What the Scheduling of Kratom by the DEA Means for Research

The DEA's plan to list kratom as a Schedule I controlled substance would make researching the possible opioid substitute much more difficult.

At the end of August 2016, the Drug Enforcement Administration (DEA) announced its intent to place the active components of kratom into Schedule I of the Controlled Substances Act, due to 15 known deaths related to kratom between 2014 and 2016, as well as its “high potential for abuse,” and lack of an “accepted medical use… in the United States.”

However, due to a widespread outcry, including a letter to the DEA from 51 members of Congress, questioning the decision and a lack of opportunity for public comment, the DEA is placing a hold on this decision.

The status moving forward is uncertain, as the DEA has not issued a public statement, but it is hoped the organization will seek out input from the public before reaching a decision. The original intent to place kratom in the Schedule I category was invoked using a rarely used emergency power that states the DEA need only issue a 30 day notice.

“The DEA’s decision to place kratom as a Schedule I substance will put a halt on federally funded research and innovation surrounding the treatment of individuals suffering from opioid and other addictions,” the members of Congress wrote in their letter to Charles P. Rosenberg, the Acting Administrator of the DEA, and to the director of the White House Office of Management and Budget.

“This significant regulatory action was done without any opportunity for public comment from researchers, consumers and other stakeholders… This hasty decision could have serious effects on consumer access and choice of an internationally recognized herbal supplement.”

Some kava bar owners as well as the American Kratom Association (AKA), an organization of kratom consumers which receives some of its funding from kratom vendors, are taking action against the proposed scheduling of kratom, questioning the DEA’s hasty decision and the quality of the research on which their decision is based.

David Fox and Lynn Mehler, partners in the Los Angeles-based law firm of Hogan Lovells, wrote a letter to the DEA stating, “AKA takes very seriously DEA’s concern that approximately 30 reports of fatalities have been linked to consumers who had ingested or possessed a kratom product. However, a close examination of these reports shows that there are no instances in which kratom itself was determined to be responsible for the cause of death[…] There is good reason to question whether these reports indeed represent a valid or meaningful signal with respect to kratom. Close review of the totality of evidence points clearly in the other direction, namely, that kratom is well tolerated and relatively mild in its effects.”

Impeding Research Opportunities?

Kratom comes from a tree in southeast Asia, the Mitrargyna speciosa korth. Its active ingredients, the opioids mitragynine and 7-hydroxymitragynine, make it a popular alternative to opioids for treating pain and for easing opioid withdrawal.

Given the opioid epidemic in the United States, researchers are hoping to find treatments for pain that are nonaddictive.

Compounds derived from the active ingredients in kratom look promising: recent research published in the Journal of Medicinal Chemistry, conducted by Susruta Majumdar, PhD, assistant attending chemist at the Memorial Sloan Kettering Cancer Center and colleagues, found that mitragynine pseudoindoxyl, a semi-synthetic opioid derived from mitragynine, one of the active ingredients in Kratom, appeared to more effectively relieve pain in mice, compared with morphine, without many of the dangers and unpleasant adverse effects caused by opioids.1

“In vitro, mitragynine pseudoindoxyl and its analogs were potent agonists in [35S] GTPγS assays at the µ-opioid receptor but failed to recruit β-arrestin-2, which is associated with opioid side effects,” the authors wrote.

“Additionally, mitragynine pseudoindoxyl developed analgesic tolerance more slowly than morphine, showed limited physical dependence, respiratory depression, constipation, and displayed no reward or aversion in Conditioned Place Preference assays, suggesting that analogs might represent a promising new generation of novel pain relievers,” they added.

Placing kratom in Schedule I of the Controlled Substances Act would impede its acquisition for research purposes forcing online kratom vendors to shut down. Researchers would have no efficient way to acquire mitragynine to produce mitragynine pseudoindoxyl, which can take as long as 5 years to create in the lab in the absence of the plant.

This seems to create a conundrum: one of the reasons the DEA cites for banning kratom is a lack of evidence for its medical use. However, if kratom is banned and becomes significantly more difficult to acquire for research, its interest for clinic use may not be demonstrated.

A similar situation exists with marijuana,  also a Schedule I drug with medical potential, difficult to acquire for research purposes.

As recently as August 11, the DEA rejected 2 petitions to downgrade marijuana scheduling, which would have allowed researchers to acquire it more easily. Unfortunately, much of the issue may lie with the Controlled Substances Act itself, which has no category for substances considered too dangerous to leave unregulated, but that may have medical potential if researched.

A categorization of kratom in Schedule I by the DEA would last for 2 years, with an option to extend it to 3, while the DEA and US Food and Drug Administration examine whether kratom has an accepted medical use and decide whether to make the Schedule I categorization permanent.

With kratom in Schedule I, researchers would have to apply for a Schedule I research license and hope that the DEA would be able to supply enough quality kratom to all of those hoping to study it, although it is unclear how they would do so.

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  1. Váradi A, Marrone GF, Palmer TC, et al. Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2. J Med Chem. 2016;59(18):8381-8397. doi:10.1021/acs.jmedchem.6b00748.