Kia Ora,

Thank you for reaching the end. We are talking about Cannabis (Taru rauhae) as a possible treatment for glaucoma (Papahewa). So far, we have learned about:

• how the eyes works,

• what glaucoma is,

• current ways to treat glaucoma, and

• the legality of cannabis.

We will look at the mechanism of cannabis in treating glaucoma. Then, we will explore its practical use.

How Cannabis protects against glaucoma

How does Cannabis help reduce glaucoma? In short, the exact mechanism is not very well understood. However, there are some proposed mechanisms.

Shown by Hepler and Frank in 1971, Cannabis reduces eye pressure by (Katz & Costarides, 2019):

• decrease AH production, and

• increase AH outflow through both the conventional and non-conventional pathway.

In addition to this, Cannabis displays neuroprotection by regulating (Passani et al., 2020):

• glutamate, and

• endothelin-1.

CB1 receptors are widely present throughout the tissues of the eye. The Cannabinoids of Cannabis works on multiple eye structures (Panahi et al., 2017). Cannabis causes vasodilation of blood vessels that surround the ciliary body. The ciliary body is responsible for aqueous humour (AH) production. Vasodilation is when the blood vessels expand in size, and this results in reduced blood pressure. Reduced blood pressure means less fluid leaves the vessels to produce AH. Less AH lowers eye pressure (Nucci et al., 2008).

In addition to this, Cannabinoids increase COX-2 expression. This increases the prostaglandins in the eye. Similar to using prostaglandin analogue eye drops, this activates matrix metalloproteinases resulting in increased outflow through the uveoscleral or non-conventional pathway. More outflow means less eye pressure (Nucci et al., 2008).

Cannabinoids also cause contraction of the ciliary muscles. Not only does this result in a slightly dilated pupil. This results in the drainage angle opening — exposing the trabecular meshwork — and improving outflow, again reducing eye pressure (Lograno & Romano, 2004).

On top of directly influencing AH production and outflow, Cannabinoids display neuroprotection by modulating neurotransmitters and signalling molecules. One of these is glutamate. High glutamate levels are toxic (Zhou & Danbolt, 2014) to retinal ganglion cells (RGCs). This is because glutamate results in nitric oxide production, which causes free radicals to increase. Too many free radical can damage cell components leading to cell death. RGCs are responsible for sending visual information from the eye to the brain. Loss of these cells results in glaucoma. CB1 activation by Cannabinoids results in less glutamate release, and therefore less RGC death (Passani et al., 2020).

Also, Cannabinoids inhibits endothelin-1 — a signalling molecule. Endothelin-1 causes constriction of blood vessels, and hence reduced blood flow. Individuals with normal tension glaucoma have higher endothelin-1 levels. Through cannabinoids' ability to reduce endothelin-1, this helps improve blood flow to the optic nerve head — the cable that connects the eye to the brain. This means the RGCs are able to receive the nourishment they need to survive (Passani et al., 2020).

These are propositions for how cannabis can protect against glaucoma. Now, let's understand how Cannabis is administered.

Administration of Cannabis

Cannabis can be consumed in four ways:

• inhalation,

• oral,

• topically, and

• intravenously.

Hepler and Frank in 1971 is the first study to explore Cannabis for glaucoma treatment. Subjects consumed Cannabis traditionally, inhaling through a water-cooled pipe. They had their eye pressure measured before and an hour after they smoked. A drop in eye pressure was observed. Further studies replicated this finding (Hepler & Petrus, 1976; Merritt et al., 1980).

Hepler & Frank also conducted experiments with an oral formulation of Cannabis (Δ⁹-THC) and too achieved a drop in eye pressure. Synthetic Cannabis forms (e.g BW146, Dronabinol, Nabilone) did observe a reduction in eye pressure as well. However, CBD did not (Passani et al., 2020).

Like most current glaucoma medication, Cannabis has been isolated in a topical eye drop formulation. Topical eye drops are challenging. The difficulty lies in passing cannabinoids through the cornea into the eye. The cornea (or front layer of the eye) is composed of multiple layers. The first layer is the corneal epithelium, which allows 'oily-like' molecules to pass through. The layer underneath is the corneal stroma, and this allows 'water-like' molecules to pass.

