by Seshata on 11/02/2013 | Medicinal

Cannabis In The Treatment Of Glaucoma

On 16-01-2019 we updated this article.

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Glaucoma Glaucoma is the leading cause of irreversible blindness worldwide. It has been known since the 1970s that cannabis is an effective treatment, but concerns about side effects have made the medical community reluctant to endorse it. This article compares cannabis with conventional treatment options, and anticipates new, superior cannabinoid based therapies.


What Is Glaucoma?

Glaucoma affects 70 million people worldwide, of which 10 % are completely blind. This insidious condition can remain symptomless until it is well advanced, making it likely that the 70 million sufferers represent the tip of an iceberg of undiagnosed glaucoma. The condition is most prevalent in older people, people of African ancestry, and those with a family history of glaucoma (1).

Cannabis and cannabinoids in the treatment of glaucoma

Glaucoma is usually associated with high pressure in the eye, or intra-ocular pressure (IOP). This pressure can cause stress and strain on the components of the eye, leading to the death of retinal ganglion cells, which are responsible for transmitting information from the retina to the brain. Patients experience irreversible vision loss once this link between the eye and the brain is severed.

Open-Angle Glaucoma And Angle-Closure Glaucoma

There are two categories of glaucoma, open-angle glaucoma and angle-closure glaucoma. The majority (80%) of sufferers are open-angle, but the less prevalent angle-closure form is more likely to lead to severe vision loss.

Both open-angle and angle-closure glaucomas are associated with high pressure in the front part of the eye which contains the cornea, iris and lens. It is normal for the eye to be under pressure – this is how the eye maintains its roughly spherical shape and keeps its walls taut. The pressure is caused by a fluid in the eye called the aqueous humor, which is like blood plasma but with less protein in it. In a healthy eye this fluid flows from the edges of the eye into the space between the iris and the lens. It passes out through the pupil into a space between the iris and the cornea, before draining out at the edge of the eye through structures known as the trabescular network.

Cannabis and cannabinoids in the treatment of glaucoma

In open-angle glaucoma, it becomes harder for the fluid to drain out through the trabescular network. Because the fluid continues to be produced at the same rate, this leads to an increase in pressure.

In angle–closure glaucoma, the iris becomes deformed, pushing up to contact the cornea, and acting as a physical barrier to fluid drainage from the eye. Again this leads to an increase in pressure. Around one third of cases are classified as the more severe acute primary angle closure. In such cases, patients may present with pain, nausea, vomiting, and visual distortions.

Much remains to be discovered about glaucoma. It is clear is that intraocular pressure is related to retinal ganglion cell death. However the biological basis of glaucoma and the factors contributing to its progression are poorly understood: some people have high pressure but never develop symptoms, and individuals with intraocular pressures within the normal range may develop glaucomatous optic neuropathy for a variety of reasons (1).

Conventional Treatments For Glaucoma

At present, lowering intraocular pressure is the only proven therapy for glaucoma. Between 1998 and 2002 several major randomised clinical trials evaluated the role of interventions to reduce intraocular pressure in preventing or delaying glaucoma development. These studies yielded clear evidence that reducing intra-ocular pressure delayed progression, but the treatment is by no means a silver bullet.

For example, in patients with ocular hypertension, application of topical medication reduced the development of glaucoma from 9.5 % of patients to 4.4 %.  In patients with newly diagnosed open-angle glaucoma, 45 % showed disease progression following treatment with β-Adrenergic blockers and laser treatment, compared to 62 % in the control group (1).

Conventional treatments focus exclusively on lowering intra-ocular pressure, despite the fact that not all sufferers have high intra-ocular pressure and some people with high intra-ocular pressure remain asymptomatic. The treatment regime varies depending on the type of glaucoma.

Treatments for open-angle glaucoma

In open-angle glaucoma, the treatment is to reduce the pressure, thereby slowing progression of the disease sufficiently to avoid vision loss. Several different classes of pressure-lowering medications are available. Prostaglandin analogues are the most effective and are usually the first line of treatment.   For patients for whom prostaglandin analogues are poorly tolerated, a range of additional options exist: β-Adrenergic blockers, α-Adrenergic agonists, carbonic anhydrase inhibitors and cholinergic agonists, though all are less effective than prostaglandin analogues.

All medications carry the risk of unwanted side effects. Prostaglandin analogues cause only minimal systemic side effects, but can cause adverse effects local to the treatment location, such as elongation and darkening of eyelashes, iris darkening, and changes to skin pigmentation around the eyes. Other glaucoma medications, including topical β-blockers, may cause significant or even life-threatening adverse effects.

