Beyond the high: Therapeutic insights into Cannabis sativa and endocannabinoid control of pain

Abstract

Chronic pain is a debilitating and progressive disorder affecting a substantial proportion of the population, with approximately 30–50% of individuals experiencing chronic pain and 10–15% reporting inadequate relief from currently available therapies. Conventional analgesics, including opioids and tricyclic antidepressants, are often limited by tolerance, dependence, sedation, and other adverse effects, highlighting the urgent need for alternative treatment strategies. Cannabis sativa has emerged as a potential therapeutic agent for pain management due to its unique phytochemical composition and its ability to modulate the endocannabinoid system (ECS). Cannabinoid receptors, particularly CB1 receptors located in the central nervous system, regulate neurotransmitter release and play a key role in pain perception, while CB2 receptors, predominantly expressed in immune cells and peripheral tissues such as dorsal root ganglia, mediate anti-inflammatory and neuroimmune mechanisms of analgesia. In addition to classical cannabinoid signaling, accumulating evidence indicates that cannabinoids also target non-canonical pain pathways, including transient receptor potential vanilloid 1 (TRPV1) channels and calcitonin gene-related peptide (CGRP) signaling, which are critically involved in nociception, peripheral and central sensitization, and neurogenic inflammation. Preclinical studies demonstrate that CB2-targeted cannabinoids alleviate inflammatory and neuropathic pain by modulating TRP channels, enhancing endocannabinoid tone, and reducing pro-inflammatory cytokine release with minimal central nervous system side effects. This review discusses the therapeutic potential of cannabis in pain management by integrating classical and non-classical mechanisms, highlighting emerging molecular targets and translational perspectives aimed at improving patient outcomes in chronic pain treatment.