Drug Researchers Raise Concern Over "Misleading" Evidence in Kratom Studies

In the midst of an opioid overdose crisis that claims tens of thousands of lives a year, the United States needs all the help it can get. The plant drug kratom has emerged as a substance that offers hope for some who are living with opioid use disorder and chronic pain conditions.

But amid advocacy from patients touting kratom as a potential solution, medical professionals are raising new questions about its safety and effectiveness. New research in the journal Pharmacotherapy suggests, like other studies before it, that kratom is unsafe. Experts point out shortcomings with the new research, but the same issues permeate the field of kratom research broadly, suggesting a bigger issue: There’s not enough evidence to say whether kratom is either a risk-free panacea or a dangerous drug of abuse.

"Kratom was a thing that kept coming up."

The new study, published in the journal’s July 2019 print issue (and online on May 16), use data from the National Poison Data System and a county medical examiner’s office in New York to conclude that kratom use is increasing — and that it’s unsafe.

While the broad strokes of this research are solid, some note that these data sources can’t tell the whole story. Kratom does not have enough clinical trials behind it to support claims that it is a safe and effective treatment for chronic pain or opioid use disorder. There’s an impasse over kratom that points to the lack of conclusive evidence on either side.

The paper’s corresponding author, William Eggleston, Pharm.D., DABAT, is a clinical assistant professor at the Binghamton University School of Pharmacy and Pharmaceutical Sciences and a clinical toxicologist at SUNY Upstate Medical University. In his clinical work, he’s encountered patients who report a broad range of positive and negative experiences with using kratom to transition off of other opioids. He and his team pursued this study to get a better picture of the substance’s risk profile.

“I’ve done a variety of research on naloxone, and looking for ways to expand community access, and kratom was a thing that kept coming up in my conversations with patients in the hospital, patients in treatment,” Eggleston tells Inverse. “I just wanted to get as much information as possible and be transparent about that information with the public and push for more research,” he adds.

In the study, Eggleston’s team combed through case reports from the United States National Poison Data System from 2011-2018, during which time the number of cases involving kratom increased from 11 a year to 357. Out of these calls, 935 involved patients who reported only taking kratom and no other substances.

Kratom’s Reported Side Effects by Medical Professionals

“The most commonly reported adverse effects were agitation (18.6%), tachycardia (16.9%), drowsiness (13.6%), vomiting (11.2%), and confusion (8.1%),” write Eggleston and his team.

“Severe adverse effects included seizure (6.1%), withdrawal (6.1%), hallucinations (4.8%), respiratory depression (2.8%), coma (2.3%), and cardiac or respiratory arrest (0.6%).”

The Issues With Medical Examiner Reports on Kratom

Meanwhile, the data from the New York county medical examiner’s office reported four deaths in which kratom was a suspected factor, two of which involved only kratom.

The topic of fatal kratom overdoses has been hotly contested. The controversy started with an FDA report in 2018 that listed 44 fatalities, almost all of which included additional substances. Then, in April 2019, the CDC issued its own report on nationwide kratom overdoses.

As Inverse reported at the time, experts questioned the CDC’s 152 “kratom-involved” deaths on the basis that almost all of them involved other substances, including the potent synthetic opioid fentanyl, that are known to be fatal on their own.

That CDC report relied on medical examiner reports, which are subject to a significant amount of human judgment. When it comes to kratom, a substance for which there is no scientifically established fatal dose for humans, medical examiners reports aren’t always reliable as the final say in what caused someone’s death, as HuffPost’s Nick Wing reported in 2018.

Marc Swogger, Ph.D., an associate professor of psychiatry at the University of Rochester Medical Center, tells Inverse that medical examiner reports aren’t very strong pieces of evidence for studying kratom. He wasn’t involved in Eggleston’s study but has studied the individual and societal effects of kratom use.

“Our societal methods for determining cause of death (i.e., often under-funded and unsupervised coroners and medical examiners) are workable but do not produce research-grade data, and may thus be misleading when culled and published in scientific journals,” he says.

Eggleston acknowledges this reality, but he says his team’s research stands on firm ground.

“Whenever you’re going to report out medical examiner data as a piece of a bigger puzzle, you go in knowing the limitations of that data,” he says.

Eggleston also insists that the medical examiner in this case, study co-author Robert Stoppacher, M.D., an associate professor of pathology at SUNY Upstate Medical University in New York, has the proper training in toxicology and pathology to make the call that the two overdose death cases cited in the study involved kratom alone.

C.M. “Mac” Haddow, the senior policy fellow for the American Kratom Association, a kratom lobbying group, tells Inverse that medical examiner reports have been a consistently unreliable source of data used by the FDA to push for a ban on kratom. He cites nine deaths that occurred in Sweden as a result of a kratom product adulterated with a synthetic opioid, which the FDA counted among its 44 case counts.

“Now the truth is — and the FDA has never responded to this — is that all nine of those deaths were the result of a kratom product that was spiked with O-desmethyltramadol,” Haddow says. As a result, he seriously questions the wisdom of repeating the FDA’s case count in the paper. “These 44 deaths don’t have any legitimate muster when it comes to developing public policy off of that data,” he adds.

