title: Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration.
abstract: BACKGROUND
  Sativex(®), a cannabis extract oromucosal spray containing Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC's effects, but it is unclear if this is due to a pharmacokinetic and/or pharmacodynamic interaction.
  
  
  METHODS
  Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board-approved study. Participants received 5 and 15 mg synthetic oral THC, low-dose (5.4 mg THC and 5.0 mg CBD) and high-dose (16.2 mg THC and 15.0 mg CBD) Sativex, and placebo over 5 sessions. CBD, THC, 11-hydroxy-THC, and 11-nor- 9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS. Lower limits of quantification were ≤0.25 μg/L.
  
  
  RESULTS
  Nine cannabis smokers completed all 5 dosing sessions. Significant differences (P < 0.05) in maximum plasma concentrations (C(max)) and areas under the curve from 0-10.5 h postdose (AUC(0→10.5)) for all analytes were found between low and high doses of synthetic THC and Sativex. There were no statistically significant differences in C(max), time to maximum concentration or in the AUC(0→10.5) between similar oral THC and Sativex doses. Relative bioavailability was calculated to determine the relative rate and extent of THC absorption; 5 and 15 mg oral THC bioavailability was 92.6% (13.1%) and 98.8% (11.0%) of low- and high-dose Sativex, respectively.
  
  
  CONCLUSIONS
  These data suggest that CBD modulation of THC's effects is not due to a pharmacokinetic interaction at these therapeutic doses.
authors.affiliation: Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Karschner
authors.forename: W David
authors.initials: WD
authors.lastname: Darwin
authors.forename: Robert S
authors.initials: RS
authors.lastname: Goodwin
authors.forename: Stephen
authors.initials: S
authors.lastname: Wright
authors.forename: Marilyn A
authors.initials: MA
authors.lastname: Huestis
mesh_terms: D000328:Adult; D002185:Cannabidiol / Q000493:pharmacokinetics*; D002188:Cannabis; D004311:Double-Blind Method; D013759:Dronabinol / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D002189:Marijuana Abuse / Q000378:metabolism; D009061:Mouth Mucosa; D010936:Plant Extracts / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D004338:Drug Combinations; D010936:Plant Extracts; D002185:Cannabidiol; C001427:11-hydroxy-delta(9)-tetrahydrocannabinol; C016780:11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid; D013759:Dronabinol; C587251:nabiximols