Cannabinoids for Glaucoma
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Role of IOP-lowering in treatment of glaucoma
The aqueous humor is a clear fluid that maintains the integrity of the eye. It is produced by the ciliary body and passes through the trabecular meshwork and Schlemm’s canal. Intraocular pressure (IOP) is determined by the amount of aqueous humor secreted, coupled with the rate of clearance from the eye. An elevated IOP leads to optic nerve deterioration and associated irreversible functional vision loss.
While glaucoma does not always present with an elevated IOP, it does represent a modifiable risk factor in all cases of the disease. Indeed, management of IOP has proven to be key in the treatment of glaucoma, as demonstrated by the results of the Ocular Hypertension Treatment Study (OHTS) in 2002 and the Early Manifest Glaucoma Trial (EMGT) in 1999. In the OHTS, the experimental group was instructed to use eyedrops only, while the EMGT participants received a combined treatment consisting of topical drug therapy and trabeculectomy. In both cases, lowering of IOP hindered the onset or progression of open angle glaucoma. All participants who underwent hypotensive therapy in the EMGT—regardless of demographics or disease status—benefitted. Reducing IOP by 25% translated into a 50% reduction in the risk of glaucoma worsening.
Potential general medical indications for medicinal marijuana
Cannabinoids are compounds derived from the flower of the cannabis plant that act on specialized receptors in the endocannabinoid system (ECS), which is integrated throughout the human body. Although known for its recreational use, studies have demonstrated marijuana’s ability to serve various medicinal purposes. Medical marijuana has been utilized to subdue the effects of nausea and emesis associated with chemotherapy in cancer patients. Cannabis has also shown to be efficacious in minimizing the symptoms of nausea and diminished appetite in HIV positive individuals. Moreover, marijuana has effectively alleviated both chronic and neuropathic pain, allaying the hallmark spasticity of multiple sclerosis as well as sensory neuropathy secondary to HIV infection.
Proposed role of cannabinoids in glaucoma treatment
Medicinal marijuana has been cited in the treatment of glaucoma by acting on the ECS to reduce IOP, as well provide neuroprotection to the retinal ganglion cells. The cannabinoid selected, the mode of administration, and the adverse side effects are factors that alter the efficacy of this potentially useful ocular hypotensive agent.
Mechanism of Action
One intrinsic way in which the IOP can be altered is through the endocannabinoid system (ECS), which is integrated throughout the eye. Two commonly studied endocannabinoids are 2-AG and AEA, whose precursor is arachidonic acid. These endogenous species bind at the cannabinoid receptor 1 (CB1) present in ciliary body, trabecular meshwork, and Schlemm’s canal2. Additionally, endocannibinoids act on various noncannabinoid receptors found in the cornea, iris, and ciliary epithelium. These compounds are routinely metabolized: 2-Ag is degraded by monoacylglycerol lipase (MAG-L) and AEA is degraded by fatty acid amide hydroxylase (FAAH).2 Notably, both 2-AG and AEA are degraded by cyclooxygenase-2 (COX-2).
The ECS is normally activated after trauma or during other inflammatory processes with the purpose of mediating against cellular injury. Improper functioning of the ECS leads to maladies such as Parkinson’s disease and Alzheimer’s disease.
Previous research has demonstrated the medicinal nature of cannabinoids in the reduction of IOP for treatment of glaucoma. Among the cited exogenous compounds introduced are Δ9-tetrahydrocannabinol (Δ9-THC), a phytocannabinoid, and WIN 55,212-2, a CB1 agonist. Cannabinoids demonstrate two key properties: they reduce IOP and provide neuroprotection. When a cannabinoid binds CB1, its effects are prolonged via blocking of FAAH, whose activity would otherwise degrade the compound. The ultimate result is a reduction in aqueous humor and a lowering of IOP. This is achieved by several mechanisms that facilitate clearance of aqueous humor: inducing contraction of the ciliary body, widening Schlemm’s canal, and promoting kinase metaloproteinkinse P42/44 function, which enhances the architecture of the trabecular meshwork. Moreover, cannabinoids not only act through the CB1 pathway, but also activate COX-2, which in turn increases the presence of prostaglandin E2 (PE2) and melloproteinases-1, -3, and -9, enhancing the outflow of aqueous humor and reducing IOP. Elevated IOP does not necessarily equate glaucoma; however, lowering of IOP is directly correlated with decreased risk of developing this ocular disease. The neuroprotective function of these compounds allows for the preservation of retinal ganglions cells by mitigating the effects of free radical injury and impeding apoptosis. Both processes are normally preceded by glutamate release. In the event of apoptosis in particular, cannabinoids inhibit the process by antagonizing the NMDA receptors and decreasing Ca2+ permeability.
