What is currently known about cannabidiol and ocular pressure

KEYWORDS:

• Cannabis
• THC
• CBD
• ocular pressure
• glaucoma

Glaucoma is a blinding disease that is estimated to afflict more than 3 million Americans and 60 million globally [1,2]. Glaucoma is a neurological disease, with the blindness developing gradually over the course of years as retinal ganglion cells, the neurons that communicate visual signals to other regions of the brain, die [3]. The chief hallmark of glaucoma is elevated intraocular pressure (IOP), and with time this elevated pressure results in the death of these projecting neurons, and a consequent progressive loss of vision. IOP is maintained via a balance of inflow and outflow, cycling four times a day. Outflow occurs via several pathways, with the largest outflow occurring via the trabecular meshwork (TM). All first-line treatments for glaucoma – including the so-called normotensive forms of glaucoma – are directed at lowering ocular pressure via eye drops.

It was recently reported by Miller et al. that cannabidiol (CBD), a popular and now widely available plant cannabinoid, raises ocular pressure [4] in a mouse model. This finding, combined with a limited prior study in humans, led to a recommendation by the American Academy of Ophthalmology against the use of CBD by individuals at risk of glaucoma. Here we will consider what is known about CBD and ocular pressure.

It has been known for nearly 50 years that cannabis inhalation lowers IOP [5]. Δ ⁹-tetrahydrocannabinol (THC) is the chief euphoric ingredient of cannabis [6] and was soon implicated as the agent responsible for the pressure-lowering effects [7]. There followed a flurry of research into the ocular effects of THC and some related plant cannabinoids but this research mostly concluded by the mid-1980s, well before it was determined that cannabinoids act on an endogenous signaling system. The first cannabinoid receptor – CB1 – was identified in 1990 [8] and has since been shown regulate important physiological systems such as pain, mood, movement and memory (reviewed in [9]). CB1 receptors are expressed throughout much of the eye [10], and CB1 receptor ligands were subsequently shown to lower ocular pressure [11]. These receptors have since been joined by several others: CB2 [12], GPR18 [13] and GPR119 [14] though there is some debate over how broadly to define the cannabinoid receptor family. We have shown that GPR18 and GPR119 also regulate ocular pressure [15–17]. All of these receptors are part of a super-family of ~500 proteins known as G protein-coupled receptors that include receptors for opiates, serotonin, dopamine, and acetylcholine, to name a few.

THC is not the only phytocannabinoid found in cannabis: cannabidiol (CBD) can be present at quantities comparable to THC, though this varies greatly by strain. Long considered inactive, CBD is now FDA-approved as an anti-epileptic in Dravet and Lennox Gastaut syndromes [18,19]. Several dozen states have now legalized medical cannabis and a dozen have legalized recreational use. CBD has been treated by many legislatures as distinct from cannabis and is now widely available even in states that have otherwise resisted moves to legalize cannabis. The reason for this has much to do with the fact that unlike THC, CBD is non-euphoric. It is commonly described as non-psychoactive, but this is not, strictly speaking, true since CBD clearly has effects on the central nervous system. But CBD will not produce the ‘high’ reported for cannabis use. CBD has also benefitted from a strong advocacy by parents of children with Dravet’s Syndrome, a devastating form of childhood epilepsy for which there are few therapeutic options. As a result CBD is now readily available even in grocery stores. Until recently, THC levels in cannabis strains exceeded those of CBD, often by a large margin. However, plant strains have now been developed (e.g. Charlotte’s Web) that have a CBD/THC ratio that is heavily skewed toward CBD. CBD is often sold as an oil but is being introduced into various products including foods, creams and beverages.

