GRAYSLAKE, Illinois — A new business touting wellness through tinctures, bath bombs, and ice cream — all containing cannabidiol (CBD) — recently replaced the dental practice on Center Street.
The village’s main drag, which bears an uncanny resemblance to Jimmy Stewart’s Bedford Falls, is home to a handful of restaurants, a toy store, and bicycle repair shop. There’s not a tattoo parlor or nightclub in sight.
Yet in recent months, the local tavern hosted a release party for a beer infused with CBD flavor-enhancing terpenes and the nearby Family Video store began selling $33 CBD „starter kits.” Even the feed mill, a downtown fixture since 1940, began selling CBD products for dogs.
What’s clear from this sleepy Chicago suburb of some 20,000 residents is that the Midwestern mentality is shifting with the rest of America. People are willing to give CBD-based products a try.
Equally evident is that there is very little science-based information physicians can offer older, vulnerable patients with heart disease on the health effects of CBD or how this component of hemp and marijuana plants interacts with standard cardiovascular therapies.
Evidence on CBD’s health effects is „almost nonexistent” among older adults, a group whose CBD and cannabis use is increasing the fastest, said Kent Hutchinson, PhD, a psychology and neuroscience professor at University of Colorado Boulder and founder of the Center for Research and Education Addressing Cannabis and Health.
„If you just go around Colorado and walk into a nicer dispensary and look around, it’s all 60-year-olds,” he said. In some parts, „the assisted living home actually brings people down in a bus to go to the dispensary. It’s definitely an area that’s super important, and given the importance of cardiovascular issues in older adults, we ought to know the impact on cardiovascular health and preconditions.”
Ground Swell of Demand
A new Gallup poll finds one in seven Americans use CBD, that 11% of users are 50 to 64 years of age, and 8% are at least 65 years. Pain relief, anxiety, insomnia, and arthritis are the top reasons for use. Nearly four in 10 Americans think CBD oils should be legally available for adults to buy over the counter.
Most CBD sales will soon take place in general retail stores, rather than cannabis dispensaries, according to a recent cannabis market report. The authors predict sales of cannabis- and hemp-derived CBD products in the United States will surge from $1.9 billion in 2018 to $20 billion by 2024.
The CBD Grayslake shop sells mainly Kansas City–based CBD American Shaman products, and most are full-spectrum CBD, meaning that under the 2018 Farm Bill they can contain no more than 0.3% tetrahydrocannabinol (THC), the psychoactive compound in cannabis. Shop owner Zac Camp describes his customers as nurses, millennials looking to tamp down anxiety before work by smoking „flower,” or CBD leaves, and area cops willing to flash their badge to get a discount on products they believe will relieve job stress or pain from their utility belts.
Camp credits CBD with getting him off the antihypertensive drug irbesartan and says his own physician, whom he declined to identify, wants more product information so he can promote CBD in his office for patients who want a „natural product.”
„Some doctors are very open to it and some doctors are very closed-minded about it,” Camp said. „And that’s fine 'cuz there are no studies. They can’t approve something they don’t know anything about.”
In 2018, the US Food and Drug Administration (FDA) approved the first CBD-based medicine to treat two severe childhood-onset epilepsies. Coming after decades of stymied research, it showed dramatic improvements in these hard-to-treat children.
Robert A. Kloner, MD, PhD, chief science officer at Huntington Medical Research Institute, Pasadena, California, and professor of medicine at the Keck School of Medicine, University of Southern California, said what little is known about CBD in the heart is primarily from preclinical studies or in isolated blood vessels and „most of the data there suggest there may be cardiovascular benefit.”
There is general agreement that CBD is a vasodilator and that its vasorelaxant effect, in part, is related to improved endothelial function, he said. CBD appears beneficial, for example, in diabetic animal models with a high-glucose environment and endothelial dysfunction. Several studies show CBD also reduces myocardial infarct (MI) size in rat models by reducing ischemia-reperfusion damage, which may be related to anti-inflammatory and antioxidant effects or to vasorelaxation.
