Cannabinoids for the Treatment of Glaucoma: A Review

Potential Mechanisms of Cannabinoids in Glaucoma

Multiple factors like oxidative stress, inflammation, and glutamatergic pathways play a role in the pathogenesis of glaucoma [27]. The presence of cannabinoid receptors CB₁ and CB₂ mRNA and protein has been recently demonstrated in the human ciliary body (Fig. 1) [30]. These receptors are class A (rhodopsin-like) G-protein coupled receptors and are present in the brain and some peripheral tissues, displaying psychoactive effects [30, 41]. THC acts on both receptors. It interacts with the CB₁ receptors as a partial agonist, stimulates G_i/o proteins, and thereby inhibits adenylyl cyclase, thus hindering the conversion of adenosine triphosphate into cyclic adenosine monophosphate [42, 43]. The regulation of potassium channel activation is performed by these cyclic adenosine monophosphates, leading to a decline in aqueous humor production and an increase in its elimination, and subsequently, to a reduction in IOP [43–45]. In glaucoma, the death of retinal ganglion cells is observed, although its mechanism is not well understood [1]; it has been suggested that blocking of both anterograde and retrograde axonal transport results in scarcity of neurotrophic signals [46]. THC also further acts on other G-protein coupled receptors like GPR55 and GPR18 as an agonist [15]. GPR18 activation also results in lowering of IOP [47]. GPR55 and CB₂ together regulate the neutrophil response, and GPR18, once activated by a metabolite of THC, contributes to cannabinoid-mediated retinal vasoactivity [48]. Furthermore, THC can operate as a COX-2-inducing cannabinoid, which lowers IOP by increasing COX-2 mRNA expression in a concentration- and time-dependent manner and phosphorylates p38 mitogen-activated protein kinase and p42/44 mitogen-activated protein kinase in a time-dependent manner [49]. This leads to the activation of peroxisome proliferator-activated receptor alpha and increases the outflow of aqueous humor [50]. The partial agonistic activity of THC at CB₁ receptors is responsible for the psychotropic effects of cannabinoids and the cannabinoid-induced “tetrad” that encompasses analgesia, hypolocomotion, hypothermia, and catalepsy [15, 19, 30]. It was also found that there was a significant reduction in aqueous humor production in patients administered THC, and this response is considered to be mediated, at least partly, via the beta-adrenergic receptors in the eye, suggesting an adrenergic link to the CB₁-mediated effects [16]. In some studies, when THC was administered to a neurally isolated eye, the reduction of IOP was diminished, which again suggests a possible sympathetic connection to the pressure-reducing action of cannabis [51]. Cannabidivarin and CBD, is gaining popularity because it has a lesser affinity for CB₁ but can serve as an antagonist on CB₁ receptors, modulating the psychoactive and other effects of THC [30]. The antagonistic effects of CBD can blunt the IOP-reducing effects of THC [47]. However, by raising the constitutional activity or “endocannabinoid tone” of CB₁ receptors, CBD also has an indirect agonistic effect [50, 52]. Calcium flow across the plasma membrane is regulated by transient receptor potential ion channels [53]. CBD acts on transient receptor potential vanilloid member 1 channels located in the optic nerve head, suggesting that calcium handling may affect optic nerve function [53]. Activation of these channels results in retinal ganglion cell apoptosis [32]. Contraction of the ciliary muscle and decreased secretion from the ciliary process via reducing noradrenaline release are other processes that lower the IOP [54]. The synthetic CB₁ receptor agonist WIN55212 significantly reduced IOP when administered topically [37]. Dronabinol is another synthetic cannabinoid that reduces IOP on oral consumption [34], although the mechanism is not completely understood; putatively, it enhances the blood flow via the iris, ciliary processes, and choroid while decreasing the production of aqueous humor; this is due to increased blood flow away from the anterior uvea, which in turn lowers the ultrafiltration pressure required for the generation of aqueous humor [55]. Inhalation of cannabis causes a decrease in blood pressure as well as IOP and an increase in heart rate. The decrease in intraocular effect is due to lowered blood pressure in the ciliary body vasculature due to the peripheral vasodilatory effects of marijuana [39].

