Placebo-controlled

A placebo-controlled trial compares an active intervention against an inert or sham treatment matched for appearance, route, and administration, allowing investigators to distinguish pharmacologic effects from expectation, regression to the mean, and other non-specific effects. In cannabis trials, placebo control is methodologically difficult because tetrahydrocannabinol (THC) produces overt intoxication—altered perception, tachycardia, conjunctival injection—that participants and raters readily detect, risking functional unblinding. Placebo cannabis cigarettes produced by NIDA (ethanol-extracted plant material) and placebo oromucosal sprays used in nabiximols trials attempt to match odor, taste, and appearance, but do not reproduce psychoactivity. The 2017 NASEM report and the Whiting et al. 2015 JAMA meta-analysis repeatedly flagged unreliable blinding as a key limitation across the evidence base. Trials of non-intoxicating cannabidiol (CBD), as in Epidiolex pivotal studies, face fewer unblinding challenges. → See also: Double-blind, Meta-analysis.