Cannabis and Glaucoma

Is cannabis a treatment for glaucoma?

Medicinal cannabis is often presented as an alternative treatment for glaucoma. Although there is evidence that cannabis lowers intraocular pressure, its role as a viable glaucoma therapy is limited by a short duration of action, psychotropic effects, and possible tachyphylaxis. Let’s explore this topic further…

What is cannabis?

This word ‘cannabis’ refers to a genus (or family) of plants best known for producing a family of compounds known as ‘cannabinoids’. Other common names for cannabis include marijuana and “weed”.

The most common variety is Cannabis sativa, a tall plant with long thin fibrous leaves, originally cultivated for fibre and animal feed.  Yes, historically its main historical use was for fibre: the first pair of Levi’s was made from hemp (the fibre found in its leaves).  It wasn’t common knowledge that this plant had psychoactive properties, perhaps because the early fibrous varieties contained little of the active component.  It is the variety which is, however, rich in THC.

The other common variety which is also known for its ‘entertainment’ qualities, is Cannabis indica, a subspecies of cannabis sativa, which is a shorter and bushier plant.  This is what is used to make hashish, and is rich in CBN or cannabinol.  Cannabis ruderalis originated in Central Russia, and is very fast growing.

Cannabinoids

While cannabis has more than 480 chemical constituents, it is only the 66 compounds made of carbon, hydrogen and oxygen that are known as cannabinoids that are of interest to us here.  Of the 66 cannabinoids that are known, two are of particular interest.  The first is THC (∆-9 tetrahydrocannabinol), which is the main psychotic agent. Nearly all research to date has been done on this.  Interestingly, it has been found that the THC concentration of marijuana (one of the many alternative names for this plant) has increased from ~3% in 1970s to ~20% today.

The other commonly known cannabinoid is cannabidiol (CBD). Cannabidiol (CBD) has no ‘elevating’ psychoactive effects, but is thought to reduce anxiety. The cannabinoid profile varies according to the species of cannabis plant, the way it is grown, and which part of the plant is harvested.

Cannabis and intraocular pressure

In 1971 it was discovered that smoking cannabis can lower intraocular pressure. To investigate the effect of cannabis on the human visual system, eleven healthy subjects underwent comprehensive eye exams before and after smoking two grams of cannabis. Unexpectedly, the subjects were found to have a change in intraocular pressure ranging from +4% to -45%. Subsequent studies have demonstrated that approximately 65% of glaucomatous eyes will experience a 30% pressure reduction after cannabis inhalation. The pressure-lowering effect lasts three to four hours and is dose-dependent.

Above: Graph showing the effect of cannabis inhalation on intraocular pressure (IOP). Image taken from Cannabinoids for treatment of glaucoma”. G D Novack. Curr Opin Ophthalmol 2016;27:146-50.

THC

THC is the main cannabinoid that lowers intraocular pressure (IOP). It does this by affecting the fluid that fills the eye (aqueous humour). THC is thought to reduce the rate that the eye produces aqueous humor and also increase the drainage of aqueous humour. The pressure-lowering effect of THC is not mediated through the central nervous system but is a local eye effect. This makes eyedrops a plausible route of administration as the THC molecules only need to reach the eye, not the brain.

THC is also claimed to have a neuroprotectant effect on the optic nerve. This means that THC may directly support the health of optic nerve cells independent of its effect on lowering intraocular pressure. However, evidence for this neuroprotectant role appears very weak.

THC has other ocular effects besides lowering intraocular pressure.  These include conjunctival hyperemia (bloodshot eyes); chemosis (conjunctival swelling); mydriasis (dilation of the pupil); sometimes to the extent that eyes are light sensitive (photophobia); reduced tears (dry eyes) and nystagmus (rapid involuntary movement of the eyes).

