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Cannabidiol and Liver Enzyme Level Elevations in Healthy Adults: A Randomized Clinical Trial

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

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

Keywords 
cannabidiol aspartate aminotransferases alanine transaminase Double-Blind Method liver cannabinoids

Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years: A systematic review and meta-analysis

Author/s: 
Velayudhan, Latha, McGoohan, Katie, Bhattacharyya, Sagnik

Background: Cannabinoid-based medicines (CBMs) are being used widely in the elderly. However, their safety and tolerability in older adults remains unclear. We aimed to conduct a systematic review and meta-analysis of safety and tolerability of CBMs in adults of age ≥50 years.

Methods and findings: A systematic search was performed using MEDLINE, PubMed, EMBASE, CINAHL PsychInfo, Cochrane Library, and ClinicalTrials.gov (1 January 1990 to 3 October 2020). Randomised clinical trials (RCTs) of CBMs in those with mean age of ≥50 years for all indications, evaluating the safety/tolerability of CBMs where adverse events have been quantified, were included. Study quality was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two reviewers conducted all review stages independently. Where possible, data were pooled using random-effects meta-analysis. Effect sizes were calculated as incident rate ratio (IRR) for outcome data such as adverse events (AEs), serious AEs (SAEs), and death and risk ratio (RR) for withdrawal from study and reported separately for studies using tetrahydrocannabinol (THC), THC:cannabidiol (CBD) combination, and CBD. A total of 46 RCTs were identified as suitable for inclusion of which 31 (67%) were conducted in the United Kingdom and Europe. There were 6,216 patients (mean age 58.6 ± 7.5 years; 51% male) included in the analysis, with 3,469 receiving CBMs. Compared with controls, delta-9-tetrahydrocannabinol (THC)-containing CBMs significantly increased the incidence of all-cause and treatment-related AEs: THC alone (IRR: 1.42 [95% CI, 1.12 to 1.78]) and (IRR: 1.60 [95% CI, 1.26 to 2.04]); THC:CBD combination (IRR: 1.58 [95% CI,1.26 to 1.98]) and (IRR: 1.70 [95% CI,1.24 to 2.33]), respectively. IRRs of SAEs and deaths were not significantly greater under CBMs containing THC with or without CBD. THC:CBD combination (RR: 1.40 [95% CI, 1.08 to 1.80]) but not THC alone (RR: 1.18 [95% CI, 0.89 to 1.57]) significantly increased risk of AE-related withdrawals. CBD alone did not increase the incidence of all-cause AEs (IRR: 1.02 [95% CI, 0.90 to 1.16]) or other outcomes as per qualitative synthesis. AE-related withdrawals were significantly associated with THC dose in THC only [QM (df = 1) = 4.696, p = 0.03] and THC:CBD combination treatment ([QM (df = 1) = 4.554, p = 0.033]. THC-containing CBMs significantly increased incidence of dry mouth, dizziness/light-headedness, and somnolence/drowsiness. Study limitations include inability to fully exclude data from those <50 years of age in our primary analyses as well as limitations related to weaknesses in the included trials particularly incomplete reporting of outcomes and heterogeneity in included studies.

Conclusions: This pooled analysis, using data from RCTs with mean participant age ≥50 years, suggests that although THC-containing CBMs are associated with side effects, CBMs in general are safe and acceptable in older adults. However, THC:CBD combinations may be less acceptable in the dose ranges used and their tolerability may be different in adults over 65 or 75 years of age.

Keywords 
RISEOK aged opioids opioid abuse cannabinoids cannabidiol

Does CBD Actually Work?

Author/s: 
Avins, Jenni

Perhaps you’ve heard a lot of people are using CBD.

The chemical compound, naturally occurring in cannabis plants, doesn’t get you high, but does have a wide swath of other purported effects making it very popular. Although clinical studies haven’t necessarily proven those results, many Americans are testing CBD (which stands for “cannabidiol”) for themselves. All over the US, people are rubbing CBD balm onto aching joints, dropping CBD tinctures under tired tongues, popping CBD gummies, and puffing on CBD oil-filled vaporizers in hopes of chilling out.

On Quartz’s behalf, Harris Poll recently surveyed more than 2,000 people in the US about their experience, knowledge, and opinions regarding CBD and found that more than 85% of Americans have heard of CBD, and of those, more than one in five have tried it.

Keywords 
CBD cannabis cannabidiol

Lack of evidence for cannabis in adults with chronic neuropathic pain

Author/s: 
McAvoy, Brian R.

Bottom Line:

There was no high-quality evidence for the efficacy of any CBM (herbal cannabis, plant-derived tetrahydrocannabinol (THC) (dronabinol), synthetic THC (nabilone), plant-derived THC/cannabidiol (CBD) com bination) in any condition with chronic neuropathic pain. The studies were two to 26 weeks long and compared an oromucosal spray with a plant-derived combination of THC and CBD (10 studies), a synthetic cannabinoid mimicking THC (nabilone) (two studies), inhaled herbal cannabis (two studies) and plant-derived THC (dronabinol) (two studies) against placebo (15 studies) and an analgesic (dihydrocodeine) (one study). Herbal cannabis was not different from placebo in reducing pain and the number of people who dropped out due to side effects. Some adverse events (particularly somnolence or sedation, confusion, psychosis) might limit the clinical usefulness of cannabis-based medicines.

Keywords 
medical marijuana cannabis neuralgia neuropathic pain cannabidiol
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