The study by Miller et al. was intended to clarify how THC and CBD regulate ocular pressure, and reported that THC lowers pressure by activating a combination of CB1 and GPR18. CBD however had the opposite effect on IOP, raising it by 18%. There are several considerations about this finding. First, the work was done in mouse, using eye drops at a relatively high concentration. It is unclear whether anyone has been taking CBD as eye drops for glaucoma or other conditions. However this is not the first study to examine the effects of CBD on ocular pressure. Four other studies had tested for effects of CBD on ocular pressure. Three of these studies reported no effect, but the fourth, albeit a small pilot study, reported a transient increase in IOP at 4 hours after a 40mg sublingual dose [20]. Taken together, these studies raise concerns about whether CBD may be problematic for individuals at risk of glaucoma, but additional well-designed studies are needed to clarify this.

The mechanism by which CBD raises ocular pressure is likely through antagonism of the CB1 receptors. THC activates CB1 receptors to lower pressure but CBD has been reported to act as a negative allosteric modulator of CB1 signaling [21–23]. Allosteric modulators differ from classical ‘orthosteric’ ligands in that they act at a secondary site to modulate the signaling of the receptor. Allosteric modulators include important classes of drugs such as the benzodiazepines and barbiturates that act on allosteric sites on the GABA-A receptors. This is significant because this means that CBD may antagonize THC signaling.

CBD has an unusual dual regulatory status. On the one hand, it is a drug approved by the FDA in the context of epilepsy treatment that is under active investigation for other applications including graft-versus-host disease, an immune disorder [24]. On the other hand CBD is enjoying a popular embrace as a cure-all, for symptoms ranging from pain and inflammation to anxiety. The FDA-approved form, epidiolex, is tightly regulated. This contrasts with the store-bought version, treated as a natural product, and there have been reports of considerable variability in actual levels of CBD relative to what is claimed on the label [25].

It seems unlikely that patients are preparing eye drops to treat glaucoma but in truth there is no data on this. If they are preparing THC-based eye drops, these may lower ocular pressure – this is a subject of some debate and outside the focus of this article – but if those drops were to include comparable amounts of CBD, or more seriously, CBD alone, then there is a risk of elevated pressure. Miller et al., also tested the effects of co-treatment with equal concentrations of THC and CBD and found that CBD blocked the pressure-lowering effects of THC. Similar considerations apply for ingested CBD though hepatic metabolism of phytocannabinoids makes the picture more complicated. Another consideration for patients who may be self-treating with eye drops is that there is now evidence that cannabinoid receptors are involved in corneal function. CB1 receptor knockout mice – engineered to remove their CB1 receptors – see delayed wound healing [26,27]. The mechanism appears to involve cannabinoid regulation of cellular migration through a complex combination of chemoattraction and chemorepulsion [27–29]. If so, then any compound that interferes with the chemical gradient that corneal epithelial cells use to find their way in the cornea run the risk of impairing normal corneal function. However this is essentially unstudied.

A final consideration is that the recent study also noted a sex-dependence of the effects of THC. The maximal effect at 4 hours was similar but by 8 hours pressure in males was still lower while pressure in females was back to baseline. Again this work was done in mice, so the difference may not translate to humans, and the sex-dependence of CBD effects was not studied but it is possible that CBD acts differently in males vs. females. Furthermore, the diurnal effects of CB1 and GPR18 activation are still unstudied and may yet yield surprises. Pressure in the eye is regulated by time of day and broadly speaking pressure is higher in humans during the day. In mice, which are nocturnal and have a reversed cycle, GPR18 appears to play a role in this regulation, actively lowering pressure. Since both THC and CBD act on GPR18 [4], there may be a diurnal component to the ocular response to these drugs. It should be noted however that in humans there is great individual variation in this diurnal regulation of ocular pressure.

In summary, the sudden widespread availability and popular embrace of CBD mean that health professionals must consider the health implications of CBD. Though there are still many unanswered questions, several studies now support the idea that CBD may raise intraocular pressure and so serve as a risk factor for glaucoma, but a final determination will require further systematic study.

Declaration of interest

The author was supported by several grants from NIH, NSF, CTSI and Johnson Foundation. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

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Funding

This paper was not funded