Cannabis in Diabetes? Patients Don't Wait for Medical Advice

Alicia Ault

Disclosures

September 25, 2019

With little official guidance available, people with diabetes are trying to figure out whether cannabis—also known as marijuana—can be a help or a harm. Though there is some evidence that certain elements of cannabis may have a positive impact on type 1 or type 2 diabetes, it's also evident that marijuana can be a dangerous gamble for some individuals with the condition.

On forums such as Reddit.com, people with diabetes who want to partake or are already users have been comparing notes. What they share is a hodgepodge of experience, rumors, and, occasionally, informed opinion.

"Look for high THCV strains if you can," said one user, who referred to a study that showed that THCV, a type of cannabinoid, reduced glucose intolerance in obese mice. "Less munchies and a slightly different effect on the head. I've also noticed an impact in how my sugars seem to level out when dosing with it."

Another Reddit user, who self-identified as having type 1 diabetes, posted on a different thread that "it doesn't really affect your BG [blood glucose]. It can give you munchies, which you need to be smart [about] or you can mess up your BG." The user added, "It can make you somewhat less able to feel lows (although I still do). Check your BG often, and bring snacks. Especially if you are not a very experienced user."

On another forum at diabetesdaily.com, one user asked, "I take metformin and blood sugar continues to stay high 160-200 in AM. Started taking CBD oil 2 x a day. Now at 120-140 for past week. Can I start reducing metformin?" When someone suggested checking with their doctor, the user said, "He doesn't seem to want to talk about CBD."

Even pharmacologists and clinicians are debating what to do. Many admit that they don't know about cannabis—and the hundreds of cannabinoids it contains, including the two main ones, tetrahydrocannabinol (THC) and cannabidiol (CBD)—and how it interacts with the human endocannabinoid system, which was only discovered in the early 1990s and is still being characterized.

"There is a promise that medical marijuana may be part of the solution to the obesity and diabetes epidemic," wrote Frank L. Greenway, MD, chief medical officer at Pennington Biomedical Research Center, Louisiana State University, in the International Journal of Obesity. "Marijuana and its components deserve consideration as a subject for investigation by the obesity research community," he wrote.

One of the somewhat surprising effects is marijuana's link to lower body weight.

"If you look at the epidemiological literature, it actually turns out that cannabis users have lower body weight, lower rates of type 2 diabetes, lower rates of metabolic disease, and better insulin function," Angela Bryan, PhD, professor of social psychology and neuroscience at University of Colorado, Boulder, told Medscape.

A particularly large study from 2012 found that adults aged 20-59 years who used marijuana had a lower prevalence of type 2 diabetes and lower odds of diabetes relative to non-marijuana users. A more recent examination of that data found that marijuana use is associated with lower fasting insulin and lower levels of HOMA-IR (homeostasis model assessment of insulin resistance) in obese—but not non‐obese—adults, even when it was used fewer than four times a month. Even former consumers with high lifetime use had significantly lower fasting insulin levels that persisted.

"How does that fit?" asked Bryan. "If we know that THC increases appetite and potentially might be associated with not being as active, how do we make those two pieces of information work together? That's a fascinating scientific question," she said, adding, "There's not a whole lot of good data out there to help us answer the question."

Meanwhile, use of cannabis, for any condition, presents myriad other issues. No one has yet determined the best delivery system, the right dosage, and, in diabetes, whether it's a help solely in type 2 or also in type 1, said Mary Lynn McPherson, PharmD, professor at the University of Maryland School of Pharmacy.

McPherson's school just launched the first master's degree program in medical cannabis. A spokesperson said the school received 506 applications for the 150 spots in the inaugural class.

"Science is desperately trying to catch up with what's available on the legal market," said Colorado expert Bryan.

Medical societies haven't weighed in yet, either. When asked for any official statements, a spokesperson for the Endocrine Society, for instance, responded, "Unfortunately, the Society doesn't have any guidelines on this topic yet."

Growing Use Among Older Americans

Recreational marijuana is legal in 11 states and Washington, DC. Medical marijuana is legal in 33 states, and another 11 states allow CBD/low-THC medical products with a high ratio of CBD to THC. Meanwhile, use is staying steady among youth, but it's rising among older Americans.

"We're seeing a large population be more accepting of cannabis-based products," said Chauntae Reynolds, PharmD, a clinical pharmacy specialist in Indianapolis, Indiana.

About 9% of adults aged 50-64 and 3% of those over 65 had used marijuana in the previous year, according to a 2016 national survey, up from 7% and 1.4%, respectively, in 2013. Given its growing popularity among older Americans, the September 2019 AARP Bulletin devoted most of the issue to a special report on marijuana.

It's not clear how many people with diabetes—young or old—use cannabis. In a recent Polish study, adolescents with type 1 had about half the rate of illicit drug use as a control group of peers: 18% vs 33%. But the authors noted that other studies, both in the United States and Europe, found higher rates of drug use among youth with type 1, especially for marijuana, with as many as 70% reporting use. Another recent survey found that 30% of adults with type 1 diabetes said they'd used cannabis in the past year.

