doi: 10.1021/acsptsci.4c00583. eCollection 2025 Apr 11.
Cannabinoids as Multitarget Drugs for the Treatment of Autoimmunity in Glaucoma
- PMID: 40242585
- PMCID: PMC11997897
- DOI: 10.1021/acsptsci.4c00583
Abstract
Diseases of multifactorial origin like neurodegenerative and autoimmune diseases require a multitargeted approach. The discovery of the role of autoimmunity in glaucoma and retinal ganglionic cell (RGC) death has led to a paradigm shift in our understanding of the etiopathology of glaucoma. Glaucoma can cause irreversible vision loss that affects up to an estimated 3% of the population over 40 years of age. The current pharmacotherapy primarily aims to manage only intraocular pressure (IOP), a modifiable risk factor in the glaucomatous neurodegeneration of RGCs. However, neurodegeneration continues to happen in normotensive patients (where the IOP is below a reference value), and the silent nature of the disease can cause significant visual impairment and take a massive toll on the healthcare system. Cannabinoids, although known to reduce IOP since the 1970s, have received renewed interest due to their neuroprotective, anti-inflammatory, and immunosuppressive effects on autoimmunity. Additionally, the role of the gut-retina axis and abnormal Wnt signaling in glaucoma makes cannabinoids even more relevant because of their action on multiple targets, all converging in the pathogenesis of glaucomatous neurodegeneration. Cannabinoids also cause epigenetic changes in immune cells associated with autoimmunity. In this Review, we are proposing the use of cannabinoids as a multitargeted approach for treating autoimmunity associated with glaucomatous neurodegeneration, especially for the silent nature of glaucomatous neurodegeneration in normotensive patients.
© 2025 American Chemical Society.
The Role of Cannabinoids in Glaucoma: A Multitargeted Approach
Glaucoma is a complex, multifactorial disease that can lead to irreversible vision loss, affecting millions globally. While intraocular pressure (IOP) is the traditional target for treatment, the neurodegenerative aspect of glaucoma—specifically retinal ganglionic cell (RGC) death—remains a significant challenge, especially in normotensive patients (those with IOP within normal limits). This underscores the need for multitargeted therapies, which is where cannabinoids are starting to shine in research.
In this article, we explore how cannabinoids—known for their neuroprotective, anti-inflammatory, and immunomodulatory effects—may hold the key to treating glaucoma from a holistic perspective. By addressing autoimmunity and neurodegeneration, cannabinoids could offer a much-needed multifaceted approach for glaucoma management, particularly in silent, normotensive cases where damage is often not detected until it’s too late.
The Traditional Approach vs. The New Paradigm
Traditionally, glaucoma treatment focuses on managing IOP, since high pressure in the eye has long been linked to RGC damage. However, the reality is that neurodegeneration continues in patients even when their IOP is normal, a phenomenon that has led researchers to rethink their approach.
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Current treatments: These primarily aim to reduce IOP, but they do not directly address the neurodegeneration process itself.
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The challenge: Glaucoma can progress without noticeable symptoms, which means the disease is often undetected until significant vision loss occurs.
This is where cannabinoids come into play. Cannabinoids have long been known to lower IOP, but recent studies have highlighted their broader potential in the neuroprotective and anti-inflammatory domains.
Cannabinoids: More Than Just IOP Reduction
While cannabinoids have shown potential in reducing IOP, their multitargeted effects make them even more compelling when looking at glaucoma’s underlying mechanisms. Here are the key aspects where cannabinoids may have an advantage over traditional therapies:
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Neuroprotection: Cannabinoids have been shown to help protect retinal ganglion cells (RGCs) from the neurodegenerative effects of glaucoma, which is not something traditional IOP-lowering treatments address.
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Anti-inflammatory Effects: Inflammation plays a significant role in glaucomatous neurodegeneration. Cannabinoids’ ability to reduce proinflammatory cytokines could help limit retinal damage and prevent further degeneration.
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Immunosuppressive Potential: Glaucoma has also been linked to autoimmunity. Cannabinoids have immunosuppressive properties that may help reduce immune cell activity that attacks retinal cells, thereby preventing autoimmune-related damage.
The Emerging Connection: Gut-Retina Axis & Wnt Signaling
Two exciting concepts are currently reshaping our understanding of glaucoma: the gut-retina axis and Wnt signaling.
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Gut-retina axis: Research suggests that the health of our gut microbiome may influence retinal health, and this new connection points to cannabinoids’ potential in regulating both. Cannabinoids have been shown to interact with the gut’s microbiome, possibly influencing the immune response that contributes to glaucoma’s progression.
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Wnt signaling: This pathway, which regulates various cellular processes, is found to be disrupted in glaucomatous neurodegeneration. Cannabinoids may help modulate Wnt signaling, offering a potential way to slow or reverse the damage caused by abnormal signaling in glaucoma.
The combined effect of cannabinoids on these emerging areas of research makes them uniquely suited to address the multiple factors at play in glaucoma’s development.
Epigenetic Influence: A New Frontier
Epigenetics refers to changes in gene expression that don’t involve alterations to the underlying DNA sequence. Research has shown that cannabinoids may influence epigenetic pathways in immune cells, potentially modifying the way immune responses occur.
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Cannabinoids in autoimmunity: By influencing gene expression in immune cells, cannabinoids could modulate the immune attack on the retina that occurs in certain autoimmune diseases related to glaucoma. This epigenetic influence could be one of the key mechanisms behind cannabinoids’ ability to help manage autoimmune diseases contributing to glaucomatous neurodegeneration.
Global Research Trends & Future Directions
The evidence for cannabinoids’ potential in treating glaucoma has been growing steadily. The USA and Italy have been at the forefront of this research, with institutions like the National Research Council of Italy and Complutense University of Madrid leading the way. Key researchers like Vincenzo Di Marzo have contributed significantly to understanding the endocannabinoid system and its therapeutic potential for conditions like glaucoma.
Recent bibliometric analyses show that the research on cannabinoids in glaucoma is expanding in scope, from understanding basic biological mechanisms to exploring clinical applications.
Looking Ahead: A Multitargeted Approach for Glaucoma Treatment
The shift from IOP-centered treatments to a multitargeted approach involving cannabinoids could change how we treat glaucoma in the future. Cannabinoids offer the ability to target multiple disease pathways—from lowering IOP to protecting retinal neurons to modulating immune responses—making them an ideal candidate for comprehensive glaucoma management, particularly in cases where IOP is not the issue.
The combination of neuroprotection, immune regulation, and epigenetic modulation holds promise for advancing glaucoma treatment, providing a more holistic solution that addresses both the symptoms and the underlying causes of neurodegeneration.
️️ Final Thoughts
The potential of cannabinoids in treating glaucoma highlights the importance of a holistic, multitargeted approach to complex diseases like this. By tackling both autoimmunity and neurodegeneration, cannabinoids could provide significant benefits, particularly in cases that are difficult to manage with traditional therapies.
As research progresses, cannabinoids may not just offer a new way to manage IOP but could become a game-changer in the multidimensional treatment of glaucoma.
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