Phytochemical Modulators of Nociception: A Review of Cannabis Terpenes in Chronic Pain Syndromes

Cannabis sativa L. is a medicinally versatile plant rich in phytochemicals, among which terpenes are gaining recognition for their potential roles in modulating pain and inflammation. Traditionally appreciated for their aromatic characteristics, terpenes such as myrcene, β-caryophyllene (BCP), limonene, pinene, linalool and humulene have demonstrated diverse biological effects relevant to chronic pain syndromes. While the analgesic effects of cannabinoids like Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been widely studied, growing evidence suggests that specific terpenes can exert antinociceptive, anti-inflammatory, and anxiolytic effects through distinct molecular mechanisms. These include activation of cannabinoid receptor 2 (CB₂) receptors, modulation of Transient receptor potential (TRP) and adenosine receptors, and inhibition of pro-inflammatory pathways such as Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Cyclooxygenase-2 (COX-2). In addition, some terpenes influence glutamatergic, GABAergic, and opioid signalling, contributing to central and peripheral analgesia. This review synthesizes the current preclinical and emerging clinical data on terpene-mediated analgesia, highlighting both monoterpenes and sesquiterpenes, and discusses their potential for synergistic interaction with cannabinoids—the so-called entourage effect. Although preclinical findings are promising, clinical translation is limited by methodological variability, lack of standardized formulations, and insufficient pharmacokinetic characterization. Further human studies are essential to clarify their therapeutic potential.