Cannabinoids are fat-soluble, which means they are 'oily-like'. Other compounds can be added to improve absorption. This is already done with current medication. For example, steroid eye drops employ cyclodextrin to pass through the cornea into the eye (Katz & Costarides, 2019).

Unfortunately, cyclodextrin does not work well with cannabinoids. Investigators in a study had to formulate a prodrug instead. A prodrug is a precursory form of the acting drug. The prodrug, with the aid of cyclodextrin, can pass into the eye. Once the prodrug enters the eye, it can transform into its active form, Δ⁹-THC. This did achieve a reduction in eye pressure (Adelli et al., 2017).

WIN 55212-2 is a synthetic cannabinoid also developed as a topical eye drop. This was also able to enter the eye and achieve a drop in eye pressure (Porcella et al., 2001).

Finally, an unusual treatment method for glaucoma is providing medication intravenously. However, Cooler & Gregg did find a reduction in eye pressure with intravenous Δ⁹-THC (Cooler & Gregg, 1976).

Efficacy of Cannabis

We know the current treatment for glaucoma is reducing eye pressure. Cannabis's has the ability to reduce eye pressure, so this sounds promising.

For all the good, now it's time to talk about the bad.

Even though these studies observe a decrease in eye pressure, the decrease is only short-lasting. Wang & Danesh-Meyer summarises the literature very well, showing that pressure reduction due to Cannabis did not last more than 4-5 hours (Wang & Danesh-Meyer, 2020).

For example, the topical synthetic Cannabinoid WIN 55212-2 effect dissipates 2 hours after instillation (Porcella et al., 2001). Another example is the THC prodrug eye drop. Compared to an existing glaucoma medication, timolol, the THC prodrug underperformed. Timolol maintains reduced eye pressure for longer (Adelli et al., 2017).

Most medications, whether taken orally or applied as an eye drop, have unintended side effects. Entering the bloodstream, medication can interact with other bodily systems (Farkouh et al., 2016). Cannabis does the same and doesn't go without side effects.

These side effects range from changes in mental status, reduced blood pressure, and increased heart rate. Most individuals with glaucoma are elderly and take medication to control blood pressure and heart rate. Cannabis can interfere with these medications, which can cause serious problems with their health (Wang & Danesh-Meyer, 2020).

Thanks to Cannabis's short-acting nature, more doses of Cannabis are required to achieve the same therapeutic effect as conventional medication. This exposes individuals more to these unwanted side effects.

Despite decreasing eye pressure and providing neuroprotection potential, the side effects and its short-acting nature make Cannabis an ineffective treatment for glaucoma at present.

Conclusion

Numerous proposed mechanism for how Cannabis can halt glaucoma damage exists. They mainly involve reducing eye pressure and neuroprotection.

Cannabis is administered through inhalation, by topical eye drops, intravenously, and orally.

Though a reduction in eye pressure is observed, the problem is that this is short-acting compared to current medication. Additionally, Cannabis comes with many harmful side effects.

Even though Cannabis has gained notoriety for its medical status (e.g. treating chronic pain), we are yet to see Cannabis convincingly treat glaucoma at the present moment. However, this will be an interesting space to watch.

Thank you so much for reaching the end of this newsletter series. I am hoping you enjoyed reading this as much as I enjoyed researching and writing this. Please share this with anyone who might find this interesting. Also, hit reply if you have anything you would like to add. Stay tuned for the blog and video on this topic.

Ngā mihi,

Shivan :)

My Favourite Things

1. Podcast Show me the money, but will it make me happy at work? Pay does not even relate the pay satisfaction. What matters is how you are paid compared to your colleagues. Money, to a certain extent, doesn't make us happier at work.

2. Article The trouble with treating VIP patients Patients who are famous may be treated worse due to the practitioner's internal biases.

Blog Posts

Cannabis: An Unconventional Way To Treat Sight-threatening Glaucoma? — shivansivakumaran.com When you have colourful friends, an occupation like mine, combined with a late night dinner conversation, the question is inevitable: can Cannabis (Taru rauhae)…

Glaucoma: how it causes blindness and how it is treated — shivansivakumaran.com Glaucoma (Papahewa) ranks as the second most cause of blindness in Kiwis over the age of 65 (Blind Low Vision New Zealand, n.d.). For any individual…

Kindle Highlight of the Week

People are smarter than you think. Give them a chance to prove themselves.

Tim Ferris, The 4-Hour Work Week