Sativex is an oromucosal cannabis-plant extract delivering delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, and cannabidiol (CBD), a non-psychotropic cannabinoid, in an approximate 1:1 ratio. Previous research indicated that CBD attenuated THC's pharmacodynamic effects, but the mechanism of interaction is unidentified. A placebo-controlled, double blind, double dummy administration study was developed to compare pharmacodynamic and pharmacokinetic profiles of oral THC, an FDA-approved pharmaceutical, and Sativex, an investigational medication for pain refractory to opiates in cancer patients. Experienced cannabis smokers (n=9) were randomly administered placebo, 5 and 15 mg oral synthetic THC and low (5.4 mg THC and 5.0 mg CBD) and high (16.2 mg THC and 15.0 mg CBD) dose Sativex over five sessions. A sensitive two-dimensional gas chromatography mass spectrometry method was validated to simultaneously quantify plasma CBD, THC, 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THCCOOH) at sub-nanogram concentrations expected after cannabinoid pharmacotherapy administration. Low calibration curves were linear from 0.25-25 ng/mL for CBD and THC, 0.125-25 ng/mL for 11-OH-THC and 0.25-50 ng/mL for THCCOOH. Analytical imprecision was <9.5%CV and bias was <9.2% of target. Inter-individual cannabinoid concentrations and pharmacodynamic responses were highly variable. Cmax and AUC0 to 10.5 were higher for all analytes after both high doses of oral THC and Sativex compared to low doses. Also, no significant pharmacokinetic differences were observed between similar oral THC and Sativex doses. THC bioavailability tended to be higher following oromucosal versus oral administration, potentially due to reduced first pass metabolism to 11-OH-THC. Similar, but moderate heart rate, "good drug effect" and anxiety increases were observed after oral THC and Sativex. Contrary to 15 mg oral THC, high dose Sativex did not significantly increase subjective "high" feelings, suggesting that CBD may attenuate euphoria. Weak linear relationships between pharmacodynamic effects and plasma THC concentrations were noted, limiting the ability to infer responses from low plasma cannabinoid concentrations. CBD did not significantly alter THC pharmacokinetics or pharmacodynamics at low, therapeutic cannabinoid doses. No strong cardiovascular or intoxication effects or serious adverse events were observed, indicating that Sativex has a pharmacodynamic safety profile comparable to oral THC at 5 and 15 mg doses.