“The endocannabinoid system (ECS) is a multicomponent signaling network that controls several physiological processes, including neurological, immune, cardiovascular, digestive, and ocular functions. The components of ECS (i.e., receptors, ligands, metabolizing enzymes, and carriers) are expressed in eye structures and neurological areas involved in the visual process. Experimental evidence supports ECS involvement in ocular pathophysiology.
Preclinical and clinical studies indicate that cannabinoids (CBs) lower intraocular pressure and exert vasoactive, anti-inflammatory, and protective effects in the retina and ocular surface. However, CBs elicit modest and transient effects while inducing tolerance, dependence, and adverse effects, which prevent their use in ophthalmic clinics.
This review summarizes experimental and clinical data on the role of ECS in ocular pathophysiology. It also reports research on the therapeutic potential of CBs in common eye disorders. Lastly, it highlights promising alternative strategies for modulating ECS and improving ocular drug delivery to improve therapeutic efficiency in ophthalmic clinics.”
“Purpose: Glaucoma is a leading cause of irreversible blindness globally, primarily driven by elevated intraocular pressure (IOP). Still, some patients progress despite significant IOP lowering, potentially due to impaired ocular blood flow. This study aimed to evaluate the effects of dronabinol, a synthetic tetrahydrocannabinol derivative, on ocular blood flow in primary open-angle glaucoma (POAG) patients.
Methods: This randomized, double-masked, placebo-controlled, cross-over study included 23 patients with treated POAG (mean age 68 ± 7 years). All participants received dronabinol (11 patients received 5 mg and 12 received 10 mg in a randomized fashion) on one study day and placebo on the other study day. The primary outcome was optic nerve head blood flow (ONHBF) measured by laser speckle flowgraphy. Mean blur rate was determined for the large vessel area (MV), the tissue area (MT) and the total ONH area (MA). Secondary outcomes included vessel densities assessed by optical coherence tomography angiography, IOP, and blood pressure.
Results: Administration of 10 mg dronabinol significantly increased ONHBF (MA: 10.8 ± 20.6%, p = 0.018, MV: 12.0 ± 24.8%, p = 0.042, and MT: 11.0 ± 22.6%, p = 0.022, each vs. placebo) up to 4 h post-administration without affecting IOP or mean arterial pressure (p > 0.548 each). Additionally, a significant increase in vessel density in the superficial vascular plexus was found after administration of 10 mg dronabinol (6.7 ± 14.7%, p = 0.040 vs. 5 mg).
Conclusion: This pilot study demonstrates that systemic dronabinol enhances ONHBF in glaucoma patients, suggesting its potential as adjunct therapy for glaucoma by targeting vascular dysfunction. Further longitudinal studies are needed to explore its long-term impact on disease progression and visual field preservation.”
“Tetrahydrocannabinol (THC) has long been considered a treatment option for glaucoma, mainly because of its IOP-lowering properties. In addition, THC may also increase ocular blood flow, at least in healthy subjects. Recent data from our laboratory confirm that even low doses of THC, which neither affect IOP nor induce systemic psychoactive side effects, can increase ocular blood flow considerably.”
“In summary, our study demonstrates that administration of 10 mg dronabinol leads to a significant increase in ocular blood flow in patients with glaucoma. The effect seems to be dose-dependent, as a single administration of 5 mg had no effect on ocular blood flow. These findings highlight the potential role of dronabinol in improving ocular perfusion in glaucoma patients but also underscore the importance of considering age and disease-related factors when assessing cannabinoid-mediated vascular effects. Further investigations with larger sample sizes, longer study durations, and multiple applications instead of single intake are warranted to evaluate the potential clinical benefits of this therapeutic approach.”
“Introduction: Cannabis is widely used and becoming legal in many countries. While some acute ocular effects of cannabis are well-known (e.g., reduced intraocular pressure, vasodilation), little is known about the consequences of long-term cannabis use for ocular health. The aim of this study was to examine the association between persistent cannabis use across adulthood and measures of ocular health in midlife.
Methods: Participants were members of the Dunedin Study (n=1037), a longitudinal cohort followed since birth. Cannabis use has been measured by self-report at every assessment from age 18 to 45. Ocular health data were collected as part of a larger assessment at age 45 (2017-2019). Statistical analysis was performed in 2022.
Results: Cannabis use and ocular health data were obtained from 887 Study members. Generalised estimating equation analysis showed higher cannabis use was associated with poorer visual acuity, wider retinal arterioles and venules, and a thicker inferior hemifield of the ganglion cell-inner plexiform layer (GC-IPL). However, when controlling for tobacco smoking and socioeconomic status (known to be associated with these ocular health domains), the associations with visual acuity, arterioles, and venules were no longer significant. The association with GC-IPL remained significant in this adjusted model.
Conclusions: Persistent cannabis use appears to be neither harmful nor beneficial to the eye at age 45, although the thicker inferior GC-IPL hemifield in users of cannabis suggests biologically plausible neuroprotection. Further assessments as this cohort ages will illuminate the relationship between persistent cannabis use and ocular neuroprotection.”
