In November of 2017, scientists at a subsidiary of Artelo Biosciences in Manchester, U.K., tasked an intern with compiling any scientific study published on the body’s absorption, distribution and metabolism of cannabidiol. The company hoped to treat stroke with the compound, which is derived from the cannabis plant and commonly known as CBD, and this background research was crucial.
When the intern returned with all the literature she could find, it was a short stack: only a couple of dozen papers. The scientists were stunned. They’d expected more from a molecule receiving so much attention from the biomedical world and consumers. As they surveyed the scant literature, they wondered: is this all there is?
The desire for more information about how CBD acts in the body is growing as various companies pursue it in drug development. It’s only in the last decade that the first CBD drugs have been approved: Sativex for multiple sclerosis symptoms, in multiple countries; and Epidiolex for certain kinds of epilepsy in children, in the U.S. GW Pharmaceuticals, the maker of both medications, expects European Union approval for Epidiolex soon. Beyond that, there are dozens of ongoing clinical trials for conditions ranging from schizophrenia to Crohn’s disease to graft-versus-host disease—not to mention the appearance of CBD in consumer products ranging from oils to coffee to tampons.
“CBD is exploding in popularity,” says Nick Jikomes, a neuroscientist and principal research scientist at the cannabis information site Leafly, in Seattle. “It seems that every corner store you walk into is selling a CBD something or other.” In the U.S. alone, a recent Gallup poll found 14 percent of Americans use CBD products, and the CBD market is projected to top $20 billion per year by 2024, according to one analysis.
CBD could, potentially, treat such a wide variety of conditions because it binds to various receptors in the body, particularly in the endocannabinoid system, which is involved in pain, mood, metabolism, reproduction, and more. These receptors are found in the nervous system, as well as many other tissues, including heart, liver and immune cells. CBD can cause side effects such as nausea, fatigue and irritability, but doesn’t make people feel high.
Considering that people have used cannabis for millennia, scientists still know surprisingly little about how CBD, often the second most prevalent active compound in the plant, is absorbed and metabolized by the body. “Unfortunately,” Jikomes adds, “we don’t have the information we would like to have about dosing."
The U.S. National Academies of Sciences, Engineering and Medicine bemoaned the lack of information to help consumers make smart choices about cannabis products in a 2017 report. The authors recommended more research on the biological actions and transportation within the body of cannabis compounds, as well as the effectiveness of different delivery avenues and dose–response curves in diverse populations. Both CBD’s complex biochemistry and government regulations that restrict cannabis studies, mostly in the U.S., have conspired to slow a detailed understanding of its metabolism.
The fact that cannabis and CBD are readily available in many parts of the world, sometimes legally and sometimes not, and with or without a prescription, has created a unique medical, commercial and legal conundrum, says Arno Hazekamp, a cannabis researcher and consultant in Leiden, the Netherlands. CBD is being tested in uncontrolled home-based experiments even as scientists strive to match defined doses to medical conditions in official trials.
In fact, GW Pharmaceuticals’ early CBD research helped give families of children with epilepsy the idea to try it, with success, well before it was an approved medication. Justin Gover, CEO of the company in Carlsbad, California, says of those families, “They inspired and motivated us.”
Dearth of data
By early 2018, Artelo had decided not to pursue CBD for stroke, but the researchers wanted to share what they’d managed to dig up on the compound. In a review of the literature on CBD processing, collaborators at Artelo and the University of Nottingham, U.K., discussed 24 papers, mostly studies of healthy adults.
According to their literature survey, CBD’s half-life ranged from one hour to five days, depending on the route of administration: delivering the compound by a mouth spray meant it lasted just hours, for example. In contrast, injected and smoked CBD persisted for about a day. One study reported that 31 percent of smoked CBD reached the bloodstream. The fraction that reaches the bloodstream from pills or mouth sprays is thought to be much lower, says Sophie Millar, the intern who had been tasked with the literature search at Artelo two years ago and who is now completing a Ph.D. in the endocannabinoid system at the University of Nottingham.
The team went further in a second article, analyzing the doses used in 35 clinical studies. The papers were a “mixed bag,” notes study co-author Andrew Yates, a consultant at Artelo Biosciences. The conditions under study included anxiety, diabetes, chronic pain and more. Doses ranged from less than 1 to 50 milligrams per kilogram body weight per day, but no study reported CBD plasma concentrations. About two-thirds of the studies reported CBD to be associated with improved outcomes.
“The more successful trials tended to use a higher dose,” Yates says. Lower doses seemed to work for anxiety, though. “More research needs to be done, and it needs to be done in a controlled, pharma-like way,” Yates says.
That’s what companies like Artelo and GW are doing. Since Millar and her colleagues completed their literature searches in August 2018, GW has published more on CBD metabolism in healthy subjects, under various dosing regimens with up to 6,000 milligrams at a time. CBD reached the blood quickly after a single oral dose, hitting its maximum plasma concentration within four or five hours. With twice-daily dosing, the compound reached fairly steady blood levels after two days, though bloodstream CBD did continue to rise over a week. The company concluded that twice-daily treatment provided a steady supply of CBD, with minimal side effects including nausea, headache and sleepiness.
