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  1. Regulatory Science in Action

CDER Investigators Address the Safety of CBD in a Randomized Trial

Background and Public Health Relevance

The Cannabis sativa L. plant, which is the source of both marijuana and hemp, contains bioactive compounds known as cannabinoids. Delta-9 tetrahydrocannabinol is a psychoactive cannabinoid and is typically found in relatively high amounts in cannabis that is used as a source of marijuana. Cannabidiol (CBD) is a nonpsychoactive cannabinoid that is present at relatively high levels in hemp, defined as cannabis and derivatives of cannabis with extremely low concentrations of delta-9 tetrahydrocannabinol.1 The Agricultural Improvement Act (Farm Bill) of 2018 removed hemp from the definition of marijuana in the Controlled Substances Act.1 Following this, many unregulated hemp-derived cannabinoid products became widely available to consumers.2 These products often contain CBD, raising various safety concerns.1,2

Only one CBD human drug product, Epidiolex®, is approved by the U.S. Food and Drug Administration (FDA) for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex.3 At labeled doses up to 25 mg/kg/day, an increased risk of liver enzyme elevation was observed.3,4 Liver enzyme elevations typically occurred after two weeks and were dose-dependent. Liver safety data are limited for lower CBD doses and inconsistent regarding the occurrence and severity of liver enzyme elevations at 200-400 mg a day.4,5 Consumer self-reporting on CBD use indicates upwards of 200 mg daily,6-9 so additional safety information at these doses is needed. Further, multiple animal studies have reported CBD effects on the endocrine system, but limited human data exist.10-14

How CDER Researchers Addressed this Public Health Concern

CDER researchers conducted a randomized, double-blinded, placebo-controlled study in healthy participants to evaluate the effects of daily CBD use at doses representative of consumer use on liver enzyme elevations and endocrine measures. Oral solution CBD at a dosage of 2.5 mg/kg twice a day (250 – 550 mg/day) was administered over 28 days. The placebo control group received an inactive oral solution. Chemistry, hematology, and endocrine assessments were performed on predetermined days and plasma concentrations of CBD were measured by validated bioanalytical methods. 

The study's liver safety endpoints included a primary endpoint of the proportion of participants with ALT (alanine aminotransferase) or AST (aspartate aminotransferase) levels exceeding three times the Upper Limit of Normal (ULN), and a secondary endpoint of the proportion of participants meeting drug-induced liver injury (DILI) criteria based on elevated liver enzymes and/or clinical symptoms. Endocrine assessments included the change from baseline in serum total testosterone, inhibin B, and thyroid hormones after CBD administration compared to placebo.

Summary of Liver Safety Study Results or Summary of CBD Liver and Hormone Effects

A total of 201 participants were enrolled and randomized into two groups with 151 participants taking CBD solution and 50 taking matching placebo. A total of 188 participants completed the trial. Among participants receiving CBD, 8 or 5.6% (95% CI, 1.8% to 9.3%) experienced ALT elevations exceeding three times the upper limit of normal (ULN) after 4 weeks of CBD dosing (Table 1). In contrast, no participants in the placebo arm exhibited ALT elevations meeting this threshold (0% [95% CI, 0% to 7.6%]). Seven or 4.9% (95% CI, 1.3% to 8.4%) of participants receiving CBD met withdrawal criteria for potential DILI (Table 1). 

Full study results can be found in this JAMA Internal Medicine publication.

Table 1. Primary and secondary liver outcomes in a randomized, double-blinded, placebo-controlled study in healthy participants to evaluate the effects of daily cannabidiol (CBD) use at doses representative of consumer use. 

 Cannabidiol (N=141a)Placebo (N=47a)
Primary Outcome
Alanine aminotransferase or aspartate aminotransferase > 3 x ULN

Number of Participants

80

Percentage based on Kaplan-Meier, 95% CI

5.6% (1.8% to 9.3%)0% (0% to 7.6%)
Secondary Outcome
Meeting withdrawal criteria for potential drug-induced liver injury

Number of Participants

70

Percentage based on Kaplan-Meier, 95% CI

4.9% (1.3% to 8.4%)0% (0% to 7.6%)

CI, Confidence Interval
aNumber of subjects at risk at week 4 of the study.

Participants did not experience clinical symptoms related to liver function during this 28-day study and hepatic enzymes returned to normal within 1-2 weeks following discontinuation (Figure 1). Enzyme elevations did not result in clinically significant liver function changes. No significant differences in change from baseline were observed between the CBD and placebo groups for all endocrine measures.

Figure 1. Laboratory values over time for a participant experiencing experienced ALT elevation exceeding three times the upper limit of normal (ULN) after 4 weeks of cannabidiol dosing.

