Endocanna Health Aims to Flag Cannabinoid Safety Risks With DNA Test

NEW YORK – When Len May was diagnosed with attention-deficit hyperactivity disorder as a child, he took prescription medications that seemed to improve his focus in class but also left him feeling dull.

Then, as a teenager, May tried cannabis recreationally, and "the windows in my head narrowed," he recalled feeling. He could focus while on cannabis, and his senses were also intact.

His own experiences spurred him to become an activist pushing to legalize cannabis and begin exploring the medicinal properties of cannabinoids. In December 2017, as a growing number of US states began to legalize cannabis to treat conditions like glaucoma — one of the most common conditions that qualify patients for medical cannabis — May launched Endocanna Health, seeking to apply genetics to inform cannabinoid use.

The company markets its EndoDNA test directly to customers, which it claims can help people identify cannabinoid formulations and ratios of CBD to THC that they're likely to experience side effects from when taken alone or with other drugs.

Endocanna, located in Burbank, California, defines cannabinoid therapies as products that stimulate or target the endocannabinoid system, or the network of neurotransmitters and receptors that bind to cannabinoids once they're in the body. The endocannabinoid system can impact various bodily functions including memory, mood, and sleep.

"It's a great idea," said Bernard Le Foll, a clinician scientist and head of the Campbell Family Mental Health Research Institute's Translational Addiction Research Laboratory at the Centre for Addiction and Mental Health in Canada, who has studied the effects of cannabis. "We know that not all people react the same way to cannabis. … It's quite possible that part of the variability in the response is driven by genetic factors."

While Le Foll felt Endocanna is pursuing an interesting approach to cannabinoids, he stressed that there's been relatively little research deeply exploring and validating the links between people's genetic factors and their varying responses to cannabinoid formulations and products. Moreover, in the medical community, there still isn't widespread consensus that cannabinoids benefit patients across different conditions.

A meta-analysis of studies published between 1980 and 2018, in which patients with a variety of mental health disorders reported use of cannabinoids, found "scarce evidence" suggesting that cannabinoids improve symptoms of depression, anxiety, and attention-deficit hyperactivity disorders, Tourette syndrome, post-traumatic stress disorder, or psychosis. Likewise, the International Association for the Study of Pain cited a lack of evidence as the reason why it could not endorse cannabinoids to treat pain in a 2021 statement.

"I do not really believe that, at this point in time, we have information to develop those types of tailored choices based on a genetic profile," Le Foll said. "It would require more validation in my view to be able to really assist people using those types of tools."

Still, Heritage Cannabis, a Canadian producer of medical and recreational products, acquired a 30 percent stake in Endocanna for $3 million in 2019. Endocanna is now in the midst of a Series B funding round, through which it hopes to raise $5 million, with cannabis-focused private equity firm Merida Capital Holdings as the lead investor in the round.

Early entry into an emerging field

Endocanna Health is an early entrant in the emerging DNA testing market for personalizing cannabinoids, a market that is growing as more US states have decriminalized medical and recreational cannabis use.

That market will become "a crowded field," suggested Howard McLeod, an expert in precision medicine and pharmacogenomics and director of the Center for Precision Medicine & Functional Genomics at Utah Tech University. And early entrants typically shoulder a lot of the scientific skepticism and questions over product readiness, McLeod added.

Endocanna's $199 direct-to-consumer EndoDNA test involves collecting customers' cheek swab sample via an at-home kit and analyzing the sample within its CLIA-certified and College of American Pathologists-accredited lab for around 672,000 SNPs associated with the endocannabinoid system and cannabinoid metabolism. Alternatively, customers can upload the raw data from tests performed by other companies like Ancestry and 23andMe, which Endocanna then analyzes for the same SNPs for $49.95. Neither service is covered by insurers, and customers pay out of pocket.

After this analysis, Endocanna provides customers with a report identifying genetic factors that might predispose them to having side effects from specific cannabinoid formulations. The report can also help customers understand how certain cannabinoids might affect symptoms they're seeking to address and includes recommended doses based on genetic variants linked to enzymes that metabolize cannabinoids, like CYP2C9, CYP2C19, and CYP3A4. Endocanna cites peer-reviewed studies to support each genetic association it reports to patients. Customers also receive a medication management report, through which they can learn about medications that may interact negatively with THC or CBD.

The company offers customers access to a personalized dashboard on its website, through which they can see the products commercially available in their geographic area that they match to based on their genetic profile. Licensed businesses can have products added to Endocanna's marketplace by providing a third-party certificate of analysis for the products, so that strains and ratios of CBD to THC can be matched to customers' results.

Endocanna doesn't sell cannabinoid products through its website; customers must click through to the retailer's website. Endocanna does, however, have patents pending for seven cannabinoid product formulations for common doses and ratios it's seen among customers, which it licenses to other companies.

Endocanna competes with a few other firms like Strain Genie and Lobo Genetics, which also claim to be able to match customers to cannabinoid products based on DNA analysis. McLeod said the existence of these companies is a step toward normalizing medical use of cannabinoids, though more research is needed. He has seen cannabinoids alleviate cancer patients' pain or nausea, but he said that most physicians haven't yet decided whether it is appropriate to give these types of therapies to patients.

Much of the research linking cannabinoids to either adverse or beneficial effects is preliminary, and to strengthen it, the results will need to be replicated in larger populations, McLeod said. Conducting that research is challenging in the US, he noted, since cannabis use is still illegal at the federal level.

