Intro/Aim: The endocannabinoid system (ECS) is a complex signalling network that regulates various aspects of homeostasis and is increasingly recognised for its role in the development of neuropsychological disorders. The role of the ECS in chemotherapy-induced neuropsychological symptoms remains unclear. As such, we aimed to explore ECS changes after chemotherapy and their association with neuropsychological symptoms and liquid biomarkers.
Method/Approach: Treatment-naïve women with breast cancer (stage I-IV) were recruited from across South Australia and neuropsychological symptoms were assessed using a comprehensive symptom questionnaire probing; cognition with the validated patient-reported outcome measure, FACT-Cog; and the symptom burden of pain, fatigue, reduced appetite, sleep disturbance, anxiety and depression (N=46). The blood biomarker brain-derived neurotrophic factor (BDNF) assessed cognition using ELISA (N=12). Circulating endocannabinoids (2-arachidonoylglyercol (2-AG) and anandamide (AEA) were quantified using mass spectrometry (LCMS) (N=13).
Results: Neuropsychological symptoms were confirmed, indicated by a decrease in FACT-Cog from baseline to cycle 1 (P=0.0092) and cycle 3 (P=0.00125); a clinically-meaningful decline in FACT-Cog (MCID ≥ 15.26 points) in 50% of participants; significantly altered temporal dynamics (P<0.05) in burden of pain, fatigue, reduced appetite and anxiety from baseline; and reduced BDNF from baseline to cycle 4 (P=0.0010). Endocannabinoid levels showed an absolute decrease of 93.3% (AEA), and 96.8% (2-AG) over the course of 3 cycles of chemotherapy. AEA concentration positively correlated with cognitive symptom burden (P=0.002).
Conclusion: Chemotherapy profoundly depletes circulating BDNF and AEA levels while inducing cognitive impairment. Notably, this study provides the first evidence linking circulating endocannabinoid components to cognitive symptom burden, highlighting the potential of exogenous ECS modulation as a therapeutic strategy for neuropsychological symptom management during chemotherapy.