Efficacy Data from Clinical Studies

The legalization of the medicinal use of cannabis and its derivatives in North America in the mid-1990s paved the way for formal clinical assessment of the products for various indications [56]. The regulatory approval in the USA and Canada, although with various restrictions and changing laws over time, led to the approval of different cannabinoids in various European countries [56]. Many early studies of cannabinoids in glaucoma assessed the effects of oral and intravenous administration on IOP, in addition to other systemic effects [57]. Although a decrease in IOP was observed, it was either accompanied by a fall in blood pressure or euphoria, depending on the route and compound assessed, both precluding long-term clinical use in glaucoma. However, the observations prompted further assessment of oral compounds and topical preparations, with varying degrees of success [58]. The modest benefits coupled with the legal/regulatory hurdles in widespread production and procurement are probably responsible for the limited number of studies available to date, with the former probably being more important. Table 1 provides a brief summary of the studies that assessed the efficacy of various cannabinoids.

The only study that evaluated the topical use of a synthetic cannabinoid was by Porcella et al. [37]. In their study, 25 μg and 50 μg doses produced a decrease in IOP by 15% and 23% in the first 30 min and by 20% and 31% after 60 min, respectively. It should be noted that the participants had glaucoma resistant to conventional therapy. At the end of 2 h, there was no statistically significant difference between the test and control eyes, indicating the short duration of action of the drug. In an uncontrolled, unblinded study conducted by Flach et al. [36] among 9 patients with open-angle glaucoma not responding to conventional treatment, 4 patients achieved the set target IOP over a treatment period of 1–9 months, the reduction in IOP being in the range of 1–5 mm Hg. Tomida et al. [35] conducted a placebo-controlled, 4-way crossover study to assess the effects of sublingual THC and CBD among 6 patients with ocular hypertension or early primary open-angle glaucoma. While the IOP reduction with CBD was not significantly different from that obtained with placebo, THC produced significant reductions (mean IOP reduction compared with baseline values, 6.55 vs. 5.17 mm Hg, respectively). However, this was a single-dose study with maximum IOP reductions seen at 6–12 h interval.

Safety Data from Clinical Studies

The description below focuses on the adverse effects of cannabis compounds in the treatment of glaucoma and excludes the possible harmful consequences, such as ganglion cell dysfunction [59], of cannabis and its products in the context of nonmedical use or abuse.

Early studies in the 1970s identified conjunctival hyperemia, decreased lacrimation, diplopia, impairment of accommodation, photophobia, nystagmus, and blepharospasm as adverse effects of topical, oral, systemic, and inhalational use of marijuana or THC [58]. Of note, on smoking 2% marijuana, the decrease in IOP was difficult to dissociate from the euphoria. An increase in the doses acutely increased the fall in IOP, but there was no significant prolongation of the duration of action. Meritt et al. [39] in their study of 900 mg marijuana cigarette containing approximately 2% THC among 18 patients with glaucoma, reported the occurrence of anxiety with tachycardia and palpitations in 8, postural hypotension in 5, alterations in sensorium (hunger, thirst, euphoria, drowsy, feeling cold) in 18, and bulbar conjunctival hyperemia and ptosis in 9. In fact, hypotension occurred even in a frequent user of marijuana for the past 5–6 years. However, the hypotensive events were corrected by placing the patient in a reclining position.

Tiedeman et al. [38] reported the occurrence of lightheadedness, constipation, and drowsiness with BW29Y (5 and 10 mg capsules); feeling lightheaded, dizzy, disoriented, or “drugged,” nausea, constipation, mildly sleepy, syncopal episode, orthostatic blood pressure drop, slight tachycardia, and slightly elevated body temperature with BW146Y (4, 8, and 12 mg capsules). Flach et al. [36] studied oral THC in various doses in 9 glaucoma patients for 3–36 weeks. In addition to the development of possible tolerance, all subjects experienced adverse effects that masked the therapeutic benefit from the patients’ perspective. Adverse effects included feeling dizzy, lightheaded, sleepy, dry mouth, confusion, weight increase, anxiety, depression, elation, and distortion of perception of varying severity. Plange et al. [34] in their study using oral dronabinol 7.5 mg on 8 healthy volunteers found no significant change in heart rate or blood pressure. In the study by Hommer et al. [33] of 5 mg of oral dronabinol in healthy volunteers, no adverse effects, including psychoactive effects, were observed nor any significant changes in heart or blood pressure.

