Effectiveness and safety of different administration routes of medical cannabis or cannabinoids for chronic pain in adults: a systematic review and network meta-analysis with GRADE assessment

Background Chronic pain lasting more than 3 months affects more than one billion people globally, ranking as the third most prevalent health burden, after cardiovascular diseases and malignancies. This study aimed to evaluate the effectiveness and safety of medical cannabis or cannabinoids for chronic pain in adults, with prespecified subgroup analyses stratified by pain etiology and administration route to support precision pain management. Methods A systematic literature search was conducted across PubMed, EMBASE, and the Cochrane Library from each database’s inception to 15 March 2025. The certainty of evidence was assessed with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. The focused outcomes were pain relief, sleep quality, physical and emotional functioning, anxiety, depression, and adverse events. Results Twenty-eight studies were involved. Compared to placebo, palmitoylethanolamide (PEA) (SMD = −0.82, 95% CI:−1.36 to −0.29; very low) and tetrahydrocannabinol (THC) (SMD = −0.41, 95% CI:−0.74 to −0.07; low) provided pain relief, and a THC/cannabidiol (CBD) combination significantly improved sleep quality (SMD = −0.43, 95% CI:−0.62 to −0.24; moderate). Regarding safety outcomes, compared to placebo, THC (RR = 3.55, 95% CI: 2.21 to 5.68; low) and THC/CBD (RR = 2.70, 95% CI: 1.60 to 4.53; high) had a relatively high rate of dizziness, and THC (RR = 2.72, 95% CI: 1.76 to 4.22; low) and THC/CBD (RR = 2.92, 95% CI: 1.74 to 4.90; high) had a significant risk of somnolence. THC/CBD elevated nausea risk (RR = 1.81, 95% CI: 1.26 to 2.60; high), while THC increased dry mouth incidence (RR = 3.14, 95% CI: 1.75 to 5.63; moderate). Additionally, compared with placebo for pain relief, CBD demonstrated the greatest effectiveness for cancer-related pain (SMD = −1.62, 95% CI:−2.03 to −1.21), whereas PEA showed optimal effectiveness in non-cancer-related pain (SMD = −0.82, 95% CI:−1.31 to −0.33). Conclusion This study suggested that medical cannabis or cannabinoids might have certain efficacy for adult chronic pain. PEA and THC provided pain relief, while the THC/CBD combination showed a potential benefit for sleep quality improvement. THC was associated with increased risks of dizziness, somnolence, and dry mouth, and THC/CBD was associated with dizziness, somnolence, and nausea. Subgroup analyses suggested that treatment response might vary by pain etiology and administration route. Given that the evidence certainty is mainly low to very low, the research conclusion still requires a large sample and high-quality randomized controlled trials (RCTs) to be verified. Systematic Review Registration https://osf.io/h56g9 , Unique Identifier: 10.17605/OSF.IO/H56G9.