The endocannabinoid system and cannabinoid-based therapies in chemotherapy-induced neuropathic pain: from preclinical promise to limited clinical evidence

Chemotherapy-induced neuropathic pain (CINP) represents a major dose-limiting side effect of widely used chemotherapy agents such as platinums, taxanes and vinca alkaloids, causing significant morbidity and severely compromising patients’ quality of life. Clinically, CINP presents with spontaneous and evoked persistent pain—frequently manifesting as mechanical and thermal allodynia—and is often accompanied by additional sensory disturbances, motor dysfunction, cognitive impairment, and affective disorders. Despite its high prevalence, estimated to affect 30–60% of patients receiving certain regimens, current preventive measures are lacking, and available treatments remain largely palliative, failing to address the underlying neurobiological mechanisms. Consequently, there is an urgent need to identify novel strategies to prevent or mitigate CINP. The endocannabinoid system (ECS) has emerged as a key endogenous modulator of pain processing under both physiological and pathological conditions. Comprising the endogenous ligands anandamide and 2-arachidonoylglycerol, their synthesizing and metabolizing enzymes, and cannabinoid receptors CB1 and CB2, the ECS exerts multifaceted regulatory effects along the pain pathway, including the periphery, spinal cord, and brain. Experimental models of CINP have demonstrated dynamic changes in ECS components, suggesting dysregulation of endogenous cannabinoid signalling and highlighting its potential as a therapeutic target. Indeed, direct or indirect modulation of cannabinoid receptors has been shown to both prevent and mitigate behavioural indicators of pain in CINP models. Preclinical studies have also explored the analgesic and neuroprotective properties of phytocannabinoids, primarily Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), derived from the cannabis plant. Evidence indicates that both compounds, alone or in combination, can alleviate neuropathic pain in CINP models. Notably, while promising preclinical data support their analgesic potential, clinical translation has been limited, with only modest or inconsistent benefits reported in patients with CINP. These discrepancies underscore the need for rigorous preclinical characterization of phytocannabinoid formulations and dosing regimens to bridge the translational gap. In this review, we integrate and critically appraise preclinical and clinical evidence on cannabinoid‑based interventions in the context of CINP, with the aim of integrating current knowledge, highlighting key translational gaps and identifying priorities for future research.