Abstract The objectives of this study were: (1) to assess the safety, tolerability, and pharmacokinetics of ascending doses of Δ9-tetrahydrocannabinol-hemisuccinate (THC-HS) after rectal administration as suppositories in male volunteers; and (2) to compare the pharmacokinetics of oral administration of Δ9-tetrahydrocannabinol (Δ9-THC) with an equivalent amount of Δ9-THC delivered as THC-HS via the suppository formulation. In support of the pharmacokinetic evaluations, an analytical method was developed and validated for the determination of Δ9-THC and for its major circulating metabolites 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) in human plasma. Δ9-THC, 11-OH-THC, and THC-COOH were extracted from plasma using solid phase extraction and analyzed by liquid chromatography-tandem...