Inhaled combusted cannabis use is associated with proatherogenic changes in young people: A cross-sectional study

This cross-sectional study demonstrates that chronic inhaled combusted cannabis use is associated with proatherogenic changes in monocytes and plasma among healthy young adults, an effect that is further amplified when combined with nicotine electronic cigarette use.

The Gist

The Big Picture: Is "Smoking Weed" Bad for Your Heart?

For a long time, many people have thought that because cannabis is natural (or at least legal in many places), it must be safe for the heart, especially compared to tobacco. While we know smoking anything isn't great, this study wanted to dig deeper. It asked: Does chronic smoking of combusted cannabis actually damage the blood vessels over time, and does mixing it with nicotine vaping make it worse?

The researchers didn't just ask people, "Do you have chest pain?" (which is too late). Instead, they looked at the very first steps of how heart disease starts, using a high-tech "test drive" for blood cells.

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The Analogy: The "Clogged Pipe" Factory

Imagine your blood vessels are like highways and your immune cells (monocytes) are like construction workers.

1. Normal Life: Occasionally, a construction worker needs to step off the highway (the blood vessel wall) to fix a small pothole. This is good.
2. Atherosclerosis (Heart Disease): This happens when the highway gets clogged with trash (fatty deposits). The construction workers get confused, jump off the highway in huge numbers, and start eating the trash. They get so full of fat that they turn into Foam Cells (literally, cells filled with foam). These foam cells pile up, creating a "fatty streak" that eventually blocks the road, leading to a heart attack.

What Did the Researchers Do?

They took blood from three groups of healthy young adults (ages 21–30):

1. The Control Group: People who don't smoke anything.
2. The Cannabis Group: People who smoke cannabis regularly.
3. The Co-Use Group: People who smoke cannabis and use nicotine e-cigarettes (vapes).

They put these blood samples into a special laboratory "simulator."

• The Simulator: Imagine a tiny, artificial highway made of a collagen gel. They added the participants' blood plasma (the liquid part) and their immune cells.
• The Test: They watched to see if the immune cells would:
  • MTEM: Jump off the highway (migrate into the wall).
  • MDFCF: Eat the fat and turn into "Foam Cells."

The Findings: The "Traffic Jam" Gets Worse

Here is what they discovered, translated into our analogy:

1. Cannabis Smokers: The Workers Are Too Eager

In the group that smoked only cannabis, the construction workers were 13% more likely to jump off the highway than the non-smokers. Even worse, once they jumped off, they were 36% more likely to turn into fat-filled Foam Cells.

• The Takeaway: Smoking cannabis makes your immune cells "angry" and eager to start building the blockage, even in young, healthy people.

2. The Co-Users: The Double Trouble

The group that smoked cannabis and vaped nicotine was the worst off. Their workers didn't just jump off the highway; they practically leaped off.

• Their Foam Cell formation was 48% higher than non-smokers.
• The Takeaway: Mixing cannabis with nicotine vaping doesn't just add the risks; it multiplies them. It's like giving the construction workers a caffeine shot and a sugar rush—they go into overdrive.

3. The "Oxidative Stress" Spark

The researchers also measured "Cellular Oxidative Stress" (COS). Think of this as rust or friction inside the cells.

• They found that the more "rusty" (stressed) the cells were, the more likely they were to turn into Foam Cells.
• Cannabis smokers had significantly more "rust" in their cells than non-smokers. This suggests that the smoke causes internal damage that triggers the clogging process.

4. The "Plasma" Test (The Liquid Factor)

The researchers did a second test where they took the liquid blood from the smokers and gave it to healthy construction workers.

• Result: The liquid from the smokers made the healthy workers turn into Foam Cells too!
• Meaning: Cannabis smoke doesn't just hurt the cells directly; it changes the environment (the blood plasma) so that it becomes toxic to everyone, even healthy cells.

Why Does This Matter?