Formulations & Routes of Administration
Smoking marijuana evidently lowers IOP; however, the tolerance that develops after repeated use, coupled with the adverse side effects, is a deterrent for this route of exposure. Nonetheless, marijuana can be administered through various means. Topical use of cannabinoids promotes localized action of the drug with minimal side effects; however, only a small portion of the dose is capable of exhibiting its modulating capabilities. This is due to the drug’s low aqueous solubility that hinders its ability to enter the anterior chamber, as well as due to its clearance in a setting of routine lacrimation. The use of eye drops is preferred over the application of an oil that can be aggravating in nature. Studies have demonstrated that topical application of Δ9-THC produced no changes in IOP compared to control groups. Moreover, the poor solubility of cannabinoids is also an area of concern in cases of oral intake. The degree and time of absorption of the drug are unreliable, making it difficult to tailor an effective, yet safe, treatment for the patient. Furthermore, in a study by Tomida and colleagues, introduction of Δ9-THC sublingually successfully decreased IOP, albeit transient. Similar results were noted in studies where Δ9-THC was administered intravenously and resulted in a significant reduction of IOP. In both cases, the efficacies of Δ9-THC and cannabidiol (CBD) were compared. CBD was tested sublingually and intravenously in the respective studies, demonstrating no IOP lowering properties. In fact, CBD temporarily increased IOP when a high dose was taken sublingually. This demonstrates that only specific cannabinoids extracted are capable of producing desired effects.
Further studies have been performed to suggest that CBD likely has an opposing effect to THC with regards to IOP-lowering. In an animal study, Miller and colleagues showed that topical THC substantially lowered mouse IOP for 8 hours while topical CBD was associated with opposing effects, interfering with THC and potentially causing an increase in IOP.
Summary of the Current Evidence
Studies correlating marijuana usage and intraocular pressure date back to the 1970s. In 1971, Hepler and Frank showed a 30% decrease in IOP between marijuana users and normal subjects.
In the 1980s, a Howard University and University of North Carolina study showed peak action found to be at 2h and a duration of 3.5h, with substantial increase in heart rate at about 45 beats/min increase and decrease in blood pressure.
More recent studies using rabbits and intravenous THC showed increase outflow facility, although this could be reproduced in beagles using topical application of THC1.2 However, immunofluorescence showed that cannabinoids do bind to CB1 receptors in mammalian models including rat, bovine, and human ciliary epithelial and trabecular meshwork cells.
Evidence has definitively demonstrated the lowering of IOP in both normal individuals and individuals from glaucoma. However, limitations prevent its widespread use and acknowledgement from the American Glaucoma Society.
Its relatively short duration of action, lasting usually between 3-4 hours, is concerning given that need for constant need for smoking marijuana. In fact, some have calculated 8 to 10 times a day, or 2920 to 3650 marijuana cigarettes must be smoked to control the 24 hour a day disease. This needs to be compared to daily, twice a day, and sometimes, three times a day glaucoma drops which are more realistic in their frequency of administration. Drug tolerance and tachyphylaxis have been discussed as a concern especially with the need for constant smoking for long-term lowering of IOP. In one case series by Panahi, seven out of nine patients ultimately lost the IOP lowering effect from treatment tolerance.
Given the euphoric effects of marijuana, it is highly addictive allowing for abuse by patients afflicted with glaucoma. While frequent use of marijuana would be required for effective lowering of IOP, it is also prone to abuse by erratic usage guided by neurogenic cravings rather than fixed dosing intervals. On the other hand, it is also prone to non-compliance as some individuals are more sensitive to the side effect profile of marijuana. Existing stigmas, beliefs, and the political climate also create concerns for some individuals. Given the scattered legalization state by state, concerns for use or interstate distribution of drugs are expected to create logistic challenges for the healthcare system. Furthermore, patient perceptions of marijuana continue to be in flux, both with regards to the efficacy in glaucoma treatment, particularly overestimating its potential, and with the drug itself with disregard for the costs and side effects.
