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Cannabis Use for Glaucoma and Associated Pain
Introduction
Glaucoma is an optic neuropathy characterized by the loss of retinal ganglion cells and subsequent progressive degeneration of the optic nerve. It is the most common cause of irreversible blindness in the world. The most significant modifiable risk factor is the control of intraocular pressure (IOP).[1]
Cannabis plants have been used as a therapeutic agent for many centuries, as early as the fourth century AD.[2] More recently, cannabis’ primary psychoactive component delta(9)-tetrahydrocannabinol (THC) and its major non-psychoactive ingredient cannabidiol (CBD) have been used for the treatment of sleep disorders, pain, skin disorders, and lowering of intraocular pressure (IOP).[3][4][5][6][7][8][9]
Cannabinoid (CB) receptors are G protein receptors with an affinity for the agonists THC and CBD. Two types of CB receptors are described: CB1 and CB2. CB1 receptors are mostly limited to the central nervous system, where they modulate neurotransmitters, while CB2 receptors are confined to the immune and peripheral nervous system and are involved in cytokine signaling.[10]
Function
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Function
Cannabinoid Receptors in the Eye
CB1 and CB2 receptors have been identified widely in the eye. CB1 receptors have been identified in corneal epithelium and endothelium, ciliary body, iris, Schlemm canal, trabecular meshwork, choroid, and many retinal layers: ganglion cell, inner and outer plexiform, inner nuclear, and outer segments of photoreceptors cells.[11] CB2 receptors have been found in the corneal epithelium and, like CB1 receptors, in many retinal layers: ganglion cell nuclear layer, inner nuclear, and inner segments of photoreceptors cells.[12][13]
Cannabinoids Effects on Intraocular Pressure
THC has been identified as the metabolite relevant to IOP-lowering, and this potential to treat glaucoma has been the subject of research over the past five decades.[8][9]
Reports about the use of THC to regulate IOP date back to 1971 when Helper and Frank published preliminary data about the effect of marijuana in lowering IOP, in which healthy patients demonstrated a 25% decrease in IOP after smoking THC.[14]. A subsequent study demonstrated a 30% decrease in IOP in glaucoma patients, although this effect lasted only 4 to 5 hours.[15] The first placebo-controlled study also demonstrated a significant but transient (four hours) decrease in IOP after inhalation of THC.[16]
Other delivery methods have been studied in human and animal models with variable results. Healthy human subjects received intravenous (IV) THC at different doses resulting in a moderate decrease in IOP (average 37% decrease) with a reported increase in heart rate and pulse.[17] Tiedeman et al. tested two oral derivatives of THC in a double-masked study in patients with ocular hypertension. Only one of the compounds effectively decreased IOP independently of blood pressure with mild subjective side effects.[18] In a cross-over study conducted by Tomida et al., sublingual THC administration at a low dose (5 mg) effectively decreased IOP after two hours, with IOP returning to baseline levels after four hours. In the same study, patients who received CBD did not show changes in IOP at any time, and patients who received a higher dose of THC (40 mg) had a transient increase in IOP.[19]
One of the challenges of topical administration of THC is its poor aqueous solubility. In a study conducted in rabbits, combining a TCH prodrug with surfactants and cyclodextrins helped improve aqueous solubility and corneal permeability compared to THC alone. Its IOP lowering capacity was comparable in duration and potency to timolol and pilocarpine.[20] In another human study, the use of a CB1 receptor agonist combined with cyclodextrin demonstrated a peak reduction of IOP after one hour of administration; this effect subsided within two hours.[21] Green et al. demonstrated that although topical administration of THC alone was not associated with any signs of ocular toxicity, it did not result in any significant decrease in IOP either.[22]
The exact mechanism by which cannabinoids decrease IOP has not been elucidated. It has been proposed that CB1 receptors in the trabecular meshwork, Schelmm canal, and ciliary body may modulate aqueous production and also improve trabecular outflow.[23][24] Also, the lowering IOP effect might be related to a decrease in systemic blood pressure with concurrently decreased pressure perfusing the ciliary body.[16] Cannabinoids’ vasodilatory effects may also play a role in promoting uveoscleral outflow with subsequent lowering of IOP.[24]
Cannabinoids: Neuroprotective Effects
It has been hypothesized that THC may play a role in neuroprotection. In one study, healthy human subjects were administered a low dose of dronabinol, a synthetic form of THC, and an improvement in optic nerve head blood flow at rest was noted. However, IOP, ocular perfusion pressure (OPP), and mean arterial pressure (MAP) did not show any changes. Also, low-dose oral administration did not induce any psychoactive side effects.[25]
In another study in healthy human subjects, oral administration of a slightly higher dose of dronabinol resulted in a significant decrease in IOP and improved retinal arteriovenous passage time, indicating an increase in retinal hemodynamics suggesting potential use in ocular disorders associated with inadequate blood perfusion. This study showed no adverse cardiovascular or respiratory side effects.[26]