Tomida et al. [35] in their study of THC and two doses of CBD sublingually in 6 patients reported oral pain/discomfort, dizziness, hypotension, nausea, panic, and photopsia with the former (3 patients); diastolic pressure increased, dizziness, disturbed attention with 20 mg CBD (2 patients); oral pain/discomfort, pharyngitis, bad taste, feeling hot, throat irritation with 40 mg CBD (5 patients); oral pain/discomfort, diastolic pressure increased, headache, hypoesthesia with placebo (2 patients). Majority of the events were mild, and there were no serious or severe AEs. Porcella et al. [37] did not report the safety aspect of the topical CB₁ agonist in their study on patients with glaucoma.

Status of Cannabinoid Use in Glaucoma

Although the medical use of cannabis derivatives has been legalized in some countries, in many countries, for example, India, cannabis or its derivatives are not approved for any clinical indication. Cannabis is a “narcotic drug” as per Section 2 (xiv) of the Narcotic Drugs and Psychotropic Substances Act (NDPSA), 1985 [60]. Although dronabinol and nabilone, synthetic derivatives of THC, have been approved by the US FDA for chemotherapy-induced nausea and vomiting, there are currently no approved medical uses for these in India. Hence, even if any of the cannabis derivatives show a potential advantage over the existing antiglaucoma drugs, the results are likely to receive more scrutiny than any other new drug given the concerns regarding their misuse and abuse potential. Despite these potential hurdles, the main factor for such clinical use would be the availability of robust data supporting its use in glaucoma. The studies so far have not been able to provide evidence of an unequivocal benefit large enough to place cannabis derivatives as a second- or third-line option in the treatment of glaucoma.

In the absence of achievement of the target reduction in IOP in a patient with open-angle glaucoma, additional topical antiglaucoma drugs may be added; however, laser trabeculoplasty or surgical treatment should be considered if the patient requires three or more drugs, if not earlier [61, 62]. The mean IOP reductions with conventional medications range from 5.61 mm Hg for prostaglandin analogs to 2.49 mm Hg for carbonic anhydrase inhibitors [63]. The only study that evaluated a topical formulation of cannabinoid showed a significant acute reduction compared with placebo, although the overall reduction in both the groups was approximately 5 mm Hg [37]. Given these findings, it is to be assessed whether cannabinoids would be useful as an add-on drug in cases of resistant glaucoma. Also to be evaluated is the potential usefulness of the drug for acutely reducing IOP in angle-closure glaucoma, although the acute effect needs to be further established. The short duration of action of the topical formulation and the potential systemic adverse effects of non-topical formulations are additional limitations compared with the existing antiglaucoma drugs. Poor water solubility impairs ocular delivery of the drug on topical administration. Although special formulations with the potential to improve ocular delivery have been attempted, most of these are in the preclinical phase [64]. Given these issues, the lack of support expressed by various specialist groups a decade ago for use of any form of cannabinoids in glaucoma, due to lack of efficacy and potential adverse effects, seems to hold good even today [65–67].

Our review has certain limitations. The search for relevant publications was limited to two databases. We focused on clinical studies in healthy volunteers or patients and did not consider the effects of cannabinoids described in the context of nonmedical use, which may be relevant in considering the risk benefit ratio and possible adverse effects in the context of overdose/toxicity. Some clinical studies included in this review did not provide precise data to estimate the exact changes in the IOP following cannabinoid use as compared to the control group; hence, the data regarding mean changes in the IOP should be considered approximate; nonetheless, the lack of precise data is unlikely to alter the main conclusion of this review.