The association of circulating endocannabinoids with cancer cachexia: A cross-sectional study

Endocannabinoids (eCBs) are involved in various physiological functions such as appetite, metabolism, and inflammation. Although deterioration of these functions is often observed in patients with refractory cancer cachexia (RCC), the relationship between circulating eCBs and cancer cachexia remains unknown. This study aimed to evaluate the relationship between circulating levels of eCBs and clinical findings in patients with RCC.

Circulating N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) levels were measured in 39 patients with RCC (36% females, median age and IQR: 79 and 69-85), and 18 age- and sex-matched controls who received medical therapy for non-communicable diseases, using liquid chromatography with tandem mass spectrometry. In the RCC group, relationships between eCB levels and clinical findings-such as anorexia, awareness of pain, performance status, and survival period-were also examined. As anti-inflammatory drugs can influence the action and metabolism of eCBs, the following two analyses were conducted. In analysis 1, all participants were included, and in analysis 2, participants receiving any anti-inflammatory drugs were excluded.

Serum AEA and 2-AG levels were more than twice as high in the RCC group than in those in the control group in both analyses. In analysis 1, only 8% of patients reported normal appetite assessed using the numerical rating scale (NRS), and serum AEA levels were negatively correlated with the NRS scores (R = -0.498, p = 0.001). Serum 2-AG levels were positively correlated with serum triglyceride levels (R = 0.419, p = 0.008). Both AEA and 2-AG levels were positively correlated with serum C-reactive protein (CRP) levels (AEA: R = 0.516, p < 0.001; 2-AG: R = 0.483, p = 0.002). Multiple linear regression analysis in the form of a stepwise procedure was performed; NRS scores and CRP levels showed a significant association with AEA levels (NRS: p = 0.001; CRP: p < 0.001), with an adjusted R² value of 0.426. Similarly, triglyceride and CRP levels showed a significant association with the log of 2-AG levels (triglycerides: p < 0.001; CRP: p < 0.001), with an adjusted R² value of 0.442. In analysis 2, serum AEA levels were negatively correlated with the NRS scores (R = -0.757, p < 0.001), whereas serum triglyceride levels were positively correlated with 2-AG levels (R = 0.623, p = 0.010).

Circulating eCB levels were significantly higher in patients with RCC than those in controls. In patients with RCC, circulating AEA may play a role in anorexia, whereas 2-AG may play a role in serum triglyceride levels.