Treating Glaucoma

Glaucoma is a group of eye diseases involving damage to the optic nerve in the back of the eye. The neurodegenerative disorder is a public health crisis and is estimated to affect more than 3 million people in the United States and more than 75 million worldwide.1,2

Of particular concern is that as many as one-half of patients are unaware they have the eye disease that’s been referred to as the “silent thief of sight” because of its ability to sneak up on its victims and slowly steal their vision.

Glaucoma is the second-leading cause of blindness after cataracts and the leading cause of irreversible vision loss.1 Furthermore, despite advancements in glaucoma identification and therapies that have helped reduce the probability of blindness due to glaucoma by nearly one-half since 1980, 1 in 10 patients with the disease who receive proper treatment will still experience vision loss.2,3 Thus, there remains a tremendous need for new treatment options.

Cannabis has been touted as a potentially viable treatment option. In light of the need for new therapies as well as the growing interest in alternative cannabis-based therapies, health care professionals should be prepared to provide appropriate guidance to patients about potential benefits as well as risks to glaucoma patients’ vision.

Intraocular Pressure
Aqueous humor, the fluid inside the eye, provides nourishment to the lens and cells of the cornea while also ensuring adequate pressure for the cornea to maintain the convex shape required for good vision. The fluid is produced by the ciliary body of the eye where it flows into the anterior chamber of the eye and then out through a spongy tissue at the front of the eye called the trabecular meshwork, into a drainage canal. In the healthy eye, intraocular pressure (IOP) is adequately maintained at a constant pressure through a balancing act of fluid production and drainage out of the eye.

Imbalances in the production or drainage of aqueous humor causes an increase in IOP and the subsequent optic nerve damage seen in glaucoma. Consequently, elevated IOP is a major risk factor for retinal ganglion cell damage and visual field loss and the only known modifiable risk factor proven to reduce the development and progression of glaucoma. Other known risk factors include advancing age and frailty, gender, myopia, genetics, family history, smoking, race, systemic hypotension and hypertension, vasospasm, use of systemic or topical steroids, migraine, and obstructive sleep apnea syndrome.4

Types of Glaucoma
Glaucoma can be broadly classified into two categories: open-angle glaucoma and angle-closure glaucoma. Both can be primary diseases or can occur secondary to other causes such as trauma, certain medications (eg, corticosteroids), inflammation, tumors, and other conditions.4

Open-angle glaucoma represents more than 80% of glaucoma cases in the United States and generally occurs as the result of excess aqueous humor and increased resistance to aqueous humor drainage. The progression of damage in open-angle glaucoma is gradual, and there are no clear signs of blockage within the eye’s drainage system. On the other hand, angle-closure glaucoma occurs when the drainage pathway is obstructed and is considered to be an ophthalmic emergency that, if not treated immediately, can quickly lead to irreversible vision loss.4

An estimated 50% to 80% of people with open-angle glaucoma have eye pressure that’s higher than average.4 Alternatively, this suggests that many persons with glaucoma experience characteristic nerve damage and visual field defects despite having normal or even low IOP. Furthermore, no specific level of elevated eye pressure necessarily leads to glaucoma, and there’s no lower level of IOP that will ameliorate a person’s risk of developing glaucoma.5 And while a strong association between elevated IOP and glaucoma is clear, it remains a mystery as to why many people with elevated IOP never go on to develop glaucoma. Despite the challenges of not being able to define the absolute pressure at which damage to the eye will occur, elevated IOP remains a consistent risk factor for the presence of glaucoma, and regardless of initial IOP, for every mm Hg reduction in IOP, there’s an approximately 10% associated reduced risk of disease progression.6

Endocannabinoid System and Glaucoma
The human body’s “natural” endocannabinoids (eg, anandamide), cannabinoid receptors (eg, CB1, CB2), and the enzymes that help break down endocannabinoids and cannabinoids make up the endocannabinoid system. The endocannabinoid system has been implicated in the pathogenesis of many neurodegenerative diseases including glaucoma.7

How Cannabis Lowers IOP
The use of cannabis as a potential treatment option for glaucoma was first reported in 1971 by Hepler and Frank, who demonstrated in a small number of subjects that cannabis inhalation (smoking) was associated with a 25% to 30% reduction in IOP.7 Despite this awareness for 50 years, the decades of restrictions on cannabis use and research severely hampered advancements in cannabis medicine, including our understanding of its potential use in glaucoma.

