Update of the statement on safety of cannabidiol as a novel food.

During the assessment of cannabidiol (CBD) as a novel food, in 2022 the NDA Panel identified significant data gaps. Concerns focused on potential adverse effects on the liver, gastrointestinal tract, endocrine, nervous and reproductive systems. Literature searches covering animal and human studies from the previous Statement until June 2024 confirmed the persistence of these gaps, as many of the new studies suffer from methodological limitations, including non-standardised protocols, short durations and concomitant treatment with medicine. Pharmacokinetic studies confirmed that CBD's bioavailability is variable, influenced by delivery matrix and food intake. Its ability to cross the placenta and accumulate systemically raises further safety concerns. Animal studies revealed consistent liver toxicity, with liver weight and histopathological changes emerging as sensitive endpoints. Human trials indicated hepatotoxic potential, particularly when CBD is used in combination with other medications. Gastrointestinal effects were reported at higher doses, while neurological and psychiatric safety data remain insufficient. Animal studies on reproductive toxicity reinforced the concern regarding this endpoint. Neurodevelopmental effects following prenatal exposure were observed, suggesting long-lasting, sex-specific outcomes. Endocrine disruptions were noted, including altered thyroid hormone levels and adrenal histopathology. No studies addressed immunotoxicity, though CBD's interaction with immune pathways warrants caution. The Panel performed benchmark dose modelling based on GLP-compliant subchronic studies to identify a toxicological reference point. By applying an uncertainty factor of 400, a provisional safe dose of 0.0275 mg/kg bw per day (approximately 2 mg/day for a 70 kg adult) was derived. This provisional safe dose applies solely to food supplement formulations with CBD purity ≥ 98%, without nanoparticles, for which the production process is considered safe and genotoxicity is ruled out. The Panel concludes that, based on all available data, the safety of CBD for individuals under 25 years of age, pregnant or lactating women, and those on concurrent medications, cannot be established.