The relationship between CUD and cancer risk remains complex and not fully established. With the growing prevalence of cannabis use, understanding its health implications is increasingly critical. Cannabis use has been associated with both an increased risk of some cancers, such as particular testicular cancers, and a decreased risk of others, such as bladder cancer [8, 9]. This variation in outcomes is often influenced by the type of cannabinoid being used and the mode of consumption. For instance, smoking cannabis is believed to increase the risk of cancers in the throat and respiratory tract due to the presence of carcinogens in cannabis smoke, which resemble those found in cigarette smoke [8, 10].

The relationship between cannabis use and cancer risk remains incompletely understood. Preclinical studies demonstrate that certain cannabinoids can inhibit tumor growth, induce apoptosis, and reduce angiogenesis in pancreatic cancer cell lines and animal models. However, several important caveats limit the interpretation of these findings. Most anti-cancer studies have been conducted in vitro or in animal xenograft models rather than clinical trials [11–14]. Cannabinoid receptors (CB1 and CB2) are expressed ubiquitously throughout the body and bind endocannabinoids, phytocannabinoids (such as THC and CBD), and synthetic cannabinoids—each with potentially different biological effects [15]. Studies demonstrating synergistic effects with chemotherapy have predominantly used synthetic cannabinoids rather than the cannabis products consumed by patients with CUD [16]. The cannabis used by patients in our cohort likely differs substantially from purified compounds studied in laboratory settings in terms of cannabinoid composition, THC: CBD ratios, route of administration, and dose.

We also found a modestly increased risk of AP flares in CP in the CUD. Whereas growing evidence suggests that cannabis use may contribute to idiopathic acute pancreatitis (AP), our study is unique in demonstrating an increased risk of AP flares, specifically within the CP population [17]. This is a pertinent novelty, as CP patients are inherently at higher risk for recurrent pancreatic inflammation, with a pressing need for the identification of modifiable risk factors in this vulnerable group.

Despite these mechanistic uncertainties, our study provides novel real-world epidemiological evidence from a large clinical population, addressing a critical knowledge gap. While preclinical data cannot be directly extrapolated to clinical outcomes, our findings generate important hypotheses that warrant prospective investigation through well-designed clinical studies and mechanistic research to clarify the relationship between cannabis use and pancreatic cancer risk in patients with chronic pancreatitis.

Our study’s strengths include the large sample size, propensity score matching to minimize confounding bias, and implementation of sensitivity analysis. The differential follow-up time between cohorts warrants consideration, with the shorter follow-up time in the CUD cohort being a potential factor for lower PC case detection. However, Cox proportional hazards regression inherently accounts for differential follow-up by estimating the instantaneous hazard at any given time point among those still at risk, rather than relying on cumulative event counts [18]. However, the study is limited by its observational nature, which means that only associations, not causal relationships, can be inferred. TriNetX relies on coded diagnostic data from electronic health records, which may be subject to coding inaccuracies and incomplete capture of clinical information. Moreover, the lack of detailed information on the frequency, duration, or type of cannabis use restricts the ability to determine dose-response relationships. Cannabinoid pharmacokinetics are influenced by numerous variables, and product labeling is often inaccurate, making the quantification of exposure particularly challenging [19–21]. Future studies incorporating more granular data on healthcare utilization patterns, socioeconomic variables, and provider-level factors would be valuable in clarifying the influence of potential unmeasured confounders on our findings.

In conclusion, these exploratory findings suggest an association between CUD and reduced PC detection during available follow-up in patients with CP. CUD was also associated with a modestly increased risk of AP flares, which aligns with emerging evidence linking cannabis use to acute pancreatitis episodes. Given the limitations of our retrospective observational study, these associations require validation in prospective studies with longer, standardized follow-up and comprehensive ascertainment of cancer outcomes before clinical implications can be determined. Future research should also investigate potential mechanisms and determine whether the observed differences reflect true biological effects or detection bias.