Cannabis smoking and the oral ingestion of several of its derivatives have been shown to cause an appreciable drop in intraocular pressure (); and it is known that patients with open angle closure glaucoma smoke cannabis for this purpose.
When smoked, cannabis containing the equivalent of 20–30 mg of THC has been shown to lower intraocular pressure in an heterogeneous group of glaucoma patients and more specifically, patients with open angle glaucoma. However, the treatment was not without side effects: six of 32 patients developed severe systemic hypotension; this was significantly greater in hypertensive glaucoma patients. Cannabis caused a dose-related, clinically significant, reduction in intraocular pressure of 25– 30%, occurring at 1 hour and lasting 5–6 hours, which was discrete from the sedative effects of the drug. Orthostatic hypotension was observed mainly in cannabis-naive patients.
Cannabis does not cure glaucoma but has been shown to slow progressive sight loss when conventional medicines have failed or where the risks of surgery are too great. Tolerance to this effect of cannabis has not been observed; but the degree of reduction in intraocular pressure seen in cannabis-naive patients may not be observed in experienced users.
THC has a comparable effect on intraocular pressure to smoking cannabis at comparable doses and is effective when administered orally, encapsulated in sesame seed oil and also by the intravenous route. The latter may however be accompanied by severe dysphoria.
Initial studies in animals suggested that formulated in a light mineral oil, THC eye drops might also be effective (); this route was also shown to be effective in hypertensive glaucoma sufferers but not in their normotensive counterparts. Studies where patients could not be taken off their existing medication, showed an additive effect for THC.
Nabilone has proven to be effective at lowering intraocular pressure in animal models and in man, where an oral dose of 1–2mg produced an average drop of 34% (range 10–54%), in 9 patients with open angle glaucoma. Failure to find a suitable vehicle for an eye drop formulation of nabilone has thwarted studies of topical application.
Attempts to develop other cannabinoid derivatives for glaucoma have not met with great success. A water soluble extract of cannabis with no demonstrable central effects, had an additive effect when administered with timolol, a beta adrenoreceptor blocking agent, in patients with refractory raised intraocular pressure (); but the active ingredient(s) in this cocktail were not identified. Green et al. () were unable to show that cannabidiol had any effect on raised intraocular pressure. This has been confirmed by Waller et al. () in both rabbit and unanaesthetised monkey models.
The compound BW 146Y, a synthetic anologue of THC, lowered intraocular pressure in glaucoma patients after oral administration, but this was accompanied by mild hypotension and subjective central side effects. The water soluble maleate salt of 1, 2-dimethylheptyl, delta-6-THC has been shown to have significant antiglaucoma activity in rabbits without significant CNS activity in monkeys. Another synthetic THC derivative, naboctate, reduced intraocular pressure when administered orally to human volunteers without subjective CNS effects.
Summarising, there is little doubt that certain glaucoma patients may benefit from cannabis or its derivatives. From a practical viewpoint, it is estimated that a daily dose of four marijuana cigarettes may be needed to control intraocular pressure; although this level of consumption may be lower if the drug is used as adjunctive therapy.
Further work is required; there is no evidence that any cannabis derivative would remain effective in controlling intraocular pressure during chronic use; and there is precious little evidence that the use of cannabinoids in glaucoma can preserve visual function. Central side effects noted in clinical trials, the risks of long term consumption, attendant driving restrictions and social stigma attached to the drug may prevent more widespread use. Glaucoma is a disease which needs close monitoring if sight is to be preserved; to this should be added the monitoring of casual use to make sure this does not get out of hand or diverted for abuse and the development of side effects to cannabis, especially postural hypotension. This advice also applies to THC, particularly as there is no feasible way of topical administration at present.
There is a need for an agent with a more specific action on the eye or a delivery system which minimises systemic effects. In the meantime, it seems reasonable to suggest that selected patients, i.e. those failing to respond to conventional medication or who cannot tolerate side effects, or where established therapies are contraindicated, should receive inhaled cannabis to augment their present therapy in the hope of preventing visual impairment.
Mode of Action
The way in which cannabis reduces intraocular pressure in glaucoma is unclear. A central mechanism has been proposed although the observation that the effect outlasts the subjective cannabis ‘high’ suggests a peripheral action. THC can decrease aqueous humor production in rabbits; although the mechanism is not known. Inhibition of prostaglandin synthesis may be at least partially responsible, as high doses of prostaglandins are known to cause intraocular hypertension in animals. Another theory is that cannabinoids act on adrenergic receptors, constricting afferent blood vessels to the ciliary epithelium, causing a fall in pressure and flow to the region of aqueous humor formation; as phentolamine, a specific alpha blocker, can inhibit the fall in intraocular pressure induced by THC.