Kratom, a little-known tree in the same family as coffee, has been getting a lot of attention lately, most of it bad. The plant only somewhat recently arrived in the United States from its native Southeast Asia, where it has been used medicinally for more than two centuries.
Ingesting the red-veined leaves of the Mitragyna speciosa tree can provide a stimulating effect, while the opioid-like properties of alkaloids found within the plant have been used to manage chronic pain and wean people off opioid addiction. Using kratom can lead to dependence, but anecdotal reports on withdrawal symptoms paint the drug as relatively mild.
As you might expect with an unregulated, psychoactive plant, the federal government has made moves to ban kratom, which is currently legal in most parts of the country. In late 2016, the Drug Enforcement Administration declared intent to place kratom’s alkaloids on Schedule I, cataloging it alongside heroin, marijuana, and other drugs with “no currently accepted medical use and a high potential for abuse.” (Schedule I substances are also incredibly difficult to conduct research with.)
But there was relentless pushback from the public and Congress, so in an unprecedented move, the DEA backed off, basically punting the decision to the Food and Drug Administration. A series of notices from the FDA, including one dubiously labeling the plant an “opioid” even though it doesn’t seem to have the same life-threatening side effects as opioids, and others citing 44 deaths ambiguously linked to the substance, have ignited fears that days of kratom’s legal status are numbered.
The FDA is pinning its concerns on the opioid overdose crisis. An FDA spokesperson tells Tonic in an email, “[W]e must pay early attention to the potential for new products to cause addiction and we must take strong, decisive measures to intervene,” adding, “We believe using the FDA’s proven drug-review process would provide for a much-needed discussion among all stakeholders. Until then, we want to be clear on one fact: there are currently no FDA-approved therapeutic uses of kratom.”
A ban wouldn't just impact the estimated 3 to 5 million Americans who use kratom, sometimes in lieu of prescription meds. A 2016 article in Scientific American warned that efforts to ban the plant could also have a chilling effect on kratom research (and research on related pain killers). It appears this is already happening.
Tonic spoke with seven kratom researchers and most agreed that the FDA is right to be preoccupied by a substance we don’t know much about. But they also unanimously expressed concern for the agency’s aggressive approach, saying too much government pressure will cripple scientific research on the plant.
It wasn’t long after the DEA’s 2016 announcement to schedule kratom that Christopher McCurdy shut down his research. McCurdy is a medicinal chemistry professor at the University of Florida who has been studying kratom for more than a decade. He sees vast potential in the plant for treating addiction and pain, but his main goal is to first unlock kratom’s pharmacology.
But he lacks a Schedule I researcher license, which is wrapped up in red tape including institutional review board approval and security of the work area. So when the DEA announced its plans to schedule kratom, McCurdy shipped all his research materials to a colleague and powered down for almost a year.
“That's a pretty big problem,” he says. “To all of a sudden be breaking the law, when you're trying to do a good thing and trying to find a solution.”
McCurdy isn’t alone. CPH Biotech, a Las Vegas-based start-up specializing in kratom research, was set to begin clinical trials. “Our private funder backed out after the FDA notice was released, so we have had to put our human study on hold until such time that we secure further funding,” a company spokesperson writes in an email. “We did complete a successful animal study.”
There’s also Andrew Kruegel, a medicinal chemist at Columbia University, who has written a number of papers characterizing the pharmacology of kratom’s active alkaloids using cell and animal models. Last year, he was approached by a team at Johns Hopkins University to conduct the first controlled human trial exploring the safety, abuse potential, and effectiveness of kratom for pain relief.
“We were starting to prepare an NIH [National Institutes of Health] grant submission to request funding for this work,” Kruegel explains. “But unfortunately, the Hopkins team decided not to proceed due to the regulatory uncertainty, as the trial would be very challenging to run if kratom or its active compounds were placed in Schedule I. Planning clinical studies and preparing grant applications is a lot of work, so they did not want to commit to this if there was a possibility the work might not even be possible.” Tonic has reached out to Johns Hopkins for comment and will update this story if we hear back.
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The body of research on kratom is relatively small. “I assessed kratom in 2017 for the American Journal of Health-System Pharmacists,” says Charles White, a professor and head of the Department of Pharmacy Practice at University of Connecticut. “And I found the animal work intriguing, but the human research almost in its infancy … There are tons and tons of anecdotal experiences, but few, if any, human studies.”
Still, he says, “I believe that many more people will die from stopping breathing on heroin or fentanyl than will be harmed from kratom, even though kratom is likely far from risk-free."
Furthermore, by banning kratom, White is concerned that we’re making another marijuana, which has “now been shown to have a role to play in [treating] seizures, chemotherapy nausea and vomiting, and severe muscle spasticity in human trials.” Once kratom crosses that line into Schedule I, it could be decades before research gets to where we are with marijuana, which still needs more scientific examination.
Clinical research isn’t the only type of kratom science threatened by scheduling. Marc Swogger is an associate psychiatry professor at University of Rochester Medical Center who studies substance use and describes the kratom conflict as a civil liberties issue. He co-authored a systematic review of all kratom literature related to mental health from 1960 to 2017. He examined 13 studies with a combined sample size of 28,745, and found “no indication that kratom use carries significant mental health risks beyond the possible development of kratom dependence, which is generally mild compared to that of opioids.”
