The Endocannabinoid System’s Contribution to Placebo Analgesia

ABSTRACT Placebo analgesia reduces pain through psychosocial mechanisms, yet the neuromodulators involved remain incompletely understood, limiting clinical translation. Endogenous opioids contribute to placebo analgesia, but do not fully account for inter-individual differences. We tested whether circulating levels of the endocannabinoid (eCB) 2-arachidonoylglycerol, the eCB and fatty acid amide hydrolase (FAAH) substrate anandamide, and FAAH substrates N -palmitoylethanolamide and N -oleoylethanolamide, contribute to placebo analgesia, and whether these effects depend on endogenous opioid activity. Forty-eight healthy adults underwent a validated placebo paradigm with blood sampling. Placebo analgesia was associated with increases in FAAH substrates, but not with 2-arachidonoylglycerol or β-endorphin alone. Critically, β-endorphin levels moderated the relationship between FAAH substrates and analgesia: when β-endorphin elevations were low, FAAH substrate increases strongly predicted pain reduction; when β-endorphin elevations were high, this relationship was absent. These findings indicate that eCB and opioid systems interact in a state-dependent manner to produce placebo analgesia in humans, with implications for harnessing endogenous analgesic mechanisms to personalize pain treatment.