• It's Not Just "Acute" Risk: We already know smoking weed can trigger a heart attack right now (like a sudden traffic accident). This study shows it also causes slow, long-term damage (like rusting the pipes over years).
• The "Young" Factor: These participants were young and healthy. If this is happening to them, it means the damage starts early, long before they feel any symptoms.
• The Vaping Danger: Many young people think vaping is "safe." This study shows that if you are already smoking cannabis, adding a nicotine vape makes the heart damage significantly worse.

The Bottom Line

Think of your blood vessels as a pristine highway.

• Non-smokers: The highway stays clean.
• Cannabis smokers: The highway starts getting potholes, and the workers start clogging the lanes.
• Cannabis + Vape smokers: The highway is under construction, the workers are panicking, and the road is getting blocked much faster.

Conclusion: Chronic smoking of combusted cannabis is not harmless to the heart. It kickstarts the process of heart disease, and mixing it with nicotine vaping turns up the volume on that danger.

Technical Summary

1. Problem Statement

While acute cannabis use is known to trigger transient cardiovascular events (e.g., myocardial infarction) via sympathetic activation, the long-term risk of chronic cannabis use on the development of atherosclerosis remains unclear. Observational human studies are confounded by co-use of tobacco, lifestyle factors, and the difficulty of accessing arterial tissue to study early disease mechanisms. Furthermore, the rise in nicotine electronic cigarette (nECIG) use among young adults, often co-used with cannabis, presents a new variable. The study aims to determine if chronic combusted cannabis use induces early proatherogenic changes in otherwise healthy young adults and if co-use with nECIGs amplifies this risk.

2. Methodology

The study employed a cross-sectional parallel group design involving 134 healthy adults (aged 21–30) with no history of traditional cigarette smoking. Participants were categorized into three groups:

1. Cannabis-only: Chronic users of inhaled combusted cannabis ($n=59$).
2. Co-users: Chronic users of both combusted cannabis and nECIGs ($n=26$).
3. Controls: Non-users of either substance ($n=49$).

Key Exclusion Criteria: Traditional cigarette smoking, obesity (BMI >30), known cardiovascular/metabolic disease, and recent use of illicit drugs other than cannabis.

Experimental Model:
The researchers utilized a novel ex vivo mechanistic model of atherogenesis using primary human plasma and autologous peripheral blood mononuclear cells (PBMCs). The assay measured two critical early steps in atherosclerosis:

• Monocyte Transendothelial Migration (MTEM): The ability of monocytes to migrate through an activated endothelial cell monolayer into a collagen gel.
• Monocyte-Derived Foam Cell Formation (MDFCF): The uptake of lipids by transmigrated monocytes, converting them into foam cells.

Assays and Measurements:

• Flow Cytometry: Used to quantify MTEM (CD11b+ macrophages in the gel) and MDFCF (percentage of CD11b+ cells positive for the lipid-binding fluorochrome BODIPY and their Median Fluorescence Intensity [MFI]).
• Cellular Oxidative Stress (COS): Measured in CD14+ monocytes using the CellROX fluorochrome to detect reactive oxygen species (ROS).
• Endothelial Cell Analysis: An exploratory analysis assessed lipid uptake in endothelial cells (CD45-) within the assay.
• Biochemical Markers: Plasma cotinine levels (for nECIG exposure) and urine toxicology (for THC) were measured. CUDIT-R scores assessed cannabis use disorder severity.

Statistical Approach:
Non-parametric tests (Kruskal-Wallis) were used for group comparisons, with Conover/Bonferroni adjustments for multiple comparisons. Spearman correlations assessed relationships between oxidative stress and atherogenic outcomes. Multivariable regression models adjusted for age, sex, and substance use intensity.