"Studies I would love to have seen will have to be done, in the short-term, in Canada or in parts of Europe because of those limitations," he said. Even among US states that have decriminalized it, each state has its own approach for how medical and recreational cannabis is regulated, so there isn't consistency in what type of uses or formulations of cannabis are allowed.

In the US, cannabis is currently classified as a schedule I substance under the Controlled Substances Act, meaning it has no accepted medical use — conflicting with many state laws. The US Drug Enforcement Administration's five-scale classification framework ranges from schedule I substances that have a high potential for abuse to schedule V substances representing those with the lowest potential for abuse.

In a letter first reported by Bloomberg, a top US Department of Health & Human Services official this week wrote to the DEA recommending it ease restrictions on cannabis and reclassify it as a schedule III substance with a moderate-to-low potential for dependence, which can be legally obtained with certain prescriptions. Ketamine, for example, is a schedule III drug. The HHS recommendation, if taken by the DEA, would stop short of legalizing cannabis federally.

The acceptance of cannabinoid products among physicians is also impacted by the fact that the US Food and Drug Administration has not approved cannabis for any medical uses. In 2018, the FDA approved Epidiolex (cannabidiol), which is the first and only cannabis-derived prescription drug to gain the agency's market authorization. Epidiolex is indicated for patients with certain rare disorders that cause seizures including Lennox-Gastaut and Dravet syndromes.

Endocanna's customers are primarily people dealing with pain, anxiety, and sleep issues, among other symptoms, as well as some healthcare providers treating such patients — a customer base that May hopes to tap into more as the company grows. He sees opportunities to expand the company's customer base among pain management specialists and orthopedic surgeons looking for alternate strategies to manage patients, especially individuals genetically predisposed to opioid dependence. Doctors ordering Endocanna's tests for their patients can access results through a physician portal.

Endocanna doesn't believe its EndoDNA test provides patients with any information that would require the FDA's approval or clearance. Additionally, May emphasized that the company doesn't identify products that will work best for customers; rather, it aims to help users avoid products that carry a risk of possible adverse reactions.

Building evidence

Michelle Weiner, director of integrative pain management at Spine and Wellness Centers of America in Florida, has ordered the EndoDNA test for some of her patients and found the test results helped those who have tried various pain management approaches, including cannabis, but haven't benefited as expected.

"The goal really is precision medicine," said Weiner, who is also a scientific adviser to Endocanna. Knowing how patients are likely to metabolize cannabinoids can help her figure out how to use the smallest dose of cannabis possible to control their pain, without unnecessarily increasing the dose if they don't respond.

Weiner, who originally wanted to learn about cannabis and its potential to decrease use of opioids in pain management, said she sees Endocanna's reports as an extension of other pharmacogenetic testing she already orders for patients. "The more knowledge we have, the better we can direct [care for] the patient," she said.

In a study published in JAMA Network Open earlier this year, researchers reported that most patients who lived in states that allowed medical cannabis and had used it for pain management, said they were substituting cannabis in place of other medications including opioids. The study authors cautioned that the high prevalence of patients swapping traditional drugs for cannabis "despite knowledge gaps" spotlights the need for additional research "to clarify the effectiveness and potential adverse consequences of cannabis for chronic pain."

Mark Bicket, an assistant professor of anesthesiology at the University of Michigan School of Medicine, and the first author on the paper, said he's seeing patients increasingly interested in discussing cannabis. At the hospital system's pain clinic, where Bicket sees patients once a week, he has noticed an uptick in patients who report either taking a cannabis product for chronic pain or who are curious about doing so. Some patients have benefited, while others have reported side effects, and Bicket acknowledged it is difficult to know how a patient might respond.

"It's a bit challenging in terms of trying to help guide patients with our current state of evidence," said Bicket, who has not used Endocanna's DNA test. He noted that the medical field is in the "beginning stages" of understanding how cannabis might fit into pain management. "Some of the high-quality evidence that I can share with patients is pretty limited, because of how varied someone's experience when it comes to using cannabis can be."

That's not only because of genetic variations but also due to how concentrations and formulations vary between products. He said he would be interested in seeing outcomes data on how patients who followed Endocanna's test recommendations fared.

According to May, Endocanna is surveying customers on their experiences using cannabis products based on its test using clinical screening tools, such as PEG-3 for measuring pain and GAD-7 for gauging anxiety. The company receives a baseline assessment on such measurements from customers, and Endocanna follows up with them monthly via email and text message to track changes in those scores over time.

May highlighted that he coauthored a paper published in Cannabis and Cannabinoid Research last year, in which investigators analyzed possible genetic mutations associated with cannabinoid hyperemesis syndrome, a rare condition in which frequent cannabis users suffer from vomiting and nausea. The company is also involved in five clinical trials, in which researchers in the US, Canada, and other countries are using the EndoDNA test to better understand people's responses to cannabinoids.

In one study, for example, investigators will evaluate the effect of CBD for patients with anxiety and assess genetic factors that might be linked to symptom improvements. In another study, investigators will study possible genetic mutations underpinning variation in how patients with pancreatic cancer respond to cannabinoids for treating pain.

The data from these studies, once published, may make physicians more confident about Endocanna's test and improve their understanding of the benefits and risks of cannabis medicinal products. "I'm enthusiastic about the principle," McLeod said. "Like all of genetics, as the field matures, the science is going to get better and better."