WHY IT MATTERS: If placebo analgesia works partly through the endocannabinoid system, patients and clinicians interpreting pain relief in cannabis studies need to understand that the line between expectation and pharmacology may be blurrier than previously assumed. CLINICAL OVERVIEW: The endocannabinoid system appears to play a meaningful role in mediating placebo analgesia, suggesting that the brain’s expectation of pain relief may partially operate through the same cannabinoid signaling pathways activated by cannabis-based medicines. This finding adds biological plausibility to the long-debated question of how much overlap exists between expectation-driven pain relief and pharmacologically induced analgesia.