MARIJUANA and GLAUCOMA

Glaucoma is regarded as a type of progressive optic nerve degeneration. A number of theories regarding the pathogenesis of this condition have been presented. These theories include the “mechanical theory” which describes glaucoma in terms of physical changes in the optic nerve due to high intra-ocular pressure (IOP), the “vascular theory” which centers around ocular blood flow and vascular dysregulation, the “biochemical theory” which is based on a number of biochemicals in ocular tissues causing GOND and the “genetic theory” which regards certain genes as the culprit in glaucoma causation. Some other relationships such as intracranial pressure, lymphatics and exposure to environmental factors are also being investigated in glaucoma causation.

Glaucoma is currently being treated by medical, laser or surgical methods. Diverse classes of drugs are being used mainly to lower IOP, the main risk factor known. Among these pharmacological agents one natural source to control glaucoma has been marijuana. This agent is being discussed in this glog post as it is an interesting agent in the medical management of glaucoma.

Marijuana as an IOP lowering agent was first reported in the 1970s. Mexican marijuana, containing 1.8-2.8% delta-9-tetrahydrocannabinol (THC), was found to consistently reduce aqueous production through the ultrafiltration mechanism. The maximum ocular hypotensive effect of 25-30% occurs between 60-90 minutes and the duration of action lasts for 3-4 hours. Thus, an individual has to smoke 8-10 cigarettes per day to achieve adequate IOP lowering.

Apart from smoking, marijuana can be administered by oral, sublingual and eyedrop instillation. Oral and sublingual routes avoid the deleterious effect of marijuana smoke on the lungs, but are still limited by the other systemic side-effects. In a study conducted on glaucoma patients, who were offered THC pills and/or smoking marijuana cigarettes, 9 out of 9 patients discontinued use by either method within 9 months due to intolerable side effects. Since glaucoma is a lifelong disease, use of THC for prolonged periods of time is not a reasonable treatment option.

Marijuana use is associated with cardiovascular changes such as tachycardia and lowered blood pressure (BP). Usually, these changes return to baseline within 3½ hours. Sudden precipitous fall in systolic BP have been reported in 18% of marijuana-naive subjects inhaling Mexican marijuana. Features of these syncopal-like effects include sudden fall in BP, lightheadedness, a faint and thready pulse, often accompanied by nausea and bradycardia. As most glaucoma patients are in the older age group, who already have a high propensity of falls, so feeling dizzy or uncoordinated is especially risky. Heart problems are also common in this age group, with marijuana induced tachycardia imposing a higher risk. Another aspect of lowered BP is reduced ocular blood flow, which could prove detrimental to the health of the optic nerve.

Other potentially risky side-effects of marijuana include:

1. Weakening of the immune system, with decreased ability to fight infections.

2. Marijuana’s mood altering effects, such as problems with memory, thinking and concentration, prevent the patient who is using it from driving, operating heavy machinery and functioning at maximum mental capacity.

3. Marijuana cigarettes also have compounds which damage lungs and the brain in the long run.

4. Smoking is a major risk factor in the development of age-related-macular-degeneration, which can aggravate vision loss from glaucoma. It is also a risk factor in the development of cataracts.

Manufacture of THC eyedrops is limited by low water solubility of the active ingredients preventing them from entering the eye. However, topical 0.1% THC in light mineral oil vehicles has been tried. The maximum ocular hypotensive effect was shown to occur at 6 hours with significant effect persisting for 8-12 hours.

Recently receptors for the active ingredients of marijuana have been found in ocular tissues, pointing to a possible role of locally administered marijuana.

Reports from brain research describe the protective effect of cannibinoid components of marijuana on nerve cells. Incidentally, such nerve cells are also present in the optic nerve where these compounds could prove useful as neuroprotective agents.

In summary, while marijuana or its active compounds may have potentially useful effects in glaucoma management, further research is required to adequately understand the usefulness of this herb.

REFERENCES:

1. Meritt JC. Glaucoma, hypertension and marijuana. Journal of the National Medical Association. 1982;74:715-6.

2. https://www.aao.org/eye-health/tips-prevention/medical-marijuana-glaucoma-treament 

3. http://www.oregoneyes.net/glaucoma-and-marijuana/

SBI-100 OPHTHALMIC EMULSION: RECENT DEVELOPMENTS

 

SBI-100 is a pro-drug of Tetrahydrocannabinol (THC), which is being evaluated as a topical agent in ophthalmic suspension form.

For further information on marijuana in glaucoma, please follow the link below:

https://ourgsc.blogspot.com/search?q=marijuana

The agent could be useful in the treatment of glaucoma and ocular hypertension.

The agent has undergone a Phase 1 study with 2 cohorts each of 8 patients.

Skye Bioscience, Inc., the parent company, has received positive recommendation following a pre-specified data review by the safety review committee (SRC). The SRC has recommended that the trial continue without modification. The company shall be recruiting the third cohort soon.

In nonclinical studies, Skye’s SBI-100 Ophthalmic Emulsion demonstrated a greater and longer-lasting reduction of IOP compared to leading commercialized drugs in the glaucoma market. These studies also demonstrated:

• SBI-100 Ophthalmic Emulsion is better at penetrating various compartments of the eye than natural THC
• THC in an ex vivo model demonstrated a reduction of biomarkers related to fibrosis and inflammation in conjunction with lowering of IOP, supporting a multimodal mechanism of action

Previous preclinical studies have shown the potential for THC to also provide neuroprotective benefit, which may be especially important to patients with glaucoma who are experiencing disease progression with normal IOP levels.

One of the major drawbacks of previous studies concerning the use of THC for glaucoma was that they relied on inhalation or ingestion of THC. These systemic routes of drug administration cause negative side effects like psychotropic changes and potentially decreasing blood pressure, which resulted in the American Academy of Ophthalmology determining that the adverse effects of systemic cannabis administration/consumption outweighed its therapeutic benefit.

Skye has chemically modified THC to create a unique synthetic molecule with the intent to safely realize the known positive effects of THC. The molecule enables enhanced local delivery in the eye, reduced systemic side effects, and the potential for neuroprotection for the treatment of ocular diseases.

HIGHLIGHTS:

SBI-100 OE is a cannabinoid receptor type 1 (CB1R) agonist delivered topically into the eye. It is a synthetic cannabinoid derivative to treat glaucoma and ocular hypertension. SBI-100 OE possesses a “novel molecular structure and formulation that was rationally designed to enable better penetration of ocular tissue and effective topical delivery of a CB1R agonist.”

https://skyebioscience.com/

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.

FOR MORE INFORMATION ON THE ROLE OF MARIJUANA IN GLAUCOMA, CLICK THIS LINK: https://ourgsc.blogspot.com/search?q=marijuana

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.