Kratom Becoming Mainstream?

Your body would never get used to the perfect painkiller, says Susruta Majumdar, a chemist at Memorial Sloan Kettering Cancer Center. So unlike the case with common opioids such as morphine or Oxycontin, you would not need to take ever-increasing doses to relieve the same amount of pain. The ideal analgesic would not have the high risk of addiction, withdrawal or fatal respiratory slowdowns that have turned opioid abuse into a massive epidemic. The holy grail of painkillers would not induce the seductive euphoria of common opioids or their less-pleasant side effects like itching or constipation.

A painkiller with just one of these properties would be great, but Majumdar thinks he has stumbled onto a class of chemicals that might have them all. They are found in kratom, a plant that the U.S. Drug Enforcement Administration intends to effectively ban from the U.S. in an emergency move as early as September 30. Without legal access to it, research on some of the most promising leads for a better painkiller may grind to a crawl.

Kratom comes from the Mytragyna Speciosa  tree native to parts of Southeast Asia, where people chew the leaves for a light, caffeine-like jolt of energy or as a traditional medicine for ailments ranging from diarrhea to pain.

Majumdar first learned about kratom via a Web search a couple of years ago. By then there were stories in the West about how kratom tea could be used to manage pain—and to mitigate brutal opioid withdrawal. That caught Majmundar’s attention, and he found research from the 1970s that described some of the basic biochemistry of kratom’s two primary psychoactive compounds, mitragynine and 7-hydroxymitragynine, as well as one more molecule called mitragynine pseudoindoxyl, which is produced when kratom ferments.

“We got excited because the chemical structure is almost completely unrelated to that of commonly used opioids,” says Andras Varadi, a colleague of Majumdar who is a medicinal chemist at Columbia University and Sloan Kettering.

When Majumdar and his team started studying the compounds in the laboratory, they realized all three molecules were binding to the mu-opioid receptor—one of three known kinds of opioid receptors in the brain—in an unconventional way. Think of this receptor as the ignition to a “hybrid car,” Varadi explains, and the opioids that bind to it as keys.

A typical opioid such as morphine turns on the “electric engine,” and that leads to a desired effect like pain relief. But it also starts up the “gas engine,” causing negative side effects. The mitragynine molecules from kratom seem to activate mostly the “good” systems, leaving behind the unwanted effects yet keeping pain relief. Scientists have been trying to develop next-generation drugs with this property. There is one candidate, pharmaceutical company Trevena’s TRV130, in clinical trials now. That’s part of what makes kratom exciting to researchers, says Laura Bohn, a biochemist at the Scripps Research Institute who was not involved with this work. “The more chemical structures you have [with this property] the more you can say, ‘here’s the right features of these, and let’s impart that into our drug development.’”

Majumdar noticed that the fermented-kratom compound mitragynine pseudoindoxyl—unlike most other drugs in development—also blocks off another opioid receptor, the delta receptor. “That’s when we got excited,” Majumdar says. Past experiments have shown that delta receptor blockers could reduce morphine tolerance and withdrawal symptoms in mice. “There were signs that delta antagonism is good,” Majumdar says. And if mitragynine pseudoindoxyl could both block the delta receptor and produce favorable behavior on the mu receptor, Majumdar says it might be better than any other pain drug science is currently investigating.

In an attempt to find out about these blocking capabilities Varadi injected mice with mitragynine pseudoindoxyl twice a day for a month. Then he checked if they could feel pain, using techniques such as putting them on a hot plate. In such experiments morphine usually loses its painkilling effects after five days. But after 30 days on a consistent dose of mitragynine pseudoindoxyl, the mice still showed numbness to pain.

“It was the most exciting experiment I’ve ever done,” Varadi says. In other experiments Varadi and Majumdar reported that the mice exhibited few withdrawal symptoms from mitragynine pseudoindoxyl—and they displayed no indication that they actually enjoyed taking the drug. “[This is] early promise it’s nonaddictive,” Majumdar says. His team reported its findings in The Journal of Medicinal Chemistry last month.

Varadi says his results indicate that mitragynine pseudoindoxyl may have the peculiar ability to both activate the mu receptor—possibly making it a powerful painkiller that also reduces addictive and potentially deadly side effects—as well as lower withdrawal and tolerance. “It’s a double whammy,” Varadi says.

Although the kratom compounds have yet to be clinically studied in humans, Andrew Kruegel, a pharmacologist at Columbia who was not involved in Varadi’s study, says the results hold promise for better designer painkillers.

“Those compounds alone may already be superior to codeine and oxycodone. At a minimum, if you can get rid of respiratory [problems] then you can save thousands of lives,” Kruegel says. “But we can tweak their properties to make them even better than the natural starting point.” Or they would do so if the research were able to legally continue, he adds.
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