Time course of the enhancement and restoration of the analgesic efficacy of codeine and morphine by Δ9-tetrahydrocannabinol

Δ9-tetrahydrocannabinol (Δ9-THC) synergizes with morphine and codeine by releasing endogenous opioids. These studies determined 1) the duration of enhancement of morphine and codeine by Δ9-THC, 2) the effect of (Δ9-THC on the time course of fully efficacious doses of the opioids, 3) restoration of efficacy of morphine and codeine by Δ9-THC, and 4) duration of restoration. Sub-active combination doses of Δ9-THC/morphine or Δ9-THC/codeine are equivalent in duration of action and efficacy to high-dose opioids alone. Δ9-THC (20 mg/kg p.o.) significantly restores the antinociceptive effects of both high-dose morphine and codeine (100 and 200 mg/kg p.o., respectively) at later time points at which morphine or codeine was no longer active (360- and 120-min post-administration, respectively). Thus, the cannabinoid/opioid combination might be useful in therapeutics to enhance opioid activity, as well as to restore the efficacy of opioids.