Vision, such as many functions of the body, is partly regulated by the endocannabinoid system. It is worth understanding the whole mechanism to take advantage of medical cannabis.
Vision is partially regulated by the endocannabinoid system
The light penetrates the eye through the anterior eye structure. It reaches photoreceptors located on the surface of the retina. Their photopigments absorb the light which initiates the conversion of light into an electric signal. The information then takes the optical neuronal pathways and is finally transferred to the visual cortex in the brain (lateral geniculate nucleus).
Focus on the retina
The retina plays a key role in vision as it is the organ that converts light into an electric information decipherable by the brain. It is often considered as an extension of the central nervous system (CNS), and brain and retina are connected by the optic nerve. To communicate with each other, the brain and the retina expresses several neurotransmitters (dopamine, serotonin, glutamate, GABA…). It can therefore be affected by drugs acting on the CNS neurotransmission such as marijuana.
How does the endocannabinoid system work?
The endocannabinoid system (ECS) is a signalling system made of receptors such as type 1 and type 2 receptors (CB1 and CB2), ligands or activators such as AEA and 2-AG – also called endocannabinoids, and the regulative enzymes such as fatty acid amide hydrolase (FAAH) which are proteins responsible for the breakdown of endocannabinoids. The ECS can be disrupted by the administration of exogenous ligands such as phytocannabinoids delta-9-tetrahydrocannabinol (THC) or cannabidiol (CBD) cannabinoids.
The ECS is involved in CNS regulation since CB1 receptors have pre-synaptic and post-synaptic localization, and their activation impacts the release of neurotransmitters. As the retina is part of the CNS, it is interesting to understand what the role of the ECS in its functioning is, and how a disruption of the ECS can impact it.
The endocannabinoid system is expressed all over the eye
In humans, the ECS has been detected in many stages of visual information processing. In ocular tissues, CB1 receptors have been detected on the ciliary body, the trabecular meshwork, the nonpigmented ciliary and the conjunctival epitheliums. AEA and 2-AG are expressed in the cornea, ciliary body, iris and choroid. In more integrated stages of visual processing, CB1 receptors have been detected in the lateral geniculate nucleus, which are central connections for the optic nerve to the occipital lobe, and in the superior colliculus, a component of the midbrain that orients movements of head and eyes. Finally, CB1 receptors can be found in the primary and secondary visual cortex.
The ECS is more precisely present all over the retina. Both cannabinoid receptors CB1 and CB2 are expressed in the retina. CB1 can be found in outer segments of photoreceptors cells, inner and outer plexiform layer, the two synaptic layers of the retina, the inner nuclear layer and the ganglion cell layer. While CB2 is present on the retinal pigment epithelium cells. 2-AG (higher levels) and AEA (lower levels) are expressed in retina as well as FAAH the enzyme that metabolizes AEA. FAAH is expressed in particular in retinal pigment epithelium cells. The presence of the ECS suggests it has a regulatory role in retinal neurobiology and in the transmission of visual information. Besides cannabis is a neuromodulator substance, which acts on inhibitory or excitatory pathways. For instance, cannabis concern neurotransmitters such as dopamine (involved in light adaptation) glutamate and GABA (both implicated in the transmission of the retinal information) It also suggests that acting on the endocannabinoid system could help to treat ocular diseases.
Exogenous cannabinoids disrupt the retinal functions through the endocannabinoid system
Few studies have been carried out so far about the effects of exogenous cannabinoids on the retina. However, against a backdrop of legalisation and decriminalization of both medical and recreational use of cannabis, pointing out their effects is important. By going throughout various studies, a review published in 2019 establishes a picture of what have been discovered so far.
Six of the 16 studies conducted on humans reported that smoking cannabis chronically can lead to neuroretinal dysfunction related to photoreceptor function (improvement in night vision, unilateral changes in visual acuity). Another clinical study showed structural and functional changes (here most of these subjects were simultaneously consuming other drugs). Delayed retinal processing in chronic cannabis users has been highlighted by one of the studies, compared with a control group.
Five studies examined the vascular effects of cannabinoids on the retina, which resulted in an alteration of the blood flow and the vascular calibre. Among clinical trials, two studies demonstrated occlusive vascular effects in males who smoked cannabis, while another one found an increase in retinal blood flow after synthetic THC (7.5mg) oral administration, which seems beneficial in ocular circulatory disorders such as glaucoma. An animal study showed that CBD had a vasorelaxant effect on precontracted arterioles while another found that CBD had vasoconstrictive effects on basal vascular tone. Given the different results that have been found, it goes without saying that further studies are needed. Nevertheless, those studies support the reasonable hypothesis that cannabinoids produce vascular effects since cannabinoid receptors are present in the retina.
