Long-term efficacy and adverse effects of cannabidiol in adjuvant treatment of drug-resistant epilepsy: a systematic review and meta-analysis.

Background: Epilepsy is one of the most common chronic brain diseases. Almost one-third of patients have drug-resistant epilepsy (DRE). Cannabidiol is being considered as a potential novel drug for treating DRE. Objectives: To investigate long-term efficacy and safety of cannabidiol in treatment of DRE and the differences in cannabidiol treatment among patients with different characteristics. Design: Systematic review and meta-analysis. Data sources and methods: Medline, Embase, and CENTRAL were searched for literature. RevMan5.4 was used for meta-analysis. The Intention-to-treat set and the random effect were used as the main analysis. Subgroup analyses were performed according to age, dose, concomitant antiseizure medications (ASMs), epilepsy syndromes, and study designs. Results: Fifty studies were included in this systematic review. A total of 4791 participants were collected. The responder rates (seizure frequency reduced at least 50%) at 12-, 24-, 48-, 72-, 96-, and 144-week were 0.40 [0.36, 0.45], 0.39 [0.34, 0.44], 0.37 [0.30, 0.44], 0.27 [0.17, 0.37], 0.22 [0.14, 0.30], and 0.38 [0.23, 0.53]. Seizure-free rates were 0.04 [0.03, 0.06], 0.04 [0.03, 0.05], 0.03 [0.02, 0.05], 0.03 [0.02, 0.03], 0.02 [0.01, 0.03], and 0.04 [0.01, 0.06]. Proportion of adverse events were 0.72 [0.61, 0.83], 0.62 [0.42, 0.81], 0.60 [0.41, 0.79], 0.35 [0.14, 0.56], 0.83 [0.75, 0.90], and 0.96 [0.94, 0.99]. The pooled 12-, 24-, 48-, 96-, and 144-week proportion of serious adverse events were 0.15 [0.09, 0.21], 0.23 [0.14, 0.31], 0.10 [0.06, 0.15], 0.31 [0.24, 0.38], and 0.40 [0.35, 0.45]. Subgroup analyses showed that there was no significant difference on efficacy and safety among age subgroups and epilepsy syndromes subgroups. For most periods, there were no significant difference on efficacy among subgroups of dose and concomitant ASMs. However, higher doses and more concomitant ASMs were associated with higher proportion of adverse events. Conclusion: Cannabidiol treatment of DRE has stable efficacy and fewer adverse events in early period. Long-term use may have decreased efficacy and increased adverse events. Dose escalation may not increase efficacy, but may increase adverse events. Furthermore, cannabidiol use may reduce dosage of other ASMs without reducing efficacy, thereby reducing adverse effects. Cannabidiol may have similar effects in various epilepsy syndromes. Trial registration: PROSPERO (CRD42022351250).