Phase I Trial of CBG/CBD Oil for Chemotherapy‑Induced Peripheral Neuropathy

Introduction: The Burden of CIPN

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating adverse effect associated with several chemotherapeutic agents, particularly platinum-based drugs (e.g., cisplatin, oxaliplatin), taxanes, and vinca alkaloids. Affecting an estimated 30–40% of cancer patients, CIPN manifests as a constellation of sensory symptoms including paresthesia, dysesthesia, numbness, tingling, and burning pain. These symptoms often emerge during treatment and may persist long after therapy concludes, substantially impairing quality of life and functional independence. In severe cases, CIPN can limit chemotherapy dosing, leading to suboptimal cancer control outcomes.

Despite its prevalence and clinical importance, treatment options for CIPN remain limited. Duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI), is the only agent with moderate clinical evidence supporting its use in CIPN. However, its modest efficacy and frequent side effects such as fatigue, nausea, and dizziness result in high discontinuation rates, often exceeding 35% in clinical trials. Other commonly used agents, including gabapentinoids and tricyclic antidepressants, lack sufficient clinical evidence for CIPN and are not routinely recommended in major oncology guidelines.

This therapeutic gap has prompted investigation into alternative, mechanism-driven strategies. Among these, cannabinoids—particularly the minor cannabinoid cannabigerol (CBG)—have emerged as promising candidates due to their multifaceted antinociceptive properties demonstrated in preclinical models.

Cannabigerol (CBG): Pharmacology and Preclinical Insights

CBG is a non-psychoactive cannabinoid found in trace amounts in most Cannabis sativa strains. It serves as the chemical precursor to the more abundant cannabinoids THC and CBD, synthesized via the intermediate cannabigerolic acid (CBGA). Unlike THC, CBG does not produce intoxicating effects and exhibits a diverse pharmacological profile, interacting with multiple receptor systems relevant to pain modulation.

Experimental data in rodent models of neuropathy—particularly those induced by cisplatin—suggest that CBG reduces mechanical hypersensitivity through several pathways. These include partial agonism at cannabinoid receptors CB1 and CB2, α2-adrenergic receptor activation, and modulation of transient receptor potential (TRP) channels such as TRPV1. In combination with CBD, CBG demonstrates a synergistic effect that appears to enhance antinociceptive efficacy without promoting psychoactivity or tolerance. Notably, repeated administration in animal models did not lead to the development of analgesic tolerance, a significant limitation of opioid-based therapies.

These findings provide mechanistic justification for human studies evaluating CBG, either alone or in combination with CBD, in conditions characterized by neuropathic pain.

Overview of the Clinical Trial: Design and Implementation

The first human study evaluating a CBG/CBD oil formulation in patients with established CIPN is currently underway at the Penn State Cancer Institute (ClinicalTrials.gov Identifier: NCT07016971). This Phase I trial is designed as an open-label, single-arm study enrolling 12 adult participants (aged ≥21) with persistent neuropathic symptoms following platinum-based chemotherapy for gastrointestinal cancers.

The primary objective is to assess the safety and tolerability of sublingually administered CBG/CBD oil over a 12-week treatment period. Secondary objectives include preliminary evaluation of efficacy in reducing neuropathic symptoms, assessment of functional improvement, and pharmacokinetic profiling of circulating cannabinoids.

Intervention Protocol

Participants receive a commercially available CBG/CBD oil preparation with a dosing schedule designed to gradually increase exposure:

• Week 1: 0.5 mL twice daily (approximately 17 mg total cannabinoids/day)

• Weeks 2–12: 1.0 mL twice daily (approximately 33 mg/day)

This titration strategy helps assess tolerability while allowing for a potentially therapeutic dose in the latter 11 weeks of treatment. Sublingual administration ensures relatively rapid systemic absorption, with minimal first-pass hepatic metabolism.

Participants are monitored weekly through safety assessments, validated symptom questionnaires (e.g., pain scores, numbness, balance), and functional evaluations. Blood samples are collected at predefined intervals to quantify cannabinoid levels and evaluate adherence and metabolism.