Three studies conducted on animals demonstrated that cannabinoids have neuroprotective effects on the retina. One of them measured neuroprotection in terms of the density of retinal ganglion cells in rats with glaucoma after administration of synthetic cannabinoids. A similar study showed that THC preserves the density of the retinal ganglion cells (assessing the optic nerve). The latest one reported that CBD treatment had not only reduced neuronal apoptosis in the retina but also the inflammatory response caused by the induced uveitis. Cannabinoids have been found to have neuroprotective effects in relation to the central nervous system, yet retina is said to be an extension of the CNS. Furthermore, retinal inflammation is not different from the ones that occur in the body, and some cannabinoids, including CBD, have anti-inflammatory properties. Consequently, those findings seem reasonable.
The review highlights that exogenous cannabinoids may have antagonistic effects of the endocannabinoid system, but also neuroprotective and anti-inflammatory effects.
Cannabinoids could help treat ocular diseases: the case of glaucoma
Glaucoma is a degenerative disease that damages the optic nerve and leads to the process of losing vision. Glaucoma is often caused by an abnormally high intraocular pressure (IOP) that compress the fibres of the nerve and the retina.
In the 1970’s, the first studies that showed that smoking cannabis helped to lower the IOP were released, but the mechanism was not understood. Even today, only hypothesises are put forward.
The distribution of CB1 receptor in ocular tissues suggests that THC regulates the trabecular and uveoscleral aqueous humour outflow and production. A study carried out in monkeys reported that the topical administration of a synthetic cannabinoid reduced by 18% the production of aqueous humour. Another one showed that THC reduced the secretion of ciliary processes and provoked a dilatation of the ocular blood vessels, reducing the pressure.
A study carried out with mice and released in 2018 shows that THC and CBD impact IOP differently.
One of the main hypotheses is that THC lowers IOP by stimulating CB1 receptors. THC was administered topically to CB1 knockout mice and it has been found that, even though they have no CB1 receptors, THC still has a small effect. The effect suggests that THC also lowers IOP via another receptor, which could be GPR18 receptors. Indeed, GRP18 receptors had been proven to lower IOP and is activated by THC. THC was administered to CB1 knockout mice that had also been administered GRP18 antagonists: not IOP-lowering effects were noticed. Consequently, THC may lower IOP by activating both CB1 and GRP18. This effect was more noticeable in male mice.
The effects of CBD were also tested: two different actions were noticed. In mice that expressed CB1 receptors, CBD increased the IOP, data suggest that CBD is a negative allosteric modulator at CB1 receptor. However, in mice that did not express CB1, CBD decreased IOP. Indeed, CBD may block FAAH, which is responsible for AEA breakdown. This would increase AEA quantity. AEA is a precursor of GPR18 ligand NAGly. The amount of NAGly had not increased, but the quantity of NOGly (which is close to NAGly) did. An overstimulation of GPR18 would help to lower IOP.
Finally, when co-administrated at equal concentrations, CBD seems to cancel the IOP-decreasing effects of THC, as both cannabinoids compete for enzymatic breakdown.
Cannabis is not recommended to treat glaucoma, but it definitely is an interesting lead for potential treatments.
The expression of the endocannabinoid system all over the eye have important consequences: its modulation, thanks to cannabinoids such as phytocannabinoids, could be a lever to treat or alleviate the symptoms of ocular disease. It is important to fully understand the mechanisms involved, all the more so since the consumption of cannabis worldwide is increasing. Further studies in human population needs to be carried out to determinate if phytocannabinoids such as THC may point to novel strategies to promote ocular health.
 Schwitzer T, et alt. The Endocannabinoid System in the Retina: From Physiology to Practical and Therapeutic Applications. Neural Plast. 2016;2016:2916732. doi:10.1155/2016/2916732
 Zantut, P. R. A., Veras, M. M., Yariwake, V. Y., Takahashi, W. Y., Saldiva, P. H., Young, L. H., … Fajersztajn, L. (2019). Effects of Cannabis and Its Components on the Retina: A Systematic Review. Cutaneous and Ocular Toxicology, 1–20. doi:10.1080/15569527.2019.1685534
 Tomida, I. (2004). Cannabinoids and glaucoma. British Journal of Ophthalmology, 88(5), 708–713. doi:10.1136/bjo.2003.032250
 Miller S, et alt. D9-tetrahydrocannabinol and cannabidiol differentially regulate intraocular pressure. Invest Ophthalmol Vis Sci. 2018;59:5904–5911. https://doi.org/ 10.1167/iovs.18-24838