Cannabinoids in Chronic Pain: Clinical Outcomes, Adverse Effects and Legal Challenges

Abstract

Cannabinoids have gained increasing attention as potential therapeutic agents in chronic pain management. Their mechanisms of action, mediated through CB1 and CB2 receptors, provide a pharmacological alternative to conventional analgesics. The evidence is strongest for neuropathic pain and multiple sclerosis-related spasticity, while the results for fibromyalgia, osteoarthritis, and musculoskeletal pain remain inconsistent. The average pain reduction is modest, often not exceeding 0.5-1.0 points on a 10-point scale, and therapeutic gains are offset by safety concerns. Quantitative data show that discontinuation rates range from 4.3% at low-dose CBD to 12.9% at high-dose CBD, compared with 3.5% on placebo, while nabiximols (THC + CBD spray) are associated with dizziness in 25% of patients, somnolence in 8%, and treatment discontinuation in 12%. High-dose CBD also carries a measurable risk of hepatotoxicity. Regulatory heterogeneity further constrains trial feasibility, scalability, and patient access, with disparities evident across the United States, Europe, Canada, and Australia. Overall, cannabinoids provide modest, condition-specific analgesia and should be considered adjunctive rather than first-line options, reserved for patients unresponsive to conventional therapy. Future progress requires standardized formulations, harmonized international regulations, long-term safety data, and large-scale randomized controlled trials to clarify their role in evidence-based pain management.

Keywords: analgesia; cannabinergic therapy; cannabis-based medicine; chronic pain management; endocannabinoid system; pain management.

Figure 1

Cannabinoid receptor-mediated mechanisms of action. Δ⁹-tetrahydrocannabinol (THC) binds to CB1 receptors on presynaptic neurons, resulting in inhibition of excitatory neurotransmitter release, and to CB2 receptors on macrophages, leading to reduced production of proinflammatory cytokines. Created in BioRender online application, available at https://app.biorender.com/ (accessed on 18 July 2025).

Figure 2

Synthesis and degradation of endogenous ligands. Anandamide (AEA) is generated by NAPE-PLD and degraded by FAAH, while 2-AG is synthesized by diacylglycerol lipases (DAGL-α/β) and degraded by monoacylglycerol lipase (MAGL). Created in BioRender online application, available at https://app.biorender.com/ (accessed on 28 August 2025).

Figure 3

Central and peripheral mechanisms of pain modulation mediated by the endocannabinoid system. Created in BioRender online application, available at https://app.biorender.com/ (accessed on 28 August 2025).

Figure 4

Postsynaptic anandamide release modulates presynaptic CB1/TRPV1, leading to depressed transmitter release and neural circuit polarization underlying central sensitization. Created in BioRender online application, available at https://app.biorender.com/ (accessed on 28 August 2025).

Figure 5

Glial modulation and neuroinflammation. CB₂ signaling dampens microglial activation and cytokine release, while astrocytic CB1 regulates gliotransmission and glutamate handling. Together with peripheral CB₂ effects, these mechanisms restore excitatory–inhibitory balance and reduce central sensitization. Created in BioRender online application, available at https://app.biorender.com/ (accessed on 28 August 2025).

Figure 6

Cannabinoid modulation of the descending pain pathway. CB1 receptors in the periaqueductal gray (PAG) and rostroventromedial medulla (RVM) regulate output to the spinal dorsal horn, while PAG inputs to the locus coeruleus shape noradrenergic antinociception. These circuits enhance descending inhibition and reduce pain transmission. Created in BioRender online application, available at https://app.biorender.com/ (accessed on 28 August 2025).