Adverse effects of cannabidiol: a systematic review and meta-analysis of randomized clinical trials

Abstract

Cannabidiol (CBD) is being investigated as a treatment for several medical disorders but there is uncertainty about its safety. We conducted the first systematic review and meta-analysis of the adverse effects of CBD across all medical indications. Double-blind randomized placebo-controlled clinical trials lasting ≥7 days were included. Twelve trials contributed data from 803 participants to the meta-analysis. Compared with placebo, CBD was associated with an increased likelihood of withdrawal for any reason (OR 2.61, 95% CI: 1.38–4.96) or due to adverse events (OR 2.65, 95% CI: 1.04–6.80), any serious adverse event (OR 2.30, 95% CI: 1.18–4.48), serious adverse events related to abnormal liver function tests (OR 11.19, 95% CI: 2.09–60.02) or pneumonia (OR 5.37, 95% CI: 1.17–24.65), any adverse event (OR 1.55, 95% CI: 1.03–2.33), adverse events due to decreased appetite (OR 3.56, 95% CI: 1.94–6.53), diarrhoea (OR 2.61, 95% CI: 1.46–4.67), somnolence (OR 2.23, 95% CI: 1.07–4.64) and sedation (OR 4.21, 95% CI: 1.18–15.01). Associations with abnormal liver function tests, somnolence, sedation and pneumonia were limited to childhood epilepsy studies, where CBD may have interacted with other medications such as clobazam and/or sodium valproate. After excluding studies in childhood epilepsy, the only adverse outcome associated with CBD treatment was diarrhoea (OR 5.03, 95% CI: 1.44–17.61). In summary, the available data from clinical trials suggest that CBD is well tolerated and has relatively few serious adverse effects, however interactions with other medications should be monitored carefully. Additional safety data from clinical trials outside of childhood epilepsy syndromes and from studies of over-the-counter CBD products are needed to assess whether the conclusions drawn from clinical trials can be applied more broadly.

Lack of evidence for the effectiveness or safety of over-the-counter cannabidiol products

“…In clinical trials, a typical CBD dose might be approximately 1000 mg/day, often taken in two divided doses. 4 For childhood epilepsy syndromes the recommended dose is 10–20 mg/kg/day. However, most OTC preparations contain much smaller amounts of CBD.…”

“… 34 This interaction with clobazam may account for the increased risk of sedation and pneumonia seen in clinical trials of CBD in Dravet and Lennox–Gastaut syndrome. 4 It is important to note that the doses used in clinical studies (at least 5 mg/kg) are much higher than in OTC preparations (5–20 mg/day). However, there are (non-peer-reviewed) reports that drug interactions may occur at doses as low as 1 mg/kg CBD.…”

“…Most of the clinical trials with positive findings have studied the effects of CBD at doses considerably higher than in OTC preparations (>300 mg/day or 10 mg/kg/day). 4 Nevertheless, at least eight randomized placebo controlled clinical trials have examined the effects of CBD (or CBD predominant CBME) at low doses ( Table 3 ). Most of these studies were small and reported limited efficacy with few adverse effects.…”

“…A recent meta-analysis of randomized clinical trials found that, compared to placebo, CBD is associated with reduced tolerability and increased risks of pneumonia, abnormal liver function tests, decreased appetite, diarrhoea, somnolence and sedation. 4 However, after excluding studies in epilepsy, in which CBD has pharmacokinetic interactions with clobazam and sodium valproate, diarrhoea was the only adverse event present. In this meta-analysis, the majority of the studies used doses above 300 mg/day or 10 mg/kg/day.…”

“…3 However, despite the widespread availability of these products, the safety and efficacy of OTC CBD are unclear. 1 , 4 We sought to address this issue in the present review.…”