New approaches to historical challenges: Avoiding the early missteps of tobacco research in cannabis studies

As cannabis use becomes increasingly mainstream for both recreational and medicinal purposes, scientific evaluation of its health effects has not kept pace with legalization and market expansion. This gap echoes historical missteps seen in tobacco regulation, where decades passed before sufficient mechanistic and epidemiologic data on health effects prompted policy action. To avoid repeating such delays in action, this paper advocates for the integration of New Approach Methodologies (NAMs) in cannabis toxicology research, particularly for inhaled products; these tools prioritize human relevance, mechanistic insight, and reduction of animal testing. We highlight three key domains of innovation: (1) air–liquid interface (ALI) exposure systems that more accurately model inhaled cannabis products; (2) human-derived cell models and organoids, including those from induced pluripotent stem cells (iPSCs), which provide insight into tissue-specific toxicity; and (3) computational toxicology platforms such as quantitative structure–activity relationship (QSAR) and physiologically-based pharmacokinetic (PBPK) modeling, which support high-throughput, mechanism-based risk assessment. Together, these tools offer a robust framework for evaluating the diverse and complex constituents of cannabis products, enabling proactive risk assessment and regulation for cannabis-based products. • Cannabis use has surged, yet scientific evaluation of the health consequences of these products remains limited. • Human-relevant models can complement epidemiological studies to strengthen causal inference on cannabis-specific health impacts. • NAMs, such as ALI exposures, primary human cells/iPSCs and computational toxicology tools, can generate mechanistic and human-relevant data to help inform regulatory policies.