Objectives
Preclinical studies of amyotrophic lateral sclerosis (ALS) have shown altered endocannabinoid (eCB) signalling that may contribute to the disease. Results from human studies are sparse and inconclusive. The aim of this study was to determine the association between serum levels of eCBs or their congeners, the so-called endocannabinoidome, and disease status and activity in ALS patients.
Methods
Serum concentrations of the eCBs 2-arachidonoylglycerol (2AG) and N-arachidonoylethanolamine (AEA), and AEA congeners, palmitoylethanolamide (PEA), oleoylethanolamide (OEA), eicosapentaenoylethanolamide (EPEA), 2-docosahexaenoylglycerol (2-DHG) and docosahexaenoylethanolamide (DHEA) were measured in samples from 65 ALS patients, 32 healthy controls (HC) and 16 neurological disease controls (NALS). A subset of 46 ALS patients underwent a longitudinal study. Disease activity and progression were correlated with eCB and congener levels.
Results
Most circulating mediators were higher in ALS than HC (all p < 0.001), but not NALS. Across clinical stages, ALS patients showed increased levels of PEA, OEA, and EPEA (all p < 0.02), which were confirmed by the longitudinal study (all p < 0.03). Serum PEA and OEA levels were independent predictors of survival and OEA levels were higher in patients complaining of appetite loss. Cluster analysis revealed two distinct profiles of circulating mediators associated with corresponding patterns of disease activity (severe vs. mild). Patients belonging to the “severe” cluster showed significantly higher levels of OEA, PEA and lower levels of 2-DHG compared to NALS and HC.
Interpretation
Circulating endocannabinoidome profiles are indicative of disease activity, thus possibly paving the way to personalised, rather than a “one-fit-all”, therapeutic approaches targeting the endocannabinoidome.