Today, much of what’s known about cannabis comes from research on its two major constituents: THC, the primary psychoactive ingredient, and CBD, a nonintoxicating ingredient that is increasingly marketed to consumers in products such as oil, gummies, creams, and health food, and also as an FDA-approved formulation for severe pediatric epilepsy. In recent years, animal and small observational studies have been conducted confirming that different cannabinoids, including CBD, cannabigerol, endogenous cannabinoids, and some synthetic cannabinoids, can reduce the IOP when administered systemically and topically.7

Glaucoma Treatment Guidelines
Despite clear evidence that cannabis can lower IOP, glaucoma treatment guidelines from the American Academy of Ophthalmology and the American Glaucoma Society don’t recommend cannabis for the routine treatment of glaucoma. The guidelines point out that available IOP-lowering therapies including medical, laser, and surgical modalities are more effective than cannabis-derived therapies, with the risks from cannabis outweighing any associated benefits, as well as other limitations.

Obstacles to Cannabis Use for Glaucoma
Systemic psychoactive effects along with concerning ophthalmic side effects limit cannabis use as a viable treatment option, as does its short duration of IOP-lowering activity, tolerance development, and variations in THC/CBD doses, as well as a lack of clear dosing guidelines, drug-delivery challenges, and conflicting reports about its overall effectiveness.

Systemic and Ophthalmic Side Effects
One of the major concerns that limits the feasibility of routine use of cannabis for glaucoma is the potential for systemic side effects. Cannabis’ psychoactive side effects limit its application for a number of disease treatments and include euphoria or dysphoria, disruption of short-term memory, cognitive impairments, sense of time distortion, reduced coordination, and sleepiness.7 Additionally, cannabis use can also cause tachycardia (increased heart rate), which, along with a potential for systemic hypotension, could lead to a decrease in ocular perfusion pressure in addition to an already compromised optic nerve.

Limited Duration of Action
A relatively short duration of action following the smoking of cannabis (three to four hours) is another major limitation. Effective management of glaucoma requires 24-hour control of IOP, and in order to avoid suboptimal treatment would require a person to smoke cannabis eight or more times a day.7 This is impractical and would be cost-prohibitive for many patients. The failure to provide adequate IOP control could lead to rebound ocular hypertension. There’s additional concern that tolerance to cannabis’ IOP-lowering effects may develop.

Drug Delivery Challenges
Efforts to develop an improved cannabis delivery system for glaucoma have yet to provide an adequate solution. Oral formulations are limited due to poor and highly variable absorption. An ophthalmic cannabis formulation (eg, eye drops) would likely be a preferred delivery form that could potentially reduce systemic side effect concerns; however, due to the lipophilic nature of cannabis, it’s been difficult to find an appropriate vehicle to ensure adequate absorption without significant irritation to the eye.7

Conflicting Effects on IOP
THC is widely accepted to be able to provide significant IOP-lowering effects; however, the famous cannabinoid is also the major contributor to the negative psychoactive effects of cannabis. And while CBD’s ability to help mitigate some of THC’s intoxicating effects is also well known and useful in many cases, CBD also appears to lessen THC’s IOP-lowering effects, which could have deleterious consequences for individuals with glaucoma.

