Combined alcohol and cannabinoid exposure leads to synergistic toxicity by affecting cerebellar Purkinje cells.

Combined use of cannabis and alcohol results in greater psychoactive toxicity than either substance alone, but the underlying central mechanisms behind this worsened outcome remain unclear. Here we show that the synergistic effect of Δ-tetrahydrocannabinol (THC) and ethanol on motor incoordination in mice is achieved by activating presynaptic type 1 cannabinoid receptors (CBR) and potentiating extrasynaptic glycine receptors (GlyR) within cerebellar Purkinje cells (PCs). The combination of ethanol and THC significantly reduces miniature excitatory postsynaptic current frequency in a CBR-dependent manner, while increasing the extrasynaptic GlyR-mediated chronic chloride current, both leading to decreased PC activity. Ethanol enhances THC actions by boosting the blood-brain-barrier permeability of THC and enriching THC in the cell membrane. Di-desoxy-THC, a designed compound that specifically disrupts THC-GlyR interaction without affecting the basic functions of CBR and GlyR, is able to restore PC function and motor coordination in mice. Our findings provide potential therapeutic strategies for overcoming the synergistic toxicity caused by combining cannabis and alcohol use.