, Volume 235, Issue 11, pp 3289–3302 | Cite as

Cannabidiol modulation of antinociceptive tolerance to Δ9-tetrahydrocannabinol

  • Nicholas Z. Greene
  • Jenny L. Wiley
  • Zhihao Yu
  • Brian H. Clowers
  • Rebecca M. CraftEmail author
Original Investigation



Humans typically self-administer cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) together repeatedly (as in cannabis, cannabis extract, or Sativex®) to relieve pain. It has been suggested that one benefit of the drug combination may be decreased tolerance development.


The present study compared the development of tolerance to the antinociceptive effects of THC given alone versus combined with CBD, in rats.


THC dose-effect curves on tail withdrawal and paw pressure tests were obtained before and after twice-daily treatment with vehicle or CBD (10 mg/kg), plus vehicle or THC (3.6 mg/kg females; 9.3 mg/kg males) for 4 days.


On the first day, THC was more potent in females than males on both nociceptive tests. From pre- to post-chronic (day 1 to day 6), THC potency on the tail withdrawal test decreased more in females than males, and rats that had been treated with CBD + THC repeatedly showed greater rightward/downward shifts of the THC dose-effect curve than rats that had been treated with THC alone. Analysis of blood samples taken after day 6 testing showed that serum THC levels were higher in CBD + THC-treated females than in vehicle + THC-treated females, and THC’s active metabolite 11-OH-THC and its inactive metabolite THC-COOH were lower in CBD + THC-treated rats than in vehicle + THC-treated rats of both sexes. CBD also increased serum levels of the active metabolite cannabinol in both sexes.


The decrease in THC’s antinociceptive effects after repeated CBD exposure may be due to CBD-induced inhibition of THC metabolism, and/or antagonism of THC effects that emerges with repeated CBD treatment.


Sex differences Cannabinoids Pain 



The authors thank Kelly Hewitt and Abby Pondelick for excellent technical assistance.

Funding information

This research was funded by NIDA DA016644 (J. Wiley, PI), by a Diversity Supplement to DA016644 (to support N. Greene), and by funds dedicated for marijuana research by the State of Washington Initiative Measure 502.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PsychologyWashington State UniversityPullmanUSA
  2. 2.RTI InternationalResearch Triangle ParkUSA
  3. 3.Department of ChemistryWashington State UniversityPullmanUSA

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