The controversial plant kratom, a drug with opioid-like properties, is directly in the crosshairs of American federal regulators. Because it has some similarities to problematic opioids like oxycodone and fentanyl, multiple government agencies have attempted, with some success, to severely curtail its availability. That’s why it was so unexpected when on Monday the University of Florida announced it had a received a $3.5 million grant from the National Institute on Drug Abuse to research the drug.

The two-year grant, awarded to researchers in the school’s College of Pharmacy, will fund studies on the dozen or so active compounds in the plant, not just mitragynine and 7-hydroxymitragynine, the two that are most commonly studied and most abundant in the plant. The hope is that understanding the various chemical ways in which kratom generates its effects will help both scientists and federal regulators determine whether kratom is safe and effective as a medicine.

“I’m actually happy to know that the National Institutes of Health is supportive of very carefully controlled research studies to generate the data that can then be used to make decisions,” Lance McMahon, Ph.D., a professor of pharmacodynamics at UF’s College of Pharmacy, tells Inverse.

Despite the somewhat inhospitable research climate, McMahon is confident that human trials using kratom could happen within five years.

Kratom is often sold in capsules that contain the dried, powdered leaves of the plant. This particular brand was one of a handful involved in an FDA recall in the spring of 2018 that involved potential Salmonella contamination. Flickr / The U.S. Food and Drug Administration

A Step in the Right Direction

To those in the kratom research community, the NIH’s move may seem surprising, since multiple branches of the federal government have cracked down on kratom in recent years. The Drug Enforcement Agency, for example, told Inverse in November that federal regulators would probably make kratom illegal or at least crack down on it severely; the DEA tried, unsuccessfully, to ban it in 2016. The drug’s opioid-like properties have garnered the ire of the Food and Drug Administration, whose top officials argue kratom has no legitimate medical purpose and have issued several public warnings about certain kratom brands having Salmonella contamination.

But kratom has shown strong potential for helping chronic pain patients and people living with opioid use disorder, who use it as an alternative to prescription or illicit opioids. McMahon is adamant that we need to understand the plant fully in order to make sensible, science-backed regulations.

“This grant, in addition to being focused on those two alkaloids, also is very interested in several of the other alkaloids that have not been discussed,” says McMahon. “They are present in relatively low concentrations, so they often get ignored, but it’s our belief that if we are to understand the plant and human use of the plant, then it’s critical to begin to understand what each of the individual alkaloids in the plant is doing.”

Kratom is a tree that's native to southeast Asia. Wikimedia / Sreejithk2000

More Than Mitragynine

For years, mitragynine and 7-hydroxymitragynine, the two most well-known active alkaloids in kratom, have received the majority of the attention from scientists and regulators. Research has shown that these alkaloids activate the body’s opioid receptors in a way that’s similar to well-known opioids like morphine, heroin, and fentanyl, but without the same kind of respiratory depression that can lead to death from those drugs. In October, a team of researchers identified the lethal dosages of the two alkaloids — in short, they’re extremely high dosages that most kratom tea drinkers would never ingest. But mitragynine and 7-hydroxymitragynine aren’t the only alkaloids present in kratom.

Recent research co-authored by the co-principal investigator on the NIDA project, Chris McCurdy Ph.D., also strongly suggests it’s worth looking into kratom’s other alkaloids. McCurdy, a professor of medicinal chemistry at the UF College of Pharmacy, showed in a Planta Medica paper in November that rats who consumed a kratom tea solution had higher blood levels of mitragynine than the rats who only got the extract, suggesting that the other alkaloids play a role in the way mitragynine is absorbed.

This kind of research can help clarify the contentious messaging and research coming from federal regulators. An FDA-sponsored analysis from February showed that, based on a computer model of how mitragynine and 7-hydroxymitragynine could activate opioid receptors, kratom is an opioid and therefore should be tightly controlled. But critics of the FDA’s analysis suggested that its computer model doesn’t give the full picture of kratom’s safety profile. And McCurdy’s past research has shown that the picture is more complicated than a simple “yes” or “no” answer to the question of whether kratom is an opioid like morphine or fentanyl.

Avoiding Abuse

In addition to studying the various compounds in kratom, the team will investigate whether lab animals respond to kratom in the way they respond to morphine by testing their desire to self-administer kratom. This should shed light on the addictive properties of the drug.

“There’s some evidence my collaborator Dr. McCurdy has published suggesting 7-hydroxymitragynine has greater misuse potential, if you will, or abuse liability, than mitragynine,” says McMahon. The study in question, published in June, showed that rats will self-administer 7-hydroxymitragynine when given the chance, but they won’t self-administer mitragynine. McMahon adds that their team has found some evidence that 7-hydroxymitragynine is only present in leaves once they’ve been heated to dry them, and may not actually exist in kratom leaves on the tree, making the picture even more complicated.

The researchers hope to build on these preliminary understandings of kratom with their research, and perhaps most importantly, they hope their work will lead to human trials in the next half-decade.

"“…there will be major efforts put forward to have those trials initiated within the next five years. So I think that’s going to happen for sure."

“I do believe that there’s great interest in doing controlled human studies with these alkaloids,” says McMahon. “I would anticipate that those experiments are high on the list of priorities for the NIH and the National Institute on Drug Abuse, and I am confident in saying that there will be major efforts put forward to have those trials initiated within the next five years. So I think that’s going to happen for sure.”

Despite FDA Administrator Scott Gottlieb, M.D.’s public comments about kratom that have been criticized as classic anti-drug scare tactics, the researchers are optimistic that the NIH is funding the search for objective information about a drug that federal regulators have seemed all-too-eager to ban in recent years.

“We can all agree that the more qualified individuals there are making these assessments, and the greater agreement there is among different individuals who are making those assessments, the better,” says McMahon.