Glaucoma

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Introduction

Glaucoma is a group of eye diseases that are characterized by degeneration or loss of the optic nerve, which is most likely due to increased eye (intra-ocular) pressure. Cannabis and in particular THC has long been known to lower intra-ocular pressure. Coincidentally, treatment of glaucoma is one of the oldest accepted therapeutic uses of cannabis.

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Phytocannabinoids

Endocannabinoids

Receptors

Enzymes

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Prescription Advice

THC, CBG and CBN were found to lower intra-ocular pressure in glaucoma. CBD was found to oppose the pressure lowering effect of THC warranting care with the prescription of CBD in case of glaucoma. Clinical trials suggest smoked/inhaled cannabis as wel as oral/sublingual application of extracts/cannabinoids may be effective.

For dose-escalation, please follow generic prescription advice.

Please note that, while based on preclinical and/or clinical research, this prescription advice is solely intended as a guideline to help physicians determine the right prescription. We intend to continuously update our prescription advice based on patient and/or expert feedback. If you have information that this prescription advice is inaccurate, incomplete or outdated please contact us here.

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Literature Discussion

In mice THC can lower intra-ocular pressure by 28% for up to 8 hours via activation of CB1 and GPR18. CBD has opposing effects on intra-ocular pressure and can oppose the pressure lowering effects of THC (Miller et al., 2018a).

In cats and rats THC and CBG were found to reduce intra-ocular pressure. This was accompanied/caused by an increase aqueous humor outflow while aqueous humor formation was unaltered (Colasanti, 1990).

In mice, 2OG was found to bind to GPR119 and to lower intra-ocular pressure providing new potential targets for the treatment of glaucoma (Miller et al., 2017).

Similarly, elevating 2AG via inhibition of MAGL, also lowered intra-ocular pressure but in a CB1-dependent way (Alapafuja et al., 2018; Miller et al., 2016).

In rat eyes, CB1 is highly expressed in the ciliary body, offering mechanistic insight for the therapeutic actions of cannabis in the treatment of glaucoma (Porcella et al., 1998).

In mice, stimulating CB1 lowered intra-ocular pressure by 30% (Miller et al., 2018b).

In rabbits several synthetic variants of THC were used to reduce intra-ocular pressure (Adelli et al., 2017).

In rabbits, THC, Δ8THC and 11-OH-THC were found to have a comparable effect in lowering intra-ocular pressure. In this study CBD, CBC and CBG were ineffective. CBN was about half as effective as THC. In rhesus monkeys neither THC nor CBG had any effect on intra-ocular pressure suggesting species differences in cannabinoid effects (Green et al., 1982).

In cats topical CBN and CBG lowered intra-ocular pressure. Chronic administration achieved larger effects than single administrations. Contrary to cannabis, THC and CBN, there was no sign of neurotoxicity after CBG administration (Colasanti et al., 1984).

 

Literature:

Adelli, G.R., Bhagav, P., Taskar, P., Hingorani, T., Pettaway, S., Gul, W., ElSohly, M.A., Repka, M.A., and Majumdar, S. (2017). Development of a Δ9-Tetrahydrocannabinol Amino Acid-Dicarboxylate Prodrug With Improved Ocular Bioavailability. Invest. Ophthalmol. Vis. Sci. 58, 2167–2179.

Alapafuja, S.O., Malamas, M.S., Shukla, V., Zvonok, A., Miller, S., Daily, L., Rajarshi, G., Miyabe, C.Y., Chandrashekhar, H., Wood, J., et al. (2018). Synthesis and evaluation of potent and selective MGL inhibitors as a glaucoma treatment. Bioorg. Med. Chem.

Colasanti, B.K. (1990). A comparison of the ocular and central effects of delta 9-tetrahydrocannabinol and cannabigerol. J. Ocul. Pharmacol. 6, 259–269.

Colasanti, B.K., Craig, C.R., and Allara, R.D. (1984). Intraocular pressure, ocular toxicity and neurotoxicity after administration of cannabinol or cannabigerol. Exp. Eye Res. 39, 251–259.

Green, K., Symonds, C.M., Oliver, N.W., and Elijah, R.D. (1982). Intraocular pressure following systemic administration of cannabinoids. Curr. Eye Res. 2, 247–253.

