H(eye) – or Low?

Scientists have known that cannabis reduces ocular pressure since the ‘60s, but the reason why has remained a mystery – until now. A team at the University of Indiana has delved into the endogenous cannabinoid signaling system and made an unexpected discovery – the drug’s two major chemical components, THC and CBD, counteract. While THC, the primary psychoactive ingredient, was found to effectively lower eye pressure, CBD appeared to block its affect. Moreover, CBD appeared to worsen the primary underpinning of glaucoma by causing a rise in intraocular pressure (an average of 18 percent for at least four hours after use). So what does this mean for patients being treated with medical marijuana? “Given the popular embrace of CBD and its recent approval for childhood epilepsy, this potential rise in IOP is a side effect that we should be aware of,” says lead author Alex Straiker, an associate scientist from the university’s Department of Psychological and Brain Sciences.

Straiker and his team used knockout mice to separate neuroreceptors in a bid to understand more about the conflicting effects of THC and CBD. They found that three different cannabinoid-related receptors – CB1, GPR18 and GPR119 – all regulate ocular pressure independently. Moreover, they identified CB1 and GPR18 as those susceptible to pressure lowering.

Interestingly, the study also found that the THC’s effect was sex-dependent; male mice experienced an average drop in eye pressure of nearly 30 percent four hours after exposure to THC alone, along with a lower pressure drop of 22 percent after   hours. On the other hand, female mice experienced an average pressure drop of just 17 percent after four hours, with no difference in eye pressure after eight hours.

“The difference seems to be due to a difference in the number of receptors but it’s hard to say why there should be a sex difference. Strangely, we find that GPR119 lowers pressure, but only in female mice. Maybe the CB1/GPR18 system is up-regulated to compensate, but we don’t know for sure,” says Straiker. Offering some explanation, Straiker notes that THC and CBD are somewhat non-specific in their action. “CBD acts as an (allosteric) antagonist at CB1, so it is opposing the pressure-lowering effects of those receptors,” he says. “The fact that the pressure rises is probably an indication that CB1 receptors are always partially activated to lower pressure. But it looks as though CBD also lowers pressure via GPR18. The truth is, we just don’t know.” 

Regardless, the study challenges long-held beliefs on cannabis as a glaucoma treatment. “The position of the medical community is that THC is ineffective in humans when applied topically. This is based on four studies from the early 1980s, three of them fairly small and with mixed-sex subject pools. Since there is a sex-dependence, they may have missed an effect,” says Straiker. “Despite all the usual caveats, such as our study being done in mice, our work suggests that the question is still open. Certainly, our study argues that lower-CBD strains would work better that existing formulas, as CBD antagonizes the salutary THC effects.”