While many previous studies have shown that a variety of cannabinoids substitute and cross-substitute for delta 9-tetrahydrocannabinol (THC) in drug discrimination procedures, few have systematically examined potential THC-like effects of non-cannabinoid compounds. The purpose of the present study was to delineate further the pharmacological specificity of THC discrimination. Rats were trained to discriminate THC (3.0 mg/kg) from vehicle. Following determination of a dose-effect curve with THC, substitution tests with selected compounds from a variety of pharmacological classes, including l-phenylisopropyl adenosine, dizocilpine, dextromethorphan, clozapine, buspirone, MDL 72222, muscimol, midazolam and chlordiazepoxide, were performed. Whereas THC produced full dose-dependent substitution, substitution tests with non-cannabinoid drugs resulted in less than chance (50%) levels of responding on the THC-appropriate lever, with the exception of (+)-MDMA (2.5 mg/kg, 50%) and diazepam (3.0 mg/kg, 67%). These results are consistent with those of previous studies and suggest that the discriminative stimulus effects of THC exhibit pharmacological specificity.