The Issues With Poison Control Data on Kratom

Swogger reiterates that poison control call reports present significant shortcomings as evidence.

“Similarly, poison control studies represent a very low level of evidence, in that symptoms reported following ingestion may or may not be due to kratom,” he says.

A February paper in Clinical Toxicology showed a rising number of calls to poison control centers for kratom, but as Inverse reported, without knowing how many people are using kratom, it’s impossible to know the likelihood of an adverse event like the ones reported in Eggleston’s study.

“An important new finding would be that the calls to poison control centers from 2017 to 2018 is continuing to rise, but does this indicate that kratom is becoming more risky over time or that more people are using it and the overall risk is still low?” C. Michael White, Pharm.D., a professor of pharmacy practice at the University of Connecticut who studies kratom and was not involved with the study, tells Inverse.

To calculate the relative risk of using kratom, one would have to divide the total number of people who experience adverse events by the total number of people who use kratom. But we have no clear data on how many people in the US use kratom.

“There is no prevalence of use for the US population and, therefore, there is no denominator for which to calculate the risks,” says White. “If one in a million people experienced one of these adverse events, the implications are far different than if it were one in 10,000.”

"To try and base health policy based on a case series like the authors intimate in their study would be wholly foolhardy."

“To try and base health policy based on a case series like the authors intimate in their study would be wholly foolhardy,” he says, but adds a crucial caveat: “It is similarly foolhardy to claim that kratom is safe, an effective pain reliever, or effective for opioid use disorder with only case report data.”

Eggleston recognizes the limitations of his team’s evidence, and says he hopes that his work on the risks of kratom will help people who start using it without an accurate perception of the potential for dependency and withdrawal — side-effects that are not generally as severe as with classic opioids, but which are still clinically significant.

In his hospital work, Eggleston had encountered enough people experiencing either positive results or physical withdrawal symptoms from kratom that he knew it could be helpful, but was also not without its risks. For this reason, he’s hesitant to recommend the substance to anyone without knowing how it compares to existing treatment strategies for chronic pain and opioid use disorder.

“We would like to see randomized controlled trials, looking at kratom, looking at the comparators that are out there, whether that be placebo or whether that be an existing medication-assisted treatment like buprenorphine, like methadone, to see, how does this drug stack up?” he says. “What is the efficacy of it compared to our existing treatment modalities? What is the risk associated with it as compared to our existing treatment modalities?”

7-Hydroxymitragynine Adulteration

In the paper, Eggleston’s team also cites previous research on 7-hydroxymitragynine, one of the two main active alkaloids in kratom. Indeed, 7-HMG has been shown to be perhaps the more concerning of the two main kratom alkaloids — the other being mitragynine — in that its opioid receptor affinity and physical effects are more similar to classic opioids. They correctly note that previous research has shown some kratom products were fortified with 7-HMG, making their potencies unpredictable.

As an unregulated herbal supplement, this is one of the issues that accompanies kratom. In the absence of federal regulation, some state governments have sought to get out ahead of such adulteration, like Utah’s “Kratom Consumer Protection Act,” which requires manufacturers to report to the state agriculture board. The American Kratom Association supported that law, and Haddow says he thinks the FDA could be a powerful force in helping consumers stay safe if it chose to pursue adulterated kratom instead of kratom writ large.

Just as with poison control reports, though, there’s not enough data on the actual prevalence of adulterated kratom products to know what kind of risk it poses.

Moving Toward Stronger Evidence

White argues that while this latest paper on kratom’s safety risks relies on evidence whose strength is limited, so do many of the available studies on kratom’s positive benefits.

“In the hierarchy of evidence, a case report/series is the weakest form of evidence. It is only descriptive, so there are many potential biases and confounders that cannot be accounted for,” he says. “Observational studies are slightly stronger, and controlled clinical trials are stronger than that. What we need are strong registries and clinical trials before we can make informed health policy.”

Haddow points out the irony that case report evidence like Eggleston’s team presents in its paper — as well as the FDA’s own data — is being used by federal regulators to push for further restrictions on kratom but wouldn’t meet the FDA’s standard of evidence for approving a product.

"…They are using the same bad data in order to push for a public ban on kratom."

“If we were to take what they publish, and we were to take it to the FDA as the basis for getting a New Drug Application or a New Dietary Ingredient, they would laugh us out of the room, because it would be data that is not sufficiently documented, yet they are using the same bad data in order to push for a public ban on kratom,” he says.

Eggleston, for his part, recognizes the limitations of this data and hopes that his research will motivate others to initiate more rigorous research, including an FDA application for an Investigational New Drug — a process that could lead to a clinical trial. And, as Inverse previously reported, a team at the University of Florida recently received a $3.5 million federal grant to study kratom and hopes to begin human trials in about five years.

Ultimately, Eggleston seems to be roughly on the same page as some of his critics. He sees the therapeutic potential of kratom but also insists on better evidence for its safety and efficacy.

“If kratom was truly working for patients, I would like to see evidence of that,” he says. “And I think we owe it to people to allow them to go into a situation in an informed way, and the best way to do that is to get data.”