Nearly half a century after reports of a salutary effect of cannabinoids on ocular pressure we still do not know the mechanism by which this occurs. Our chief findings in normotensive mice were that THC lowers pressure substantially and for at least 8 hours, through a combined action at two receptors, CB1 and GPR18. This effect was sex-dependent, with much stronger responses in male mice. CBD in contrast had two opposing actions on IOP: raising IOP in wild-type animals but lowering it in CB1 knockout mice likely via GPR18. Finally, at equal concentrations CBD prevented the IOP-lowering effects of THC.
Sex-dependent effects have been reported for cannabis (e.g., in the study by Cooper and Haney
28) but sex dependence had not been explored for cannabinoid regulation of IOP. Phytocannabinoids are not currently considered a suitable first-line therapeutic for glaucoma (e.g., American Academy of Ophthalmology [AAO] position statement 2014,
www.aao.org); however, this may be based on limited evidence. The central argument is that topical THC is not effective, therefore necessitating treatment via cannabis inhalation. Cannabis inhalation, in turn, has assorted shortcomings: (1) psychoactivity, (2) short action (<4 hours), and (3) elevation of blood pressure. A key question then is whether topical THC works in humans. The negative conclusion is based on four studies, three of which pool male and female subjects. In the two 1981 studies by Merritt et al.,
29,30 most subjects are female (4/6, 7/8). Green and Roth
31 (1982) do not specify the makeup of their subject pool but exclude pregnant subjects, implying the presence of females, leaving only one study that includes only males.
32 The sex dependence of THC regulation of IOP, with the robust effects in males that we report here, combined with topical THC studies in animals (e.g., Merritt et al.,
29 Green et al.,
33 ElSohly et al.,
34), suggests that the question of topical THC as a means to lower ocular pressure may merit some reconsideration.
It is notable that no less than three cannabinoid related receptors, namely, CB1, GPR18, and GPR119, each lower IOP when activated. Moreover, they all exhibit sex dependence, but differentially. mRNA expression of CB1 and GPR18 is elevated in male mice relative to female mice. It must be noted that differential mRNA expression does not necessarily correspond to protein levels (e.g., Western blot). However the difference in mRNA is consistent with our finding that dual activation of these receptors by THC yields a stronger effect in males. In contrast, the X-linked GPR119 receptor lowers IOP preferentially in female mice.
15 Our results also raise the possibility that the diurnal variation of IOP, in which GPR18 plays a role,
35 is sex-dependent.
The elevation of IOP by CBD is consistent with CB1 antagonism. If CBD truly interferes with the actions of THC then low-CBD strains may offer superior results for studies involving cannabis inhalation. The second mechanism of action for CBD—the one that underlies IOP—reduction—may be due to direct or indirect activity at GPR18, since there is no effect on IOP by CBD if GPR18 and CB1 are both blocked/deleted. As noted above, CBD has been shown to be active at GPR18
19,20 and may block FAAH,
21 which could also elevate acylethanolamines, as we have recently shown,
35 including AEA, a precursor for GPR18 ligand NAGly.
9 Our lipidomic analysis revealed rises in several cannabinoid-related lipids. Levels of GPR18 ligand NAGly were not elevated but we did see a rise in the closely related NOGly, which may also activate GPR18 (data not shown). This may account for the observed GPR18-dependent effects. Levels of four of the six acylethanolamines tested were seen to rise after CBD treatment. Interestingly, of these, oleoylethanolamide (OEA) and palmitoylethanolamide have been shown by Syed et al.
36 to activate GPR119, which can also lower ocular pressure in female—but not male—mice when activated.
15 Moreover, levels of 2-oleoylglycerol, a GPR119 ligand that also lowers IOP,
15 were also seen to rise and may contribute to the signaling profile of CBD.
One consideration in interpreting the duration of effects of THC and CBD relates to rates of metabolism and clearance. We did not assess the pharmacokinetics of these compounds. Since they are structurally quite similar (with identical molecular weight), it is unlikely that one of the original compounds is removed much more rapidly than the other. However, while the hepatic metabolism of these compounds has been studied extensively, potential metabolism in the eye is unstudied. In principle, the apparent temporal difference between CBD and THC effects in the eye may be a function of differential ocular metabolism. In principle CBD and THC may also impact each other's metabolism, the so-called entourage effect. Competition for enzymatic breakdown is generally hypothesized to enhance the signaling of THC, whereas we saw a diminished response, but it is difficult to ascertain without further, explicit study of THC/CBD pharmacokinetics in the eye.
It is valuable to understand the mechanisms by which THC and CBD regulate intraocular pressure, particularly at a time when their changing legal status and the perception of phytocannabinoids as safe contribute to a continued growth in their availability and popular embrace. CBD in particular has recently been approved by the FDA as an antiepileptic and is available in many grocery stores. We find that the regulation of ocular pressure by THC and CBD is more complex than previously appreciated. THC acts via a combination of CB1 and GPR18 receptors in a sex-dependent manner, while CBD can both raise IOP and interfere with the effects of THC. The potential of CBD to elevate ocular pressure should be evaluated further as a potential deleterious side effect, particularly with long-term use. Our finding of sex dependence of cannabinoid regulation of ocular pressure suggests that the current academic view that topical phytocannabinoids are without effect (e.g., the 2014 AAO position statement on cannabis and glaucoma) may be premature. Most of the studies on which this position is based include female subjects but are underpowered to evaluate a potential sex dependence of effect. However, it should be stressed that the findings presented here highlight the complex endogenous cannabinoid signaling system that can be selectively targeted and harnessed to lower ocular pressure by other means. For instance, we have shown that it is possible to enhance endogenous cannabinoid signaling by blocking the cannabinoid-metabolizing enzyme monoacylglycerol lipase
37 and so lower ocular pressure. Similarly, we have found that activating CB1 directly
38 can achieve the same outcome. Our findings for THC suggest that a dual CB1/GPR18 agonist may prove advantageous. The study of phytocannabinoids such as THC and CBD, but also others derived from the plant, may therefore point to novel strategies to promote ocular health.