Significant consideration has been given for approaches to avoid the loss of effect, possibly with endogenous endocannabinoid signaling rather than marijuana intake especially given evidence that there have been decreased sensitization when endogenous pathways are activated with inflammatory pain. Additionally, allosteric modulators have been considered to both decrease behavioral side effects and addictive potential while maintaining desired efficacy in lowering IOP.
Furthermore, when assessing the potential role for marijuana in glaucoma treatment, it is important to consider the specific strain and chemical composition. Strains with higher CBD:THC ratios may paradoxically raise IOP.
As described above, oral, sublingual, and topical marijuana have been devised which may circumvent the concerns for constant smoking. However, drug absorption is noted to be most optimal with smoking thus limiting other means by the already existing short half-life of the drug. The potency of THC as well as other active molecules including cannabinol and cannabidiol are believed to vary from strain to strain given the lack of regulation. Furthermore, as it is botanical source, contaminants from pesticides, lack of proper development and storage raise concerns. Specifically, little is known about drug-drug interactions, drug-vehicle interactions, carcinogenicity, safety in pregnancy.
Finally, cost considerations must be considered. Glaucoma medications are estimated to hover around $60 US per month. However, marijuana costs approximately $15/g and given a cigarette being 0.5g on average and at least 3 cigarettes per day would be required for daytime therapy, the monthly cost would be estimated at $690, significantly more than the cost of current medications.
Side Effect Profile
In association with the short half-life of marijuana and the constant need for smoking, an extensive side effect profile must be considered. Over 480 chemical, including 66 cannabinoids exist in marijuana. Acutely, the lowering of blood pressure which can be deleterious in patients with orthostatic hypotension, increased heart rate, conjunctival hyperemia, decreased lacrimation exist. Decreased lacrimation has shown to be a consistent concern although some studies show that even with placebo, there were no changes in corneal irritation. Similarly, vehicle alone was found to lead to conjunctival hyperemia when given topical tetrahydrocannabinol to patients in one case series. More concerning are the long-term effects which are altered respiratory, hormonal, and neurogenic effects. Multiple studies have shown that individuals with cannabinoid use have higher occurrence of psychosis, impaired immune system response, motor coordination. Emphysematous changes in the lungs from constant smoking of marijuana have been linked to the release of tars, carcinogens, and volatile materials. Given the lack of long-term studies with any of the cannabinoid-based drugs, it is difficult to understand physiological and psychological effects.
In summary, while there is some laboratory and scientific support for the use of marijuana in lowering IOP in animal models and patients, more investigation is necessary to address the numerous limitations and side effect profile of cannabinoid-based drugs. Basic principles of pharmacology including dosage, route of administration, and dosing frequency require further research. In addition to IOP lowering, cannabinoids’ potential role in neuroprotection have driven interest.
In 1999, the Institute of Medicine noted that possibility of a longer-lasting cannabinoid drug for IOP lowering. Subsequently, multiple pharmaceutical companies received approval to develop cannabinoid therapeutics including CannaPHarmaRx, NEMUS Bioscience, Zynerba.
In 2010, the Canadian Ophthalmological Society (COS) noted that the COS does not support the medical use of marijuana for the treatment of glaucoma due to the short duration of action, the incidence of undesirable psychotropic and other systemic side-effects, and the absence of scientific evidence showing a beneficial effect on the course of the disease. This is in contrast to other more effective and less harmful medical, laser, and surgical modalities for the treatment of glaucoma.” In 2010, Dr. Jampel published from the American Glaucoma Society that “marijuana can lower the IOP, its side effects and short duration of action, coupled with a lack of evidence that its use alters the course of glaucoma, preclude recommending this drug in any form of the treatment of glaucoma at the present time.” In 2014, the American Academy of Ophthalmology reinforced this statement that marijuana was not yet a proven treatment for glaucoma.
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