Adverse Events Associated with Oral CBD According to Controlled Trials

Cannabidiol (CBD) is a compound extracted from the cannabis plant. It is increasingly found within healthcare settings as a prescription-only medicine, but also commercially in food, drink and wellness products. 

There are a growing number of studies – including randomised controlled trials (RCTs) – being published with the aim to evaluate the safety and efficacy of such products. 

With respect to its use as a medicine in the UK, Epidyolex (GW Pharmaceuticals), a CBD isolate medication, is licensed and available on the NHS in conjunction with clobazam for children with treatment-resistant epilepsy in the context of Lennox-Gastaut and Dravet Syndromes. This is replicated in many other jurisdictions with some also licensing the medication for those with Tuberous Sclerosis Complex. CBD may also form part of a preparation of an unlicensed cannabis-based medicinal product. 

Anecdotal evidence continues to reveal how consumers are purchasing more non-medial CBD products than ever before; however, there is currently little evidence to suggest the efficacy of commercial CBD products for these uses. 

CBD is commonly reported by proponents to have a favourable side effect profile. For example, the most commonly reported side effects of Epidyolex include sleepiness, decreased appetite, diarrhoea, increased liver enzymes, sleep problems, and rash.

Two recent systematic reviews, however, may indicate that CBD exposure may be linked to more serious adverse events (SAEs), such as elevated liver enzymes, convulsion, sedation, lethargy, and upper respiratory tract infections, though both reviews reported being limited to childhood epilepsy which may indicate that CBD may have interacted with other medications such as clobazam or sodium valproate. With an increased demand for CBD-containing medicines and wellness products, it is, therefore, crucial to better understand the full side effect profile of CBD and its potential drug-drug interactions.

A 2022 systematic review aimed to “address this issue by updating previous systematic review on the SAEs of CBD and its interactions with other drugs in randomised clinical trials.” The present review is an update on a previous systematic review that assessed the adverse effects associated with oral CBD in studies between 1980 and early 2020.

Design and Methods 

Relevant double-blind, randomised controlled clinical trials that “reported data on adverse effects from controlled trials using repeated oral administration in humans with formulations containing purified CBD (≥98% CBD)” were included for review. Open-label studies that did not compare CBD with placebo or another drug or studies that lasted for less than seven days were excluded. The researchers conducted a search of EMBASE, MEDLINE/PubMed, and Web of Science databases to identify eligible studies published between January 2019 and May 2022.

Findings of the Review

A total of 12 RCTs that involved 745 randomised participants were included in the final systematic review. Eleven of the included studies were placebo-controlled, and one used an active control, with 454 participants using oral CBD across the trials. Daily CBD doses included fixed doses (300mg/day to 800 mg/day) and doses adjusted by weight (from 20 mg/kg/day to 50 mg/kg/day) and most studies (9/12) used CBD in addition to other drugs. 

All of the included studies assessed the effects of CBD on clinical populations, including patients with epilepsy (2), cocaine use disorder (2), psychosis (1), high risk of psychosis (1), drug-resistant seizures in tuberous sclerosis complex (1), cannabis use disorder (1), COVID-19 (1), rapid eye movement sleep disorder (1), behavioural problems in children and adolescents with intellectual disability (1), and functional dyspepsia (1).

Adverse Effects of CBD

Most studies included in the present review (9/12) found that CBD was associated with mild and moderate adverse effects (AEs). The most common AEs included gastrointestinal symptoms (59.5%), somnolence (drowsiness) (16.7%), loss of appetite (16.5%), increased ALT/AST liver enzymes (12.8%), and fatigue (11.4%). SAEs were significantly less common. SAEs were reported in only three of the 12 included studies – all of which were observed in participants with epilepsy. 

In each incidence, SAEs were reported in the context of using CBD at doses between 20-50 mg/kg/day as an add-on therapy to anticonvulsant medications, including clobazam and valproate. The most common SAEs were raised liver enzymes (ALT/AST) with serum levels elevations greater than three times the upper limit (6.4%), seizures (1.3%), and rash (1.1%). Overall, dosages of over 25 mg/kg/day were associated with higher incidences of SAEs.

Discussion and Conclusions

The author’s previous systematic review on this topic – published in 2020 – reported that “CBD had mild to moderate adverse effects in most studies, the most common being drowsiness, sedation, fatigue, dizziness, headache, diarrhoea, nausea, decreased appetite, and abdominal discomfort.” The earlier review also found that the highest incidence of SAEs occurred in RCTs on epilepsy; the most common were severe drowsiness, lethargy, elevated liver enzymes, rash, and pneumonia with or without respiratory failure.

The authors note that their most recent systematic review offers an update to the existing literature, including data from the most recently published RCTs. However, it is noted that the conclusions drawn by this review may be limited by the relatively small sample size of the included RCTs and the absence of studies with low doses of purified CBD. Nonetheless, as demand for CBD-based therapies continues to rise, this review offers valuable insight into the side effect profile of purified oral CBD. Existing studies suggest that “the most common adverse effects are mild and moderate, and serious adverse effects are rare and have been only reported in epilepsy studies, with concomitant use of CBD with antiepileptic drugs.”

The researchers conclude their review with the suggestion that future studies assess the safety and efficacy of CBD through clinical trials with larger samples, different dosages, and different products (e.g., comparing purified CBD with broad- or full-spectrum CBD extracts).