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We identified 29 animal and 35 human studies. In mice, a meta-analysis of pooled studies showed that treatment of osteolysis-bearing males with the endocannabinoids AEA and 2-AG (mean difference [MD] \u2212\u200924.83, 95% confidence interval [<jats:sup>95%<\/jats:sup>CI] \u2212\u200934.89, \u2212\u200914.76, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.00001) or the synthetic cannabinoid (CB) agonists ACPA, WIN55,212-2, CP55,940 (CB<jats:sub>1\/2<\/jats:sub>-non-selective) and AM1241 (CB<jats:sub>2<\/jats:sub>-selective) (MD \u2212\u200928.73, <jats:sup>95%<\/jats:sup>CI \u2212\u200945.43, \u2212\u200912.02, <jats:italic>p<\/jats:italic>\u2009=\u20090.0008) are associated with significant reduction in paw withdrawal frequency. Consistently, the synthetic agonists AM1241 and JWH015 (CB<jats:sub>2<\/jats:sub>-selective) increased paw withdrawal threshold (MD 0.89, <jats:sup>95%<\/jats:sup>CI 0.79, 0.99, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.00001), and ACEA (CB<jats:sub>1<\/jats:sub>-selective), AM1241 and JWH015 (CB<jats:sub>2<\/jats:sub>-selective) reduced spontaneous flinches (MD \u2212\u20094.85, <jats:sup>95%<\/jats:sup>CI \u2212\u20096.74, \u2212\u20092.96, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090. 00001) in osteolysis-bearing male mice. In rats, significant increase in paw withdrawal threshold is associated with the administration of ACEA and WIN55,212-2 (CB<jats:sub>1\/2<\/jats:sub>-non-selective), JWH015 and AM1241 (CB<jats:sub>2<\/jats:sub>-selective) in osteolysis-bearing females (MD 8.18, <jats:sup>95%<\/jats:sup>CI 6.14, 10.21, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.00001), and treatment with AM1241 (CB<jats:sub>2<\/jats:sub>-selective) increased paw withdrawal thermal latency in males (mean difference [MD]: 3.94, <jats:sup>95%<\/jats:sup>CI 2.13, 5.75, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), confirming the analgesic capabilities of CB<jats:sub>1\/2<\/jats:sub> ligands in rodents. In human, treatment of cancer patients with medical cannabis (standardized MD \u2212\u20090.19, <jats:sup>95%<\/jats:sup>CI \u2212\u20090.35, \u2212\u20090.02, <jats:italic>p<\/jats:italic>\u2009=\u20090.03) and the plant-derived delta-9-THC (20\u00a0mg) (MD 3.29, CI 2.24, 4.33, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.00001) or its synthetic derivative NIB (4\u00a0mg) (MD 2.55, <jats:sup>95%<\/jats:sup>CI 1.58, 3.51, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.00001) are associated with reduction in pain intensity. Bioinformatics validation of KEGG, GO and MPO pathway, function and process enrichment analysis of mouse, rat and human data revealed that CB<jats:sub>1<\/jats:sub> and CB<jats:sub>2<\/jats:sub> receptors are enriched in a cocktail of nociceptive and sensory perception, inflammatory, immune-modulatory, and cancer pathways. Thus, we cautiously conclude that pharmacological modulators of CB<jats:sub>1\/2<\/jats:sub> receptors show promise in the treatment of cancer-induced bone pain, however further assessment of their effects on bone pain in genetically engineered animal models and cancer patients is warranted.<\/jats:p>","DOI":"10.1038\/s41598-024-56220-0","type":"journal-article","created":{"date-parts":[[2024,3,9]],"date-time":"2024-03-09T06:01:44Z","timestamp":1709964104000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Classical cannabinoid receptors as target in cancer-induced bone pain: a systematic review, meta-analysis and bioinformatics validation"],"prefix":"10.1038","volume":"14","author":[{"given":"Feier","family":"Zeng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbie","family":"Wade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kade","family":"Harbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrina","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua S.","family":"Holley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia K.","family":"Dehghanpuor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Hopwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Marino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Sophocleous","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aymen I.","family":"Idris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,9]]},"reference":[{"key":"56220_CR1","first-page":"381","volume":"3","author":"H Nersesyan","year":"2007","unstructured":"Nersesyan, H. & Slavin, K. 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