The positive results reported by patients in this case series are consistent with the current literature that cannabis products can decrease neuropathic pain in people, from a variety of conditions, including CIPN. Most of the patients reporting benefit described a partial decrease in painful CIPN symptoms with the onset of perceived benefit in about 10 to 15 minutes; this benefit generally lasted a few hours up to 24 hours. However, a minority of patients using topical products did not report any benefit. Only 1 patient reported a side effect, that being transient worsening of neuropathic pain: this patient discontinued use of the cream.

There are multiple preclinical models to suggest mechanisms by which cannabinoids may help alleviate CIPN. In rodent models of CIPN, a decrease of endocannabinoid levels has been observed, suggesting activation of the system may provide benefit.^{47bibr48-15347354211061739-49} Indeed, THC and additional CB₁ and CB₂ receptor agonist, or modulators of the endocannabinoid system, have been shown to suppress neuropathic pain, by several different mechanisms, ²⁹ including in models of CIPN. ²⁶ Cannabinoid receptors, in particular CB₁ receptors, can alter the activity of GABAergic and glutamatergic signaling in the brain and spinal cord. ⁵⁰ In rats, a mixed CB₁ and CB₂ receptor agonist suppressed nociception via a CB₁ specific mechanism ⁵¹ as well as vincristine associated neuropathy via CB₁ and CB₂ receptor activation. ⁵² In another rat model, a CB₂ selective agonist attenuated painful neuropathy induced by paclitaxel. ⁵³ The authors suggest that activation of CB₂ suppresses nociception and central sensitization in a variety of tissue and nerve injury models of persistent pain. ⁵⁴ Neuropathic pain may also involve abnormal hyper-excitability in skin afferent nerves. Skin cells express CB2 and endothelin receptors, and when activated, release B-endorphin, which can reduce hyperalgesia mediated by pro-inflammatory pathways.^55,56

An additional potential mechanism of CB₁ and CB₂ receptor activation leading to suppression of neuropathic pain is from modulation of immune system function. THC and the endocannabinoid system can inhibit the release of pro-inflammatory cytokines throughout the inflammatory response, by targeting T and B cells, and macrophage activity. ²⁹

Similar to CB₁ and CB₂ receptors agonists, the neuroprotective and anti-inflammatory properties of CBD provide a potential mechanism for the protective effects of CBD in neuropathic pain, including CIPN. ⁵⁷ For example, CBD has been shown to directly or indirectly modulate several receptors involved in modulating pain signaling, including 5-HT_1A, ³⁴ and transient receptors TRPV1 and TRPA1.^28,31 TRPV1 receptors are present in sensory peripheral nerves as well as keratinocytes and are activated by capsaicin, as well as by endogenous cannabinoids. ⁵⁸ Capsaicin is a TRPV agonist that has been extensively studied in pain and has activity in treating neuropathic pain. It leads to overstimulation and desensitization of nociceptors and may lead to nerve regeneration and restoration. ⁵⁹ A placebo-controlled, double-blinded, crossover trial of a capsaicin cream demonstrated that it substantially decreased chronic post-surgical scar pain and its benefit persisted after stopping the capsaicin. ⁶⁰ CBD may also act as a neuroprotective agent as a result of direct antioxidant activity. ⁶¹ During secondary injury, CBD can reduce intracellular calcium levels and have neuroprotective effects. ⁶² CBD reduces mitochondrial damage during events of cellular stress, thereby diminishing generation of inflammatory and oxidative products. ⁶³ CBD also inhibits microglial proliferation and pro-inflammatory cytokines and increases anti-inflammatory cytokine production in vivo.^31,32,64

Patients in this case report reporting benefit were using both topical CBD alone (n = 12) and a combination of CBD/THC topicals (n = 10). Given that CBD is a negative modulator of CB1, it would seem that topical THC working via a CB1 mechanism would not be involved in anti-nociception. The role of CBD and THC or the combination would need to be studied in a clinical trial to determine the contribution of each compound toward pain relief. Cannabis contains not only CBD and THC but many other cannabinoids and terpenoids which appear to play a role in its activity. The “entourage effect” describes the synergy of all of the compounds observed when using whole plant-based products which may be more effective than isolated compounds. ⁶⁵ However, conducting research using THC and/or whole plant extracts is very difficult given federal regulations and extreme heterogeneity in types and concentrations of products.

This case series has limitations given the retrospective nature of the study, the lack of control groups, and wide heterogeneity of products used by patients. The placebo effect has also been demonstrated in a study in which an experimental product was shown to help symptoms regardless of whether subjects received cannabis or not. ⁶⁶ However, experience in the clinic suggests that more patients surveyed responded to topical cannabis products than did not and provides the rationale for proceeding with a randomized placebo-controlled trial using a standardized product to determine the actual efficacy of such treatment.