Highlight
Chronic cannabis use—both inhaled marijuana smoking and oral THC edibles—was associated with impaired brachial artery flow‑mediated dilation (FMD) compared with nonusers in a cohort of healthy, young adults. Serum from marijuana smokers (but not edible users) reduced VEGF‑stimulated nitric oxide production in cultured endothelial cells, implying that smoked cannabis may harm the endothelium via circulating toxicants, whereas ingested THC may act by different pathways.
Background
Cannabis use has increased in jurisdictions that have legalized medical and recreational use. While acute cardiovascular effects of cannabis (tachycardia, transient blood pressure changes) are documented, the long‑term vascular consequences are less clear. Endothelial dysfunction is an early, reversible marker of vascular injury and a predictor of atherosclerosis and cardiovascular events. Flow‑mediated dilation (FMD) of the brachial artery is a widely used noninvasive physiologic measure of endothelial nitric oxide (NO)–dependent vasodilator function.
Understanding whether and how chronic cannabis exposure affects endothelial function is important for clinicians counseling patients, for public health policy, and for prioritizing mechanistic research. The CANnabis: Does It Damage Endothelium (CANDIDE) study (Mohammadi et al., JAMA Cardiol 2025) addresses this question by comparing physiologic and in vitro endothelial measures among chronic marijuana smokers, THC‑edible users, and nonusers.
Study design
Population and setting
CANDIDE is a cross‑sectional study enrolling age‑matched healthy adults aged 18–50 years in the San Francisco Bay Area who did not use tobacco, did not vape, and had minimal secondhand smoke exposure. Recruitment occurred October 2021 to August 2024; analysis completed September 2024. The analytic sample included 55 participants: 3 cohorts—chronic marijuana smokers, chronic THC‑edible users, and nonusers.
Measurements and endpoints
Primary physiologic endpoints were brachial artery flow‑mediated dilation (FMD), a measure of endothelium‑dependent vasodilation, and carotid‑femoral pulse wave velocity (PWV), a measure of arterial stiffness. For mechanistic insights, human umbilical vein endothelial cells (HUVECs) were incubated with participants’ sera, with and without vascular endothelial growth factor (VEGF) stimulation, and VEGF‑stimulated nitric oxide production was measured.
Key findings
Demographics
Of 55 participants, mean age was 31.3 years (SD 8.4); 63% were male and 37% female. Groups were age‑matched and were screened to exclude tobacco and vaping exposure.
Main physiological results
– Brachial FMD was significantly lower in both cannabis user groups compared with nonusers. Mean FMD: nonusers 10.4% (SD 5.2%), marijuana smokers 6.0% (SD 2.6%) and THC‑edible users 4.6% (SD 3.7%). Differences were statistically significant (P = .004 for smokers vs nonusers; P = .003 for edibles vs nonusers).
– Carotid‑femoral PWV and other vascular properties showed no significant group differences in this young, healthy cohort.
Cellular mechanistic results
– VEGF‑stimulated nitric oxide levels in HUVECs incubated with sera from marijuana smokers were lower than in cells treated with nonuser sera (mean 1.1 nmol/L [SD 0.3] vs 1.5 nmol/L [SD 0.3]; P = .004).
– Sera from THC‑edible users did not reduce VEGF‑stimulated NO production compared with nonusers (both mean 1.5 nmol/L; P = .81).
Dose–response and correlation
– Flow‑mediated dilation was inversely correlated with reported smoking frequency (r = -0.7; P < .001) and with amount of THC ingested (r = -0.7; P = .03), suggesting a dose‑related association.
Interpretation of effect sizes
– The reduction in FMD observed in both cannabis groups approximates magnitudes reported for tobacco smokers in prior studies; an absolute reduction of several percentage points in FMD is physiologically meaningful and has been associated with increased cardiovascular risk in cohort studies. In this study, the effect was present in a young, otherwise healthy population.
Expert commentary and mechanistic considerations
The CANDIDE study provides clinically relevant and biologically plausible evidence that chronic cannabis use associates with endothelial dysfunction. Several mechanistic hypotheses arise from the divergent in vitro findings between smoked and ingested cannabis:
– Smoked cannabis may deliver combustion byproducts and reactive oxidant species (similar to tobacco smoke) or lipophilic smoke constituents that alter circulating factors and reduce endothelial NO bioavailability. The observation that serum from smokers inhibited VEGF‑stimulated NO production in HUVECs supports the presence of circulating mediators of endothelial injury (toxicants, inflammatory cytokines, oxidized lipids) in smokers’ serum.
