Cannabidiol (CBD) is a naturally occurring, non-psychotropic cannabinoid of the hemp plant Cannabis sativa L. and has been known to induce several physiological and pharmacological effects. While CBD is approved as a medicinal product subject to prescription, it is also widely sold over the counter (OTC) in the form of food supplements, cosmetics and electronic cigarette liquids. However, regulatory difficulties arise from its origin being a narcotic plant or its status as an unapproved novel food ingredient. Regarding the consumer safety of these OTC products, the question whether or not CBD might be degraded into psychotropic cannabinoids, most prominently tetrahydrocannabinol (THC), under in vivo conditions initiated an ongoing scientific debate. This feature review aims to summarize the current knowledge of CBD degradation processes, specifically the results of in vitro and in vivo studies. Additionally, the literature on psychotropic effects of cannabinoids was carefully studied with a focus on the degradants and metabolites of CBD, but data were found to be sparse. While the literature is contradictory, most studies suggest that CBD is not converted to psychotropic THC under in vivo conditions. Nevertheless, it is certain that CBD degrades to psychotropic products in acidic environments. Hence, the storage stability of commercial formulations requires more attention in the future.

In the European Union (EU), cannabidiol (CBD) products extracted from Cannabis sativa L. require pre-marketing authorisation under the novel food regulation. Currently, 19 CBD applications are being assessed by the European Food Safety Authority (EFSA). During the initial assessment of the dossiers, the EFSA Panel on Nutrition, Novel Foods, and Food Allergens (NDA) identified several knowledge gaps that need to be addressed before the evaluation of CBD can be finalised. The effects of CBD on the liver, gastrointestinal tract, endocrine system, nervous system, psychological function, and reproductive system need to be clarified. The contribution of this research is to provide an evidence-based assessment of the potential risks associated with CBD products, and to provide recommendations for risk management in the European Union while awaiting the finalisation of novel food applications. The available literature allows for a benchmark dose (BMD)–response modelling of several bioassays, resulting in a BMD lower confidence limit (BMDL) of 20 mg/kg bw/day for liver toxicity in rats. Human data in healthy volunteers showed increases in the liver enzymes alanine aminotransferase and aspartate aminotransferase in one study at 4.3 mg/kg bw/day, which was defined by the EFSA NDA panel as the lowest observed adverse effect level (LOAEL). The EFSA NDA panel recently concluded that the safety of CBD as a novel food cannot be assessed, resulting in a so-called clock stop for the applications until the applicants provide the required data. The authors suggest that certain CBD products still available on the EU market as food supplements despite the lack of authorisation should be considered “unsafe”. Products exceeding a health-based guidance value (HBGV) of 10 mg/day should be considered “unfit for consumption” (Article 14(1) and (2)(b) of Regulation No. 178/2002), while those exceeding the human LOAEL should be considered “injurious to health” (Article 14(1) and (2)(a) of Regulation No 178/2002).

Information about unsafe foods or feeds must be exchanged between European Union (EU) member states as quickly as possible. This is why the EU’s Rapid Alert System for Food and Feed (RASFF) exists. It helps to ensure that products that may be harmful to health do not enter the market or can be specifically withdrawn from the market. Different notifications are used depending on the risk and urgency. This article provides an overview of the 61 notifications in the RASFF between 2020 and 2022 on the Δ⁹-tetrahydrocannabinol (Δ⁹-THC) content in cannabidiol (CBD) oils and CBD food supplements. These products are available on the EU market despite the lack of novel food approval. Δ⁹-THC is a naturally occurring psychotropic compound extracted from the hemp plant Cannabis sativa that can have adverse effects on consumers (such as drowsiness, dizziness, tachycardia, or changes in blood pressure). In a previous German national survey, 23 of the 125 products tested (18%) exceeded the lowest observed adverse effect level (LOAEL) of Δ⁹-THC. In comparison, for products identified as a serious risk in the RASFF, the Δ⁹-THC concentrations were generally higher (up to 2410 mg/kg) and 14 of 34 products (41%) exceeded the LOAEL. Considering these data, a threshold of 500 mg/kg (0.05%) may be proposed to define a serious risk, as the LOAEL would not be exceeded in typical consumption scenarios below this level and serious risks, as well as narcotic effects in the product group of food supplements, could be excluded. This threshold could be used in the interim until the full toxicological assessment is available within the novel food approval procedure.

