cbd oil for glaucoma in cats

CBD Oil For Dogs & Cats With Glaucoma

Pet glaucoma is a serious condition. While age is still the common cause of glaucoma in pets, there are other things that may trigger this painful plight.

So, does your dog have glaucoma?…

Table of Contents

What Is Glaucoma in Dogs?

Glaucoma does not only affect dogs, even cats get glaucoma. Glaucoma causes both cats and dogs constant pain and in worse cases, permanent loss of vision on the affected eye.

Pet glaucoma is pretty much like human glaucoma. It’s caused by an increase in the aqueous humor or the clear and watery fluid found inside the eyes of humans, canines, and felines. The aqueous humor should be able to drain normally by itself but because it can’t, it results in the accumulation of the same fluid that causes pressure inside the eye.

Glaucoma causes your pet’s eye to stretch, affecting the optic nerve and basically damaging the overall integrity of the affected eye. As you can imagine, glaucoma causes severe pain, sharp pangs that may occur intermittently or incessantly.

Unfortunately, 40% of dogs diagnosed with glaucoma will end up blind. Majority of cats with glaucoma will show a substantial loss of vision, both partial and total, even before clinical manifestations of the condition are observed.

Different Types of Glaucoma

There are two types of glaucoma that affects both cats and dogs – primary and secondary.

Primary glaucoma is caused by a predisposed trait or an inherited genetic condition. This means that your pet has higher chances of developing primary glaucoma the closer it is to a name that had glaucoma in the pedigree. Sires and dams that have predecessors who had recorder cases of glaucoma will most likely pass it on to the litter.

In dogs, breeds that have a genetic predisposition to the condition range from breeds of different sizes. Larger breeds like Great Danes, Samoyeds, Alaskan Malamutes and Chow Chows are victims of primary glaucoma. Medium-sized breeds like Siberian Huskies and Dalmatians are also known for developing primary glaucoma. In smaller breeds, it’s common for Chihuahuas, Basset Hounds, Cocker Spaniels, Poodles, Beagles, and Jack Russel Terriers to have glaucoma.

In cats, a number of breeds like Burmese Cats and Siamese Cats are breeds known to have predisposed glaucoma.

Secondary glaucoma in both cats and dogs is developed instead of having been inherited. Several conditions can trigger and cause secondary glaucoma to develop. In both dogs and cats, eye injuries are the number one cause of secondary glaucoma.

Once the eye of your pet is injured, it may bleed and swell. Inflammation will eventually damage the tissues in the injured eye and will cause scar tissues to form. In most cases, scar tissues can block the exit point of the aqueous humor and excessive fluid is accumulated.

Other conditions affecting secondary glaucoma in pets include infection of the eye, tumor on or near the eye, advanced eye cataracts, and chronic retinal detachment, a condition caused by a hole or by a tear in the retinal tissue.

Unfortunately, secondary glaucoma can be triggered by something as simple and as preventable as an untrimmed toenail that can scratch your dog or your cat’s eye.

To put it simply, primary glaucoma is passed down to later generations in a pedigree while secondary glaucoma can be acquired or developed as a result of several injuries and medical conditions.

How to Prevent Glaucoma in Dogs

Unfortunately, primary glaucoma is not a preventable condition. Because primary glaucoma is a result of a genetic flaw and of asymmetrical physical development, it cannot be corrected without surgery.

However, dogs that inherited primary glaucoma will most likely not have primary glaucoma in its other eye. Nevertheless, living with one eye blind leaves a dog or even a cat partially handicapped.

On the other hand, secondary glaucoma is preventable.

Trim their Nails:

Long nails can poke your pet’s eye when they scratch their face. Make sure to take your pet to the groomer or you can just trim it yourself. For dogs, just make sure you take them out regularly for walks, walking on pavement (cool pavement of course) can cause the nails to wear down to a point that they won’t pose danger to your pets.

Create a Safe Space:

There’s nothing better than creating a safe environment for your pets. Clean your backyard or your pet’s play area and remove sharp objects that might cause eye injury. Also, make sure to clean the area to ensure that your pet will not catch anything that might give it an infection later on.

Keep them Healthy:

A healthy pet has higher chances of brushing off infection and diseases than a frail and an unhealthy one.

Visit the Vet Regularly:

Take regular trips to the vet. Your veterinarian will help you identify and treat infections as well as secondary glaucoma early on.

