Cerebrovascular Effects of Alcohol Combined with Tetrahydrocannabinol

Introduction: Alcohol (ethanol) and cannabis are among the most widely used recreational drugs in the world. With increased efforts toward legalization of cannabis, there is an alarming trend toward the concomitant (including simultaneous) use of cannabis products with alcohol for recreational purpose. While each drug possesses a distinct effect on cerebral circulation, the consequences of their simultaneous use on cerebral artery diameter have never been studied. Thus, we set to address the effect of simultaneous application of alcohol and (-)-trans-Δ-9-tetrahydrocannabinol (THC) on cerebral artery diameter. Materials and Methods: We used Sprague-Dawley rats because rat cerebral circulation closely mimics morphology, ultrastructure, and function of cerebral circulation of humans. We focused on the middle cerebral artery (MCA) because it supplies blood to the largest brain territory when compared to any other cerebral artery stemming from the circle of Willis. Experiments were performed on pressurized MCA ex vivo, and in cranial windows in vivo. Ethanol and THC were probed at physiologically relevant concentrations. Researchers were "blind" to experimental group identity during data analysis to avoid bias. Results: In males, ethanol mixed with THC resulted in greater constriction of ex vivo pressurized MCA when compared to the effects exerted by separate application of each drug. In females, THC, ethanol, or their mixture failed to elicit measurable effect. Vasoconstriction by ethanol/THC mixture was ablated by either endothelium removal or pharmacological block of calcium- and voltage-gated potassium channels of large conductance (BK type) and cannabinoid receptors. Block of prostaglandin production and of endothelin receptors also blunted constriction by ethanol/THC. In males, the in vivo constriction of MCA by ethanol/THC did not differ from ethanol alone. In females, the in vivo constriction of this artery by ethanol was significantly smaller than in males. However, artery constriction by ethanol/THC did not differ from the constriction in males. Conclusions: Our data point at the complex nature of the cerebrovascular effects elicited by simultaneous use of ethanol and THC. These effects include both local and systemic components.