Importance The wide use of unregulated cannabidiol (CBD) products among consumers raises safety concerns. Most research on CBD has studied the relatively high doses used by patients taking prescription CBD. However, limited safety data are available at lower doses.

Objective To study the effects of 4-weeks of twice-daily CBD use on the liver and endocrine hormones using a dose within the range consumers are taking with unregulated CBD products.

Design, Setting, and Participants This randomized double-blinded placebo-controlled trial from January to August 2024, using per protocol analysis, included healthy adults recruited from a clinical pharmacology unit (Spaulding Clinical Research in West Bend, Wisconsin).

Interventions Healthy participants were randomized to CBD, 5 mg/kg/d (2.5 mg/kg/d twice daily), or placebo for 28 days with weekly laboratory assessments.

Main Outcomes and Measures The primary end point was the percentage of participants with an alanine aminotransferase or aspartate aminotransferase level elevation greater than 3 times the upper limit of normal during the study.

Results In 201 healthy participants (median age, 36 years [IQR, 30-43 years]; 89 women [44%]), 8 participants (5.6%; 95% CI, 1.8%-9.3%) in the CBD group and 0 participants (0%; 95% CI, 0%-7.6%) in the placebo group had liver enzyme level elevation greater than 3 times the upper limit of normal. Seven participants met withdrawal criteria for potential drug-induced liver injury, detected at day 21 in 2 participants and day 28 in 5 participants. No differences in change from baseline were observed between the CBD and placebo groups for total testosterone and inhibin B in male participants or thyrotropin, total triiodothyronine, and free thyroxine in all participants.

Conclusions and Relevance In this study, the incidence of elevated alanine aminotransferase or aspartate aminotransferase coupled with the finding of increased eosinophilia, underscores 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.

Trial Registration ClinicalTrials.gov Identifier: NCT06192589

Author/s:

Jeffry Florian, Pablo Salcedo, Keith Burkhart, Aanchal Shah, Lakshmi Manasa S Chekka, Dro Keshishi, Vikram Patel, ShanChao Yang, Melanie Fein, Ryan DePalma, Murali Matta, David G Strauss, Rodney Rouse