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Pharmacological interactions between cannabidiol and oxycodone in the brain

Niall Murphy
University of Florida

Co-Authors: Ariana C. Brice-Tutt, Alexandria S Senetra, Tyler Serres, Abhishek Gour, Marcelo Febo, Adriaan W Bruijnzeel, Wendi Malphurs, Azin Behnood-Rod, Cassidy Kramer, Robert M Caudle, Barry Setlow, Abhisheak Sharma, and John K Neubert
University of Florida

Background: We previously showed that co-administering cannabidiol (CBD) potentiates the analgesic actions of the opioid oxycodone in a rat model. In contrast, CBD does not potentiate the rewarding actions of oxycodone in the absence of
pain. CBD also has little effect on behavioral sensitization to oxycodone. Given
the apparent contrasting effects of CBD on oxycodone’s analgesic and rewarding properties, we sought to elucidate peripheral and central sites at which CBD and oxycodone may interact.

Objective: Determine pharmacokinetic interactions between CBD and oxycodone in the plasma and brain, and the impact of co-administration on brain neurochemistry.

Methods: Male and female Sprague Dawley rats were allocated to one of three treatment groups: CBD (10 mg/kg), oxycodone (0.56 mg/kg), or CBD plus oxycodone (10 and 0.56 mg/kg respectively). Rats received daily intraperitoneal administration of drugs for two weeks. Blood samples were taken periodically. Brains were extracted after the final drug administration. Tissue punches of the periaqueductal gray, nucleus accumbens and anterior cingulate cortex were collected from 100 micrometer frozen sections. Plasma and brain tissue were analyzed using mass spectrometry for CBD, oxycodone, their metabolites, and a panel of neurochemicals including monoamines and acetylcholine.

Results: Co-administration of CBD with oxycodone generally potentiated plasma and brain levels of oxycodone, and impeded oxycodone’s metabolism. In contrast, CBD metabolism appeared to be slightly accelerated by the presence of oxycodone. Rats given oxycodone alone generally had the largest positive difference in brain neurochemical content, particularly serotonin. In contrast rats given CBD plus oxycodone generally exhibited similar brain neurochemical content as rats given CBD alone. These results suggest that CBD co-administration might attenuate the neurochemical effects of oxycodone.

Conclusions: The apparent paradox of CBD’s ability to potentiate oxycodone analgesia without potentiating oxycodone’s rewarding effects cannot be explained by a generalized potentiation of oxycodone bioavailability. Our findings suggest
that CBD co-administration might normalize the impact of oxycodone on brain neurochemical activity, thus providing an explanation for why CBD does not impact the rewarding actions of oxycodone; however, the sites at which CBD potentiates the analgesic actions of oxycodone remains undetermined.