DEA ban puts damper on research into kratom’s painkilling effects

The Drug Enforcement Administration (DEA) has announced it will temporarily list two compounds that occur naturally in the leaves of a Southeast Asian tree as Schedule I substances, effective Sept. 30.

The new classification not only bans the alkaloid compounds—mitragynine and 7-hydroxymitragynine—but also constitutes a de facto ban on the plant, known colloquially as kratom (pronounced kra-tum) and scientifically as Mitragyna speciosa. Assigning the alkaloids to the most restrictive category of the U.S. Controlled Substances Act was deemed “necessary to avoid an imminent hazard to the public safety,” according to an Aug. 31 Federal Register notice by DEA acting administrator Chuck Rosenberg.

People across the globe self-treat with kratom for chronic pain, alcohol and opioid dependence, and anxiety. Others report taking concentrated kratom extracts to induce euphoria.

These largely anecdotal uses owe to the alkaloids’ effects on opioid receptors in the body. For instance, over the summer, a team led by Dalibor Sames and Andrew C. Kruegel of Columbia University published a paper in the Journal of the American Chemical Society showing that mitragynine and 7-hydroxymitragynine bind to and partially activate human µ-opioid receptors, the same receptors fully triggered by morphine (DOI: 10.1021/jacs.6b00360).

Beyond their abuse potential, Schedule I drugs are defined as those that have no currently accepted medical use in the U.S. and lack acceptable safety for use under medical supervision. Current Schedule I substances include LSD and marijuana.

DEA cited “numerous reports” of adverse reactions and deaths from kratom. But in the published reports where mitragynine was detected in postmortem blood, other drugs were present that could have contributed to the deaths, such as O-desmethyltramadol and benzodiazepines.

Kratom advocacy groups have criticized DEA’s rationale for the new classification. In a survey of an online drug buyer’s forum, University of Massachusetts emergency physician Edward W. Boyer found that 42% of kratom discussion threads mentioned purchase and use of kratom for medical purposes.

Meanwhile, research continues on kratom—at least for the moment. Susruta Majumdar’s group at Memorial Sloan Kettering Cancer Center recently showed that the compound mitragynine pseudoindoxyl, generated by fermenting mitragynine, is an even more potent activator of µ-opioid receptors than mitragynine and 7-hydroxymitragynine (J. Med. Chem. 2016, DOI: 10.1021/acs.jmedchem.6b00748). Mice treated with a typical painkilling dose of mitragynine pseudoindoxyl experienced little respiratory depression, a common side effect of opioids such as morphine. Mitragynine pseudoindoxyl is not included in DEA’s ban.

Stressing that these studies were in mice and that “mice are not humans,” Majumdar does not oversell the findings. “But we are certainly seeing early therapeutic promise” for the plant compounds and for mitragynine pseudoindoxyl, a derivative that can be created semisynthetically.

The DEA ban comes just as significant progress is being made toward the necessary human trials. Majumdar, Sames, and Kruegel all expressed strong concerns that further research will be stalled. Even with a DEA Schedule I research license, researchers are hindered by restricted importation of raw plant material.

“Placing these compounds into Schedule I will erect an enormous barrier to scientific research in this field and will dramatically curtail our work with this exciting plant,” Kruegel says.

This article has been translated into Chinese and Spanish

To see all of C&EN’s articles that have been translated into Chinese, visit http://cen.acs.org/cn.html.