Signs and Symptoms of Glaucoma in Dogs

Your pet can’t tell you it’s suffering from glaucoma; they don’t show they’re hurting like how humans do. Glaucoma symptoms are often subtle and are hard to notice.

One thing you should take note of is that glaucoma, both primary and secondary, gives both cats and dogs a great deal of pain.

Dogs will often press their heads against a wall or rub their eyes in your legs and even on furniture.

Pay attention to your pets when you see them do this.

Symptoms on cats are even harder to spot. Only the most observant of cat owners will notice pets squint or develop clouds that tend to grow progressively over time.

Overall, dogs and cats suffering from pain will find daily activities a little less interesting. You’ll notice subtle changes in the amount of food they eat and the amount of activities they do in a day.

Dog Glaucoma Natural Home Remedies

Unfortunately, there aren’t many home remedies that will help you manage and let alone treat glaucoma. However, there are some herbs that can help you reduce the pressure in your pet’s eyes which will reduce pain and discomfort.

Ginko:

Though it’s not common to find Ginko in many households, you can use this herb to help alleviate the pain your pet is experiencing because of glaucoma. Ginko is a great for blood circulation and can be used together with the herb Bilberry.

Bilberry:

Bilberry is a natural agent that reduces pressure in the inner eye. It is also rich in vitamins and minerals that help keep the eyes healthy.

CBD is an active ingredient found in hemp and is good in eliminating inflammations. CBD oils not only reduce inflammation allowing the aqueous humor to normally drain but it also helps calm cats and dogs and help them manage pain from glaucoma.

How much CBD should I give my dogs with glaucoma?

Different companies use different dosages of CBD. Make sure to check with the manufacturer with how potent the CBD oil is.

For managing pain and inflammation, the basic rule is to administer a minimum of 1 and a maximum of 5 mg of CBD for every 10 pounds of your pet’s body weight. Depending on the severity of the glaucoma, you can use a lower dosage of 1 mg of CBD. For medium dosage 3 mg of CBD is normally the level you’d want to go for and for pets suffering extreme pain, 5 mg of CBD is recommended.

CBD is safe for pets as long as it contains very minimum amounts of THC.

References:

tetrahydrocannabin dog Glaucoma natural home remedies
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Best CBD Oil for Cats and Dogs with Glaucoma

If you have a pet, there is little worse than seeing them under the weather, or worse. You want to make sure that your pet is healthy and happy whatever the cost and that can involve supplements, medication and other expenses.

One disease not often discussed is glaucoma, whilst it is relatively uncommon in people, it is something that your pet can suffer with, especially if they are a particular breed where their eyes are naturally bigger and can bulge. Glaucoma is particularly prevalent in dog breeds such as Huskies, Poodles and Chow-chows and in cats, it can be prevalent in the Burmese and Siamese variety.

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What Is Glaucoma?

Glaucoma in dogs is a serious condition affecting the eyes. It is where pressure is placed or builds around the eye, the results of the pressure cause the eye to inadequately drain, thus increasing the pressure further. The pressure is caused by a fluid build-up behind the lens which is unable to train adequately, this build up impacts vision.

The results of glaucoma can be devasting for dogs and cats and if left untreated can result in permanent damage to the optic nerve which is then followed by blindness. Unfortunately, some breeds of dogs are more predisposed to others and will often have to have their eye removed within one year of diagnoses due to how quickly the disease can take hold.

Types of Glaucoma

Primary glaucoma is rare, this disease is very rarely inherited from parents or other genetic partners, this is only really seen in Burmese and Siamese cats. Both cats and dogs suffer from secondary glaucoma, which unfortunately is random and cannot be predicted. One or both eyes can be affected but having two eyes infected is quite rare. You can help your pet avoid glaucoma by keeping your house free from dust, making sure chemicals are kept away and no sharp objects can penetrate their eyes.

What Are The Symptoms Of Glaucoma?

Early symptoms of glaucoma can be difficult to spot, and it requires you to know your pets normal behaviour and very nuanced changes in how they interact. In its early stage’s glaucoma won’t present as a visible illness, it will however manifest itself in the early stages by giving your pet a headache. You may find that your cat or dog no longer wants to play as much, they don’t like their face or head being touched and their appetite has vastly reduced.

You may find that your cat or dog increases pressing their head, either against you or another surface to reduce the pain the pressure is putting on their face. Later, symptoms can include red and cloudy eyes, the apparent loss of vision, constriction of the pupil and a receding eyeball.