These clinical findings were demonstrated in a study from 2018 by Miller and colleagues, who treated live mice with topical THC and CBD. To clarify the effects of these agents, the investigators tested them in CB1 knockout mice and normal mice. Topical THC was found to lower IOP eight hours after administration, whereas topical CBD produced a substantial increase in IOP. Interestingly, this effect wasn’t observed in CB1 knockout mice, suggesting that CBD may have an antagonistic effect to THC at this receptor. The simultaneous application of THC and CBD had no appreciable effect on mouse IOP, presumably because the effect of each agent was cancelled out.8

Miller and colleagues found that THC lowers IOP significantly and for at least eight hours through action of at least two cannabinoid-related two receptors, CB1 and GPR18, and, perhaps, a third (GPR119). They also found that THC’s IOP-lowering effects were sex specific, with decreased male mice experiencing a drop in eye pressure of nearly 30% eight hours after exposure to THC, while the effect on IOP in female mice after eight hours was negligible. At four hours after THC application, the pressure reduction was 22%, while female mice experienced a more modest reduction of only 17%. These findings suggest that females may be less sensitive to the pressure-lowering effects of THC. The study also found that CBD may worsen glaucoma by raising eye pressure, as it caused an 18% increase in IOP for at least four hours after use, and that when using equal concentrations, CBD blocked THC’s IOP-lowering effects.8

An earlier study, from 2006, assessed the effect on IOP and the safety and tolerability of oromucosal administration of a low-dose THC and CBD. For the study, the researchers utilized a randomized, double-masked, placebo-controlled, four-way crossover study at a single center, using a cannabis-based medicinal extract of THC and CBD. Six patients with ocular hypertension or early primary open-angle glaucoma received one sublingual dose at 8 am of 5 mg THC, 20 mg CBD, 40 mg CBD, or placebo. The main outcome measured was IOP, with secondary outcomes including visual acuity, vital signs, and psychotropic effects. Those administered 5 mg THC experienced significantly lower IOP after two hours compared with placebo (23.5 mm Hg vs 27.3 mm Hg, p=0.026). IOP returned to baseline level at four hours. CBD failed to reduce IOP at any point, but the highest dosage (40 mg) produced a transient increase in IOP four hours after administration, from 23.2 to 25.9 mm Hg (p=0.028). There was no significant change in vital signs or visual acuity. One patient in the THC group experienced a transient and mild paniclike reaction after administration, but, for most participants, THC reduced IOP temporarily and was well tolerated.9

Strains and Dosing Challenges
There’s additional concern for patients due the lack of clear guidance regarding the appropriate dosing of cannabis products. This is further complicated since the dose of THC and CBD can vary significantly by strain, which can lead to significant variability in the expected effect.

Future Research
An ideal treatment for glaucoma would be one that lowers IOP while also providing neuroprotective benefits to help prevent nerve damage altogether. Even though evidence suggests there are significant concerns associated with the use of cannabis in glaucoma, it shouldn’t be interpreted as indicating that cannabis-based therapies could not be of significant value in the future.

Keeping in mind the reality that cannabis medicine and the associated research is in its infancy, there’s quite a bit of preliminary evidence that suggests cannabis-based molecules—whether naturally occurring or synthetically modified—could potentially provide significant benefits in the treatment of glaucoma and possibly help preserve vision through neuroprotective mechanisms involving anti-inflammatory and antioxidant actions. For instance, there’s evidence that cannabinoids can protect neuron cultures from glutamate-induced death.10 This is based on studies showing that glutamate causes apoptosis of retinal neurons via the excessive formation of peroxynitrite, and that THC or CBD’s neuroprotective effects are mediated through attenuation of this formation. Furthermore, inflammation has been implicated in a number of neurodegenerative diseases, and CBD is believed to be able to modulate a number of processes thought to be involved in the cause and progression of these diseases.

Final Thoughts
As discussed, glaucoma treatment guidelines clearly recommend against the use of cannabis for the routine treatment of glaucoma due to the potential for significant systemic effects and other limitations. Of additional concern is the possibility that CBD (widely available in over-the-counter products) may increase IOP or that the effect is dose dependent. Until additional research can better define the benefits and risks, it’s imperative for health care professionals to counsel patients about the potential for significant issues that may place glaucoma patients at an even greater risk for vision loss.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

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