The aim of the present study was to develop a simple and sensitive LC–MS method for the estimation of Δ 8 -tetrahydrocannabinol (Δ 8 -THC) and its metabolite, 11-nor-Δ 8 -tetrahydrocannabinol-9-carboxylic acid (11-nor-Δ 8 -THC-9-COOH), in guinea pig plasma after topical drug application. The plasma samples were analyzed by LC–MS using negative-mode electrospray ionization detection and a simple liquid–liquid extraction technique. The mean recoveries for Δ 8 -THC and its metabolite, 11-nor-Δ 8 -THC-9-COOH, were 96.6 and 88.2%, respectively. The lower limits of quantification (LLOQ) for Δ 8 -THC and 11-nor-Δ 8 -THC-9-COOH were 3.97 and 7.26nM, respectively. The topical treatment steady-state plasma concentrations of Δ 8 -THC and 11-nor-Δ 8 -THC-9-COOH were 8.24–27.63 and 19.66–23.17nM, respectively, with a lag period of 0.3–2.2h. This assay method is selective, sensitive, and reproducible for the determination of Δ 8 -THC and 11-nor-Δ 8 -THC-9-COOH at low concentrations in small volumes of plasma.