“Aims: A review of the published literature was done to understand the role of endocannabinoids in glaucoma.
Background: As evidence mounts that intraocular pressure (IOP) is not the only factor in the pathogenesis and progression of glaucoma, a look into other aspects is the need of the hour. From the first instance of a drop in IOP linked to marijuana in the 1970s to the present, research has been ongoing, mostly in animals and in vitro models, with a scarcity of human studies, to delve into the world of the endocannabinoid system (ECS).
Methods: PubMed, ScienceDirect, and Google Scholar were searched for studies relating to endocannabinoids and their role in glaucoma.
Results: The ECS comprises ligands, receptors, and the synthesizing and degrading enzymes and is ubiquitous throughout the human body, including the visual system, from the eye to the occipital lobe. Apart from the IOP-lowering effect of the system, another property being investigated and implicated as an attribute of its receptors is neuroprotection. This neuroprotection seems to be mediated by excitotoxicity reduction and changes in vascular tone by acting on cannabinoid receptors.
Conclusion: The possibilities are indeed immense, and further research into the complex relationship between ECS and glaucoma is imperative to enable us to develop therapies for this otherwise chronic, progressive neuropathy, where the only armament in our hands is early diagnosis and maintenance therapy.
Clinical significance: We still do not have drugs for the prevention of retinal ganglion cell loss and for neuroprotection in glaucoma. Drugs that target cannabinoid receptors can revolutionize glaucoma management owing to their IOP-lowering action and neuroprotective effects. Based on the findings, we argue that further studies on the ECS and its implications in glaucoma are warranted to develop newer, effective, and better-targeted treatment strategies.”
“Currently, no drugs can target the loss of RGCs in glaucoma. Therefore, drugs that can target CB1 receptors can change the course of glaucoma treatment, as they can exert hypotensive and neuroprotective effects in conjunction.”
“Diseases of multifactorial origin like neurodegenerative and autoimmune diseases require a multitargeted approach.
The discovery of the role of autoimmunity in glaucoma and retinal ganglionic cell (RGC) death has led to a paradigm shift in our understanding of the etiopathology of glaucoma. Glaucoma can cause irreversible vision loss that affects up to an estimated 3% of the population over 40 years of age. The current pharmacotherapy primarily aims to manage only intraocular pressure (IOP), a modifiable risk factor in the glaucomatous neurodegeneration of RGCs. However, neurodegeneration continues to happen in normotensive patients (where the IOP is below a reference value), and the silent nature of the disease can cause significant visual impairment and take a massive toll on the healthcare system.
Cannabinoids, although known to reduce IOP since the 1970s, have received renewed interest due to their neuroprotective, anti-inflammatory, and immunosuppressive effects on autoimmunity. Additionally, the role of the gut-retina axis and abnormal Wnt signaling in glaucoma makes cannabinoids even more relevant because of their action on multiple targets, all converging in the pathogenesis of glaucomatous neurodegeneration. Cannabinoids also cause epigenetic changes in immune cells associated with autoimmunity.
In this Review, we are proposing the use of cannabinoids as a multitargeted approach for treating autoimmunity associated with glaucomatous neurodegeneration, especially for the silent nature of glaucomatous neurodegeneration in normotensive patients.”
“Cannabidiol (CBD) has emerged as a promising treatment for conditions like retinal ischemia, characterized by reduced blood flow to the retina and significant vision loss. Despite its therapeutic potential, CBD’s clinical application could be limited by due to its low bioavailability.
This study investigates the efficacy of CBD-loaded niosomes as a neuroprotective formulation for the use in ocular therapies related to retinal ischemia. We investigated the neuroprotective effects of CBD using a nanodispersed system (niosomes) administered via intravitreal injection in rats’ eyes.
Niosomes underwent characterization for size, distribution, zeta potential, morphology, and encapsulation efficiency. Safety and neuroprotective activity were assessed by electroretinography (ERG), confocal and transmission microscopy and histology. Niosomes exhibited nanometric size (100-400 nm) and stability, showing good tolerance in animals.
ERG results demonstrated higher b-wave amplitudes in animals pre-treated with niosomes + CBD compared to the control group following ischemic injury induced by a sudden increase in IOP. Histological and confocal microscopy analyses of retinas from the niosomes + CBD group showed preserved structure compared to the ischemic control group, suggesting significant retinal protection by intravitreally injected niosomes + CBD before ischemia. CBD-loaded niosomes effectively preserved retinal function, highlighting the neuroprotective potential of CBD against retinal ischemia.
This formulation presents a promising and innovative treatment for ischemic retinal diseases.”
“Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis sativa, shows promise in treating retinal ischemia due to its previously described combined anti-inflammatory and neuroprotective effects.”
“This study highlights the neuroprotective potential of CBD encapsulated in niosomes against retinal ischemia. Our findings indicate that pre-treatment with CBD-loaded niosomes effectively preserved retinal function, as demonstrated through histological, fluorescence, and electroretinography analyses.”