How Can CBD Products Help?

CBD is mostly notably known for its ability to reduce pain, it with the endocannibal receptors found in mammal brains to increase comfort level and reduce anxiety. It does this by increasing the blood flow in the area of the brain that triggers anxiety and pain. This effect of CBD is well documented and the fact that it can be used to both manage pain and reduce anxiety can help increase your pets comfort level.

Stress can increase the veracity of glaucoma, so giving your dog or cat CBD can reduce the overall anxiety and stress that is felt when they are in pain. Regularly dosing your pet will keep the CBD in their blood maintained at a level so that they remain calm and content. However, if you do think that your pet is suffering from glaucoma, consult a vet first before you begin any at home remedies in case they need to intervene. If the disease is still in its early stages, consult them as to how they think you should dose your pet with CBD and if it will interact with other medications your pet may be taking at that present time.

CBD Oils

A study conducted by McGrath in 2008 looked to see which CBD products had the best effect on pets in discomfort, whom were suffering from a variety of conditions. The results uncovered through the research showed that giving your pet CBD oil products ensured that their comfort level was maintained over a longer period of time when measured against other products.

It was quicker to stabilise in their blood stream and would last upward of 12 hours, whereas other products didn’t stabilise as quick or at the same level. CBD oils also consistently out-performed in how quickly they entered the blood stream and took effect when measured against edibles and topical creams. The best products and most trusted products are those that have been developed through Verma farms, as their CBD products are tried and tested by millions of users per year.

How To Give Your Pet CBD Oil

Cats and some dogs can smell medicine a mile off and can be very unwilling participants in their own health, especially when it doesn’t smell like their normal food. One way of making sure your pet gets their dose is to put it into a treat and hide it in a lump of cheese, this is particularly effective in dogs. For cats, use food items such as salmon and prawns as their distinct smell can mask that of the oil. If you really are struggling to get your pet to take CBD oil, then look for CBD infused treats, these will have the smell taken out of them so that your pet will take them without realising they are being medicated.

Final Thoughts

Glaucoma can be a scary thing and if you think your pet has the early onset, then it is best to get to the vet straight away. CBD will be an excellent addition to their pain management medications and will also decrease anxiety and alleviate the stress often felt when your pet is in pain and having to visit the vet. Always consult your vet prior to any treatment, but CBD will be an excellent compliment to the medications they are taking.

Δ 9 -Tetrahydrocannabinol and Cannabidiol Differentially Regulate Intraocular Pressure

It has been known for nearly 50 years that cannabis and the psychoactive constituent Δ 9 -tetrahydrocannabinol (THC) reduce intraocular pressure (IOP). Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a major cause of blindness. THC likely acts via one of the known cannabinoid-related receptors (CB1, CB2, GPR18, GPR119, GPR55) but this has never been determined explicitly. Cannabidiol (CBD) is a second major constituent of cannabis that has been found to be without effect on IOP in most studies.

Methods

Effects of topically applied THC and CBD were tested in living mice by using tonometry and measurements of mRNA levels. In addition the lipidomic consequences of CBD treatment were tested by using lipid analysis.

Results

We now report that a single topical application of THC lowered IOP substantially (∼28%) for 8 hours in male mice. This effect is due to combined activation of CB1 and GPR18 receptors each of which has been shown to lower ocular pressure when activated. We also found that the effect was sex-dependent, being stronger in male mice, and that mRNA levels of CB1 and GPR18 were higher in males. Far from inactive, CBD was found to have two opposing effects on ocular pressure, one of which involved antagonism of tonic signaling. CBD prevents THC from lowering ocular pressure.

Conclusions

We conclude that THC lowers IOP by activating two receptors—CB1 and GPR18—but in a sex-dependent manner. CBD, contrary to expectation, has two opposing effects on IOP and can interfere with the effects of THC.

