The cannabis conundrum

July 25, 2018
Yes, marijuana lowers intraocular pressure. No, it’s not a practical therapy. But why?
The cannabis conundrum - Medical Marijuana

Excerpted from page 20 of the July/August 2018 edition of AOA Focus.

Marijuana has no effect, whatsoever, on glaucoma. Period.

If only it were that simple.

"Most eye care practitioners understand that marijuana is really ineffective in the management of glaucoma," says Robert Prouty, O.D., of Colorado.

A lecturer on the subject, Dr. Prouty says the modicum of truth to marijuana's intraocular pressure (IOP)-lowering abilities is just enough—right or wrong—for the pro-legalization crowd to lump glaucoma among the maladies that could benefit from marijuana.

Although cannabis' clinical utility for certain conditions is well documented, glaucoma isn't one. But, those smallest of cracks revealed by prevailing research are enough to give patients and the public green-tinted lenses on the matter.

"The hard part is when you get out into the public literature and you look at pro-marijuana advocates taking a broad-brush stroke, saying 'marijuana lowers IOP, therefore it treats glaucoma,'" Dr. Prouty says. "So, right now, it's pretty convoluted in the popular public space, and optometry has an opportunity to address this."

Public, political perception

Growing public support for marijuana continues to run concurrent to state efforts to legalize the drug for medicinal and even recreational purposes. Now, 29 states and Washington, D.C., have some form of medical marijuana laws on the books that run counter to federal law, the Marijuana Policy Project notes.

In a country often mired in partisan divides, marijuana legalization isn't one. About 61% of Americans believe marijuana should be legalized, with nearly 70% of Democrats, 65% of Independents and 43% of Republicans saying so, per a January 2018 Pew Research report.

There isn't much of a generational divide either: 56% of baby boomers, 66% of Generation Xers and 70% of millennials support legalization.

"It honestly doesn't surprise me to see a change in attitude across the nation," Dr. Prouty says. His state, Colorado, was among the first states to legalize marijuana. "I think most folks are still endorsing and accepting medical use. I'm not sure it's as wide-open for recreational use, but medical use is certainly showing that trend."

A Schedule 1 drug by Drug Enforcement Agency (DEA) standards, marijuana is lumped into the same category as heroin, cocaine or methamphetamine—in other words, the "no accepted medical uses" moniker. While the DEA reaffirmed marijuana's scheduling in 2016, many argue that available research proves that classification is unwarranted and, ultimately, a barrier to further studies.

That said, the Food and Drug Administration (FDA) approved the use of a cannabidiol (CBD)-based epilepsy medication in June. However, the action may trigger a reclassification discussion that could see CBD scheduled separately from cannabis.

Murray Fingeret, O.D., clinical professor at State University of New York College of Optometry and the first doctor of optometry appointed to The Glaucoma Foundation Board of Directors, says federal restrictions mean there's a dearth of good research into marijuana and glaucoma.

"There is literature—the literature isn't new—that shows marijuana can reduce the IOP, it just doesn't last long," Dr. Fingeret says. "You can't get away from the issue that marijuana can lower eye pressure, but the extent is still open for debate and the data is so old, who knows what we would find now."

That sentiment, especially the latter, is part of the prevailing thought behind a recent report making waves among marijuana research.

Where's the evidence?

In 2017, the National Academies of Sciences, Engineering and Medicine (NASEM) published a report, titled, "The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research," that summed up the research supporting cannabis' therapeutic uses, its deleterious effects and areas where additional research is necessary.

Pertaining to glaucoma, the NASEM report identified one good-quality systematic review that evaluated medical cannabis for glaucoma treatment, finding no differences in IOP between placebo and cannabinoids. Yet, the committee noted that the quality of evidence for finding no effect is limited. Toward that end, the NASEM report concluded: "There is limited evidence that cannabinoids are an ineffective treatment for improving [IOP] associated with glaucoma."

