Nearly 100 deaths in the United States involved kratom, the Centers for Disease Control and Prevention (CDC) revealed last week, highlighting potential concerns over the safety of the botanical.

But the CDC report doesn’t establish kratom actually caused any of the deaths, said C.M. Haddow, senior fellow on public policy with the American Kratom Association (AKA), a nonprofit whose mission is to promote access to the botanical.

Kratom, otherwise known as Mitragyna speciosa, is a tree native to Southeast Asia that is taken as a pill and consumed in various other forms by millions of Americans—including those seeking to wean off opioids.

In an examination of more than 27,000 overdose deaths in 27 states between July 2016 and December 2017, CDC identified 152 decedents who tested positive for kratom. The coroner or medical examiner determined kratom “to be a cause of death (i.e., kratom-involved)” in 91 cases, the health protection agency reported , although CDC noted nearly all of the people tested positive for other substances, such as fentanyl.

Haddow said coroners and medical examiners don’t know the level at which pure kratom is toxic.

“Documentation of postmortem toxicology testing protocols is needed to further clarify the extent to which kratom contributes to fatal overdoses,” CDC concluded.

The report suggested determining the exact causes of the deaths is complicated because nearly all the decedents tested positive for other substances, including heroin, fentanyl—the powerful synthetic opioid—and cocaine.

In seven deaths, the individuals only tested positive for kratom, but CDC couldn't rule out the presence of other substances.

In about 80% of deaths involving kratom, “the decedents had a history of substance misuse, and approximately 90% had no evidence that they were currently receiving medically supervised treatment for pain,” CDC divulged.

Similarly, a recent analysis of 15 deaths in Colorado attributed to kratom revealed virtually all of them were confirmed to involve multiple substances, including analogues of fentanyl—suggesting kratom alone was unlikely the cause of the fatalities.

The findings, published in the New England Journal of Medicine , suggest kratom might contribute to “some dangerous conditions when combined with other drugs,” such as respiratory depression, said Daniel Vigil, M.D., of the Colorado Department of Public Health and Environment (CDPHE), in an interview with Nutrition Business Journal (NBJ). (Editor’s note: Informa plc owns both NBJ and Natural Products INSIDER).

However, it’s unknown what role kratom played in the deaths, and Vigil said it’s possible kratom didn’t contribute at all to the fatalities. The Colorado health official agreed more research is needed to study kratom’s potential adverse effects.

FDA previously disclosed in 2018 the use of kratom was associated with 44 deaths. But the deaths involved products intentionally adulterated with other dangerous substances and other factors, Haddow said. For example, one person died in a homicide due to a gunshot wound to the chest, Jane Babin, Ph.D., wrote in a white paper the AKA released in August 2018.

In reporting the 44 deaths associated with kratom over a nine-year period, FDA failed to “independently verify or perform any due diligence on the death reports, and worse, FDA’s own documents indicate that every reported case involved other factors,” Babin proclaimed.

On its website , the National Institute on Drug Abuse (NIDA) noted many of the deaths reported by FDA appeared to have stemmed from adulterated products or taking the botanical with other powerful substances, such as alcohol, illegal drugs and opioids. The government institute also cited reports of kratom packaged as dietary supplements or dietary ingredients but spiked with other compounds that caused fatalities.

Haddow said “bad actors” are spiking kratom to enhance its effects.

“What you have is a dietary ingredient and herbal supplement that is popular that is being used by these bad actors,” he said in a phone interview. “That’s why you are seeing these kratom-involved deaths.”

FDA has expressed repeated concerns that kratom presents health risks to consumers and could dissuade opioid addicts from seeking conventional medical treatment and obtaining drugs proven to be effective and safe.

FDA in early 2018 determined the compounds in kratom share structural similarities with controlled opioids such as morphine derivatives. Using a computational model developed by FDA scientists, the agency found two of the most prevalent compounds in kratom—including mitragynine, which researchers have described as kratom’s primary active constituent—activate opioid receptors.

Several months later, the agency announced sending warning letters to kratom vendors for making claims to “relieve opium withdrawals” and treat various other ailments, including alcoholism, depression and diabetes.

FDA’s then-Commissioner, Scott Gottlieb, M.D., said his agency was hardly alone in its concerns over what he described as “opioids found in kratom.” A number of states and municipalities in the U.S. have banned the substance, and kratom is illegal or controlled in several other countries, including Australia, Denmark, Germany, Malaysia and Thailand, he noted.

Adding to FDA’s concerns: Recent laboratory testing of 30 different kratom products from various sources in which the agency identified “significant levels of lead and nickel at concentrations that exceed safe exposure for oral daily drug intake.”

“Based on these test results,” FDA concluded, “the typical long-term kratom user could potentially develop heavy metal poisoning, which could include nervous system or kidney damage, anemia, high blood pressure and/or increased risk of certain cancers.”

DEA is considering whether to regulate kratom as a controlled substance in response to a recommendation from FDA. In a letter to DEA partially obtained by the media company STAT, HHS recommended mitragynine and 7-OH-mitragynine be permanently controlled in Schedule I of the Controlled Substances Act (CSA).

“Individuals are taking the substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community,” the letter proclaimed.

Advocates of the botanical maintain a U.S. ban on kratom could exacerbate the nation’s opioid crisis by depriving consumers of a safe alternative to addictive and dangerous drugs.

In September 2018, the AKA requested the Department of Health and Human Services (HHS)—of which FDA is a part—recall its scheduling recommendation to DEA. FDA has no “scientific basis” for its claim that kratom is “dangerously addictive,” AKA Chairman Dave Herman said in a letter to HHS. Addressing whether kratom is dangerous, he referenced NIDA’s statements.

“Congress never intended for the Controlled Substances Act … to be used to ban substances that were deliberately adulterated with other toxic or deadly drugs that cause deaths, and nothing in the statute or the legislative history permits this abuse of discretion in the scheduling recommendation initiated by the FDA,” Herman wrote.

There is no deadline for the scheduling process, and it could take years, Barbara Carenno, a DEA spokeswoman, said in a November 2018 email. If DEA ultimately decides to schedule kratom, the agency will publish a notice, and the public will have an opportunity to submit comments during which time kratom would remain unscheduled, she said.