Cannabis has a long and storied history tracing back thousands of years. Only recently have we begun to understand how its constituents act in the body. Δ 9 -tetrahydrocannabinol (Δ 9 -THC, THC) is understood to be the chief psychoactive ingredient of cannabis. 1 The year 1971 marked the publication of the first work by Hepler and Frank 2 demonstrating that cannabis inhalation has a salutary effect on intraocular pressure (IOP). This set in motion a flurry of research to learn the nature of this effect. Remarkably, however, we still do not know through which receptors the principal components of cannabis regulate IOP. It is often assumed that THC does this via cannabinoid CB1 receptors, since CB1 receptor agonists lower IOP 3 but this has not been demonstrated. Ocular research into the two principal phytocannabinoids—THC and the noneuphoric cannabidiol (CBD)—largely ceased after the early 1980s, well before the first cannabinoid receptor was identified in 1990. 4 CB1 receptors remain the best-characterized cannabinoid receptor and are widely distributed in the brain 5 and eye 6 and regulate important physiological systems such as pain, mood, movement, and memory (for review see Ref. 7 ). But the cannabinoid signaling system consists not only of CB1 receptors but also of CB2, 8 GPR18, 9 and GPR119 10 and perhaps others, as well as enzymes that produce and metabolize the lipid cannabinoid messengers (for review see Refs. 11 and 12 ).

We have determined that at least three cannabinoid-related receptors (CB1, GPR18, GPR119) regulate IOP in the vertebrate eye. 13 – 15 Of these, THC activates CB1 and GPR18 16 , 17 and perhaps GPR119. This means that the action of THC may be quite complex.

THC is not the only phytocannabinoid found in cannabis: CBD can be present at quantities comparable to THC and plant strains have now been developed (e.g., Charlotte’s Web) that have a CBD to THC ratio that is heavily skewed toward CBD. Long considered inactive, CBD has shown benefit in clinical trials as an antiepileptic in Dravet’s syndrome 18 and has recently been approved by the US Food and Drug Administration (FDA) as an antiepileptic. But CBD is also assigned many other properties, including activity at GPR18 19 , 20 and the cannabinoid-metabolizing enzyme FAAH (fatty acid amide hydrolase), 21 but CBD may act as a negative allosteric modulator of CB1 signaling. 22 , 23 This is significant because this means that CBD may antagonize THC signaling. Three of four studies that have tested CBD for effects on IOP have reported no effect, but the fourth has reported an increase in IOP. 24

The current study was an examination of the receptor dependence of the actions of THC and CBD on IOP.

Methods

Animals

Experiments were conducted at the Indiana University campus. All mice used for IOP experiments were handled according to the guidelines of the Indiana University animal care committee and in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Mice (male and female, age 3–8 months) were kept on a 12-hour (6:00 AM–6:00 PM) light/dark cycle, and fed ad libitum. Male and female mice were used for these experiments as noted and were obtained from the colony of Ken Mackie (Indiana University, Bloomington, IN, USA). Mice were C57BL/6J (C57) strain except CB1 −/− mice, which were on a CD1 strain background. We have previously shown that mice on a CD1 background see reductions in ocular pressure upon topical treatment with CB1 cannabinoid agonists WIN55212 and CP55940, which are absent in CB1 knockouts. 14 Mice were allowed to acclimatize to the animal care facility for at least a week before their use in experiments. A total of 85 mice were used in these experiments. CB1 −/− mice were kindly provided by Ken Mackie. The knockouts were global knockouts. CB1 −/− animals were originally received from Catherine Ledent (Catholic University, Leuven) as heterozygotes. 25

Intraocular Pressure Measurements

IOP was measured to test the effects of topically applied THC and CBD in living mice by rebound tonometry, using a Tonolab (Icare Finland Oy, Helsinki, Finland). To obtain reproducible IOP measurements, mice were anesthetized with isoflurane (3% induction). The anesthetized mouse was then placed on a platform in a prone position, where anesthesia was maintained with 2% isoflurane. Baseline IOP measurements were taken in both eyes. Measurements were initiated promptly (typically within a minute) after successful induction of anesthesia. Depth of anesthesia was assessed by paw press. A “measurement” consisted of the average value of six readings. One eye was then treated with drug (dissolved in Tocrisolve [Tocris Biosciences, Ellisville, MO, USA]), a soya-based solvent, 3 5 μL final volume, applied topically), while the other eye was treated with vehicle. Mice recover rapidly from isoflurane anesthesia. After an hour the animal was again anesthetized as above. IOP was then measured in the drug-treated and vehicle-treated contralateral eye. This procedure (recovery from anesthesia, return to cage, reanesthetization, measurement of IOP) was repeated at the 4- and 8-hour time points as necessary.

IOP measurements following drug administration were analyzed by paired t-tests comparing drug-treated eyes to contralateral vehicle-treated eyes except for animals that had a time series (1, 4, and 8 hours), in which case a 2-way ANOVA with Bonferroni post hoc test was performed.