3. Key Contributions

• Mechanistic Evidence: This is among the first studies to provide direct mechanistic evidence in humans linking chronic combusted cannabis use to specific cellular and molecular changes driving atherosclerosis, bypassing the limitations of observational epidemiology.
• Dual-Pathway Analysis: The study successfully dissected cellular effects (using autologous PBMCs) vs. circulating/plasma effects (using pooled control PBMCs with participant plasma), revealing that cannabis impacts both the cells and the systemic environment.
• Co-use Amplification: It specifically isolates the additive risk of combining cannabis with nECIGs, a prevalent behavior in young adults that was previously under-studied in the context of atherogenesis.
• Endothelial Foam Cells: The study provides exploratory data suggesting endothelial cells themselves can become foam cells in the presence of cannabis user plasma/monocytes, a less characterized pathway in atherogenesis.

4. Key Results

A. Proatherogenic Changes in Monocytes (PBMC-Plasma Assay)

• MTEM: Cannabis-only users showed a 1.13-fold increase in monocyte migration compared to controls ($p<0.0001$). Co-users showed a trend toward even higher migration (1.22-fold vs. cannabis-only), though this specific comparison was not statistically significant ($p=0.17$).
• MDFCF (Foam Cell Formation): Cannabis-only users had significantly higher foam cell formation (1.36-fold increase in % BODIPY+ cells; $p<0.00001$) and higher lipid content (1.24-fold increase in BODIPY MFI) compared to controls.
• Co-use Effect: The co-use group exhibited the highest levels of MDFCF (1.83-fold increase vs. controls; $p<0.00001$) and significantly higher lipid content than cannabis-only users ($p<0.00001$).

B. Plasma vs. Cellular Contributions

• When using control PBMCs with participant plasma (isolating circulating factors):
  • Plasma from cannabis users still induced higher MDFCF (1.38-fold vs. controls), suggesting circulating proatherogenic factors.
  • However, the magnitude of the effect was generally greater in the autologous (PBMC-plasma) assay, indicating that cannabis induces both systemic (plasma) and intrinsic (cellular) proatherogenic changes.

C. Cellular Oxidative Stress (COS)

• COS Levels: Both cannabis-only and co-use groups had significantly elevated cellular oxidative stress in monocytes compared to controls (measured by % CELLROX+ and MFI).
• Correlation: In the control group, COS was strongly negatively correlated with MTEM but strongly positively correlated with MDFCF ($r_s \approx 0.79-0.81$). In cannabis users, COS remained strongly positively associated with foam cell formation (BODIPY MFI), suggesting oxidative stress is a key driver of lipid accumulation in these cells.

D. Endothelial Cell Findings

• Co-users showed significantly increased lipid uptake in endothelial cells (both % BODIPY+ and MFI) compared to controls and cannabis-only users, suggesting a synergistic proatherogenic effect on the vascular lining.

E. Regression Analysis

• Multivariable models confirmed that CUDIT-R scores (cannabis severity) and plasma cotinine levels (nECIG use) were independently associated with increased MDFCF and BODIPY MFI. Age and sex were not significant predictors in this young cohort.

5. Significance and Conclusion

This study challenges the perception that cannabis is a "safe" alternative to tobacco regarding long-term cardiovascular health.

• Pathophysiological Impact: Chronic combusted cannabis use is associated with proatherogenic phenotypes in young, otherwise healthy adults, specifically accelerating the early steps of atherosclerosis (monocyte migration and foam cell formation).
• Synergistic Risk: The co-use of nECIGs with cannabis amplifies these risks, leading to the highest levels of foam cell formation and oxidative stress.
• Mechanism: The data suggests that cellular oxidative stress is a primary mediator linking substance use to foam cell formation.
• Public Health Implication: Given the high prevalence of cannabis and nECIG co-use in young adults, these findings suggest a potential for accelerated development of inflammatory atherosclerosis, which could manifest as premature coronary artery disease decades later. The study advocates for viewing chronic combusted cannabis use as a significant cardiovascular risk factor.

Limitations: The study is cross-sectional (cannot prove causality over time), relies partly on self-reported usage (though validated by biomarkers), and focuses on young adults, so the long-term clinical outcomes (e.g., heart attacks) are inferred from mechanistic markers rather than observed directly.