CBD (Cannbidiol)

It has been shown that CBD partially blocks the pressure-lowering effect of THC. This is important, as cannabis plants contain a mixture of cannabinoids including both THC and CBD. Therefore, it is expected that the pressure-lowering effect would be minimal if the form of cannabis consumed contains a significant proportion of CBD.

Tolerance to cannabis

You can develop neurological tolerance to cannabis, and similarly, it is likely that you can also develop tolerance to its pressure-lowering effect. This would mean that over time, eye pressure may no longer fall after each exposure to cannabis.

Cannabis delivery to the eye

In theory, eyedrops would be the ideal route to deliver cannabis to the eye, as this dramatically reduces side effects on the body. However, cannabis eyedrops are problematic because cannabinoids are highly hydrophobic, which means they don’t mix well with the tear film or aqueous humour. Cannabis eyedrops will therefore need to be formulated in a vehicle that increases their water solubility, such as a microemulstion or with a cyclodextrin.

Don’t smoke cannabis for glaucoma!

Not only would this expose your lungs to harmful tars and carcinogens, but in order to achieve continuous 24 hour control of intraocular pressure you would need to smoke between eight and ten marijuana cigarettes a day.  Apparently this would cost around US$2000 per month at current figures.

Oral consumption of cannabis?

Oral ingestion is not suitable as absorption is slow and variable.  Rectal application would in fact be better (ie a cannabis rectal suppository!), because absorption via the rectum is more consistent and this route bypasses metabolism in the liver. However a rectal product is unlikely to be developed for obvious reasons.

Problems using cannabis to treat glaucoma

There are several problems with using cannabis to treat glaucoma.

Firstly, the pressure-lowering effect is brief (three to four hours), which necessitates frequent dosing. This is impractical for a chronic disease that requires continuous, lifelong control. It is estimated that 24hr IOP control would require eight to 10 marijuana cigarettes. This dose would have significant psychoactive and cardio-pulmonary side effects and would also be more expensive than conventional glaucoma treatments.

Secondly, tachyphylaxis is another limiting factor (ie loss of the pressure-lowering over time). One study treated nine end-stage glaucoma patients with inhaled THC capsules every four hours. All had a reduction in intraocular pressure but seven of nine patients lost the beneficial effect due to tolerance. All patients elected to discontinue treatment by one to nine months due to loss of benefit or systemic side effects.

Possible solutions

Side effects of cannabis could be reduced by manufacturing synthetic cannabinoids without psychoactive properties or administering the cannabinoids as an eye drop. Both possibilities are being pursued. A synthetic analogue of THC known as HU211 has minimal psychoactive effects but still achieves pressure-lowering. Intraocular penetration of cannabinoid eyedrops has been unsuccessful so far due to their hydrophobic nature, however this could be overcome by using a microemulsion or cyclodextrin to help penetrate the tear film.

The future promise of cannabis in glaucoma treatment

The cannabinoids hold promise as a new glaucoma drug therapy. Since they act via a different family of receptors, they could work synergistically with existing glaucoma treatments. However, inhaling or ingesting cannabis as a glaucoma treatment makes little sense due to side effects on the brain and body, short duration of action, and likelihood of tachyphylaxis (loss of the pressure-lowering benefits over time).

Future studies need to focus on individual chemicals rather than non-standardised plant material. In my opinion, if cannabinoids have a role in glaucoma care it will be a synthetic analogue of THC delivered topically to the eye.

REFERENCES

  1. Cannabinoids for treatment of glaucoma. G D Novack. Curr Opin Ophthalmol 2016;27:146-50.
  2. The arguments for and against cannabinoids application in glaucomatous retinopathy. Y Punahi et al.  Biomedicine & Pharmacotherapy, 86 (2017) 620-7.
  3. Cannabinoids and glaucoma. I Tomida et al. Br J Ophthalmol 2004;88:708-13.
  4. Marihuana Smoking and Intraocular Pressure. RS Hepler and IR Frank. JAMA 1971, 217:1392.

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