risk and a 16% increase in any stroke were observed, though these findings showed some variability across studies.
• Cocaine: Linked to nearly double the risk of non-specific stroke, ischemic stroke, and hemorrhagic stroke.²
• Amphetamines: Demonstrated a markedly higher stroke risk, with pooled odds ratios of 2.37 for ischemic stroke and 2.83 for hemorrhagic stroke.²
• Opioids: No significant overall association was found, although limited sample sizes warrant caution in interpreting these results.

In individuals under 55, cannabis, cocaine, and amphetamine use showed similar risk patterns. Unexpectedly, opioid use was associated with lower stroke risk in this age group, which researchers attribute to potential selection bias and modest sample sizes.

Genetic Liability and Stroke Subtypes

MR analyses provided further insights into the causal links between substance use and specific stroke subtypes:

• Overall SUD: Genetically predicted SUD was associated with a 33% higher risk of any stroke and an eight-fold risk of intracerebral hemorrhage.²
• Cannabis Use Disorder: Linked to an 11% increased risk of any stroke and a 35% increase in large artery stroke.²
• Cocaine Dependence: Associated with an 8% higher risk of cardioembolic stroke and a 38% increase in intracerebral hemorrhage.²
• Problematic Alcohol Use: Genetic liability was associated with a roughly 50% increase in cardioembolic stroke risk and a doubling of large-artery stroke risk.
• Alcohol Use Disorder: Linked to modestly increased risks of any stroke and cardioembolic stroke.
• Problematic Opioid Use: Linked to a modest increase in any stroke and ischemic stroke risk.
• Nicotine: No association with stroke risk was observed.

Biological Mechanisms and Future Research

The study suggests that drug-related vascular effects may contribute to stroke risk. Substances like cannabis, cocaine, and amphetamine can cause hypertension and cerebral vasospasm, potentially through sympathetic activation. Cannabis also stimulates platelet aggregation. Further genetic studies are needed to strengthen the causal evidence for amphetamine, given these plausible biological mechanisms.

Study Limitations

The researchers acknowledge several limitations, including the fact that most studies originated in the USA, limiting generalizability. Many studies relied on hospital records, introducing potential selection bias. Inconsistent exposure reporting also hindered the ability to fully adjust for confounding factors. Finally, the study population was limited to individuals of European ancestry.

Implications for Public Health

This research underscores the importance of considering substance misuse as a modifiable risk factor for stroke. The findings suggest that prevention strategies targeting substance use disorders could play a crucial role in mitigating stroke risk.³