Other animal studies have shown that systemic administration of cannabinoids may increase blood flow to the choroid, iris, and ciliary body and reduce retinal ganglion cell layer loss in animal models of ischemic/traumatic optic nerve injury.[27][28][29] In one animal model of ischemia-reperfusion, IOP was artificially elevated, and animal groups were treated with either CB1 receptor agonists alone or combined with CB1 antagonist at different concentrations, followed by quantification of any ischemic damage to retinal ganglion cells (RGC). RGC density was noticeably higher in the group treated with CB1 agonist alone. Co-treatment with antagonists almost completely abolished the neuroprotective effect.[30]
There are three proposed pathways through which cannabinoids exert their neuroprotective effect: inhibition of glutamate, nitric oxide, and endothelin-1. It is known that glutamate is toxic to RGC in glaucoma and has been implicated in progressive degeneration in chronic optic neuropathies.[31] Glutamate activates nitric oxide synthase with a subsequent increase in oxidative damage.[32] Activation of CB1 and CB2 receptors leads to inhibition of glutamate release, suggesting that activating these receptors could be a way to protect RGCs from glutamate-induced death.[33] At the same time, such activation in the retina and central nervous system inhibits nitric oxide production and inflammatory cytokines that contribute to oxidative stress and loss of RGCs.[34]
Cannabinoids also have vasodilation properties; once CB1 and CB2 receptors are activated, there is an inhibition of endothelin-1 release. Inhibition of endothelin-1 vasoconstrictive effect results in increased blood supply to the optic nerve head, which can play a neuroprotective role in disease progression.[35]
Issues of Concern
Cannabinoids: Deleterious Effects in the Retina
Some published data suggest that cannabinoids may be deleterious to retinal and ganglion cells. Lucas et al. studied the relationship between cannabis use and retinal neural activity in a resting state in the absence of stimulation, a phenomenon known as background noise. Their findings suggest that THC use is associated with increased neuronal background noise in the retina and the brain. This may reflect the neurotoxicity of cannabis on retinal neuron dynamic, likely attributable to altered neurotransmitter release.[36]
Schwitzer et al. have shown a delay in responses of ganglion and bipolar cells in regular cannabis users that translate into delay of visual information transmission from the retina to the brain. Utilizing multifocal electroretinogram, they demonstrated that this delay in transmission could translate into alterations in precise and color vision. This same author also published a report of transient dysfunction of retinal activity thirty minutes after cannabis use by smoking. There was a marked decrease in the amplitude of the a-wave in electroretinogram compared with the responses five hours after smoking.[37][38][39] These data have opened the field for further investigations about the impact of cannabis on retinal processing.
Cannabinoids: Systemic Side Effects
Cannabis use is associated with behavioral and end-organ toxicity and is contraindicated in the context of significant hepatic, renal, cardiovascular, or psychiatric disease.[40][41][42] Its use produces impairment in social and cognitive functions and may be associated with the use of other illicit drugs.[43] Acute effects are euphoria, relaxation, time distortion, perceptual alteration, and intensification of normal sensory experiences. Acute cannabis intoxication can cause impairment of short-term memory, attention, reaction time, and motor skills. Some users can develop anxiety and panic reactions.[44] It can also cause tachycardia within minutes of use and hypotension. Other systemic effects associated with chronic use of cannabis are impaired cell-mediated and humoral immunity, chronic bronchitis, increased risk of lung cancer, and male and female infertility.[45][44]
Clinical Significance
Further studies may help elucidate any IOP-independent potential neuroprotective benefits. In a 2009 statement, the American Glaucoma Society recommended against marijuana use in any form for the treatment of glaucoma.[46]
Enhancing Healthcare Team Outcomes
Managing patients who may independently choose to use cannabinoids to treat glaucoma requires an interprofessional team of healthcare professionals that may include a nurse, pharmacist, and several physicians in different specialties to improve outcomes and reduce morbidity. A patient may report their use of cannabinoids to the ophthalmic nurse or technician, and the ophthalmologist must educate the patient about the lack of clear evidence demonstrating these agents' usefulness in the treatment of glaucoma as the importance to not stop using proven glaucoma therapies.[47] [Level 1]
The care of such a patient does not stop at this discussion. Because of cannabinoids' potentially addictive nature, secondary systemic and psychotropic side effects, very short duration of action, management of chronic cannabinoid use in a patient, especially in the presence of comorbidities or mobility impairments, will also require the collaboration of the patient's primary care doctor, behavior and mental health professionals, and home health aides.[40][41][40] [Level 5, 3]
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