Glaucoma is a severe health issue expected to impact nearly 80 million individuals by 2020. It primarily exists in two forms: open-angle and closed-angle glaucoma. Primary open-angle glaucoma (POAG) involves retinal ganglion cell loss due to optic neuropathy, with the presence of elevated intraocular pressure (IOP) being variable. IOP has been found to change throughout the day, typically peaking in the morning.
The primary aim of glaucoma treatment is to lower IOP since the Early Manifest Glaucoma Trial (EMGT) demonstrated that reduced IOP slows glaucoma progression. In the EMGT, participants with lowered IOP experienced a slower disease progression compared to the control group. Specifically, each mm Hg decrease from the baseline correlated with an approximate 10% reduction in progression risk.
Numerous medication classes and individual drugs are employed in eye formulations to decrease IOP as a component of glaucoma treatment. A frequently used combination is latanoprost and timolol eye drops, which have been proven to reduce IOP in 73.5% of patients by over 30%.
As natural health products gain popularity, marijuana (Cannabis) has emerged as a potential alternative for lowering IOP. Cannabis contains cannabinoids, which may produce therapeutic effects. The primary contributors are believed to be cannabidiol (CBD) and tetrahydrocannabinol (THC). THC and CBD interact with endocannabinoid receptors, of which there are two types in humans: CB1 and CB2.
Only CB1 receptors have been confirmed to be present in eye tissues, while the evidence for CB2 receptors in the eye is less certain. Activation of CB1 receptors may be linked to an effect on IOP, suggesting a potential mechanism through which cannabis could be utilized in glaucoma treatment.
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The goal of this paper is to assess the existing evidence supporting the use of cannabis in lowering IOP for glaucoma patients.
Glaucoma & Cannabis:Research Methodology
A comprehensive search of PubMed, Embase, and the Cochrane Database was conducted for studies published up to January 2018, utilizing keywords such as “canna*,” “marijuana,” “marihuana,” “open,” “angle,” and “glaucoma.” Since none of the studies had glaucoma progression as an outcome, the decrease in IOP was used as a substitute. After removing duplicate entries, 77 distinct articles were identified, with one more article discovered through reference review, bringing the total to 78 articles. The authors independently assessed these 78 articles and subsequently convened in person to discuss their findings. They collectively agreed on five articles, which were deemed the most reliable evidence available.
Glaucoma & Cannabis: Findings
The available evidence concerning glaucoma and cannabis is restricted due to insufficient research and small study populations. Selected studies evaluated different methods of cannabis administration (e.g., smoking, oral ingestion, topical application), with the most reliable evidence chosen for each form based on the research methodology employed (e.g., randomized, placebo-controlled). This report emphasizes studies that assessed the impact of cannabinoids on IOP in glaucoma patients.
Five randomized controlled trials investigating cannabis as an IOP-lowering agent were identified as the most credible evidence. One study involved smoked cannabis, two used topical drops, one employed a sublingual oromucosal spray, and one utilized oral capsules. None of the articles directly compared cannabis to the standard of care, only to a placebo.
Merritt et al. conducted a study with 18 adults (six with secondary glaucoma and 12 with primary open-angle glaucoma, including seven with juvenile open-angle glaucoma) who discontinued their prescribed glaucoma treatment 48 hours before smoking either cannabis or placebo cigarettes. The study did not specify which glaucoma medications were stopped at the beginning of the washout period. Placebo cigarettes had the same smell and taste as cannabis cigarettes, as they were cannabis cigarettes with alcohol-extractable cannabinoids removed, leaving only sugar and cellulose residue to maintain binding. Each cannabis cigarette contained 2% delta-9 THC by weight. The authors did not report the CBD percentage in the cannabis cigarettes.
On average, the treatment group experienced a 6.6 ±1.5 mm Hg decrease in IOP at 90 minutes, with no difference observed in the placebo group during the same time frame (p <0.05). This reduction lasted for about three hours, but various side effects were noted (e.g., altered perception), with severe hypotension being the most significant (Table 1). One patient’s blood pressure dropped drastically, resulting in an IOP of 1-2 mm Hg in their right eye. A second patient experienced a similar blood pressure response, with their IOP dropping to 3 mm Hg in their left eye and 14 mm Hg in their right eye (normal IOP range is 12-22 mm Hg). Both patients had their blood pressure spontaneously restored by reclining.
This trial was limited by its small sample size but found statistical significance in IOP reduction using smoked cannabis, indicating sufficient power for this outcome. The authors did not describe the randomization method. Although this study was blinded, the strength of blinding is unclear, as there is no way to confirm if the placebo and cannabis cigarettes truly had the same smell and taste, which serves as an additional limitation. Furthermore, the authors did not state the CBD concentration in either cigarette, so it is unknown how CBD affects the outcome. Lastly, there was no repeat administration; only one cigarette, cannabis or placebo, was smoked by each adult. Due to the lack of repeat administration, there is no data on the long-term efficacy and safety of smoking cannabis for IOP reduction.
Merritt and colleagues carried out an additional study using ocular cannabis to assess if an alternative delivery method would be as effective as cannabis cigarettes while causing fewer systemic side effects. The study involved six participants with primary open-angle glaucoma. They stopped taking their glaucoma medications 36 hours before using the eye drops in the study. The eye drops used contained 0% (placebo), 0.05%, or 0.1% THC in light mineral oil. The treatment was assigned randomly, and after application, each participant’s IOP was measured hourly for 10 hours. This process was repeated until each participant had tried all three drops, with a minimum of 24 hours between treatments.
