Effects of ketamine enantiomers on morphine and THC subjective effects in rats

Ketamine, known for its rapid-acting antidepressant effects, is often coadministered with other psychoactive drugs, including opioids and cannabinoids, in both clinical and recreational settings. We investigated whether ketamine (R-, S-, or racemic R, S-) isoforms alter the subjective effects of morphine or Δ⁹-tetrahydrocannabinol (THC) and whether the interoceptive effects of ketamine overlap with these drugs.

Rats were trained to discriminate morphine (6.4 mg/kg) or THC (3 mg/kg) from their respective vehicle controls. Subsequently, different ketamine isoforms were administered at doses of 5, 10, or 30 mg/kg either prior to or instead of the training drug.

In drug interaction tests, naltrexone (0.1 mg/kg) fully antagonized morphine's effects, and rimonabant (0.32, 1, and 3.2 mg/kg) partially inhibited THC cue. However, ketamine isoforms did not fully block the discriminative stimulus effects of morphine or THC. In generalization tests, as expected, fentanyl (0.1 mg/kg) fully substituted for the morphine cue, and cannabidiol did not substitute (10 mg/kg) or partially substituted (3 and 50 mg/kg) for the THC cue. However, none of the ketamine isoforms fully substituted for the morphine or THC cue. Ketamine isoforms did not alter response rates in the morphine experiment, but suppressed responding in the THC experiment.

These findings indicate that ketamine isoforms do not produce opioid- or cannabis-like subjective effects and are unlikely to fully mask the interoceptive effects of morphine or THC. However, their coadministration with cannabinoids may lead to pronounced sedative-like suppression. This warrants further investigation into the safety and interaction profiles of such drug combinations, particularly in therapeutic settings.