Clinical Endpoints

• Primary Endpoints: Incidence of adverse events, participant adherence, and continuation of treatment beyond Cycle 1.

• Secondary Endpoints: Changes in neuropathic symptom scores, functional improvement (e.g., mobility, dexterity), and cannabinoid/metabolite pharmacokinetics.

Unmet Needs in CIPN Treatment

CIPN remains a largely intractable condition due to a lack of effective, mechanism-specific therapies. Duloxetine remains the only intervention with repeatable, albeit modest, efficacy in randomized controlled trials. Other common pharmacologic strategies—including pregabalin, gabapentin, tricyclic antidepressants, and NSAIDs—are often extrapolated from other neuropathic pain conditions but lack specific validation in CIPN. Furthermore, these agents frequently produce side effects that limit tolerability, especially in older or comorbid populations.

Importantly, no existing therapy is disease-modifying; current strategies primarily mask symptoms without repairing underlying nerve damage. The chronic nature of CIPN—sometimes lasting years—places a considerable burden on cancer survivors and contributes to long-term disability and reduced quality of life.

Significance and Prospects of the CBG/CBD Trial

This Phase I trial represents a critical milestone in the translation of preclinical cannabinoid research into clinical oncology. It is the first human study to specifically evaluate the role of CBG in CIPN, building on a mechanistically grounded rationale and leveraging the potential of cannabinoid synergy.

The inclusion of both CBG and CBD provides a pharmacodynamic advantage known as the “entourage effect,” wherein multiple cannabinoids act together to enhance therapeutic impact while mitigating adverse effects. In contrast to THC-containing products, this CBG/CBD oil is non-intoxicating, broadening its clinical acceptability among physicians and patients.

The trial also reflects a rigorous early-phase design, emphasizing safety, tolerability, and pharmacokinetics over subjective efficacy endpoints. These data will be critical for informing dosing, duration, and formulation decisions in future Phase II/III trials.

Challenges and Future Directions

Several challenges remain in the development of cannabinoid-based therapeutics for neuropathic pain:

• Regulatory Standardization: Ensuring GMP-compliant production of cannabinoid formulations is essential for reproducibility and regulatory approval. The rapidly evolving legal landscape around hemp-derived cannabinoids also complicates multi-center trial design.

• Scaling Up: Transitioning from a single-arm proof-of-concept study to randomized, placebo-controlled trials will require broader institutional support and significant funding.

• Mechanistic Clarification: Incorporating nerve conduction studies, inflammatory biomarkers, and possibly neuroimaging will help clarify mechanisms of action and patient response profiles.

• Personalized Medicine: Future studies may incorporate pharmacogenomics and SNP screening to identify patient subgroups most likely to benefit from CBG/CBD therapies and to refine dosing strategies.

Conclusion

The Phase I clinical evaluation of a CBG/CBD oil formulation for chemotherapy-induced peripheral neuropathy marks an important step in addressing a long-standing therapeutic gap in oncology. Drawing on robust preclinical data and a focused, mechanism-driven design, the study aims to lay the groundwork for cannabinoid-based interventions that are safe, effective, and scalable. If successful, this trial may catalyze a broader shift toward plant-derived, non-opioid modalities in the management of chronic neuropathic pain syndromes.

References

1. Loprinzi CL, Lacchetti C, Bleeker J, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: ASCO guideline update. J Clin Oncol. 2020;38(28):3325–3348.

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3. Rock EM, Sticht MA, Limebeer CL, et al. Cannabinoid-induced reduction of mechanical hypersensitivity in a mouse model of chemotherapy-induced neuropathic pain is mediated by CB1 and CB2 receptors. Neuropharmacology. 2016;110(Pt A):93–102.

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5. ClinicalTrials.gov Identifier: NCT07016971. “Phase I Study of CBG/CBD Oil in Patients With Chemotherapy-Induced Peripheral Neuropathy.”

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8. Hershey Medical Center and Penn State Cancer Institute. CBG/CBD Phase I trial protocol documents (via ctv.veeva.com).