Figure 1. Laboratory values over time for a participant experiencing experienced ALT elevation exceeding three times the upper limit of normal (ULN) after 4 weeks of cannabidiol dosing.

Figure 1. Laboratory values over time for a participant experiencing experienced ALT elevation exceeding three times the upper limit of normal (ULN) after 4 weeks of cannabidiol dosing.

How Does this Research Advance Regulatory Science? 

This clinical trial represents a significant advancement in regulatory science by providing rigorous human safety data for CBD at doses consistent with unregulated consumer products. As part of FDA's broader efforts to understand CBD product safety, this research directly addresses a critical regulatory gap that emerged with the proliferation of CBD products following the 2018 Farm Bill’s removal of hemp-derived products from schedule I control status under the Controlled Substances Act. By demonstrating that CBD use, at doses representative of those commonly reported by consumers of unregulated consumer products, can lead to liver enzyme elevations in healthy adults not taking any other medications—with a quantifiable 5.6% risk rate—this study provides evidence that can be used to understand the safety of CBD products and inform discussions about appropriate safeguards.

The findings also have important implications for consumer safety. Since CBD users may not notice asymptomatic liver changes on their own, the research reveals safety risks that consumers may otherwise be unaware of and highlights the need for caution and potentially routine monitoring in CBD users. Additionally, CBD is frequently used by older adults, particularly for conditions such as pain, anxiety, insomnia, and arthritis, who may be at higher risk than the healthy study population. According to the 2022 National Survey on Drug Use and Health, 20% of adults reported using CBD products within the past year, highlighting the widespread exposure to these potential risks. These findings underscore the need for further investigation on the long-term effects of CBD use, its impact on various populations, and the safety of lower doses commonly used by consumers.

References

  1. Food and Drug Administration. Background materials for the June 14, 2022, meeting of the Science Board to the FDA. Washington, DC: FDA, 2022.
  2. Harlow AF, Leventhal AM, Barrington-Trimis JL. Closing the Loophole on Hemp-Derived Cannabis Products: A Public Health Priority. JAMA. 2022;328(20):2007–2008.
  3. Food and Drug Administration. Cannabidiol (Epidiolex) prescribing information. Washington, DC: FDA, 2018.
  4. Lo LA, Christiansen A, Eadie L, et al. Cannabidiol-associated hepatotoxicity: a systematic review and meta-analysis. Journal of Internal Medicine, 2023; 293:724-752.
  5. Crippa JAS, Zuardi AW, Guimarães FS, et al. Efficacy and safety of cannabidiol plus standard care vs standard care alone for the treatment of emotional exhaustion and burnout among frontline health care workers during the COVID-19 pandemic: a randomized clinical trial. JAMA Network Open, 2021; 4:e2120603.
  6. Brightfield Group. Consumer insights report 2023. Chicago: Brightfield Group, 2023.
  7. Moltke J, Hindocha C. Reasons for cannabidiol use: a cross-sectional study of CBD users, focusing on self-perceived stress, anxiety, and sleep problems. Journal of Cannabis Research, 2021; 3:5.
  8. Binkowska AA, Jakubowska N, Redeł A, et al. Cannabidiol usage, efficacy, and side effects: analyzing the impact of health conditions, medications, and cannabis use in a cross-sectional online pilot study. Frontiers in Psychiatry, 2024; 15:1356009.
  9. Kaufmann R, Bozer AH, Jotte AK, Aqua K. Long-term, self-dosing CBD users: indications, dosage, and self-perceptions on general health/symptoms and drug use. Medical Cannabis and Cannabinoids, 2023; 6:77-88.
  10. Patra PB, Wadsworth RM. Quantitative evaluation of spermatogenesis in mice following chronic exposure to cannabinoids. Andrologia, 1991; 23:151-156.
  11. Rosenkrantz H, Fleischman RW, Grant RJ. Toxicity of short-term administration of cannabinoids to rhesus monkeys. Toxicology and Applied Pharmacology, 1981; 58:118-131.
  12. Mandal TK, Das NS. Testicular toxicity in cannabis extract treated mice: association with oxidative stress and role of antioxidant enzyme systems. Toxicol Ind Health. 2010;26(1):11-23. doi:10.1177/0748233709354553
  13. Huang HF, Nahas GG, Hembree WC 3rd. Effects of marihuana inhalation on spermatogenesis of the rat. Adv Biosci. 1978;22-23:419-427.
  14. Dixit VP, Gupta CL, Agrawal M. Testicular degeneration and necrosis induced by chronic administration of cannabis extract in dogs. Endokrinologie. 1977;69(3):299-305.
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