But that doesn’t mean other CBD oils would work similarly. “Those data are specific to Epidiolex and the formulation,” says Gover. “One can’t just read through from Epidiolex data into other CBD formulations.”
The lack of reliable data on dosing means that some clinical trials might fail not because CBD doesn’t help, but because they didn’t use the right amount. Other trials may land on a dose that’s OK, but doesn’t maximize benefit while minimizing side effects.
Many patients aren’t waiting around for more information on dosing. They are eager to try CBD products for many different ailments and going to their physicians for guidance. But in a recent review, physicians noted that many clinicians don’t know how much CBD to prescribe, especially if they venture beyond well-understood indications such as epilepsy and psychosis.
It would help if doctors had formulas to predict a starting dose for a given individual with a particular condition, says Jennifer Martin, a pharmacologist and physician at the University of Newcastle in Australia. For many other medications, such as antibiotics, doctors and pharmacists can enter a patient’s characteristics—such as age, sex or kidney function—into such equations to receive a suggested dosage. This can be particularly helpful if trials haven’t offered up dosing data for every possible patient group, such as people of certain races, Martin says. She is working on such formulas for CBD and THC, another prominent cannabis compound that is responsible for marijuana’s high but also has medical benefits.
When Martin searched the literature for CBD dose-guidance equations for a recent review, she, like Millar, came up short. She couldn’t find even one paper that met her criteria: intravenous dosing and reporting of individual patient bloodstream concentrations. In contrast, 12 studies were available for THC, which has a longer clinical history.
Martin and her colleagues are now collecting the necessary CBD data: they need correlations between plasma concentration and effects, starting with healthy volunteers, as well as those with liver or kidney problems that might alter drug processing. Data from people who use CBD to treat specific conditions would be useful, too.
“It’s a bit scary, really, isn’t it?” Martin says. “There’s not really much evidence to tell us how much better it [CBD] is than other therapies that we’ve currently got, how much better it is than placebo, and also what dose we should use.”
CBD’s behavior makes it tricky to understand. It may bind to different cell receptors in the endocannabinoid system and beyond—including receptors in the serotonin, opioid and dopamine systems. And where it binds depends on the dose, Jikomes says. At different concentrations, “it can essentially behave as a different drug,” he says. So, more isn’t necessarily better. In fact, in one study, antianxiety effects peaked after a 300-milligram dose; 900 milligrams proved less effective.
Another complication: CBD is oil-soluble. The amount of drug absorbed into the bloodstream increases if it’s taken with food or infused into oils. GW reported in its 2018 study that plasma concentrations more than quadrupled when the liquid medicine was taken with a high-fat meal including fried eggs and bacon, compared to the medicine alone. CBD can also be absorbed by the body’s fat stores and released later.
All of this means that the ideal prescription will vary by many factors, including but not limited to sex, weight and medical conditions. In the case of the Sativex mouth spray, new users start with one spritz in the evening and slowly work up to an effective dose, with a maximum of 12 sprays daily. Sativex also contains THC, so patients can feel when they’ve had too much. With Epidiolex, kids start at 5 milligrams per kilogram body weight per day, but can go as high as 20 milligrams if needed to reduce seizures.
Whatever the indication, the best approach is to start with a low dose and raise it slowly over up to two weeks, says Ethan Russo of Vashon, Washington, director of research and development for the International Cannabis and Cannabinoids Institute in Prague.
Another issue is that CBD is a botanical, from a plant that makes more than 100 compounds that come only from cannabis, called cannabinoids, plus other potentially bioactive molecules such as terpenoids. Cannabis extracts available over the counter contain varying amounts of CBD itself, along with other compounds. Indeed, some over-the-counter products, upon testing, turn out to have no CBD at all. Even if some CBD is present, it’s probably not enough to have an effect, says Hazekamp. “People are massively underdosing themselves.”
Even more-standardized products, from pharmaceutical companies or the government, can vary in form and purity. “We’re not dealing with a single molecule, in known amounts, as it would be with standard pharmaceutical agents,” Russo says. That means that aside from the two government-approved medications, doctors cannot necessarily look to clinical trials to find the right dose to prescribe a patient, who might get the product from a different source.
There are some in the scientific community who believe that the myriad chemicals in cannabis extracts might be a good thing. The additional compounds can create a sort of synergy known as the “entourage effect.” In fact, one review found that CBD-rich extracts, compared to purified CBD, worked against epilepsy at lower doses and with fewer side effects. Using such extracts could result in more effective, less expensive medications, Russo suggests. On top of all that, CBD trialists must also consider drug-drug interactions. Like grapefruit juice, CBD can block liver enzymes that break down other drugs.
Despite these myriad challenges, researchers are forging ahead. Some are monitoring people who are already using over-the-counter CBD, from diverse sources and for a variety of ailments, to get a better sense of how much of the compound might work for different conditions. “If you have those data, it doesn’t mean you have proof, but then you can narrow down the combinations of products and diseases that really seem to matter,” Hazekamp says.
Martin notes that after she published her review on the dearth of data on CBD, she received many calls from scientists eager to collect and share the right information.
“I have not believed how much this community has come together to try and fast-track this research,” Martin says.
This article is reproduced with permission and was first published on September 6, 2019.