Chapter 3: CBD and Ocular Disorders and Diseases

Oxidative stress describes the effect of an imbalance between the production of free radicals and the body’s ability to neutralize or detoxify their harmful effects with antioxidants. Glaucoma, uveitis, macular degeneration and diabetic retinopathy are all oculus diseases that directly correlate to oxidative stress.

Oxidative stress happens when an intense inflammatory response is stimulated to relieve damage (i.e., injury, infection) through microglial and macrophage discharge. This discharge correlates with the release of glutamate, reactive oxidative species (ROS), nitric oxide (NO), and tumor necrosis factor (TNF); a release that would intensify inflammation, vascular decay and biodegradation. These are all remnants of metabolic syndromes; ocular health is affected profoundly by metabolic diseases. Age-related cataracts, glaucoma, maculopathy and diabetic retinopathy become more likely to occur if combined with metabolic syndrome.

A functioning endocannabinoid system correlates with prevention and treatment of metabolic diseases. Therefore phytocannabinoids are already proposed for the prevention of several ocular disorders. CBD studies have found it a suitable candidate for hindering oxidative stress response that is activated by microglial cells and thereby decreasing any damages that might result from inflammatory response.^{7, 9, 11, 15}

Glaucoma

Eye diseases that result from intraocular pressure elevation or imbalance are categorized as Glaucoma. This ocular disease is a leading cause of irreversible damage to the optic nerve, loss of vision and ultimately leads to blindness. Intraocular pressure can elevate when either the fluid production in the eye is excessive, or when the trabecular meshwork becomes blocked.

Studies have shown that when the retinal ganglion cells release excessive amounts of glutamate (an essential neurotransmitter), ischemia-related neurotoxicity and cell death arise. In this case, CBD already reduces the production of ROS or reactive oxygen species and therefore is a promising non-inebriating antioxidant. In these studies, CBD is suitable for protection from retinal injuries induced by glutamate; it prevents the formation of compounds essential for the development of glaucomas such as lipid peroxides, nitrite, nitrate, and nitrotyrosine.^{5, 7}

CBD can be a further used to prevent the apoptosis and retinal ganglion cell death, which are the two leading pathways to visual loss. Current studies propose CBD’s neuroprotective properties as a suitable glaucoma treatment. Periodic doses of administered CBD reduce the intraocular pressure, which in turns would hinder the development of neurodegenerative and apoptotic processes.  The therapeutic applications of CBD for glaucoma treatment is well documented.^{5, 6, 13}

Uveitis

Uveitis is an inclusive word that represents an assortment of inflammatory diseases, which destroys eye tissues and produces swelling. These diseases can result in vision reduction or severe loss of vision. The term “uveitis” is practiced because the disease can often affect the uvea in the eye; however, uveitis implicates more than just the uvea. Other affected oculus parts could include the lens, retina, optic nerve and vitreous, all of which can lead to a vision reduction or total blindness.

The disease occurs either from issues implicating the eye itself and could also be triggered by an inflammatory disease that is affecting another part of the body. Uveitis is further classified into four subcategories that include:

1. Anterior uveitis: is often associated with infectious, rheumatologic, gastrointestinal and lung diseases; however healthy people may also be affected.
2. Intermediate uveitis: it affects the core of the eye, the vitreous and is linked to disorders such as sarcoidosis and multiple sclerosis.
3. Posterior uveitis: affecting mostly the retina and choroid in the back of the eye; relates to choroiditis and infectious diseases.
4. Panuveitis: Behcet’s disease is a more widely used name for this disease, that inflames all central parts of the eye, producing extra damage to the retina.

All four types of uveitis have shown a positive response to anti-inflammatory treatment with CBD, which reduces inflammation, blocks oxidative stress and alleviates damages resulting from endotoxins. CBD’s neuroprotective capacities are promising for the treatment of autoimmune and infectious diseases.^{3, 4, 9, 10, 11}

Macular Degeneration

Macular degeneration is a disease that eliminates sight gradually through blurring or the loss of central vision. Often, this is a result of the macula deterioration, a yellow pigmented structure at the rear end of the eye, which is responsible for full-color vision ability. The severity of the disease varies on each person and on how soon it is detected.

Primary inflammatory diseases cause tissue damage and macular degeneration through the activation of microglial cells in the retina. The neuroprotective and anti-inflammatory properties have been illustrated in several studies. This supports the likely effectiveness of CBD in the prevention and treatment of macular degeneration.^{4, 8, 11, 14}

Diabetic Retinopathy

Diabetic retinopathy impacts blood vessels in the retina (a light-sensitive tissue) at the rear of the eye. Amongst diabetic people, it is the most common cause of vision loss. It is also one of the primary causes of vision impairment and blindness. Patients with diabetes mellitus have an imbalance in glucose metabolism that aggravates cellular hyperpermeability in the retina. Consequently, the retina becomes amenable to injuries; reactive oxidative species and nitrative stress cause the most damage.^{11, 12, 14}

Diabetes development is closely linked to maladaptive lifestyle factors resulting in an idiopathic autoimmune CECD. Even though research suggests a genetic element in the progression of diabetes, it is often an acquired disease; unhealthy diets and obesity both have robust associations with diabetes.