Data are also lacking on drug–drug interactions, which are a major concern in older patients on polypharmacy. A recent case report identified a significant interaction between warfarin and Epidiolex in a 44-year-old man who had a nonlinear rise in International Normalized Ratio values with uptitration of CBD. Epidiolex also carries a warning advising that liver enzymes be monitored to avoid liver toxicity.
„There are several different cytochrome (CYP) P450s that physicians have to take into account when they are thinking of drug–drug interactions,” said Ziva Cooper, PhD, research director of the UCLA Cannabis Research Initiative. „The blood thinners are particularly important because of the narrow therapeutic window.”
She noted that CBD inhibits several different CYP P450 enzymes, such as CYP3A4, CYP2C9, CYP2D6, and CYP2C19. Epidiolex prescribing instructions list the potential for drug interactions with moderate or strong inhibitors of CYP3A4 or CYP2C19 and with strong inducers of CYP3A4 or CYP2C19. Interactions may require dose adjustments, notably in opposite directions, for inhibitors vs inducers. Similarly, the package insert for the antiplatelet ticagrelor (Brilinta), which is metabolized by CYP3A4/5, also cautions about its use with strong CYP3A inhibitors and inducers.
„What CBD does in vitro, how it impacts the cytochrome P450s in vitro, is different than how it’s going to interact with drugs in the body,” Cooper said. „Because there’s been so little data, so few controlled studies on the effects of cannabidiol, we don’t actually know the impact of cannabidiol on the pharmacokinetics of these drugs because those studies haven’t necessarily been done yet. But it’s still really important for physicians to be aware of these drug–drug interactions.”
Neither the American College of Cardiology nor the American Heart Association have position statements on the cardiovascular effects of medical marijuana or CBD. „To date, there is little published scientific evidence backing the majority of health claims, other than those associated with the four FDA-approved CBD medications,” AHA spokesperson Michelle Kirkwood explained via email.
Mislabeling, „Fanciful” Claims
The bioavailablity of active cannabinoids in CBD is also difficult to predict because of differences in delivery systems (smoking, vaporizers, edibles). In the absence of CBD production, testing, and labeling standards, mislabeling is common. In a 2017 study, only 31% of 84 online CBD products were accurately labeled (within 10% of the claimed amount).
Last year, the Centers for Disease Control and Prevention (CDC) warned of acute poisoning in 52 Utah residents, who had symptoms, such as hallucinations, nausea, vomiting, and seizures, after exposure to products labeled CBD or Yolo CBD oil. In many cases, tests showed the products contained a synthetic cannabinoid. More than a quarter of patients were using the product for medicinal reasons.
The FDA has issued warning letters to four firms that market CBD products so far this year, including one last month to Curaleaf over unsubstantiated treatment claims. The agency’s recent hearing on public health and safety concerns related to cannabis and cannabis-containing products attracted more than 113 speakers, including health professionals, patients, manufacturers, retailers, and government officials — a testimony to this white-hot topic.
In a recent Washington Post opinion piece, former FDA commissioner Scott Gottlieb, MD, said CBD may offer potential benefits, but can cause liver damage at high doses, may have a cumulative effect, and that currently marketed products may contain undeclared ingredients and impurities, including THC.
He urged the agency to create a regulatory pathway for CBD that would obligate manufacturers to file new dietary ingredient notifications or food additive petitions, which would include toxicity studies to evaluate the safety of CBD.
„Many of the compound’s expansive benefits are fanciful, and in fact, the sale of much of the product is illegal under current law,” Gottlieb said. In a subsequent CNBC interview, he went a step further saying: „Right now, all of this CBD is illegal that’s being put in food and dietary supplements.”
Easier to Buy on the Streets
Under the 2018 Farm Bill, hemp is no longer a controlled substance but is still subject to rules from the FDA and US Drug Enforcement Agency (DEA). Marijuana remains a schedule 1 drug. Although marijuana is available in many states for recreational use, researchers seeking to use it for clinical trials have to go through a series of regulatory hoops, including obtaining a schedule 1 license. The DEA also requires that all marijuana used for federally sponsored research be grown on the cannabis farm at the University of Mississippi run by the National Institute on Drug Abuse (NIDA).