Quantitative RT-PCR

Primers for selected components of the endocannabinoid system were designed by using Primer-Blast (http://www.ncbi.nlm.nih.gov/tools/primer-blast, in the public domain) and the corresponding mouse gene. Primer sequences are as listed below:

CB1 S: 5′ CTG ATC CTG GTG GTG TTG ATC ATC TG 3′

CB1 AS: 5′ CGT GTC TGT GGA CAC AGA CAT GGT 3′

Eyes were extracted, the lens removed, and were then immediately stored at −80°C. RNA was extracted with a Trizol reagent (Ambion, Austin, TX, USA) and genomic DNA was removed with DNase (NEB, Bethesda, MD, USA) following the manufacturer’s instructions. RT-PCR was performed by using a one-step, Sybr Green amplification process (PwrSybr; Applied Biosystems, Carlsbad, CA, USA). Quantitative PCR was performed with an Eppendorf RealPlex2 Mastercycler thermocycler (Eppendorf, Hauppauge, NT, USA).

A primer for glyceraldehyde 3-phosphate dehydrogenase was used as an internal control for each experimental condition with the threshold cycle set within the linear range (10-fold above baseline). Once the standard critical threshold (Ct) was set, the relative expression levels for genes were determined.

Lipid Extraction and LC/MS/MS Analysis and Quantification

Enucleated eyes were flash frozen in liquid nitrogen and frozen at −80°C until used for lipid analysis. Levels of ∼35 cannabinoid-related lipids as well as arachidonic acid and several prostaglandin-family metabolites were measured by liquid chromatography (LC)/mass spectrometry (MS) from whole eyes as previously described. 15 , 26 Briefly, eyes were homogenized, centrifuged at 19,000g at 24°C for 20 minutes and supernatant was collected. Compounds were isolated by using a partial purification of the 25% organic solution. C18 solid-phase extraction columns (Agilent Technologies, Santa Clara, CA, USA) were used with an elution of 100% methanol.

Samples were placed in an autosampler and held at 24°C (Agilent 1100 series autosampler; Palo Alto, CA, USA) for LC/MS/MS analysis. Ten to 20 μL of eluents were injected for each sample, which was rapidly separated with a C18 Zorbax reversed-phase analytic column (Agilent Technologies) to scan for individual compounds. Gradient elution (200 μL/min) then was accomplished under pressure (Shimadzu 10AdVP pumps; Shimadzu Scientific Instruments, Columbia, MD, USA). The electrospray ionization was done by using an API3000 triple quadrupole mass spectrometer (Applied Biosystems/DSM Sciex; Foster City, CA, USA). A multiple reaction monitoring (MRM) setting on the LC/MS/MS was used to analyze levels of each compound. Synthetic standards were used to generate optimized MRM methods and standard curves for analysis.

Individual animals in each of the treatment groups were coded and experiments were analyzed in a blinded fashion.

Materials

Δ 9 -THC and CBD were obtained through the National Institutes on Drug Abuse drug supply program. O-1918 and Tocrisolve were obtained from Tocris Bioscience.

Results

THC Lowers IOP in a Sex-Dependent Manner

We found that THC when applied topically (5 mM) lowered IOP relative to the vehicle-treated contralateral eye in male mice. This resultant drop in IOP was quite pronounced at 8 hours, with a nearly 30% drop in IOP ( Fig. 1 A, IOP in THC [5 mM]–treated versus vehicle-treated contralateral eye in males; 1 and 4 hours: n = 7, 8 hours: n = 8; *P < 0.05 by 1-way ANOVA with Bonferroni post hoc test versus contralateral eye at corresponding time point). Strikingly however, in female mice given the same treatment there was a more modest effect at 4 hours than the corresponding time point in males and no effect at 8 hours ( Fig. 1 B, IOP in THC [5 mM]–treated versus vehicle-treated contralateral eye in females; 1 and 4 hours: n = 20, 8 hours: n = 8; *P < 0.05 by 1 way ANOVA with Bonferroni post hoc test versus contralateral eye at corresponding time point). The effect of THC was therefore sex-dependent.

THC substantially lowers IOP for at least 8 hours but in a sex-dependent manner. (A) Topically applied THC (5 mM) lowers IOP relative to contralateral vehicle-treated eye in mouse. Effect persists for 8 hours. (B) In contrast, females only see an effect of THC at 4 hours. *P < 0.05, 1-way ANOVA with Bonferroni post hoc test versus contralateral eye at corresponding time point.