– THC edibles produced a similar physiologic deficit in FMD but did not reduce VEGF‑stimulated NO production in the HUVEC assay. This suggests alternative or additional mechanisms for edible THC, such as central and peripheral autonomic effects (sympathetic activation), direct cannabinoid receptor (CB1/CB2) signaling on endothelial cells or vascular smooth muscle, altered shear stress patterns, or transient hemodynamic effects that cumulatively impair endothelial function without altering serum factors measurable by this specific HUVEC/VEGF‑NO assay.
– The endocannabinoid system (through CB1 receptor activation) has been implicated in vasodilation and vasoconstriction depending on tissue context; chronic receptor modulation may alter vascular reactivity. Distinguishing acute pharmacologic effects of THC from chronic exposure effects on endothelial repair and NO signaling will require longitudinal and mechanistic studies.
Strengths
– Careful exclusion of tobacco and vaping exposure reduces major confounding.
– Use of both physiologic (FMD, PWV) and translational laboratory measures (HUVEC VEGF‑stimulated NO) enhances mechanistic inference.
– Dose–response relationships strengthen causal inference within the limits of cross‑sectional data.
Limitations
– Cross‑sectional design precludes determination of temporality and causation. Reverse causation (preexisting endothelial differences influencing cannabis use) cannot be fully excluded.
– Small sample size and recruitment from a single geographic region (San Francisco Bay Area) limit generalizability.
– Cannabis exposure relied on participant report; objective biomarkers (plasma/urine cannabinoids, exposure to combustion products) were not reported in the summary and could refine exposure assessment.
– HUVECs are a model of macrovascular endothelial biology but cannot replicate all in vivo complexities (shear stress, immune cell interactions, metabolism) and the serum‑incubation assay tests some but not all potential circulating mediators.
– The edible user group likely had heterogeneous dosing and absorption kinetics; acute timing relative to testing was not described in the summary, which could affect physiologic measures.
Clinical and public health implications
– Clinicians should be aware that chronic cannabis use, whether smoked or ingested, may not be neutral for vascular health. In young, otherwise healthy adults, both inhaled and oral THC were associated with lower FMD—an early marker of endothelial dysfunction.
– Counseling about potential cardiovascular risk should be included in discussions of chronic cannabis use, particularly for individuals with other cardiovascular risk factors.
– Policymakers and regulators should consider these emerging vascular safety data when framing public health messaging and labeling requirements for potency and dose, particularly for high‑THC products.
Research priorities
– Longitudinal cohort studies to evaluate whether cannabis‑associated endothelial dysfunction persists, progresses, or reverses with cessation.
– Randomized cessation or controlled exposure studies to distinguish acute versus chronic effects and to clarify dose–response relationships using objective exposure biomarkers.
– Mechanistic studies to identify circulating toxicants, inflammatory mediators, oxidative stress markers, and cannabinoid receptor signaling pathways responsible for the observed effects.
– Studies in older adults and patients with established cardiovascular disease to define clinical relevance for high‑risk populations.
Conclusion
The CANDIDE cross‑sectional study adds significant evidence that chronic cannabis use—both smoked marijuana and THC edibles—is associated with endothelial dysfunction as measured by reduced brachial FMD in young adults. The differential effect of user serum on endothelial VEGF‑stimulated NO production between smoked and edible users suggests distinct mechanisms: circulating toxicants from smoke may play a role in smokers, while edible THC may impair vascular function via other pathways. Larger, prospective and mechanistic studies are needed to confirm causality, quantify clinical risk over time, and inform clinical guidance and public health policy.
Funding and clinicaltrials.gov
Funding sources and trial registration are reported in Mohammadi L et al., JAMA Cardiol. 2025 (see original article for details). ClinicalTrials.gov registration was not specified in the summary provided.
References
1. Mohammadi L, Navabzadeh M, Jiménez‑Téllez N, et al. Association of Endothelial Dysfunction With Chronic Marijuana Smoking and THC‑Edible Use. JAMA Cardiol. 2025 Aug 1;10(8):851‑855. doi:10.1001/jamacardio.2025.1399
2. Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial‑dependent flow‑mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. Circulation. 2002;106(3):353‑359.
3. Thijssen DHJ, Black MA, Pyke KE, et al. Assessment of flow‑mediated dilation in humans: a methodological and physiological guideline. J Physiol. 2011;589(Pt 4): 607‑619.
4. National Academies of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press; 2017.
5. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all‑cause mortality with arterial stiffness: a systematic review and meta‑analysis. J Am Coll Cardiol. 2010;55(13):1318‑1327.
Thumbnail prompt
A high‑resolution editorial image: a clinical exam room table with a stethoscope and a small glass jar labeled “THC edibles” next to a single cannabis leaf and a pair of latex gloves; muted clinical lighting, shallow depth of field, subtle vignette, realistic style suitable for a medical news article.
