Authors
Shrishti Tyagi, Shreya Shrivastava, Vipin Kumar, Satyender Kumar, Sachin Gulia, Ujjawal Singh, Megha Thakur
Published in
Central nervous system agents in medicinal chemistry. Jul 03, 2026. Epub Jul 03, 2026.
Abstract
Neuropathic pain (NP) continues to be a significant clinical issue because the existing treatment modalities have very low efficacy and tolerability. An increasing body of mechanistic and translational data is identifying the endocannabinoid system (ECS) as a key regulator of nociceptive transmission, neuroinflammation, and maladaptive synaptic plasticity. This review critically synthesizes preclinical actions, pharmacological variety, and clinical trial evidence supporting cannabinoid-based interventions to NP, alongside identifying translational challenges, safety concerns, and emerging precision- medicine strategies.
The approach adopted was a narrative review approach. To identify the relevant literature, published within the last two decades, PubMed, Scopus, Web of Science, Google Scholar were searched using the keywords that are related to cannabinoids, endocannabinoid system, neuropathic pain, phytocannabinoids, and clinical trials. Relevance was used to select preclinical, mechanistic, and clinical studies. The article is written in the form of a narrative review and is not organized in the system of a systematic review.
The preclinical evidence demonstrates that cannabinoids regulate NP by acting through CB1- and CB2-mediated, inhibitory effects on the release of neurotransmitters, central sensitization, neuroinflammation and regulation of transient receptor potential (TRP) channels. Phytocannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), as well as synthetic cannabinoids, are effective in various experimental NP models. Clinical trials report variable but clinically significant decreases in the intensity of pain, sleep disturbance, and allodynia; although results vary depending on formulation, dose, route of administration, and heterogeneity of patients. Safety data show dose-related adverse effects, such as dizziness, cognitive impairment, and psychoactive effects, with CBD showing a relatively positive tolerability profile. Although there is a high level of mechanistic support, the translation to consistent clinical benefit is still limited due to pharmacokinetic variability, variation in the ratio of THC:CBD, and patient-specific factors. Other issues are standardization of formulations, safety testing in the long term, and variability in regulations.
The varied actions of cannabinoids on NP pathophysiology, through CB1/CB2 agonism, neuroinflammation suppression, and TRP modulation, are strongly supported by preclinical evidence, but are hampered by pharmacokinetic variability, inconsistent THC: CBD ratios and inconsistent patient response. CBD has a good tolerability despite the challenges such as regulatory barriers and lack of long-term safety evidence, which highlights the potential of CBD in precision tactics. To enhance the reliability of treatments, our findings demonstrate that the same delivery mechanisms and tailor-made dosages are needed.
Cannabinoids are a promising but emerging treatment option of neuropathic pain. Despite the strong preclinical evidence, the clinical outcomes are still heterogeneous. The future research should focus on optimizing cannabinoid-based therapies compositions, designing better delivery systems, and conducting a long-term safety evaluation to fully realize the translational potential of cannabinoid-based therapies in the management of NPs.
PMID:
42411099
Bibliographic data and abstract were imported from PubMed on 07 Jul 2026.
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