„For universities like Colorado or California that have federal funding, they cannot afford to violate the federal law, so they can only get their materials from NIDA. That’s been the rub,” said Larry Walker, PhD, director emeritus of the National Center for Natural Products Research at Ole' Miss.
„All the researchers are mad about it and I don’t blame them,” Walker said. „We’re mad about it too. Even we, who grow the stuff for NIDA, we can’t use it in a research study unless we apply with schedule 1 license and all those things that any other university has to do.”
Things are beginning to relax, however, with the DEA signaling it will change its policy to allow other marijuana growers, Walker said. „They haven’t done it yet, but they said they’re going to.”
Researchers and cannabis producers are also looking to alternative sources for cannabinoids. Researchers at the University of California, Berkeley reported earlier this year that they had bioengineered yeast strains to produce THC and CBD and that the approach could produce naturally occurring and brand-new cannabinoids.
In the meantime, CU Boulder, which receives more than $300 million each year in federal grants, has created a workaround in the form of two mobile laboratories, dubbed the „CannaVan.” The vans don’t dispense cannabis products but allow researchers to collect blood immediately before and after people use cannabis in their own homes. Two ongoing studies are looking at potential risks associated with high-potency cannabis and the impact of cannabis use in patients with chronic pain and anxiety.
„Obviously, one small government-run facility can’t really keep up with a $20 billion industry,” CU’s Hutchinson said. „A lot of older adults use edibles. Well what is the impact of that when you take it orally on different systems? You’d never know that using the government-provided cannabis. From a public health perspective, it’s very important to study the products people are actually using.”
Hutchinson and colleagues published genomic research showing that federally grown cannabis strains are limited in terms of cannabinoid diversity and average about 5% THC content, but those sold recreationally in Denver and Seattle are closer to 20%.
Jawahar Mehta, MD, PhD, the Stebbins Chair in Cardiology at the University of Arkansas for Medical Sciences, Little Rock, said the current CBD craze is reminiscent of the early days of cigarette ads touting only the benefits of smoking.
„There are hardly any studies of CBD in patients with heart disease, but when I did a web search today, there are hundreds of sites saying what a wonderful thing it is — absolutely apple pie,” he said.
Unfortunately, he added, older adults with heart conditions and other comorbidities are the ones who are actually looking for these „so-called food supplements” that they can buy over the counter. And they face a higher risk for drug–drug interactions given the increasing number of medications, vitamins, and supplements they take.
„We don’t have any controlled studies to say if it’s good or bad,” but „I’m a very scientifically based person and I tell my patients, 'please don’t take anything unless it is regulated',” Mehta said.
Hutchinson said it’s logical for people to turn to their physician for answers, but often „they shrug their shoulders and say, 'I have no idea what to tell you. We definitely need some common pieces of information.”
To fill this gap for consumers, bud-tenders, and physicians alike, CU teamed up with a global online learning platform to offer a first-of-a-kind four-part educational series: Medical Cannabis: Health Effects of THC and CBD . Some content can be audited for free; a certificate of completion requires a $49 subscription. Launched in June, early demographics show older adults are among its biggest users, according to Hutchinson, who wants at some point to offer a condensed version for continuing medical education.
CBD Grayslake owner Camp said half of his customers know what they want, but others are looking for information. A colorful infographic, pulled from the Internet and resting on the counter, lists 18 purported benefits, including „reduces risk of artery blockage,” „inhibits cancer cell growth,” and „reduces blood sugar levels.”
„A majority try to do Internet research and then they see different stories and then their mind’s all torn apart because they don’t know which one to believe, so they come in and ask for information,” he said. „Some questions I obviously can’t answer, but I can tell them about my products.”
Cooper reports research funding from Insysis and serving on the scientific advisory board for FSD Pharma. Hutchinson, Walker, and Mehta report no relevant conflicts of interest.