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Alex Straiker, Sally Miller; Δ9-THC AND CBD DIFFERENTIALLY REGULATE INTRAOCULAR PRESSURE. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6040.
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© ARVO (1962-2015); The Authors (2016-present)
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.
We explored Δ9-THC and CBD effects on intraocular pressure in the eyes of normotensive mice.
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.
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.
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