Cannabidiol-Δ9-tetrahydrocannabinol interactions on acute pain and locomotor activity

Abstract

Background: Previous studies suggest that cannabidiol (CBD) may potentiate or antagonize Δ⁹-tetrahydrocannabinol's (THC) effects. The current study examined sex differences in CBD modulation of THC-induced antinociception, hypolocomotion, and metabolism.

Methods: In Experiment 1, CBD (0, 10 or 30mg/kg) was administered 15min before THC (0, 1.8, 3.2, 5.6 or 10mg/kg), and rats were tested for antinociception and locomotion 15-360min post-THC injection. In Experiments 2 and 3, CBD (30mg/kg) was administered 13h or 15min before THC (1.8mg/kg); rats were tested for antinociception and locomotion 30-480min post-THC injection (Experiment 2), or serum samples were taken 30-360min post-THC injection to examine CBD modulation of THC metabolism (Experiment 3).

Results: In Experiment 1, CBD alone produced no antinociceptive effects, while enhancing THC-induced paw pressure but not tail withdrawal antinociception 4-6h post-THC injection. CBD alone increased locomotor activity at 6h post-injection, but enhanced THC-induced hypolocomotion 4-6h post-THC injection, at lower THC doses. There were no sex differences in CBD-THC interactions. In Experiments 2 and 3, CBD did not significantly enhance THC's effects when CBD was administered 13h or 15min before THC; however, CBD inhibited THC metabolism, and this effect was greater in females than males.

Conclusions: These results suggest that CBD may enhance THC's antinociceptive and hypolocomotive effects, primarily prolonging THC's duration of action; however, these effects were small and inconsistent across experiments. CBD inhibition of THC metabolism as well other mechanisms likely contribute to CBD-THC interactions on behavior.

Keywords: Cannabinoids; Gender; Pain; Sedation; Sex differences.

Figure 1

Experiment 1. Time-response curves on the tail withdrawal test in male rats (left), female rats (center) and both sexes combined (right). CBD was administered 15 min before THC. THC-induced antinociception was greater in females than males, with no significant CBD enhancement of THC’s effect in either sex. Each point is the mean ± 1 S.E.M of 10 male or female rats (left and center panels), or 20 total rats (right panel).

Figure 2

Experiment 1. Time-response curves on the paw pressure test in male rats (left), female rats (center) and both sexes combined (right). CBD was administered 15 min before THC. THC-induced antinociception was greater in females than males, and CBD enhanced THC’s effect at 240 and 360 min post-THC injection. Each point is the mean ± 1 S.E.M of 10 male or female rats (left and center panels), or 20 total rats (right panel).

Figure 3

Experiment 1. Time-response curves on the locomotor activity test in male rats (left), female rats (center) and both sexes combined (right). CBD was administered 15 min before THC. CBD potentiated THC’s effect at lower THC doses at later time points. Each point is the mean ± 1 S.E.M of 10 male or female rats (left and center panels), or 20 total rats (right panel). *significant difference, CBD-treated group compared to vehicle-treated group (p<0.05).

Figure 4

Experiment 2. Time-response curves on the tail withdrawal test (top row), paw pressure test (middle row) and locomotor activity test (bottom row) in male rats (left column), female rats (middle column), and both sexes combined (right column). CBD 30 mg/kg was given either 13 hr or 15 min before THC 1.8 mg/kg. CBD pretreatment time did not significantly alter the CBD-THC interaction on any test. Each point is the mean ± 1 S.E.M of 12–14 male or female rats (left and center panels), or 24–28 total rats (right panels).

Figure 5

Experiment 3. Serum CBD, THC, 11-OH-THC, THC-COOH and CBN levels in male and female rats. Vehicle or CBD 30 mg/kg was given 13 hr or 15 min before THC 1.8 mg/kg. Each point is the mean ± 1 S.E.M of 4–6 rats. *significant difference compared to THC-only control; #significant sex difference at same CBD-THC dose combination.