Δ⁹-THC AND CBD DIFFERENTIALLY REGULATE INTRAOCULAR PRESSURE

Abstract

Purpose : It has been known for nearly 50 years that marijuana and its chief psychoactive constituent Δ⁹-tetrahydrocannabinol (Δ⁹-THC) lower intraocular pressure (IOP). Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a condition that places millions at risk of blindness. Despite considerable early interest in (and continued public perception of) Δ⁹-THC as a potential glaucoma therapeutic, we do not know how Δ⁹-THC regulates IOP. It is commonly assumed that Δ⁹-THC acts via cannabinoid receptors CB₁ and/or CB₂, but Δ⁹-THC also activates other receptors, including GPR18, a receptor we have shown to regulate IOP. Cannabidiol (CBD) is a second major constituent of marijuana that has mostly been found to be without effect in studies of intraocular pressure.

Methods : We explored Δ⁹-THC and CBD effects on intraocular pressure in the eyes of normotensive mice.

Results : We now report 1) Δ⁹-THC acts via a combination of two receptors and in a sex-dependent manner and, 2) CBD has two opposing actions on IOP. In our model a single topical application of Δ⁹-THC lowers IOP substantially (~28%) for eight hours. This effect is partly ablated in CB₁ knockout mice, but fully blocked by topical pretreatment with the GPR18 antagonist O1918 in CB1 knockouts, indicating that Δ⁹-THC acts through CB₁ and GPR18. We also found that effect in males was sex-dependent. In female mice Δ⁹-THC was slower to act and half as effective. Surprisingly, topical CBD raised IOP, but even more surprisingly, CBD lowered IOP in CB₁ knockout mice, indicating that CBD has two opposing actions, one CB₁-dependent, the other CB₁-independent. CBD also opposes the beneficial effects of Δ⁹-THC. The mechanism of the IOP reduction by CBD remains unknown.

Conclusions : The mechanism by which Δ⁹-THC regulates intraocular pressure is complex, involving two receptors - CB₁ and GPR18. The finding of sex-dependence of Δ⁹-THC action is significant both for interpreting the existing literature on cannabinoid regulation of IOP and in the design of potential drug trials in animals and humans. Lastly, our CBD findings raise the intriguing possibility that CBD interferes with the actions of Δ⁹-THC while the second mechanism of CBD action, once identified, may yield a novel therapeutic target for treatment of glaucoma.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.