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Consumer use of cannabidiol (CBD) for personal wellness purposes has garnered much public interest. However, safety-related data on CBD in the public domain are limited, including a lack of quality studies evaluating its genotoxic potential. The quality of available studies is limited due to the test material used (e.g., low CBD purity) and/or study design, leading some global regulatory agencies to highlight genotoxicity as an important data gap for CBD. To address this gap, the genotoxic potential of a pure CBD isolate was investigated in a battery of three genotoxicity assays conducted according to OECD testing guidelines. In an in vitro microbial reverse mutation assay, CBD up to 5000 μg/plate was negative in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, and Escherichia coli strain WP2 uvrA, with and without metabolic activation. Testing in an in vitro micronucleus assay was negative in human TK6 cells up to 10-11 μg/mL, with and without metabolic activation. Finally, an in vivo micronucleus assay conducted in male and female rats was negative for genotoxicity up to 1000 mg/kg-bw/d. Bioanalysis of CBD and its primary metabolite, 7-carboxy CBD, confirmed a dose-related increase in plasma exposure. Together, these assays indicate that CBD is unlikely to pose a genotoxic hazard., Competing Interests: Declaration of competing interest This work was funded by Canopy Growth Corporation. Authors KRT, TWL, and MOB-M were employees of Canopy Growth Corporation during the conduct and drafting of this study; during their employment, they received stock options. ToxStrategies, a private consulting firm providing services on toxicology and risk assessment issues, received funds for conducting this work. Authors RGH, SJB, and MMH are employees of ToxStrategies., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

An important data gap in determining a safe level of cannabidiol (CBD) intake for consumer use is determination of CBD's potential to cause reproductive or developmental toxicity. We conducted an OECD Test Guideline 421 GLP-compliant study in rats, with extended postnatal dosing and hormone analysis, where hemp-derived CBD isolate (0, 30, 100, or 300 mg/kg-bw/d) was administered orally. Treatment-related mortality, moribundity, and decreased body weight and food consumption were observed in high-dose F 0 adult animals, consistent with severe maternal toxicity. No effects were observed on testosterone concentrations, F 0 reproductive performance, or reproductive organs. Hepatocellular hypertrophy in the 100- and 300 mg/kg-bw/day groups correlated with hypertrophy/hyperplasia in the thyroid gland and changes in mean thyroid hormone concentrations in F 0 animals. Mean gestation length was unaffected; however, total litter loss for two females and dystocia for two additional females in the high-dose group occurred. Other developmental effects were limited to lower mean pup weights in the 300 mg/kg-bw/d group compared to those of concurrent controls. The following NOAELs were identified for CBD isolate based on this study: 100 mg/kg-bw/d for F 0 systemic toxicity and female reproductive toxicity, 300 mg/kg-bw/d for F 0 male reproductive toxicity, and 100 mg/kg-bw/d for F 1 neonatal and F 1 generation toxicity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work was funded by Canopy Growth Corporation. Authors KRT, TWL, and MOB-M were employees of Canopy Growth Corporation during the conduct and drafting of this study; during their employment, they received stock options. ToxStrategies, a private consulting firm providing services on toxicology and risk assessment issues, received funds for conducting this work. Authors RGH, JMR, and SJB are employees of ToxStrategies; and author BTW was an employee of ToxStrategies during the conduct and drafting of this study., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Use of cannabidiol (CBD) in humans has increased considerably in recent years. While currently available studies suggest that CBD is relatively safe for human consumption, data from publicly available studies on CBD conducted according to modern testing guidelines are lacking. In the current study, the potential for toxicity following repeated oral exposure to hemp-derived CBD isolate was evaluated in male and female Sprague Dawley rats. No adverse treatment-related effects were observed following administration of CBD via oral gavage for 14 and 90 days at concentrations up to 150 and 140 mg/kg-bw/d, respectively. Microscopic liver and adrenal gland changes observed in the 90-day study were determined to be resolved after a 28-day recovery period. CBD was well tolerated at these dose levels, and the results of this study are comparable to findings reported in unpublished studies conducted with other CBD isolates. The current studies were conducted as part of a broader research program to examine the safety of CBD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work was funded by Canopy Growth Corporation. Authors KRT, TWL, and MOB-M were employees of Canopy Growth Corporation during the conduct and drafting of this study; during their employment, they received stock options. ToxStrategies, a private consulting firm providing services on toxicology and risk assessment issues, received funds for conducting this work. Authors RGH, SJB, and MMH are employees of ToxStrategies., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Robust assessment of potential adverse outcomes is needed to determine a safe cannabidiol (CBD) intake level for consumer use. To assist in identifying knowledge gaps and inform future decision making regarding systematic development of health-based benchmarks, we have developed the first systematic map of the safety-related information available for CBD in the peer-reviewed literature. Literature searching conducted according to a published protocol yielded a total of 4186 unique titles and abstracts published through 2020. These were screened using DistillerSR for studies that evaluated at least one potential health outcome following exposure to CBD and/or other hemp-derived substances. Additional categorization was conducted for a subset of 1001 studies in which CBD was administered alone. Studies that investigated CBD most frequently reported on neurological outcomes (532), carcinogenic outcomes (129), and pharmacokinetics (118). Less frequently studied categories included developmental and reproductive, hepatic, and gastrointestinal outcomes. The primary outcomes associated with the most adverse events reported in the literature were neurological (13) and developmental and reproductive (12). Based on the studies identified, reproductive and developmental toxicity was identified as a data gap that warrants conducting a well-designed, guideline-compliant reproductive toxicity study on CBD. In addition, immune outcomes were noted as a potential emerging research area for CBD. This systematic map provides an important baseline from which to identify topics that may be suitable for further research related to the safe use of CBD. Implications for future potential work and limitations of the mapping exercise are discussed.

Consumer use of hemp-derived products continues to rise, underscoring the need to establish evidence-based safety guidance. The present study sought to develop recommendations for oral upper intake limits of cannabidiol (CBD) isolate. Sufficiently robust and reliable data for this purpose were identified from published human clinical trials and guideline-compliant toxicity studies in animal models. Based on the metrics used in this assessment, a potential Acceptable Daily Intake (ADI) value of 0.43 mg/kg-bw/d (e.g., 30 mg/d for 70-kg adult) was determined for the general population based on liver effects in human studies. This value applies to the most sensitive subpopulations, including children, over a lifetime of exposure and from all sources, including food. For dietary supplements with adequate product labeling intended for use by healthy adults only, a potential Upper Intake Limit (UL) of 70 mg/d was determined based on reproductive effects in animals. For healthy adults, except those trying to conceive, or currently pregnant or lactating, a conservative dietary supplement UL of 100 mg/d was identified based on liver effects; however, as the target population excludes individuals at risk for liver injury, an alternative dietary supplement UL of 160 mg/d for this population can also be considered. • Potential Acceptable Daily Intake value of 0.43 mg/kg-bw/d was derived for the general population. • ADI applies to sensitive subpopulations, including children, and from all sources, including food. • Upper Intake Limit (UL) of 70 mg/d was developed for dietary supplement use by all healthy adults. • ULs of 100 and 160 mg/d derived for healthy adults not trying to conceive, pregnant, or lactating. • Recommendations are based solely on the authors' assessments and are not regulatory guidelines. [ABSTRACT FROM AUTHOR]