THC Lowers IOP Through Combined Activation of CB1 and GPR18 Receptors

As noted in the introduction, THC lowers IOP but the mechanism by which it does this remains undetermined. A preferred hypothesis is that THC lowers IOP via CB1 receptors. We therefore tested whether the effect of THC would be absent in CB1 receptor knockout mice. Interestingly, we found that CB1 deletion only partly eliminated the effect of THC ( Figs. 2 A, ​ A,2B; 2 B; IOP in THC [5 mM]–treated versus vehicle-treated contralateral eye in CB1 knockout (KO) males; 1 and 4 hours: n = 12; *P < 0.05 by paired t-test versus contralateral eye at corresponding time point). This suggests that CB1 also acts via a second receptor. One likely candidate for this is the GPR18 receptor since, as noted previously, GPR18 can lower IOP in mice and is activated by THC. We therefore tested whether the GPR18 antagonist O-1918 (5 mM) applied topically to CB1 knockout mice would prevent the effect of THC. We found that there was no effect at 1 or 4 hours under this condition ( Figs. 2 C, ​ C,2D; 2 D; IOP in O1918 pretreated [5 mM topical] CB1 KOs: THC [5 mM]–treated versus vehicle-treated contralateral eye; 1 and 4 hours: n = 5; *P < 0.05 by paired t-test versus contralateral eye at corresponding time point). This argues that THC lowers IOP through a combination of CB1 and GPR18.

THC lowers IOP through combined activation of CB1 and GPR18 receptors. (A, B) THC treatment in CB1 KO males still results in a partial drop in IOP at 1 hour but not at 4 hours. (C, D) THC treatment in CB1 KO mice pretreated with GPR18 blocker O1918 (5 mM) does not result in a drop in IOP relative to contralateral vehicle-treated eye. *P < 0.05, paired t-test versus contralateral eye.

CBD Has Two Independent Opposing Actions on IOP

As noted above, CBD has been tested in several studies for effects on IOP. Three of those studies found no effect, while the last saw an increase in IOP. CBD has been proposed to act on a large and growing number of receptors including recent evidence that CBD is a negative allosteric modulator at CB1 receptors. 23 , 27 When tested in our model, we found that CBD (5 mM) in male mice substantially raised IOP at 1 and 4 hours ( Figs. 3 A, ​ A,3B; 3 B; IOP in CBD [5 mM]–treated versus vehicle-treated contralateral eye in wild type (WT) males; 1 hour: n = 13; 4 hours: n = 19; *P < 0.05 by paired t-test versus contralateral eye at corresponding time point). Female mice saw a similar rise at both time points (data not shown). Strikingly, the same experiment in CB1 knockouts resulted in a decrease in ocular pressure at 1 hour but no effect at 4 hours ( Figs. 3 C, ​ C,3D; 3 D; IOP in CBD [5 mM]–treated versus vehicle-treated contralateral eye in CB1 KO males; 1 and 4 hours: n = 7; *P < 0.05 by paired t-test versus contralateral eye at corresponding time point). This indicates that CBD has two opposing effects on IOP. The first and dominant effect of raising IOP is likely CB1-dependent since the effect is absent in CB1 knockout mice and may be a consequence of cannabinoid receptor antagonism. We tested whether the IOP reduction was due to activity at GPR18 receptors, since GPR18 activation can lower IOP. 13 CBD had no effect on IOP in animals pretreated with the GPR18 antagonist O1918 (5 mM) ( Figs. 3 E, ​ E,3F; 3 F; IOP in O1918-pretreated animals [5 mM topical], CBD [5 mM]–treated versus vehicle-treated contralateral eye in CB1 KO males; 1 and 4 hours: n = 7; not significant (NS) by paired t-test versus contralateral eye at corresponding time point).

CBD has two independent opposing actions on IOP. (A, B) CBD (5 mM) raises IOP at 1 and 4 hours. (C, D) CBD treatment in CB1 knockout mice unmasks a drop in IOP at 1 hour but not at 4 hours. (E, F) Pretreatment with the GPR18 antagonist O1918 in CB1 knockouts prevents the IOP-lowering effect of CBD at 1 hour. *P < 0.05, paired t-test versus vehicle-treated contralateral eye.