Miller, S., Leishman, E., Hu, S.S., Elghouche, A., Daily, L., Murataeva, N., Bradshaw, H., and Straiker, A. (2016). Harnessing the endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model. Invest. Ophthalmol. Vis. Sci. 57, 3287–3296.

Miller, S., Hu, S.S.-J., Leishman, E., Morgan, D., Wager-Miller, J., Mackie, K., Bradshaw, H.B., and Straiker, A. (2017). A GPR119 Signaling System in the Murine Eye Regulates Intraocular Pressure in a Sex-Dependent Manner. Invest. Ophthalmol. Vis. Sci. 58, 2930–2938.

Miller, S., Daily, L., Leishman, E., Bradshaw, H., and Straiker, A. (2018a). Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Regulate Intraocular Pressure. Invest. Ophthalmol. Vis. Sci. 59, 5904–5911.

Miller, S., Kulkarni, S., Ciesielski, A., Nikas, S.P., Mackie, K., Makriyannis, A., and Straiker, A. (2018b). Controlled-Deactivation CB1 Receptor Ligands as a Novel Strategy to Lower Intraocular Pressure. Pharm. Basel Switz. 11.

Porcella, A., Casellas, P., Gessa, G.L., and Pani, L. (1998). cannabinoid receptor CB1 mRNA is highly expressed in the rat ciliary body: implications for the antiglaucoma properties of marihuana. Brain Res. Mol. Brain Res. 58, 240–245.

Clinical Trials

In 6 patients sublingual administration of THC (5 mg), CBD (20 mg, 40 mg) and placebo was tested in a 4-way crossover trial. THC significantly reduced intra-ocular pressure after two hours. 20 mg CBD was ineffective while 40 mg CBD increased intra-ocular pressure (Tomida et al., 2006).

In 9 patients, inhaled cannabis or ingested THC decreased intra-ocular pressure. In 4 of these patients the reduction reached the therapeutic goal set by the investigator (Flach, 2002).

In 8 healthy volunteers, 7.5 mg THC reduced intra-ocular pressure and improved retinal blood flow (Plange et al., 2007).

In 18 patients, smoked cannabis reduced intra-ocular pressure (Merritt et al., 1980).

The drop in intra-ocular pressure achieved by THC is greater in hypertensive patients than in normotensive patients (Crawford and Merritt, 1979).

In one trial, smoked cannabis reduced intra-ocular pressure by 16-45% in 9 out of 11 patients (Hepler and Frank, 1971).

Topical application of THC analog WIN55,212-2 achieved a reduction in intra-ocular pressure of 20% (25 microgram) to 30% (50 microgram) (Porcella et al., 2001).

Literature:

Crawford, W.J., and Merritt, J.C. (1979). Effects of tetrahydrocannabinol on arterial and intraocular hypertension. Int. J. Clin. Pharmacol. Biopharm. 17, 191–196.

Flach, A.J. (2002). Delta-9-tetrahydrocannabinol (THC) in the treatment of end-stage open-angle glaucoma. Trans. Am. Ophthalmol. Soc. 100, 215–222; discussion 222-224.

Hepler, R.S., and Frank, I.R. (1971). Marihuana smoking and intraocular pressure. JAMA 217, 1392.

Merritt, J.C., Crawford, W.J., Alexander, P.C., Anduze, A.L., and Gelbart, S.S. (1980). Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology 87, 222–228.

Plange, N., Arend, K.O., Kaup, M., Doehmen, B., Adams, H., Hendricks, S., Cordes, A., Huth, J., Sponsel, W.E., and Remky, A. (2007). Dronabinol and retinal hemodynamics in humans. Am. J. Ophthalmol. 143, 173–174.

Porcella, A., Maxia, C., Gessa, G.L., and Pani, L. (2001). The synthetic cannabinoid WIN55212-2 decreases the intraocular pressure in human glaucoma resistant to conventional therapies. Eur. J. Neurosci. 13, 409–412.

Tomida, I., Azuara-Blanco, A., House, H., Flint, M., Pertwee, R.G., and Robson, P.J. (2006). Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study. J. Glaucoma 15, 349–353.