THC enhanced the pain-blocking effects of oxycodone and delayed the development of tolerance in mice, according to a new study published in The Journal of Pharmacology and Experimental Therapeutics that was conducted by researchers at Washington University in St. Louis.
For the study, researchers examined how delta-9 THC and oxycodone affected antinociception, physical dependence, circadian activity and reward in male and female mice.
Both THC and oxycodone produced dose-dependent antinociception, meaning they reduced the animals’ behavioral response to a painful stimulus. Researchers tested this using a hotplate assay in which mice were placed on a heated surface and the time before a paw response was measured.
For the combination experiments, mice received 3 milligrams per kilogram of THC, 3 mg/kg of oxycodone, both drugs together or a placebo twice daily for five days. The THC dose was selected because it did not produce significant antinociception on its own.
When THC and oxycodone were administered together, the combination produced greater antinociception than either drug alone on the first day. As the researchers put it, the two drugs “produced greater and longer-lasting antinociception when coadministered.” The enhanced effect remained evident on day three, when tolerance had developed to the individual treatments. By day five, however, tolerance had developed across all groups.
The researchers also examined whether adding THC worsened physical dependence associated with repeated oxycodone exposure. Oxycodone caused signs of physical dependence in both male and female mice, but THC did not exacerbate those effects. The researchers said THC “does not exacerbate μ-opioid receptor physical dependence” at doses that enhanced antinociception. In male mice, the combination actually reduced naloxone-induced jumping, a measure of opioid withdrawal, although the reduction was not observed in females.
THC also did not worsen oxycodone-related changes in circadian activity. Oxycodone increased activity during periods when the mice would normally be less active, while THC alone had little effect. Researchers said THC “did not alter oxycodone’s circadian impact.” Combining the two therefore offered no apparent benefit for the circadian disruption caused by oxycodone, but it also did not make the disruption worse.
Combining 1 mg/kg of oxycodone with 3 mg/kg of THC produced a sustained dopamine response in the nucleus accumbens that approached the response produced by three times as much oxycodone alone. Researchers said the finding provides a possible mechanism for the increased reward response observed behaviorally.
Overall, the researchers conclude by stating:
Our results indicate that coadministration of Δ9 -THC with oxycodone produces a potentiation-like effect on antinociception and delays antinociceptive tolerance, although this delay was restricted to a single dose pair and the 30 minutes timepoint. The combination did not augment μ-opioid receptor dependence and conferred no benefit for oxycodone-induced circadian disruption. However, it produced CPP at doses that were not preferenceproducing alone and potentiated NAc dopamine release at an otherwise subeffective oxycodone dose. Δ9 -THC coadministration may recruit the rewarding properties of oxycodone at otherwise subthreshold doses, so any therapeutic implementation of cannabinoid—opioid combinations must weigh a potentiation-like antinociceptive benefit against a concurrent increase in abuse liability. Future studies in the context of ongoing pain will determine whether this tradeoff is favorable.
