GLAUCOMA

BY MICHELLE MARTIN

Promising results hint that THC might one day treat glaucoma.

Glaucoma is an umbrella term for a group of diseases that damage the optic nerve— the signaling pathway bringing color and image information from the retina to the brain. 1 Damaged nerve cells in the eye can narrow a person’s field of vision and even lead to complete blindness. According to the World Health Organization, about 4.5 million people are blind as a result of glaucoma in the world—that’s slightly more than 12 percent of all human blindness. 2 About three million people who suffer from glaucoma are in the United States, according to the American Glaucoma Society. 3 Unfortunately it’s a bit sneaky in that patients often only notice the decrease in their peripheral vision after a large swath of cells is already dead and the disease is in the advanced stages. 3,4 Currently, there is no known cure, and patients typically manage the condition for the rest of their lives with medicine, surgery, or both.

Although the exact ways in which the diseases work are poorly understood, two aspects are well known: damage to the cells of the optic nerve, and in most cases, there is an increase in pressure within the eye. The most effective medicines used to treat glaucoma aim to lower the pressure within the eye. 1,5 Researchers published a study in 1971, in the prestigious “Journal of the American Medical Association” showing that smoking marijuana decreased intraocular pressure. 7 We know today that THC is at least one of the components responsible for this effect.

Keeping intraocular pressure low seems to work to hold off the worst glaucoma has to offer. Even so, for a minority of patients who are successfully keeping eye pressure low, the disease still progresses. That is why some researchers are looking beyond pressure-lowering medicines and taking a closer look into medications that can also protect the nerve cells from damage4—something THC has also been shown to do. 5

THC seems like a good candidate to treat glaucoma because of the combination of its ability to protect neurons as well as lower intraocular pressure. THC affects change in the body by connecting to at least two cannabinoid receptors. 7 One of these is the well-known cannabinoid CB1 receptors. They are found throughout the brain and eyes and can affect pain, mood, movement and memory. 5,8,9 As it turns out, CBD is actually not well-suited to the job according to results we’ll get to below.

Smoking cannabis as a way to treat glaucoma has drawbacks. It lasts a short duration (three to four hours according to the American Glaucoma Society), 10 has potentially undesirable psychoactive and other side-effects, as well as the possibility of building up resistance. The society issued a position statement in 2009 saying it does not recommend cannabis for glaucoma treatment. However, the statement hints that the position might change if more promising research becomes available.

In the 11 years since the statement came out, there have been more studies. Recent research in animal models highlights the possibility that some form of THC might one day be available to treat glaucoma.

Since smoking has its challenges, researchers have tried delivering THC and CBD under the tongue (THC lowered eye pressure for four hours and CBD had no effect or raised the pressure) and via eye drops. 11 The eye drops failed at first, because the THC didn’t get very far into the eye, due to its love of lipids or lipophilic nature. A team of pharmaceutical researchers from the University of Mississippi has been tackling this problem. They published a study last year in the journal “Translational Vision Science and Technology” pointing to early success in developing a new eye drop. 12,13 It allowed the THC to penetrate more deeply into rabbits’ eyes and decreased intraocular pressure for six hours. They were able to override THC’s hydrophobic nature by attaching it to molecules that made the whole nano-sized medicine able to sink all the way into the rabbit’s eye. In their paper, the researchers also point out that, ifrecent findings are correct, THC can protect the cells in the optic nerve from damage and deeper penetration may help increase this positive effect.

In a 2018 study published by the online journal “Investigative Ophthalmology & Visual Science,” Indiana University researchers investigated on which receptors THC and CBD were working in mice. 7 They found the two compounds were working with different receptors. THC lowered eye pressure. CBD, though it may have neuroprotective effects, worked against THC and kept the pressure from decreasing and, in some cases, could even have the unwanted effect of increasing eye pressure.

In one surprise result, they found a marked difference in how the cannabinoids affected male and female mice. Males had a much more pronounced decrease in eye pressure from THC. When they looked into this, they found the males had more of the relevant receptors. 7

In short, before THC could be a good long-term solution to this life-long condition, there are some hurdles to overcome. In their position statement, the American Glaucoma society states: “Unless a well tolerated formulation of a marijuana-related compound with a much longer duration of action is shown in rigorous clinical testing to reduce damage to the optic nerve and preserve vision, there is no scientific basis for use of these agents in the treatment of glaucoma.” 10 Rigorous clinical testing is the gold standard for choosing a safe and effective treatment. Such research will continue to be difficult to conduct as long as cannabis is still listed as “Schedule 1” under the Controlled Substances Act, meaning it is considered to be a substance with no medical use and a high potential for abuse. If Congress or the federal administration changes the classification, researchers will likely have more opportunities to conduct relevant research in humans.

References: 1. https://higherlogicdownload.s3.amazonaws.com/AMERICANGLAUCOMASOCIETY/4ca07187-fb0f-4dc3-a19c-33093862484d/UploadedImages/Documents/559_cyclophoto4_final.pdf 2. https://www.who.int/blindness/causes/priority/en/index6.html 3. https://www.americanglaucomasociety.net/patients/glaucoma-faqs 4. Bucolo, C., Plantania, C.B.M., Drago, F., Bonfiglio, V., Reibaldi, M., Avitabile, T., Uva, M. (2018). Novel Therapeuticsin GlaucomaManagement. doi: 10.2174/1570159X15666170915142727. 5. Rapinoa, C., Tortolania, D., Scipionib, L. & Maccarroneb, M. (2018). Neuroprotection by (Endo)Cannabinoids in Glaucoma and Retinal Neurodegenerative Diseases. Current Neuropharmacology (16), 959-970. 6. Hepler R.S., Frank I.R. (1971) Marihuana smoking and intraocular pressure. JAMA (217),1392. 7. MillerS., DailyL., Leishman E., BradshawH., StraikerA. (2018). D9-tetrahydrocannabinoland cannabidiol differentiallyregulateintraocularpressure. InvestOphthalmol VisSci (59), 5904–5911. 8. Piomelli D. (2003). The molecular logic of endocannabinoid signalling. Nat Rev Neurosci (4), 873–884. 9. Straiker, A.J., Maguire, G., Mackie, K., Lindsey, J. (1999). Localization of cannabinoid CB1 receptors in the human anterior eye and retina. Invest Ophthalmol Vis Sci. Sep (40:10), 2442-2448. 10. https://www.americanglaucomasociety.net/about/statements 11. Tomida, I., Azuara-Blanco, A., House, H., Flint, M., Pertwee, R.G., Robson, P.J. (2006). Effectofsublingual application ofcannabinoidson intraocularpressure: apilotstudy. Journal of Glaucoma: Oct15(5), 349-53. 12. 2019: Taskar, P.S., Patil, A., Lakhani, P., Ashour, E., Gul, W., El Sohly, M.A., Murphy, B., Majumdar, S. (2019) D9-Tetrahydrocannabinol derivative-loaded nanoformulation lowers intraocular pressure in normotensive rabbits. Trans Vis Sci Tech: 8(5),15.https://doi.org/10.1167/tvst.8.5.15 13. Adelli, G.R., Bhagav, P., Taskar, P., et al. (2017). Development of a D9-tetrahydrocannabinol amino acid-dicarboxylate prodrug with improved ocular bioavailability. Invest Ophthalmol Vis Sci. (58), 2167–2179. doi: 10.1167/iovs.16-20757