The researchers discovered no significant difference between the three treatments, as the mean ± standard deviation for the IOP measurements of the treatment groups overlapped at all measurement times. Moreover, the same eye was used for different treatments, but the study did not mention any contralateral effects. Additionally, it is unclear how mineral oil impacts the penetration of the active ingredient into the eye’s tissues. Another limitation of this study is the 24-hour duration of each treatment, which might have been insufficient for the medication to have a potential effect on IOP if one were to occur. Furthermore, two-thirds of the patients had previous eye surgery for their POAG, indicating that the results might not be applicable to the average patient with POAG.
Porcella and colleagues also utilized topical therapy on eight participants, with only one being identified as having open-angle glaucoma, while the remaining seven had other types of glaucoma that were resistant to conventional therapy at the time of publication. Participants were given topical WIN55-212-2, a synthetic CB1 agonist, in either 25 or 50 mcg doses, following a 12-hour washout period. IOP measurements showed a maximum decrease of 20 ± 0.7% for the 25 mcg dose (P<0.05) and 31 ± 0.6% for the 50 mcg dose (P<0.01) one hour after administration compared to baseline. In this study, each participant acted as their own control, as only one eye received treatment. The authors mentioned an effect on the untreated contralateral eye, which was not found to be statistically significant. IOP was measured twice and averaged 30 minutes before treatment and every fifteen minutes for three hours after administration, with no direct placebo comparison. An observer who was unaware of the treated eye conducted the IOP measurements. However, the study’s sample size was small, and the untreated eye also exhibited a decrease in IOP one hour after the dose.
In a study conducted by Tomida et al., the focus was on patients with POAG, with three participants actively undergoing glaucoma treatment and three not receiving any IOP-lowering medication. Before the study began, patients using IOP-lowering medications went through a washout period of four to six weeks. The study required participants to attend weekly visits for a duration of six weeks. At the first visit, baseline IOP measurements were taken, but no treatment was provided. Over the next four weeks, all six participants were administered a single dose of an extract containing THC (5 mg), CBD (20 mg or 40 mg), or a placebo, using an oromucosal spray. The doses were assigned randomly, and each patient received all four treatment options over the course of the study. The authors, however, did not mention any other compounds that could have been present in the extract since they used the entire plant. IOP measurements were taken before administering the medication, and then at one, two, three, four, six, and twelve hours after treatment. At each time interval, two to three IOP measurements were recorded and averaged. The gathered data were evaluated using t-tests for paired samples to compare the treatment groups to the placebo. The analysis revealed that THC significantly reduced IOP (14% decrease) compared to the placebo (0.04% decrease) (p=0.026), and a 40 mg dose of CBD also showed a significant decrease in IOP four hours post-treatment (6% decrease) compared to the placebo (15% decrease) (p=0.028). However, the authors noted that these findings were not clinically significant (Table 1). The study had limitations, such as an unclear determination of the sample size (only six participants) and a lack of explanation for the final weekly visit’s purpose. Additionally, the statistical data was incomplete as confidence intervals were not described, and the double-masking method was not clarified.
The research studies in our analysis exhibited several shortcomings. The washout periods for prior glaucoma medications differed considerably across studies, spanning from 12 hours to six weeks, with one study omitting such details. Numerous studies incorporated patients with various glaucoma types, not solely POAG. These constraints hinder the applicability of these findings to the typical glaucoma patient. Additionally, the specific glaucoma medications used by participants before joining the studies were not consistently disclosed. A key weakness in all the trials was the absence of specified timings for IOP measurements. Since IOP varies throughout the day, lacking a standardized time may affect the results.
All the trials contained multiple limitations, particularly the utilization of distinct dosage forms and varying THC and CBD ratios. As previously mentioned, these trials fail to offer long-term safety and efficacy information.
Several side effects were reported across the trials, such as altered sensations, dizziness, nausea, increased appetite, and fatigue. The most severe side effects documented were tachycardia accompanied by anxiety and extreme hypotension.
It is important to acknowledge that both the Canadian Ophthalmological Society and the American Academy of Ophthalmology currently do not endorse cannabis as a glaucoma treatment. The scarcity of evidence supporting its use as a long-term treatment, the brief duration of action, the potential for unwanted side effects, and the absence of substantial evidence on the drug’s long-term safety all contribute to the lack of recommendation for cannabis as a therapy for elevated IOP in glaucoma cases.
Glaucoma & Cannabis: Conclusion
While research suggests that cannabis may possess the capability to decrease IOP, the existing literature is of low quality. The reviewed studies displayed considerable inconsistencies in their methodologies and selected patient populations, rendering it impossible to currently endorse any form of cannabis as a substitute for conventional glaucoma treatments. Until more robust evidence from RCTs supports the utilization of cannabis for IOP reduction, it should not be recommended at this point. Concerning IOP reduction, all the employed dosage forms demonstrated a brief duration of action, and the longevity of this effect remains uncertain, as does its ability to prevent long-term glaucoma progression. If patients were to adopt this treatment, they would need to administer doses frequently, which could negatively impact patient compliance and elevate the likelihood of medication side effects.
MACMILLAN, Kathleen, KEDDY, Amanda, et FURLONG, James. Cannabis and glaucoma: A literature review. Dalhousie Medical Journal, 2019.
MacMillan, Kathleen, Amanda Keddy, and James Furlong. “Cannabis and glaucoma: A literature review.” Dalhousie Medical Journal (2019).