While that statement alone seems a deadpan conclusion, it's a start, Dr. Prouty says. In his opinion, the report as a whole is among the best studies published regarding marijuana's role in medicine since the '90s, and the real breakthrough is NASEM's attempt to set a research agenda.

"They really only wrote a few sentences about eye care and glaucoma, but it follows the vast majority of studies in glaucoma," Dr. Prouty says. "However, I'm pleased that NASEM gives us a chance to research and better understand this issue."

So, what do the vast majority of studies regarding marijuana and glaucoma say?

Katherine Shen, O.D., of Washington, who has researched cannabinoids' IOP-lowering abilities, says studies do show that marijuana lowers IOP by up to 45%; however, it peaks at 30 minutes and decreases after 60 minutes, generally lasting only three to four hours. Marijuana's short duration of action precludes it from being an effective glaucoma treatment compared with existing glaucoma medications.

But the devil is in the details. Cannabinoids, the active chemical compounds in cannabis, are responsible for the physical effects of marijuana. The two most abundant cannabinoids are the nonpsychoactive, CBD, and the psychoactive, delta-9 tetrahydrocannabinol (THC). Many studies have found CBD to possess antioxidant and neuroprotective properties for disorders such as Alzheimer's disease, multiple sclerosis or even seizures. However, CBD isn't the cannabinoid responsible for IOP reduction. A 2007 study published in the British Journal of Ophthalmology found sublingual and intravenous THC administration significantly lowered IOP transiently, but CBD—in large doses—had the opposite effect, temporarily increasing IOP.

"When smoked, THC goes from the lung into the bloodstream and then crosses the blood-brain barrier into the brain," Dr. Shen says. "Topical THC drops are a challenge in the same way glaucoma drops have a challenge because the cornea is lipophilic. Formulations also can cause ocular irritation and stimulate tears, which would reduce the amount of absorption."

Historically, it's been demonstrated that smoking marijuana lowers IOP. In 1971, the famous Hepler and Frank study reported IOP reduction among 11 youthful subjects smoking marijuana, in the 25 to 30% range for three to four hours. Another study in 1997 found equal IOP reduction among nonusers and long-term marijuana users of a decade or more.

However, smoking is linked to a number of deleterious side effects, including the release of tars, carcinogens and other materials into the lungs. So, too, marijuana consumption can lower blood pressure, alter blood sugar and create dizziness, shallow breathing, dry mouth and slowed reaction time.

Dr. Shen notes the various effects of marijuana on the eye. On the one hand, marijuana can have neuroprotective properties, such as protection against traumatic, ischemic, inflammatory and neurotoxic damage in the central nervous system, as well as antioxidant and vasorelaxant properties.

On the other hand, marijuana can decrease visual acuity, vision dimness, decrease photosensitivity, decrease dark adaption and cause vasodilation, photophobia, blepharospasm, decreased lacrimation and reduced blink rate.

"Optometrists in those states that have legalized marijuana should be educated about the effects of marijuana," Dr. Shen says. "It has effects on binocularity—causing accommodation/refractive changes."

Adds Dr. Fingeret, "There have been several very good papers in the past 30 years that show marijuana does reduce IOP, and in the level neighborhood of what an eye drop may do, but it's a very short half-life. It would require somebody to use the agent continuously, and on top of that, the psychoactive effects during that time would preclude the use, especially in the guise that there are other agents that don't have these psychoactive effects or last longer and lower IOP better.

"There are just too many associated side effects that you wouldn't want a patient to have."

AOA provides practical guidance

Concurrent to the NASEM report, AOA's Health Promotions Committee (HPC) also sought to set the record straight in a 2017 position paper that built upon the preeminent research regarding marijuana's IOP-lowering effect. In summary, the HPC paper concluded:

The use of marijuana (in any form) as a medication to reduce eye pressure in glaucoma is not safe or practical. Marijuana is also not a medication that would reduce the risk of developing glaucoma. There are many medications that are FDA-approved to treat eye pressure that have very few side effects and need only be used once or twice daily in the form of an eye drop or pill. Additionally, there are some laser and surgical procedures that can help reduce eye pressure. These procedures may eliminate or reduce the number of other medications used to treat eye pressure. Glaucoma can be a difficult disease to diagnose and treat. It requires frequent testing of eye pressure, monitoring of visual field loss, and optic nerve evaluations.

