Cannabidiol modulation of antinociceptive tolerance to Δ9-tetrahydrocannabinol

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.

Disease-modifying effects of natural Δ9-tetrahydrocannabinol in endometriosis-associated pain

“…Repeated exposure to THC 2 mg/kg, once daily for 32 days, provided a sustained alleviation of mechanical pain during the whole treatment period (Figure 3a and Figure 3 - figure supplement 1) without inducing tolerance. The absence of tolerance to THC-induced antinociception is in contrast with the tolerance described at higher THC doses in other pain models (Greene, Wiley, Yu, Clowers, & Craft, 2018; Lafleur, Wilson, Morgan, & Henderson-Redmond, 2018; Wakley, Wiley, & Craft, 2014). Our experimental conditions showed no significant effects of repeated THC on anxiety-like behavior in sham or endometriosis mice (Figure 3b).…”

Vaporized Cannabis Extracts Have Reinforcing Properties and Support Conditioned Drug-Seeking Behavior in Rats

“…Blood was collected vial the tail vein in sterile tubes containing 10 ml of ethylenediaminetetraacetic acid, centrifuged at 4°C at 4000 ϫ g for 15 min, and stored at Ϫ20°C. THC and CBD concentrations in plasma were quantified immediately after the session as described previously (Britch et al, 2017;Greene et al, 2018).…”

“…For example, CBD is a CB1R negative allosteric modulator and inhibits THCdependent intracellular signaling and ␤-arrestin-2-mediated CB1R internalization (Laprairie et al, 2015(Laprairie et al, , 2016. CBD attenuates THC-induced paranoia and memory impairments in humans (Englund et al, 2013) but can also increase THC serum concentrations when co-administered with THC (Greene et al, 2018). Therefore, THC administration alone may not produce effects that are representative of the effects of cannabis exposure in humans.…”

Vaporized cannabis extracts have reinforcing properties and support conditioned drug-seeking behavior in rats

“…Brains were extracted to analyze THC and CBD tissue levels. THC and CBD concentrations in plasma and brain were quantified as described previously [10,28] (see Supplement).…”

“…For example, CBD acts as a CB1R negative allosteric modulator and inhibits THC-dependent intracellular signaling and beta-arrestin-2-mediated CB1R internalization [7,8]. CBD attenuates THC-induced paranoia and memory impairments in humans [9] but can also increase THC serum concentrations when co-administered with THC [10]. Therefore, THC administration alone may not produce effects that are representative of the effects of cannabis exposure in humans.…”