Type 1: More Harm Than Good?

Cannabis has some biological plausibility as a beneficial agent in obesity and diabetes, but its potential for harm is frequently glossed over by users, particularly younger users.

The body makes its own cannabinoids, and thus has cannabinoid receptors and transmitters, which have been determined to be essential to homeostasis. Humans have two major types of cannabinoid receptors, type 1 and type 2.

The endocannabinoid system has a role in inflammation, insulin sensitivity, and fat and energy metabolism, with receptors found throughout the body, including the skin, immune cells, bone, fat tissue, liver, pancreas, skeletal muscle, heart, blood vessels, kidney, and gastrointestinal tract.

Given that type 1 diabetes is an autoimmune disorder resulting in the chronic destruction of insulin-producing pancreatic beta cells, it might make sense that cannabis could help ameliorate the condition through its anti-inflammatory properties. According to a 2016 review, cannabinoids can inhibit leukocyte proliferation, induce apoptosis of T cells and macrophages, and reduce secretion of proinflammatory cytokines. Cannabinoids have reduced inflammation in arthritis and multiple sclerosis, and have had a positive effect on neuropathic pain and type 1 diabetes—all in mouse models.

"Theoretically, cannabinoids can help with the suppression of autoimmune disease," said Yu-Fung Lin, PhD, associate professor of anesthesiology at the University of California, Davis. People with type 1 diabetes "can benefit from the use of the right type of cannabis," she said.

In contrast, some human studies have suggested that cannabis can be harmful in type 1 diabetes, but not because it has an effect on the underlying disease.

"If they take something that is higher in THC compounds, that will stimulate appetite," said Lin, noting that it could, in turn, elevate blood glucose—unless individuals make good choices about what they eat when they have the munchies.

The Colorado scientists reported an almost doubling of the risk for diabetic ketoacidosis in cannabis users with type 1 diabetes compared with non-users.

Stronger Evidence in Type 2

The story in type 2 diabetes is different. More is understood about the links between cannabis, obesity, and insulin resistance, and more studies in humans have been published.

Activation of cannabinoid receptor 1 (CB1 receptor), especially in hepatic cells, is associated with obesity, insulin resistance, and impaired metabolic function, according to a 2019 overview from South Korean researchers. CB1 receptors are found mainly in the central nervous system and the brain but can also be expressed in the liver, muscle, pancreas, and adipose tissue.

Excess food intake and obesity activate CB1 receptors, resulting in a cascade of problems, including impairment of insulin signaling, beta-cell apoptosis, and insulin deficiency or resistance. And that leads to type 2 diabetes, according to the South Korean researchers.

Thus, when the CB1 receptor is overstimulated, it increases the likelihood of weight gain and rising blood glucose levels, said Reynolds. If something could be found that would bind to the CB1 receptor and antagonize it, that would probably lower blood sugar and obesity, she said. As it happens, THC has an affinity for the CB1 receptors; it also binds to CB2, but it's the action on CB1 that is of interest.

In a recent commentary, Thomas Clark, PhD, of Indiana University noted that THC stimulates the CB1 receptor, causing acute increases in appetite, hyperphagia, and hypothermia—but that cannabis users still have lower obesity rates. This may be because "cannabis use causes a rapid and long-lasting downregulation of CB1R, reducing the sensitivity of the endocannabinoid system," said Clark. Essentially, it brings the system back into homeostasis.

But THC also has well-known psychoactive effects. Sanofi-Aventis tried to get past that by creating rimonabant, a CB1 receptor blocker, which would theoretically reduce the receptor's activity to below the baseline level. The drug was approved in Europe in 2006, due to its demonstrated ability to let users shed pounds, but was withdrawn in 2008 because of psychiatric side effects.

In 2016, British researchers tested CBD and another nonpsychoactive cannabinoid, tetrahydrocannabivarin (THCV), in patients with type 2 diabetes in a randomized, placebo-controlled trial. They found that CBD was not so effective, but THCV significantly decreased fasting plasma glucose and improved pancreatic beta-cell function.

Trickle of Research

LSU's Greenway and others have lamented the state of cannabis research in the United States, which is hampered by the federal prohibition on marijuana.

The Drug Enforcement Administration (DEA) controls how much marijuana can be produced for research. In September, the agency proposed increasing the amount from 2450 kg in 2019 to 3200 kg in 2020, almost triple what was allowed in 2018. As of January 2019, 542 individuals had been approved to conduct research with marijuana.

LSU is a state-appointed grower and has partnered with a commercial company to produce oil extracts, said Greenway. "Research scientists will need to familiarize themselves with the regulations that are applicable to their state and tailor their studies to the legal framework that best suits each state," he said.

Despite its new graduate program on medical cannabis, the University of Maryland doesn't allow research on marijuana because it accepts funding from the National Institutes of Health. "We can't do research on an illegal product and still hope to compete for research dollars," said McPherson.

