Opioids are, by definition, compounds that interact with opioid receptors; that doesn’t make them good or bad.
Feb 8 2018, 6:08pm
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On Tuesday the Food and Drug Administration issued another warning about the alleged dangers of kratom, the herbal supplement used as a pain reliever and to treat opioid withdrawal symptoms. The agency says it used a computer model to assess the molecular structure of compounds found in the plant and declared them opioids with “potential for abuse.” It also released data on what it says are 44 deaths associated with kratom use, up from 36 kratom-linked deaths in a November warning.
But critics say the FDA’s computer model isn’t the “novel science” it claims, and that the list of kratom-related deaths—the implication being that the plant may be killing people—isn’t as clear-cut as it may seem. While the agency touts its “significant steps to advance the scientific understanding,” other researchers are skeptical about the FDA’s approach.
In its press release, the FDA describes what it calls “the Public Health Assessment via Structural Evaluation (PHASE) methodology.” This involves building a three-dimensional molecular model of compounds under agency review, then using those models to predict how the compounds will affect the body.
In this case, the agency looked at 25 compounds found in kratom, an herb derived from leaves of a Southeast Asian tree. (Because it’s a plant, it contains a number of potentially active compounds, which makes it complex to study; marijuana poses a similar challenge.) The model showed that the compounds would bind to the mu opioid receptors, meaning they would activate those receptors. (Scientists recently modeled a different set of receptors, the kappa opioid receptors, as an early step toward developing less addictive painkillers.)
“The data from the PHASE model shows us that kratom compounds are predicted to affect the body just like opioids,” FDA commissioner Scott Gottlieb said in a statement. “Based on the scientific information in the literature and further supported by our computational modeling and the reports of its adverse effects in humans, we feel confident in calling compounds found in kratom, opioids.” It also touted the power of its model to quickly analyze other natural or synthetic opioids that may appear.
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But Andrew Kruegel, a Columbia University pharmacologist who has extensively studied kratom, is less than impressed. “I don’t really see what this adds to this field or adds to the body of knowledge around kratom,” he tells Tonic. “It’s very strange to me.”
He’s perplexed from a scientific perspective as to why the FDA issued its statement. The technique used by the agency—attempting to match a computer model of a compound with its receptors in the body—is called molecular modeling or molecular docking, he says. It’s used in the early stages of drug development: By choosing a receptor to target, researchers could cycle through tens of thousands of compound models, looking for one that might activate the receptor.
“But that’s a very early step in drug development,” Kruegel says. “You would not be very confident in the results of that assay. It’s all done virtually in a computer.” There’s still the laborious process of producing the compound and testing it in actual living things—with no guarantee it’ll have the expected effect.
Moreover, researchers have already demonstrated that compounds in kratom bind to mu opioid receptors. “We’ve known that since that 1990s,” he says. He points to his own research, published in 2016, which examines how compounds in kratom, particularly mitragynine, only partially activate certain opioid receptors, yet have distinct pharmacological properties. Kratom doesn’t seem to share the dangerous side effect of respiratory depression that other opioids have—that’s when someone’s breathing slows down and could stop completely. Better understanding how certain opioids produce certain effects is key to developing safer painkillers.
Kruegel’s point is that opioids are, by definition, compounds that interact with opioid receptors. But not every opioid has the same effect. Naloxone, for example, binds to opioid receptors, but is actually used to reverse opioid overdoses. (Addiction treatment medications buprenorphine, naltrexone, and methadone also attach to opioid receptors.) That’s why researchers carefully examine how opioids actually work in the body.
“The problem with saying it’s ‘an opioid’ without qualification is that it just paints everything with this broad brush, and obviously carries a negative connotation given what’s going on in the country right now,” Kruegel says.
Dubbing kratom an opioid may be overgeneralizing. If so, then so too must be the FDA’s claim of 44 deaths associated with kratom. Last November, the agency saidit had reports of 36 deaths associated with the plant. Since then it’s received new reports, and made public some of the data behind its claims in two PDFs.
As Nick Wing noted in HuffPost, the evidence is less than persuasive—at least for the implication that kratom is, by itself, killing people. The FDA maintains a system for reporting adverse effects from food or drugs, and the 44 kratom-associated deaths are drawn from that database.
But the agency indicates that these reports are provided in their original form, and that “reports [do] not always contain sufficient information for FDA to determine whether there is a correlation between the reported event and use of the product.”
In other words, the data’s evidentiary value varies. Included in the FDA’s count, for example, are nine deaths from Sweden involving a kratom-based product called Krypton, which also contained a synthetic opioid. In that case, it’s hard to know exactly what may have caused the deaths.
Adulterated kratom is a very real problem, says Walt Prozialeck, professor and chair of the department of pharmacology at the Chicago College of Osteopathic Medicine at Midwestern University. Because it’s sold as an herbal supplement, there’s little to no oversight of quality control or marketing material. People buying kratom online may not know what they’re actually getting. Prozialeck thinks that, rather than banning the plant, the FDA ought to consider labeling requirements and quality control—a common request among kratom advocates.
While uncertainty about just what’s definitely an issue, when it comes to deaths, Prozialeck says, “I think there may be some excessive blame being put on kratom in the reports.” Almost every case, he notes, involved multiple drugs, a user with confounding health conditions, or a possible underlying seizure disorder. That means to really understand what caused these deaths, we have to account for the possibility of drug interactions, pre-existing conditions, and other possible factors. “There’s just nothing known about kratom to list it as the cause of death,” he says.
We don’t even know what a fatal dose of kratom might be, Prozialeck says. Even if we grant the FDA’s numbers, he says, we also have to account for the more than three million people who use the plant in the US, according to a trade group. In a population that size, Prozialeck says, “Forty-four deaths is not that many.”
Which raises the question of what federal authorities plan to do now that they’ve declared kratom an opioid. Jag Davies, director of communications strategy at the Drug Policy Alliance, points out that the Drug Enforcement Agency has the power to criminalize kratom—it already considered making it Schedule I, on the same prohibition level as heroin, until users raised a public outcry. The DEA backed off, at least for now, and Davies says the battle has largely shifted to the states, some of which have banned kratom (often lumping it in with synthetic opioids).
“The urge to ban kratom is coming from this abstinence-only mindset,” he says, arguing that transitioning people addicted to opioids to using kratom should be considered a success. Yet most drug treatment centers work on the assumption that the only way to be healthy is to completely eliminate drug use. That thinking, Davies says, dismisses what we know about harm reduction; that weaning users onto less dangerous drugs, for example, can save lives.
Davies, like Kruegel and Prozialeck, would like to see more authorities recognize kratom’s potential and the need for more research. While the FDA says “there is no reliable evidence to support the use of kratom as a treatment for opioid use disorder,” there are testimonials from people who’ve used it for exactly that. Research, meanwhile, suggests kratom doesn’t work the same way as the dangerous opioids the FDA has lumped it in with. And if the agency’s “novel science” becomes a reason for banning kratom at the federal level, it will make it almost impossible for scientists to do the work necessary to know for sure.