Where drug treatment is ineffective at reducing intra-ocular pressure, or where severe side effects are observed, surgery or laser treatments can be used. Due to the risks of sight-threatening complications inherent in conventional surgery, laser trabeculoplasty is generally preferred. This treatment is generally effective in reducing intra-ocular pressure, though the effects do gradually wear off (1).

Treatments For Angle-Closure Glaucoma

In angle-closure the first line treatment is to make a hole in the iris using laser peripheral iridotomy. If this doesn’t reduce pressure, drug treatments similar to those used in open angle glaucoma can be used.

Acute angle-closure glaucoma is treated as a medical emergency due to the risk of vision loss. First, medications are used to effect an immediate reduction in pressure.  An iridotomy is then performed (1).

Effect Of Cannabis On Glaucoma

The efficacy of cannabis in lowering intra-ocular pressure is well known, having been first reported in 1971 (2). The pharmacologist Prof. Manley West and his ophthalmologist colleague Dr. Albert Lockhart reported the use of cannabis in the treatment of glaucoma in 1978 (3). West went on to develop cannabis-based eye-drops for the treatment of glaucoma and in 1987 gained approval to market them in Jamaica under the name “Canasol”. Canasol contains no psychoactive cannabinoids. Though approved for use in Jamaica only, it has reportedly also been prescribed in a number of countries around the world (4).

West has further developed Canasol into Cantimol, a combination of Canasol and the beta-blocker Timolol Maleate. Animal and clinical trials of Cantimol have been carried out in Jamaica and the drug will be available in Jamaican pharmacies once it has cleared the local approval and registration process (5). Like Canasol, Cantimol is likely to remain a Caribbean secret, for there are no plans to submit the drug for the prohibitively expensive FDA approval process required to market it in the USA.

Why Have The Medical Community Been Reluctant To Accept Cannabis As A Treatment For Glaucoma?

West’s work has been largely ignored by the medical profession, in part due to its publication in obscure journals and conference proceedings. In 1996 he published a letter in the British Journal of Anaesthesia, in which he drew attention to published data demonstrating that the efficacy of Canasol was comparable to existing treatments for glaucoma (6). This appears to have fallen on deaf ears.

Indeed, a recent review by the ocular pharmacologist Gary Novack (7) completely neglected to mention the long-established use of Canasol in Jamaica. Novack acknowledged that cannabis was effective in reducing intra-ocular pressure, but highlighted an absence of scientific evidence showing a beneficial effect on the course of the disease. He drew attention to a number of potential drawbacks: psychoactive side effects, a short duration of action that might require frequent and costly dosing, and the possibility of tolerance developing. He also speculated that cannabis might reduce blood flow to the eyes, reducing its ability to lower intra-ocular pressure.

The main barrier to acceptance is a lack of studies of the effects of cannabinoids on intra-ocular pressure in humans. A recent review summarised nine such studies: there are five studies of smoked cannabis, four of which had fifteen or less subjects; Two with oral or sublingual THC or CBD, and two with synthetic cannabinoids (8). It will take large-scale, high quality controlled trials to convince the medical community. Running such trials requires the deep pockets of a pharmaceutical company, and at present there is little incentive for them to do so.

Towards A Balanced View Of Cannabis And Glaucoma

Contradictions abound in the literature on cannabis and glaucoma. Is cannabis a safe, efficacious and cost-effective therapy, in line with the Jamaican experience, or is it actually bedevilled with side effects, relatively ineffective and prohibitively expensive? There are a number of studies that seem to contradict the prevailing medical orthodoxy.

Cannabis Treatment Need Not Be Accompanied By Undesirable Side Effects

The key challenge with using eye drops for drug delivery is that most of an ophthalmic dose misses the target and is absorbed systemically. Novel drug delivery systems such as cyclodextrins and microemulsions have enabled topical applications that decrease intra-ocular pressure, and may so at dosages sufficiently low to avoid psychoactivity (9).

A study in which cannabinoids were applied sublingually (below the tongue) concluded that a single 5 mg sublingual dose of Δ-9-THC reduced the IOP temporarily and was well tolerated by patients. Interestingly, given the reported efficacy of the hemp-based medicine Canasol, sublingual administration of 20 mg CBD did not reduce IOP, whereas 40 mg CBD produced a transient increase in intra-ocular pressure (10).

