Functional and MRI improvement followed by a mixed trajectory during cannabinoid-terpenoid exposure in glioblastoma: a case report

Technical Summary: Functional and MRI Improvement Followed by a Mixed Trajectory During Cannabinoid-Terpenoid Exposure in Glioblastoma

Problem Statement
Glioblastoma (GBM) presents a significant clinical challenge due to limited salvage options and the difficulty in distinguishing viable tumor recurrence from treatment-related changes (e.g., radiation necrosis, postoperative changes, edema) using standard Magnetic Resonance Imaging (MRI) and clinical assessment. The standard overall survival for GBM remains approximately 12–16 months. While intranasal perillyl alcohol has been evaluated in malignant glioma and preclinical evidence exists for alpha-bisabolol and cannabinoids, clinical studies for these agents remain in early phases. This case report addresses the complexity of interpreting longitudinal clinical and radiological data in a patient undergoing a non-standard, multimodal exposure to cannabinoid-terpenoid compounds alongside standard care.

Methodology
This is a single-patient, uncontrolled case report describing a 48-year-old male with IDH-wildtype, MGMT-promoter-methylated glioblastoma. The study design involved a descriptive review of clinical records, serial MRI examinations, and signed radiology reports.

• Patient History: The patient underwent two surgeries, radiotherapy, and concomitant/adjuvant temozolomide. Temozolomide was discontinued at the patient's request after three adjuvant cycles.
• Exposure Protocol: Starting in April 2025, the patient entered a "non-standard exposure state" comprising:
  • Intranasal perillyl alcohol (~900–1,200 mg/day, initially 95% purity).
  • Intranasal alpha-bisabolol (~600 mg/day, initially 95% purity).
  • Individualized cannabinoids administered rectally, sublingually, and/or orally in medium-chain triglyceride (MCT) oil.
  • Docosahexaenoic acid (2,000 mg/day).
  • Controlled Variable: Dexamethasone was fixed at 2 mg/day throughout the entire exposure and imaging interval.
• Data Collection: Seven MRI time points were analyzed from November 2023 to June 2026. The study explicitly did not perform blinded central neuroradiology review, standardized volumetry, or formal RANO 2.0 adjudication. Imaging analysis was descriptive, relying on routine clinical reports and source image review.
• Interruption: Intranasal terpenes were interrupted due to commercial access restrictions from September 2025 to April 2026, while cannabinoid exposure continued.

Key Results

• Baseline and Progression: Prior to April 2025, serial MRIs documented tumor progression. Molecular profiling confirmed CDKN2A/B homozygous deletion, EGFR/MET amplification, and TERT promoter mutation.
• Early Improvement (April–Mid 2025): Coinciding with the initiation of the cannabinoid-terpenoid exposure, the patient experienced a documented functional improvement from hemiplegia (Karnofsky Performance Status [KPS] 50) to hemiparesis with regained walking (KPS 80). Radiologically, mid-2025 MRI showed reduced irregular, thickened contrast enhancement around the resection cavity compared to the pre-exposure progressive sequence.
• Mixed Trajectory (Late 2025–June 2026): Following the interruption of terpenes and subsequent reintroduction at different purities, the trajectory became discordant:
  • Supratentorial: The postoperative cavity and T2/FLAIR extent remained substantially stable. However, medial enhancement along the cavity increased (from 27 mm to 36 mm).
  • Infratentorial: New and increasing enhancing foci appeared in the right cerebellum (increasing from 10 mm to 14 mm) and a new contralateral cerebellar focus (13 mm) emerged.
  • Perfusion: June 2026 dynamic contrast-enhanced perfusion curves were low-amplitude without pathological hyperperfusion, a finding that supports but does not definitively establish radiation necrosis over viable tumor.
• Outcome: The patient survived for a total of 45 months from diagnosis, passing away after the June 2026 imaging window.

Key Contributions and Claims
The paper presents a longitudinal record of a complex clinical course characterized by:

1. Temporal Concurrence: The observation of functional and radiological improvement (reduced enhancement) occurring during a specific exposure window on a fixed corticosteroid background.
2. Biological Indeterminacy: The subsequent development of a "mixed trajectory" where anatomical progression (new enhancing foci) occurred alongside stable tumor volume (T2/FLAIR) and low-amplitude perfusion, making it impossible to exclude a mix of viable tumor and treatment effect (radiation necrosis).
3. Survival Context: The documentation of an overall survival of 45 months, which is noted as "extraordinarily" long for this patient profile, particularly given the early discontinuation of adjuvant temozolomide.

Significance and Limitations
The authors explicitly state that this report does not establish treatment causality, survival benefit, formal tumor response, or component-specific efficacy.

• Modest Claims: The paper emphasizes that the observed improvement cannot be attributed to the specific compounds due to the lack of a control group, changing formulation purities, treatment interruptions, and the absence of blinded review.
• Interpretation of Imaging: The authors caution that the low-amplitude perfusion curves and mixed radiological findings do not confirm radiation necrosis nor exclude viable tumor.
• Conclusion: The study serves as a descriptive case report of an "unexpected event" followed by a complex, indeterminate trajectory. It highlights the challenges in interpreting GBM progression in the context of multimodal, non-standard exposures and underscores the need for future prospective studies with locked formulations, standardized dosing, and independent radiological adjudication to verify any potential benefits. The paper concludes that while the 45-month survival is clinically noteworthy, the single-case nature prevents definitive conclusions regarding the efficacy of the cannabinoid-terpenoid exposure.