The retina is inclusive of the endocannabinoid system, where research has shown the effectiveness of CBD in the reduction of oxidative and nitrative stress. The properties of CBD that are effective in diabetes treatment such as anti-inflammatory, neuroprotective, are also essential for the prevention of diabetic retinopathy.^{1, 2, 4, 9, 11, 12}

References:

1. Russo E. B, Neuro Endocrinol Lett. 2004 Feb-Apr;25(1-2):31-9. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Available at https://www.ncbi.nlm.nih.gov/pubmed/15159679
2. Gruden, G., Barutta, F., Kunos, G., and Pacher, P. (2016) Role of the endocannabinoid system in diabetes and diabetic complications. Br J Pharmacol, 173: 1116–1127, available at https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.13226
3. Roger G. Pertwee, Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities, Phil. Trans. R. Soc. B 2012 367 3353-3363; available at http://rstb.royalsocietypublishing.org/content/367/1607/3353.long
4. George W. Booz, Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress, Free Radical Biology and Medicine, Volume 51, Issue 5, 2011, Pages 1054-1061, ISSN 0891-5849, available at: http://www.sciencedirect.com/science/article/pii/S0891584911000116
5. Crandall J, Matragoon S, Khalifa Y, M, Borlongan C, Tsai N, -T, Caldwell R, B, Liou G, I, Neuroprotective and Intraocular Pressure-Lowering Effects of (–)Δ⁹-Tetrahydrocannabinol in a Rat Model of Glaucoma. Ophthalmic Res 2007;39:69-75, available at https://www.karger.com/Article/Abstract/99240#
6. Novack GD, Cannabinoids for treatment of glaucoma. Current Opinion in Ophthalmology 27:146–150, MAR 2016, available at https://insights.ovid.com/pubmed?pmid=26840343#
7. El-Remessy, Azza B. et al. Neuroprotective Effect of(−)Δ9-Tetrahydrocannabinol and Cannabidiol in N-Methyl-d-Aspartate-Induced Retinal Neurotoxicity. The American Journal of Pathology , Volume 163 , Issue 5 , 1997 – 2008, available at https://ajp.amjpathol.org/article/S0002-9440(10)63558-4/fulltext
8. Wei, Y., Wang, X., Zhao, F., Zhao, P., & Kang, X. (2013). Cannabinoid receptor 1 blockade protects human retinal pigment epithelial cells from oxidative injury. Molecular Vision, 19, 357–366, available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3580988/
9. Liou G, El-Remessy A, Ibrahim A, et al. Cannabidiol As a Putative Novel Therapy for Diabetic Retinopathy: A Postulated Mechanism of Action as an Entry Point for Biomarker-Guided Clinical Development. Current pharmacogenomics and personalized medicine. 2009;7(3):215-222. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955420/
10. Chen, J., Simon, P. & Fliri, H. Abnormal Cannabidiols as Agents for Lowering Intraocular Pressure. 2, 1-13 (2013), available at https://patents.google.com/patent/US7618966B2/en
11. Gregory I. Liou, John A. Auchampach, Cecilia J. Hillard, Gu Zhu, Bilal Yousufzai, Salman Mian, Sohail Khan, Yousuf Khalifa; Mediation of Cannabidiol Anti-inflammation in the Retina by Equilibrative Nucleoside Transporter and A2A Adenosine Receptor. Invest. Ophthalmol. Vis. Sci. 2008;49(12):5526-5531. Available at http://iovs.arvojournals.org/article.aspx?articleid=2164704
12. El-Remessy, Azza B. et al. Neuroprotective and Blood-Retinal Barrier-Preserving Effects of Cannabidiol in Experimental Diabetes The American Journal of Pathology, Volume 168, Issue 1, 235 – 244 (2006) available at https://ajp.amjpathol.org/article/S0002-9440(10)62086-X/fulltext
13. Tomida, I. et al. Effect of Sublingual Application of Cannabinoids on Intraocular Pressure: A Pilot Study. Journal of Glaucoma. 15(5):349-353, OCT 2006, available at https://insights.ovid.com/pubmed?pmid=16988594#
14. Yu, Y., Chen, H., & Su, S. B. (2015). Neuroinflammatory responses in diabetic retinopathy. Journal of Neuroinflammation, 12, 141. Available at http://doi.org/10.1186/s12974-015-0368-7
15. Tezel, G., Yang, X., Luo, C., Peng, Y., Sun, S. L., & Sun, D. (2007). Mechanisms of Immune System Activation in Glaucoma: Oxidative Stress-Stimulated Antigen Presentation by the Retina and Optic Nerve Head Glia. Investigative Ophthalmology & Visual Science, 48(2), 705–714. Available at  http://doi.org/10.1167/iovs.06-0810