When the ban came down, McCurdy and the pharmacologist Bonnie Avery, a collaborator who performed the analytical work on the adulteration study and prepared the dosing information for the mice models, were working on developing kratom as a botanical drug. Botanical drugs are a class created by the FDA for drugs consisting of vegetable materials with complex mixtures that can be consumed as powders, tablets, solutions and the like.
“We had to stop everything we were doing because of the pending scheduling,” says McCurdy. “We literally packed up 12 years’ worth of research and shipped it to one of our collaborators that does have a schedule I license, just in case the DEA decided to announce that it was schedule I. We would have had enough material in our possession to be considered as one with intent to distribute, so I didn’t want to be on the illegal list all of a sudden.”
McCurdy’s kratom supplies are currently in the hands of his colleague Scott Hemby, a pharmacologist at High Point University in Highpoint, North Carolina. McCurdy and Avery, who are married, recently relocated to the University of Florida in Gainesville, and are both currently faculty members in its College of Pharmacy.
“He sent me raw material — literally a box full of things,” says Hemby, who has had a schedule I license and worked with controlled substances such as heroin and cocaine for several years. Since receiving the kratom from McCurdy, Hemby has performed a number of experiments with mitragy nine and 7-hydroxymitragynine in rats.
In one self-administration experiment, Hemby and his colleagues trained rats to press a lever to receive intravenous infusions of morphine. Due to the opiate’s euphoria-inducing effects, the rats would continue pressing the lever to receive morphine. After three doses, the researchers replaced the morphine with saline, at which point the mice stopped pressing the lever. When the researchers then replaced the saline with mitragynine or 7-hydroxymitragynine, they noticed something strange.
“The animals really wouldn’t respond if you gave them mitragynine,” says Hemby. “But if we looked at 7-hydroxymitragynine, they would self-administer. So it was interesting that one of these compounds does seem to have some abuse liability and the other one doesn’t, at least in this substitution paradigm.”
A more disconcerting disparity between the two mitragynine compounds appeared when Hemby and his colleagues once again exposed rats that had gone through the same procedure to morphine.
“We gave them access to morphine again, and, interestingly, they increased their morphine intake two- to three-fold after they had a history of 7-hydroxymitragynine,” says Hemby. “Some of the newer imports are being spiked with 7-hydroxy, and that may increase subsequent morphine intake. That’s one of the subsequent concerns that we have … there are a lot of things we just simply don’t know about the mechanism behind what’s going on here.”
A scaffold for the future
Five floors down from McCurdy’s office in the College of Pharmacy, his collaborator Jay McLaughlin is working with Susruta Majumdar at the Memorial Sloan-Kettering Cancer Center in New York to develop novel analgesics based on kratom’s molecular scaffolding.
Majumdar and McLaughlin recently published a paper in the Journal of Medicinal Chemistry detailing the analgesic effects of the modified kratom analog mitragynine pseudoindoxyl.
When Majumdar and his colleagues examined the analog’s efficacy in mouse models, “we found that it’s a potent analgesic, three to five times more potent than morphine,” says Majumdar.
The researchers also examined its efficacy as a delta receptor-antagonist, which is a property that causes users to develop less of a tolerance to a drug that acts as a mu agonist. Across the board, pseudoindoxyl appeared to be a more potent delta antagonist in isolated in vitro receptors than either mitragynine or 7-hydroxymitragynine.
“Mitragynine pseudoindoxyl is also the first molecule in a kratom-derived template that shows no abuse potential and has far reduced respiratory depression (compared to) all clinically used opioids in mice, possibly because of its non-beta arrestin recruiting mechanisms,” he says.
Despite these benefits, “mitragynine pseudoindoxyl is more of a therapeutic for tomorrow,” he says.
In the meantime, McLaughlin is hoping to begin studies at the University of Florida with Avery and McCurdy examining pharmacodynamic properties of mitragynine pseudoindoxyl, such as its longevity in the body, byproducts and mechanisms of elimination.
The earliest noted record of kratom use in the United States appeared in the 1999/2000 issue of the now-defunct quarterly publication Entheogen Review, a self-described “Journal of Unauthorized Research on Visionary Plants and Drugs” that ran in a confidential, underground manner from 1992 to 2008.
Today, researchers are starting to get a better idea of the demographic groups using kratom in the U.S. and their reasons for doing so. Oliver Grundmann, a toxicologist and pharmacologist at the University of Florida, recently published the initial findings from a survey of 10,000 self-reported kratom users conducted with the assistance of the American Kratom Association. The paper appeared in the journal Drug and Alcohol Dependence.
Grundmann and his colleagues found that, out of the 8,049 kratom users who completed the entire survey, less than 1 percent had experienced physical or psychological incidents that required hospitalization or treatment by a physician.
“That was a very low incidence rate, overall, compared to many other drugs … even among those that are common prescription drugs,” says Grundmann. The authors also found that, while 68 percent of kratom users were using it to self-treat pain, some 66.5 percent were using it to self-treat conditions such as anxiety, depression or post-traumatic stress disorder.