CBD Interferes With the IOP-Lowering Effects of THC

If CBD is raising pressure by acting as a negative allosteric modulator at CB1, then it is possible that coapplication of CBD and THC would cancel out the salutary effects of THC. To test this we treated mice (C57Bl/6J) with combined CBD/THC (5 mM/5 mM) and found that there was no effect on IOP relative to vehicle ( Fig. 4 , IOP in THC and CBD [5 mM each]–treated versus vehicle-treated contralateral eye in WT males; 1 and 4 hours: n = 7; NS by paired t-test versus contralateral eye at corresponding time point).

CBD may interfere with the IOP-lowering effects of THC. (A, B) A combined treatment of CBD and THC (5 mM each) in WT males does not result in a drop in IOP at 1 or 4 hours relative to contralateral vehicle-treated eyes. NS by paired t-test.

mRNA Levels for CB1 and GPR18 Are Higher in Eyes of Male Than Female Mice

If there is a sex dependence in the effect of THC, what is the basis of that difference? Are there fewer CB1 receptors, or GPR18 receptors, or both? One way to test this is to examine the mRNA expression of these receptors in the eyes of male versus female mice. We examined mRNA expression for CB1 and GPR18 by using quantitative PCR, finding that mRNA levels of CB1 and GPR18 were lower in female mice than male mice ( Fig. 5 ; n = 9 per condition; *P < 0.05 unpaired t-test male versus female).

mRNA expression for CB1 and GPR18 is lower in females. mRNA expression for (A) CB1 and (B) GPR18 receptors is relatively higher in the eyes of male than female mice. *P < 0.05 unpaired t-test.

Cannabinoid-Related Lipid Species Are Elevated After CBD Treatment

Though the IOP-lowering effect is blocked by a GPR18 antagonist, the action of CBD may be direct or indirect, particularly since, as noted previously, CBD has been shown to act at the endocannabinoid-metabolizing enzyme FAAH. To explore this we measured levels of ∼35 cannabinoid-related lipids as well as several prostaglandins and related lipids 1 hour after treatment with CBD. In a given animal, one eye received CBD while the contralateral eye received vehicle (N = 6). As shown in the Table , the levels of most acylethanolamines rose, though not arachidonoyl-ethanolamine (AEA), an endogenous ligand for CB1/CB2 receptors. Levels of two N-acyl-gammaaminobutyric acid (GABA) and N-acyl-taurine species were elevated. Intriguingly, levels of the GPR18 ligand N-oleoylglycine (NOGly) and the GPR119 ligand 2-oleoylglycerol were also elevated.

Table

Cannabinoid-Related Lipidomic Profile in Eye After CBD Treatment

Discussion

Nearly half a century after reports of a salutary effect of cannabinoids on ocular pressure we still do not know the mechanism by which this occurs. Our chief findings in normotensive mice were that THC lowers pressure substantially and for at least 8 hours, through a combined action at two receptors, CB1 and GPR18. This effect was sex-dependent, with much stronger responses in male mice. CBD in contrast had two opposing actions on IOP: raising IOP in wild-type animals but lowering it in CB1 knockout mice likely via GPR18. Finally, at equal concentrations CBD prevented the IOP-lowering effects of THC.

Sex-dependent effects have been reported for cannabis (e.g., in the study by Cooper and Haney 28 ) but sex dependence had not been explored for cannabinoid regulation of IOP. Phytocannabinoids are not currently considered a suitable first-line therapeutic for glaucoma (e.g., American Academy of Ophthalmology [AAO] position statement 2014, www.aao.org); however, this may be based on limited evidence. The central argument is that topical THC is not effective, therefore necessitating treatment via cannabis inhalation. Cannabis inhalation, in turn, has assorted shortcomings: (1) psychoactivity, (2) short action (<4 hours), and (3) elevation of blood pressure. A key question then is whether topical THC works in humans. The negative conclusion is based on four studies, three of which pool male and female subjects. In the two 1981 studies by Merritt et al., 29 , 30 most subjects are female (4/6, 7/8). Green and Roth 31 (1982) do not specify the makeup of their subject pool but exclude pregnant subjects, implying the presence of females, leaving only one study that includes only males. 32 The sex dependence of THC regulation of IOP, with the robust effects in males that we report here, combined with topical THC studies in animals (e.g., Merritt et al., 29 Green et al., 33 ElSohly et al., 34 ), suggests that the question of topical THC as a means to lower ocular pressure may merit some reconsideration.

