ORAL CANNABINOID (PEA) FOR GLAUCOMA TREATMENT

 

A cannabinoid system composed of several receptors and endogenous cannabinoids, including anandamide (AEA) and 2-arachidonylglycerol (2-AG), has been identified in the brain, the peripheral tissue, and the eye. Two principal cannabinoid receptors have been described (CB1, which is predominant in neurons, and CB2, which is localized in immune cells and peripheral tissue cells).

In the human eye, CB1 receptors have been reported from the trabecular meshwork (TM) and Schlemm canal cells. Also, CB2 receptors have been demonstrated in porcine TM cells in culture.

AEA and the CB1- and CB2-selective agonists enhance aqueous humor outflow through the conventional pathway and significantly decrease intra-ocular pressure (IOP) in rabbits, primates, and humans after topical application. Conversely, CB1 antagonists elevate IOP.

AEA, the most investigated endo-cannabinoid, acts as a partial CB1 agonist and a weak CB2 agonist and activates the vanilloid type 1 receptor.

Palmitoyl-ethanol-amide (PEA) is an endogenous congener of AEA that is co-synthesized with AEA by most cell types.

PEA does not bind to CB1 or CB2 receptors, but it is a competing substrate with AEA for the enzyme fatty acid amide hydrolase (FAAH) active site, and it has been hypothesized to increase or prolong the effect of AEA (entourage effect) without the systemic side effects of cannabinoids.

A study was reported by Gagliano et al., to assess the effect of oral PEA administration on IOP in primary open angle glaucoma (POAG) and ocular hypertension (OH). In the study, 42 patients with POAG or OH who were treated with timolol 0.5% and whose IOP was between 19- and 24-mm Hg received oral PEA (300-mg tablets twice a day) or placebo (PEA vehicle tablets twice a day) for 2 months (period 1), and, after a 2-month washout, received the other treatment for 1 month (period 2). [1]

After PEA treatment (mean baseline IOP, 21.6 ± 1.7 mm Hg), IOP was reduced by 3.2 ± 1.3 mm Hg at 1 month and by 3.5 ± 1.2 mm Hg (15.9% ± 5.1%) at 2 months (ANOVA, P < 0.001; both Tukey-Kramer, P < 0.01 vs. baseline).

Conversely, after placebo (mean baseline IOP, 21.5 ± 1.5 mm Hg), IOP was reduced by 0.4 ± 1.2 mm Hg at 1 month and by 0.3 ± 1.3 mm Hg at 2 months (t-test at both time points, P < 0.001 vs. PEA). No statistically significant vital signs, visual field, visual acuity changes, or adverse events were detected in either group.

No specific side effects were reported with PEA, and no contraindications have been defined.

The study found no significant changes in systemic blood pressure. Although, cannabinoids reduce blood pressure, with an effect particularly involving CB1 receptors.

The decrease in IOP was 16% of the baseline level, which was comparable to the levels achieved with other currently used anti-hypertensive medications, such as topical Carbonic Anhydrase Inhibitors and alpha agonists.

Kumar et al., have also performed a study to analyze the effect of PEA on aqueous humor outflow facility. According to them PEA caused a concentration-dependent enhancement of outflow facility through the trabecular meshwork. These effects are mediated by GPR55 and PPARα receptors through activation of p42/44 MAPK. [2]

Another novel and significant effect of PEA is neuroprotection. We know that glaucoma is a neuropathy affecting the nervous tissue of the retina and the optic nerve. It is presumed that this neuropathy has an inflammatory component, especially in the glia (neuroinflammation). It is known that PEA has significant anti-inflammatory effects and this property could contribute to neuroprotection by reducing the inflammatory component of glaucoma. [3]

Strobbe et al., have found that PEA improves the endothelium-dependent flow-mediated vasodilation (FMD) characteristics in OH patients. These patients have elevated plasma and aqueous levels of endothelin-1 (ET-1), causing chronic impairment of ocular blood flow, especially of the optic nerve head. [4]

Therefore, PEA, a drug of a class that has been proposed for the treatment of glaucoma but that is not used because of concerns about side effects, could be a valuable tool in the treatment of such diseases.

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REFERENCES:

1.  Gagliano C, Ortisi E, Pulvirenti L, Reibaldi M, Scollo D, Amato R, Avitabile T, Longo A. Ocular hypotensive effect of oral palmitoyl-ethanolamide: a clinical trial. Invest Ophthalmol Vis Sci. 2011 Aug 3;52(9):6096-100. doi: 10.1167/iovs.10-7057. PMID: 21705689.
2. Kumar A, Qiao Z, Kumar P, Song ZH. Effects of palmitoylethanolamide on aqueous humor outflow. Invest Ophthalmol Vis Sci. 2012 Jul 3;53(8):4416-25. doi: 10.1167/iovs.11-9294. PMID: 22589443; PMCID: PMC4625824.
3. https://areaoftalmologica.com/en/blog/glaucoma/palmitoylethanolamide-pea-a-new-focus-on-the-treatment-of-glaucoma/
4. Strobbe E, Cellini M, Campos EC. Effectiveness of palmitoylethanolamide on endothelial dysfunction in ocular hypertensive patients: a randomized, placebo-controlled cross-over study. Invest Ophthalmol Vis Sci. 2013 Feb 1;54(2):968-73. doi: 10.1167/iovs.12-10899. PMID: 23307959.