Long Term Users Do Not Develop Tolerance To The Pressure-Lowering Properties Of Cannabis

The development of tolerance to the intra-ocular pressure lowering properties of cannabis have been reported (11). However on closer examination this was a very small study in which oral THC was administered to nine patients. While patients experienced an initial reduction in intra-ocular pressure, this was not sustained for the duration of the study. The authors attribute this to either the development of tolerance or, more likely, because the subjects simply stopping taking the THC.  As is generally the case when THC is administered in isolation, without the modulating effects of other cannabinoids and terpenoids, side effects including dizziness, nausea, anxiety and confusion were experienced.

Cannabis and cannabinoids in the treatment of glaucoma

A study compared the ophthalmological characteristics of Costa Ricans who had used cannabis for ten years or more with those of cannabis-naïve controls. If significant tolerance to the intra-ocular pressure lowering properties of cannabis had developed in the cannabis users, the two groups would be expected to have the same IOP.  Despite between three and ten hours enforced abstinence prior to ophthalmological testing, the cannabis users exhibited lower intra-ocular pressure than the non-users, suggesting that the intra-ocular pressure lowering properties of cannabis were still apparent after ten years of daily use (12).

Is Cannabis Treatment More Expensive Than Traditional Pharmaceuticals?

Novack states that the cost of treating glaucoma with cannabis would exceed the cost of prescription pharmaceuticals. In 1999 the cost was estimated at US $ 720 per year. To calculate an updated figure, Novack assumed that a user would have to smoke 1.5 grams of cannabis per day,  (3/8 of an ounce per week) to provide symptomatic relief, at an estimated cost of US $8,820 per year (7).

In marked contrast, Cantimol produced in Jamaica is expected to retail for about $250 per vial, compared to pharmaceutical treatments, which range between $546 and $1,100 per vial (5).

Future Directions

Recent years have seen the demonstration of endocannabinoid intra-ocular pressure mechanisms and the discovery of CB1 receptors within the eye. This suggests that cannabinoids are involved in the regulation of normal ocular tension, and has led to widespread interest in the development of cannabinoid-based glaucoma drugs (9).   Topical delivery of such drugs directly to the site of action should eliminate psychoactivity. Armed with such new medicines, the management of glaucoma will be able to move beyond the simple intra-ocular pressure reduction offered by conventional therapies (9), unlocking the following additional mechanisms through which the development of glaucoma may be managed (8):

  • Neuroprotection
  • Vasodilation
  • Antioxidation
  • Anti-inflammation

Such new therapies are will be particularly welcomed by individuals with who develop glaucomatous optic neuropathy despite having intraocular pressures within the normal range. Provided such new therapies are supported by high quality clinical trials, it seems inevitable that the medical profession will eventually overcome its aversion to cannabinoid based, and perhaps even cannabis based, glaucoma treatments.

This article was updated with the contributions of independent scientist Dr Gavin Macfie, to ensure accuracy and academic rigour.

References

  1. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA. 2014;311:1901-1911.
  2. Hepler RS, Frank IR. Marihuana smoking and intraocular pressure. JAMA. 1971;217:1392.
  3. West ME, Lockhart AB. The treatment of glaucoma using a non-psychoactive preparation of Cannabis sativa. West Indian Medical Journal. 1978;27:16-25.
  4. West M. Cannabis Derivatives (Canasol) in Glaucoma. In: Mathre ML, editor. Cannabis in Medical Practice: A Legal, Historical and Pharmacological Overview of the Therapeutic Use of Marijuana. McFarland; 1997. p. 103-111.
  5. Thompson E. Ganga in Jamaica. 2018
  6. West ME, Homi J. Cannabis as a medicine. British Journal of Anaesthesia. 1996;76:167-172.
  7. Novack GD. Cannabinoids for treatment of glaucoma. Curr Opin Ophthalmol. 2016;27:146-150.
  8. Panahi Y, Manayi A, Nikan M, Vazirian M. The arguments for and against cannabinoids application in glaucomatous retinopathy. Biomedicine & Pharmacotherapy. 2017;86:620-627.
  9. Järvinen T, Pate DW, Laine K. Cannabinoids in the treatment of glaucoma. Pharmacology & Therapeutics. 2002;95:203-220.
  10. Tomida I, Azuara-Blanco A, House H, Flint M, Pertwee RGR, PJ. Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study. Journal of Glaucoma. 2006;15:349-353.
  11. Flach AJ. Delta-9-tetrahydrocannabinol (THC) in the treatment of end-stage open-angle glaucoma. Transactions of the American Ophthalmological Society. 2002;100:215-224.
  12. Dawson WW, Jimenez-Antillon, CF, Perez JM, Zeskind JA. Marijuana and vision–after ten years’ use in Costa Rica. Investigative Ophthalmology & Visual Science. 1977;16:689-699.

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