It is notable that no less than three cannabinoid related receptors, namely, CB1, GPR18, and GPR119, each lower IOP when activated. Moreover, they all exhibit sex dependence, but differentially. mRNA expression of CB1 and GPR18 is elevated in male mice relative to female mice. It must be noted that differential mRNA expression does not necessarily correspond to protein levels (e.g., Western blot). However the difference in mRNA is consistent with our finding that dual activation of these receptors by THC yields a stronger effect in males. In contrast, the X-linked GPR119 receptor lowers IOP preferentially in female mice. 15 Our results also raise the possibility that the diurnal variation of IOP, in which GPR18 plays a role, 35 is sex-dependent.

The elevation of IOP by CBD is consistent with CB1 antagonism. If CBD truly interferes with the actions of THC then low-CBD strains may offer superior results for studies involving cannabis inhalation. The second mechanism of action for CBD—the one that underlies IOP—reduction—may be due to direct or indirect activity at GPR18, since there is no effect on IOP by CBD if GPR18 and CB1 are both blocked/deleted. As noted above, CBD has been shown to be active at GPR18 19 , 20 and may block FAAH, 21 which could also elevate acylethanolamines, as we have recently shown, 35 including AEA, a precursor for GPR18 ligand NAGly. 9 Our lipidomic analysis revealed rises in several cannabinoid-related lipids. Levels of GPR18 ligand NAGly were not elevated but we did see a rise in the closely related NOGly, which may also activate GPR18 (data not shown). This may account for the observed GPR18-dependent effects. Levels of four of the six acylethanolamines tested were seen to rise after CBD treatment. Interestingly, of these, oleoylethanolamide (OEA) and palmitoylethanolamide have been shown by Syed et al. 36 to activate GPR119, which can also lower ocular pressure in female—but not male—mice when activated. 15 Moreover, levels of 2-oleoylglycerol, a GPR119 ligand that also lowers IOP, 15 were also seen to rise and may contribute to the signaling profile of CBD.

One consideration in interpreting the duration of effects of THC and CBD relates to rates of metabolism and clearance. We did not assess the pharmacokinetics of these compounds. Since they are structurally quite similar (with identical molecular weight), it is unlikely that one of the original compounds is removed much more rapidly than the other. However, while the hepatic metabolism of these compounds has been studied extensively, potential metabolism in the eye is unstudied. In principle, the apparent temporal difference between CBD and THC effects in the eye may be a function of differential ocular metabolism. In principle CBD and THC may also impact each other’s metabolism, the so-called entourage effect. Competition for enzymatic breakdown is generally hypothesized to enhance the signaling of THC, whereas we saw a diminished response, but it is difficult to ascertain without further, explicit study of THC/CBD pharmacokinetics in the eye.

It is valuable to understand the mechanisms by which THC and CBD regulate intraocular pressure, particularly at a time when their changing legal status and the perception of phytocannabinoids as safe contribute to a continued growth in their availability and popular embrace. CBD in particular has recently been approved by the FDA as an antiepileptic and is available in many grocery stores. We find that the regulation of ocular pressure by THC and CBD is more complex than previously appreciated. THC acts via a combination of CB1 and GPR18 receptors in a sex-dependent manner, while CBD can both raise IOP and interfere with the effects of THC. The potential of CBD to elevate ocular pressure should be evaluated further as a potential deleterious side effect, particularly with long-term use. Our finding of sex dependence of cannabinoid regulation of ocular pressure suggests that the current academic view that topical phytocannabinoids are without effect (e.g., the 2014 AAO position statement on cannabis and glaucoma) may be premature. Most of the studies on which this position is based include female subjects but are underpowered to evaluate a potential sex dependence of effect. However, it should be stressed that the findings presented here highlight the complex endogenous cannabinoid signaling system that can be selectively targeted and harnessed to lower ocular pressure by other means. For instance, we have shown that it is possible to enhance endogenous cannabinoid signaling by blocking the cannabinoid-metabolizing enzyme monoacylglycerol lipase 37 and so lower ocular pressure. Similarly, we have found that activating CB1 directly 38 can achieve the same outcome. Our findings for THC suggest that a dual CB1/GPR18 agonist may prove advantageous. The study of phytocannabinoids such as THC and CBD, but also others derived from the plant, may therefore point to novel strategies to promote ocular health.

Acknowledgments

Supported by a grant from the National Institutes of Health (EY024625).

Disclosure: S. Miller, None; L. Daily, None; E. Leishman, None; H. Bradshaw, None; A. Straiker, None