The endocannabinoid system that includes endogenous cannabinoids and cannabinoid receptors [11] regulates pain-related processes [10]. This system is highly integrated within the nervous system circuitry and has an effect upon multiple signaling pathways, as well as being affected by these pathways [11]. Disruption of the endocannabinoid system can contribute to persistent pain [10]. Cannabis strains contain various cannabinoids at different concentrations that bind to cannabinoid receptors found in the brain and peripheral areas [10]. We had previously shown that the use of cannabis can alleviate symptoms of CIPN in patients undergoing chemotherapy [15]. In order to further substantiate the efficacy of medical cannabis and to enhance our understanding of pharmacodynamics, we now retrospectively analyzed variations in THC and CBD doses and their correlation with CIPN symptom alleviation. Our results showed an improvement in all symptoms after six months of uninterrupted cannabis consumption, as well as an overall improvement in ADL and QOL in both groups. We also found that higher doses of both THC and CBD were associated with greater improvement in symptoms.

CB1 and CB2 are the most studied cannabinoid receptors in the human body [11]. CB1 is widely expressed in regions of the brain, including those associated with pain processing and modulation [5,7,9], while CB2 is primarily found in immune cells and in the spleen [6,7,9]. THC is a partial agonist for CB1 and CB2 receptors [5,9]. It produces a psychoactive effect, as well as analgesic, anti-inflammatory, and anti-oxidant effects [6]. In contrast, CBD does not directly interact with the endocannabinoid system due to its low affinity for CB1 and CB2 receptors. However, it may act as a non-competitive inverse agonist, blocking the activation of these receptors [11].

Our findings carry several potential clinical implications. The significant improvement in CIPN symptoms, ADL, and QOL, particularly in the THC-high cluster, supports the clinical use of medical cannabis as a complementary therapeutic option for patients with chemotherapy-induced neuropathy who experience limited relief from standard therapies. The dose-dependent effect of both THC and CBD observed in this study suggests that individualized dose titration, based on patient-reported symptom profiles, may optimize therapeutic benefit while minimizing adverse effects. Moreover, the observed improvement in functionality (ADL) underscores the potential of cannabis to improve daily living and overall patient well-being, aspects often overlooked in traditional CIPN management. Finally, given the additive effect of CBD on THC-induced symptom improvement, clinicians may consider strain selection and ratio adjustment as part of a personalized treatment approach.

This study has several limitations that bear mention. First, its retrospective design relies upon pre-existing data, which limits the ability to control for confounding variables and establish definitive causal relationships between cannabis treatment and its outcomes. Additionally, the study was conducted at a single facility in Israel, which may constrain the generalizability of the findings to other regions or healthcare settings. The participants were individuals who were actively seeking cannabis therapy, thereby introducing potential selection bias and reducing the representativeness of the sample relative to the broader patient population. Moreover, the study focused solely upon two primary cannabinoid dosages, and there are numerous active compounds in cannabis-based treatments that could have impacted the outcomes. The unequal sample sizes between the CBD-high (n = 620) and THC-high (n = 131) clusters, as well as overlapping dose ranges, may affect the validity of the observed differences and require cautious interpretation.

Finally, the data that were derived from self-reports by the participants increased the risk of recall bias and potential inaccuracies.