“CBD-loaded niosomes offer a new approach for treating ischemic retinal diseases.”
“Cannabidiol (CBD) is one of the principal constituents of Cannabis Sativa with no psychoactive properties. CBD is a promising neuroprotective compound bearing anti-inflammatory and antioxidant properties. However, considering its low solubility, CBD delivery to the retina represents an unresolved issue.
The first aim was to investigate the potential neuroprotective effects of CBD in an in vivo model of retinal excitotoxicity induced by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA).
Rats underwent intravitreal co-injection of AMPA (42 nmol) and CBD (10-4 M). The neuroprotective effect of CBD was investigated with histology and immunohistochemical evaluation of inflammatory and oxidative stress biomarkers.
CBD reversed the AMPA-induced total retinal, inner nuclear layer and inner plexiform layer shrinkage and loss of amacrine cells. Moreover, CBD decreased the AMPA induced number of cleaved caspase-3, Iba-1 and nitrotyrosine (NT) positive cells.
Based on this evidence, we developed a nanotechnological formulation of CBD to overcome critical issues related to its eye delivery. Particularly, nanostructured lipid carriers (NLC) loaded with CBD were prepared, optimized and characterized.
Due to the optimal physicochemical characteristics, CBD-NLC3 has been selected and the in vitro release profile has been investigated. Additionally, CBD-NLC3 was topically administered to rats, and retinal CBD levels were determined. CBD-NLC3 formulation, after a single topical administration, efficiently delivered CBD in the retina (Cmax= 98 ± 25.9 ng/mg; Tmax = 60 minutes), showing a high translational value.
In conclusion, these findings showed a good PD/PK profile of CBD warranting further pre-clinical and clinical evaluation of the new formulation for the treatment of retinal degenerative diseases.”
“Cannabis sativa is a plant of the Cannabaceae family, whose molecular composition is known for its vast pharmacological properties. Cannabinoids are the molecules responsible for Cannabis sativa potential effects, especially tetrahydrocannabinol and cannabidiol.
Scientific development has shown interest in the potential of cannabidiol in various health conditions, as it has demonstrated lower adverse events and great pharmacological potential, especially when administered topically.
The present study aims to carry out a scoping review, focusing on the use of cannabidiol, in vivo models, for topical administration. Thus, the methodological approach used by the Joanna Briggs Institute was applied, and the studies were selected based on previously established inclusion criteria.
Even though more information regarding the dose to achieve pharmacological potential is still needed, cannabidiol demonstrated potential in treating and preventing different conditions, such as glaucoma, atopic dermatitis, epidermolysis bullosa, and pyoderma gangrenosum.”
“Glaucoma is a leading cause of irreversible blindness worldwide. To date, intraocular pressure (IOP) is the only modifiable risk factor in glaucoma treatment, but even in treated patients, the disease can progress. Cannabinoids, which have been known to lower IOP since the 1970s, have been shown to have beneficial effects in glaucoma patients beyond their IOP-lowering properties. In addition to the classical cannabinoid receptors CB1 and CB2, knowledge of non-classical cannabinoid receptors and the endocannabinoid system has increased in recent years. In particular, the CB2 receptor has been shown to mediate anti-inflammatory, anti-apoptotic, and neuroprotective properties, which may represent a promising therapeutic target for neuroprotection in glaucoma patients. Due to their vasodilatory effects, cannabinoids improve blood flow to the optic nerve head, which may suggest a vasoprotective potential and counteract the altered blood flow observed in glaucoma patients. The aim of this review was to assess the available evidence on the effects and therapeutic potential of cannabinoids in glaucoma patients. The pharmacological mechanisms underlying the effects of cannabinoids on IOP, neuroprotection, and ocular hemodynamics have been discussed.”
“The endocannabinoid (eCB) system is critically involved in the modulation of synaptic transmission in the central nervous system, playing an important role in the control of emotional responses, neurodevelopment and synaptic plasticity among other functions. The eCB system is also present in the retina, with studies indicating changes in function after application of cannabinoid receptor agonists, antagonists and in knockout models. Whether eCBs are tonically released in the retina and their physiological functions is, however, still unknown. We investigated the role of the eCB system in the modulation of response strength of retinal ganglion cells (RGCs) to light stimulation, their receptive field organization, contrast sensitivity and excitability properties by performing whole-cell patch-clamp recordings in mouse RGCs before and after bath application of URB597, an inhibitor of the enzyme that degrades the eCB anandamide. Our results show that URB597 application leads to a reduction in the strength of synaptic inputs onto RGCs but paradoxically increases RGC excitability. In addition, URB597 was shown to modulate receptive field organization and contrast sensitivity of RGCs. We conclude that tonically released eCBs modulate retinal signaling by acting on traditional cannabinoid receptors (CB1R/CB2R) as well as on non-cannabinoid receptor targets. Thus, a thorough understanding of the effects of drugs that alter the endogenous cannabinoid levels and of exogenous cannabinoids is necessary to fully comprehend the impact of their medical as well as recreational use on vision.”
