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Psychopharmacology (Berl). 2018 Nov;235(11):3289-3302. doi: 10.1007/s00213-018-5036-z. Epub 2018 Sep 20.

Cannabidiol modulation of antinociceptive tolerance to Δ9-tetrahydrocannabinol.

Author information

1
Department of Psychology, Washington State University, Pullman, WA, 99164-4820, USA.
2
RTI International, Research Triangle Park, NC, USA.
3
Department of Chemistry, Washington State University, Pullman, WA, USA.
4
Department of Psychology, Washington State University, Pullman, WA, 99164-4820, USA. craft@wsu.edu.

Abstract

RATIONALE:

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.

OBJECTIVE:

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

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

KEYWORDS:

Cannabinoids; Pain; Sex differences

PMID:
30238130
PMCID:
PMC6454895
[Available on 2019-11-01]
DOI:
10.1007/s00213-018-5036-z
[Indexed for MEDLINE]

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