Introduction:The IASP ICD-11 chronic primary pain (CPP) definition includes 19 different painful conditions. In recent years, interest in the potential role of cannabinoids in the management of CPP has increased, since they demonstrated a possible efficacy in treating pain, especially in secondary pain conditions. However, limited evidence is available for patients with CPP. The aim of this systematic review and meta-analysis is to evaluate the efficacy and safety of cannabinoid administration in CPP. Methods: PubMed, EMBASE, and Cochrane Library were searched form the beginning up to 31 October 2021 to retrieve published articles of randomized controlled trials (RCTs) or observational, retrospective or prospective, studies, investigating cannabinoids in CPP. The study screening process was completed during November 2021. The primary outcome was pain reduction by means of the visual analogue scale (VAS). Secondary outcomes were quality of life by means of the fibromyalgia impact questionnaire (FIQ) or other available scales, appetite, anxiety, depression, and sleep by means of any available scales. Safety was assessed with the reporting of serious adverse events (SAE) and discontinuation due to adverse events. Risk of bias was assessed. The weighted generic inverse Riccardo Giossi and Federica Carrara have equally contributed to this study.