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Natural Products

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

Schedule I listing may stall testing of plant’s natural compounds and derivatives

by David Kroll, special to C&EN
September 8, 2016 | APPEARED IN VOLUME 94, ISSUE 36

Credit: David Becker/ ZUMA Press/Splash News/Newscom
Credit: David Becker/ ZUMA Press/Splash News/Newscom
DEA’s ban will stop kratom from being sold at herb shops such as this one.

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



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Andras Varadi (September 9, 2016 1:37 PM)
As one of the lead authors on this manuscript (J. Med. Chem. 2016, DOI: 10.1021/acs.jmedchem.6b00748), I would like to point out that mitragynine pseudoindoxyl, unlike morphine, did not show reward (addiction) in the conditioned place preference model in mice. We also observed that upon chronic dosing, it took mice 30 days to become tolerant to mitragynine pseudoindoxyl – that is approximately 6-times longer than it took to develop tolerance to morphine under the same conditions. And when mice finally became tolerant, we observed only mild withdrawal after giving a dose of the opioid antagonist naloxone.

We believe the advantageous side effect profile of mitragynine pseudoindoxyl may be the result of the unique pharmacological attributes of the molecule. Firstly, it is an agonist on mu opioid receptors (very much like most of the opioids used in clinical practice) but at the same time, it antagonizes delta receptors. Secondly, mitragynine pseudoindoxyl acts as a G-protein biased agonist on mu receptors, recruiting no beta-arrestin-2 upon activation. Mu agonism/delta antagonism and G-protein bias have been shown to reduce the severity of opioid side effects, however, mitragynine pseudoindoxyl is the first compound known to exhibit the combination of these two effects.
anon (September 13, 2016 9:49 AM)
Thanks for sharing
Gary Parillo (September 9, 2016 4:21 PM)
I am a 63 year old disabled man who is in constant and chronic pain.I started making kratom tea 3 years ago.I have found kratom not only beneficial in pain control,but it has also reduced my need for any increase in pharmaceutical pain medicine.I have been able to keep other treatment to an absolute minimum.I have found this herb to be safe and with very little to no side effects.With Kratom there is also a mild lifting of depression and alleviation of anxiety but without any high or psychoactive distortions.Kratom has enabled me to go outside several times a day and sit up and even take short painfree walks with my cane or walker.Banning this effective and safe herb will cause immense harm to many and is totally unnecessary,as kratom is virtually non addictive and impossible to overdose on.In higher amounts the most problem it will cause is some nausea and desire to sleep.Since higher amounts are not pleasant I honestly can see little to no abuse potential.I would urge the authorities to please reconsider this ban and take into account that by doing this you will be responsible for doing far more harm than good to millions of responsible and good people.
Vince (September 9, 2016 10:21 PM)
Don't you love it when the government limits your freedom for your own good?
(September 13, 2016 5:42 PM)
I dont take opioids after 15yrs.l use cannabis I have never related to somthing so well and I am opioid free 4ever.
Erik (September 20, 2016 11:15 AM)
the Big Pharma Cartel doesn't like competition! Of course they go after natural plants and throw people in jail and wreck their life if we DARE to not use their prescription garbage.

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