Background <p>Headache disorders, specifically migraine headaches, are highly debilitating neurological disorders, with the potential to incapacitate an individual for several hours. Cannabinoid receptors are present in both peripheral and central nervous tissue, which serve as a potential target for the treatment of migraine. <i>Cannabis sativa</i> is a medicinal plant that has been used as self-medication for the treatment of headaches, but insufficient scientific information is currently available regarding their interactions with receptors, as well as intranasal delivery. The intranasal route of administration offers the potential for systemic delivery, as well as delivery into the brain. Nose-to-brain delivery offers a pathway directly to the brain via olfactory epithelium and trigeminal nerves and bypasses both the first-pass metabolism and the blood-brain-barrier (BBB).</p> Methods <p>Known phytochemicals of <i>C. sativa</i> were docked in silico into the active site of the 6KPC crystal structure of the cannabinoid type 2 (CB2) receptor to screen for receptor affinity. Ex vivo permeation studies were done on these four selected cannabinoid compounds across excised sheep nasal epithelial tissue.</p> Results <p>Four cannabinoid compounds were identified with affinity for the CB2 receptor that may provide activity against migraine, namely cannabicyclol, cannabidiolic acid, cannabicitran and cannabielsoin. The ex vivo membrane permeation results revealed that some of the cannabinoids can be delivered to a similar extent than moderately permeable model drugs across nasal epithelium for systemic delivery and potentially also for direct nose-to-brain delivery.</p> Conclusion <p>Through affinity for the CB2 receptor, the identified compounds have shown potential in migraine treatment. There is also potential for nose-to-brain delivery.</p> Graphical abstract <p></p>