Cannabidiol (CBD), a non-psychotropic main component of the Cannabis plant, has been approved as a drug in the European Union (EU) under the name “Epidyolex”. However, its approval process as a food ingredient under the Novel Food Regulation was paused by the European Food Safety Authority (EFSA) due to a lack of safety data. Nevertheless, there is a growing, unregulated market in which CBD is advertised with various health claims and dosage instructions. Of particular concern is its toxic effect on the liver and possible reproductive toxicity in humans. Studies suitable for calculating the benchmark dose were identified from the available data. Animal studies yielded a benchmark dose lower confidence limit (BMDL) of 43 mg/kg bw/day, which translates into a safe human dose of approximately 15 mg/day. Only the Lowest-Observed-Adverse-Effect Level (LOAEL) of 4.3 mg/kg bw/day could be identified from the human data. This updated risk assessment confirmed a health-based guidance value (HBGV) of 10 mg/day based on human LOAEL. Despite the existing data gaps, preliminary regulation appears advisable because the current form of the gray CBD market is unacceptable from the standpoint of consumer safety and protection.

In the European Union (EU), cannabidiol products require pre-marketing authorisation under the novel food regulation. Currently, 19 CBD applications are under assessment at the European Food Safety Authority (EFSA). During the initial assessment of the application files, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) located several knowledge gaps in their 07 June 2022 statement on safety of cannabidiol as a novel food that need to be addressed before the evaluation of CBD can be concluded. Namely, the effect of CBD on the liver, gastrointestinal tract, endocrine system, nervous system, psychological function, and reproductive system needs to be clarified. Nevertheless, the available literature allows a benchmark dose (BMD)-response modelling of several bioassays, resulting in a BMD lower confidence limit (BMDL) of 20 mg/kg bw/day for liver toxicity in rats. Human data in healthy volunteers found increases in the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in a study at 4.3 mg/kg bw/day, which was defined by EFSA NDA panel as a lowest observed adverse effect level (LOAEL). The EFSA NDA panel currently concluded that the safety of CBD as a novel food cannot be evaluated, leading to a so-called clock stop of the applications until the applicants provide the required data. Meanwhile, the authors suggest that CBD products still available as food supplements on the EU market despite the lack of authorisation must be considered as “unsafe”. Products exceeding a health-based guidance value of 10 mg/day must be considered as being “unfit for consumption” (Article 14(1) and (2) (b) of Regulation No 178/2002), while the ones in exceedance of the human LOAEL must be considered “injurious to health” (Article 14(1) and (2) (a) of Regulation No 178/2002).

Zusammenfassung: Das Vorsorgeprinzip ist in der Rechtsprechung und Gesetzgebung der Europäischen Union (EU) fest verankert. Im Lebensmittelrecht wurde das Vorsorgeprinzip in Art. 7 der Lebensmittel-Basisverordnung (EG) Nr. 178/2002 (BasisVO) etabliert. Dennoch findet das Vorsorgeprinzip sowohl in der Überwachungspraxis als auch in der nationalen Rechtsprechung nicht die angemessene Beachtung. Neben der historischen Entwicklung und der Anwendung in der nationalen und europäischen Rechtsprechung werden in diesem Beitrag die Möglichkeiten und Grenzen der Anwendung des Vorsorgeprinzips nach Art. 7 BasisVO am Beispiel von cannabidiolhaltigen (CBD) Produkten beleuchtet. Im Ergebnis wird festgestellt, dass die Behörden im Sinne des Vorsorgeprinzips aufgrund eines wahrscheinlichen Gesundheitsrisikos prioritäre Schutzmaßnahmen ergreifen können, die über die ohnehin erforderlichen Maßnahmen der Novel Food-Verordnung hinausgehen.