UC Boulder has figured out a way to conduct its research so that it does not violate any federal laws, said Bryan. The school cannot have marijuana on campus, as that would break the Drug-Free Campus rules. Instead, the researchers have a mobile lab that goes to where students—its trial participants—are using cannabis.

Bryan just received a grant from the National Institute on Drug Abuse to evaluate the impact of THC and CBD on obesity and insulin resistance. When the participants are about to use cannabis, the van goes to them and collects blood before, during, and after, measuring THC and CBD levels as well as certain inflammatory biomarkers. The researchers are also examining the immediate impact of cannabis on insulin function in infrequent users, and then will conduct a study in sustained users, adding in measures of diet and physical activity.

Serum THC and CBD are objective measures and help control for variations like exposure, Bryan said. The team is also hoping that the cannabis products used won't be another confounder. Trial participants are urged but not required to buy cannabis products that Bryan and her colleagues have set aside at dispensaries. These products have specific concentrations of THC, CBD, or both. She and her colleagues hope to have some initial data within a year.

Federal legislation has been introduced to help speed research. The Medical Cannabis Research Act of 2019, introduced in the House in January, and the Cannabidiol and Marijuana Research Expansion Act, introduced in the Senate in June, have not attracted many co-sponsors, however, and have not seen much congressional action.

What Can Doctors Tell Patients?

In the meantime, individuals, especially in states where cannabis is legal, are likely to keep using the products, whether or not they are proven to help medically. So, what should clinicians do?

"I always ask, 'Are you using any CBD products and/or are you using any marijuana products?'" said pharmacist Reynolds, who is also a diabetes educator. "It's important that you know that information, just from a health standpoint, to make sure we're making the right recommendations and that we're monitoring the situation," she said. "With it being something that's not prescribed, of course there's no way to know unless we ask."

The Institute for Safe Medication Practices (ISMP) recommends that clinicians clearly tell patients that cannabis products are not approved by the US Food and Drug Administration (FDA) for any medical condition (except for the drug Epidiolex, approved for seizures associated with Lennox-Gastaut syndrome or Dravet syndrome).

The CBD-only products sold online and pretty much everywhere have also not been evaluated by the FDA. ISMP notes that there are many reports of CBD-only products containing either no detectable CBD or significantly more than is on the label. That puts consumers unknowingly at risk for impairment or testing positive on urine drug screens.

The FDA occasionally warns CBD manufacturers that they are violating the law, noting that any product promoted for health purposes is considered a drug and must go through the agency's formal review process, which includes a battery of animal and human testing.

Cannabis can cause drowsiness and lethargy, which is a concern especially if someone is using it in combination with alcohol or benzodiazepines, said Reynolds. Not only will it enhance somnolence or intoxication, but it could also "influence their ability to recognize signs and symptoms of low blood sugar," she said.

So far, it has not been documented that cannabis has a direct interaction with insulin or typical diabetes medications. However, several studies have found that some components of cannabis are metabolized by the cytochrome P450 enzyme system, which is the major pathway for the body's elimination of medications. As a result, said Reynolds, the effects of cannabis can be intensified or minimized, or the drug can alter the effects of prescribed therapies.

Cannabis seems to interact with blood pressure medications, antidepressants, antibiotics, anticoagulants, and blood thinners, said Reynolds, "and those are medications people with diabetes take because they have comorbid conditions."

For someone taking a blood thinner and using cannabis, the prescribed medication is likely to be present in a higher concentration for a longer period of time than normal, said Lin. The physician needs to know whether patients are using cannabis and "whether it is from the plant or another format. The patient really needs to inform the doctor so the doctor can take a look at other medications to see whether it's safe," she said.

McPherson notes the dearth of knowledge about cannabis—and not just among clinicians. "What is the educational background of somebody who's working in the dispensary?" she asks. "I mean, were they selling tires yesterday at Mr. Tire?"

In addition to the new Maryland master's program, UC Davis offers a "Physiology of Cannabis" course for undergraduate students and a graduate course that provides a scientific overview of the biology, genetics, biochemistry, and pharmacologic potential of Cannabis sativa. UC Boulder also offers a free online, semester-length, beginner-level course on cannabis, aimed at clinicians.

McPherson said the educational opportunities can't come quickly enough. "People are desperate for some shred of credibility here," she said.

Will Cannabis Be the Cure?

With so much conflicting evidence, it's hard to see just yet whether cannabis could be a crucial approach to tackling obesity and diabetes.

Lin believes that it holds promise. "You think about how cannabinoids affect the energy status in our body and control homeostasis," she said. "A disease like diabetes would be an important area to put more research into."

In the meantime, some experts remain cautious.

"Better not run off to the dispensary just yet," said McPherson. She said she has too many concerns about the negatives associated with cannabis.

"Should everybody start smoking weed when they're 12 years old to prevent type 1 diabetes, when we know that down the road you can see a reduction in cognitive functionality from smoking weed all those years?" she asked. "Of course not. That would be a sucker bet."

Follow Medscape on Facebook, Twitter, Instagram, and YouTube

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....