The contribution of baseline circulating endocannabinoids to individual differences in human pain sensitivity: a quantitative sensory testing study

The endocannabinoid (eCB) system comprises cannabinoid receptors; endogenous ligands, including anandamide (AEA), 2-arachidonoylglycerol (2-AG); and related N -acylethanolamines (NAEs), N- palmitoylethanolamide (PEA), and N- oleoylethanolamide (OEA); and metabolizing enzymes (eg, fatty acid amide hydrolase [FAAH]). The eCB system modulates nociceptive circuits in rodents. In humans, the FAAH C385A polymorphism is associated with reduced pain sensitivity, suggesting eCB tone contributes to individual pain differences, but this has yet to be tested. Here, we determined whether the eCB system is associated with somatosensory and pain sensitivity measured with quantitative sensory testing (QST) in 91 healthy participants (39 males, 52 females). We tested 3 hypotheses: (1) FAAH C385A polymorphism, cannabis use, and sex affect serum eCB/NAE concentrations; (2) FAAH C385A carriers show altered pain sensitivity vs noncarriers; and (3) baseline serum eCB/NAE concentrations are associated with QST measures. eCB/NAE concentrations were not statistically different based on sex ( P > 0.05), FAAH genotype ( P > 0.05), or cannabis use ( P > 0.05). To address collinearity of AEA, OEA, and PEA, we performed a principal components analysis, which identified a single component of FAAH substrates. Linear regressions found that FAAH genotype did not affect QST measures and that baseline 2-AG and FAAH substrate concentrations were not associated with QST measures, except pressure pain thresholds (PPT; P = 0.003), which were associated with AEA and OEA. Baseline eCB/NAE levels and FAAH genotype are not associated with the outcome measures of standard QST tests that rely on point estimates in healthy adult humans; nonetheless, circulating FAAH substrate levels were associated with PPT.