Ultimately, marijuana as a glaucoma therapy comes down to the fact that its side effects outweigh the medical benefit, says Dan Bintz, O.D., AOA HPC member. The marginal IOP effect and short duration, combined with marijuana's intoxicating effect, ends the story there: "The patient would have to be intoxicated 24 hours per day to get even a marginal decrease in intraocular pressure."

Dr. Bintz adds, "There has been enough research to know it really isn't effective. That could change if new research emerges using formulas that could eliminate the undesirable side effects and increase the pressure-lowering ability. But, again, there are already many of these medications available with some now available as generics."

Brad Lane, O.D., AOA HPC member and contributor to the marijuana position paper, brought perspective to the report from a provider practicing in a state where marijuana is legal medically—West Virginia. Although glaucoma is not a qualifying condition under West Virginia's marijuana legislation, the attention surrounding the legislative battle and medical marijuana, generally, has queued up interesting patient conversations.

These dialogues fall less under the header of "prescription seekers," and more along the lines of "does it really work?" It's the kind of patient education and awareness opportunity that Dr. Lane is happy to address, and precisely why HPC drafted its paper.

"I feel that I have fairly open and honest conversations with my patients. Nothing is really off limits, and I'm comfortable asking if I suspect a patient is using recreational drugs," Dr. Lane says. "I have a few patients who have told me that they use marijuana medicinally, as well as recreationally, and we have an open discussion of the potential side effects."

This is the new reality of marijuana use in the United States, and until more awareness and education of what marijuana can (and cannot) do is available, doctors should prepare for these conversations. As advocates continue their push for legality, glaucoma will be one condition that's repeatedly roped in despite the literature.

"It's human nature to try to justify behaviors that are not totally socially acceptable," Dr. Bintz says.

An evergreen discussion

From infamy to the infirmary, marijuana's stigma is dissolving under changing public opinions, ongoing policy discussions and a greater understanding of its legitimate therapeutic uses. At the same time, the way in which people choose to imbibe the drug also is changing.

Edible marijuana, or simply "edibles", is a growing slice of the cannabis pie as the overall smoking rate among adults continues trending downward. In fact, a 2017 Forbes report found Washington's edibles sales increased 121% in 2016 while California reported $180 million worth of edibles sales that year, good for 10% of statewide cannabis sales. Furthermore, when it comes to medical marijuana patients, upward of 26% consume edibles. But that sweet tooth shift has left a bitter aftertaste.

While edibles lack the harmful byproducts of smoking, they also may contain significantly more or less concentration of THC or CBD. Despite suppliers' labeling requirements, a 2015 JAMA study determined only 17% of edibles tested from randomly selected dispensaries in San Francisco, Los Angeles and Seattle were accurately labeled. Moreover, greater than 50% of products contained less cannabinoid content than labeled, and some so low as to have little or no therapeutic effect.

That's why Dr. Prouty believes there should be more scrutiny given to edibles, as well as more awareness among patients who wrongly believe their marijuana consumption is keeping their glaucoma in check.

"So, 83% of the time people don't know what they've got and that's really dangerous, especially among those who self-medicate," Dr. Prouty says. "When it comes to marijuana, not only is duration of action short but also the sample size numbers in these studies are small."

It's clear that marijuana still has a long way to go to be considered an "acceptable" option in many eyes, regardless of form. But Dr. Prouty is heartened to see reports, such as NASEM, push for much-needed research. Although marijuana isn't feasible as a glaucoma therapy, future research may parse and build upon the IOP-lowering properties to develop new treatment options.

"Optometry is the first layer of care and discovery when it comes to most glaucoma cases in the country right now, so it really is beneficial to read this literature and have an idea of what's happening in the science to be able to answer our patients' questions," Dr. Prouty says.

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