“Because I do research in criminal justice systems, a ban would change the nature of my work in a bit of a tragic way,” Swogger says. “Now, I'm studying how citizens have found a plant that they indicate helps them with pain, anxiety, or opioid addiction. If there's a ban, I may be studying ways in which the government has made criminals of these individuals and created an illicit market for kratom in the latest drug war mistake.” "Many years ago, citizens were robbed of the opportunity to understand medical benefits of cannabis and psychedelics for political reasons,” Swogger adds. “It's 2018, and there's no reason something similar should happen with kratom.”
The little we do know about kratom is promising. There are at least 40 active compounds, called alkaloids, found in the leaves, but the two best understood are mitragynine and 7-hydroxymitragynine, which act differently on the opioid receptors (more on that below). There’s also mitragynine pseudoindoxyl, which can be produced when kratom is fermented, and appears to be a potent pain reliever that's unlikely to lead to physical dependence.
About two-thirds of kratom’s total chemical content is mitragynine, a substance that binds to the mu-opioid receptors, which are involved in pain management and addiction, but it doesn’t activate the β-arrestin protein, which is known to cause constipation, slowed breathing, and other opioid side effects. (Morphine and other opioids do activate β-arrestin.) In other words, kratom could theoretically work as an opioid-like painkiller without the same risk of dependence and life-threatening overdose.
According to Kruegel, in unadulterated, raw leaf or tea form, kratom is harder to abuse. This "provides a further margin of safety by limiting the maximum practical exposure to the active compound, since one can only eat so much powdered leaf matter," he says. "Likewise, the widely-used leaf preparations cannot be injected or insufflated (snorted), which prevents use via the most favorable administration routes for drug abuse."
There’s a lot we can learn from studying kratom, but going forward with research will not be easy. “We haven't spoken directly to the FDA about clinical trials, but we've had consultants to try to help us prepare the investigational drug application,” McCurdy says. “[They’ve] told us that there's a very low likelihood that the FDA would approve any human research," even before it's classified as a Schedule 1 drug.
Another problem with kratom is that it's currently completely unregulated, so consumers don't know what they're getting. The FDA categorizes kratom as a nutritional supplement, which means it’s not subject to the same market regulations as pharmaceuticals, according to Walter Prozialeck, a professor and chairman of the Department of Pharmacology at Midwestern University. He’s taught about pain management and drug abuse for more than 30 years, and in 2012, he published one of the first kratom reviews. He says banning kratom would be a “stretch,” but notes that kratom sellers desperately need quality control.
“In the US, people who buy kratom products don't know what they're getting. And that's a huge problem,” Prozialeck says. Kratom comes in several forms and the capsules, liquid energy shots, and gum can often have more unpredictable effects compared to the raw leaves.
McCurdy agrees that it’s a “real buyer beware marketplace,” as he puts it. Sometimes products have been adulterated with synthetic opioids such as O-desmethyltramadol, which could lead to fatal overdoses. And on April 18th, NGB Corp., a kratom distribution company from Utah voluntarily recalled 1,100 units of product in response to a salmonella outbreak.
The FDA has been aggressively pursuing salmonella outbreaks in kratom lately and, on April 5th, it reported 132 illnesses associated from kratom products. No deaths have been reported. While that number is high, it’s also worth noting such outbreaks are not uncommon, even in better-regulated industries. About 1.2 million Americans contract salmonella each year, according to the Centers for Disease Control and Prevention. Some kratom advocates are concerned that FDA will use these salmonella outbreaks to recall all kratom products on the market.
On April 25th, two leading kratom researchers issued a press release suggesting these outbreaks are actually a consequence of FDA meddling. “By imposing an effective ban on importing kratom (including seizures at ports), the FDA forced manufacturers to shift from high-quality sources of the herb to lesser suppliers, thus increasing the potential for issues such as salmonella, which had never previously been an issue with kratom in the US,” they wrote.
One of the authors, Jack Henningfield, was hired in 2016 to conduct an eight-factor analysis of kratom’s abuse potential for the American Kratom Association, which concluded, “Although kratom appears to have pharmacological properties that support some level of scheduling, if it was an approved drug, placing it into Schedule I, thus banning it, risks creating public health problems that do not presently exist."
The FDA has completed its own eight-factor analysis on mitragynine and 7-hydroxymitragynine, which it submitted to the DEA. According to the FDA spokesperson, "That analysis is with the DEA and no additional information, including any scheduling recommendation, can be shared at this time by the FDA as it’s considered to be pre-decisional." The FDA has rejected Freedom of Information Act requests related to the analysis.
Studying a Schedule I substance isn’t impossible, but it’s quite a headache. All clinical research must be first appraised by an institutional review board (IRB), many of which won’t even consider studying Schedule I drugs, Prozialeck says. And it’s quite expensive—the mandatory, preliminary literature review alone can cost around $30,000. But then there’s a mountain of paperwork and additional requirements, including the aforementioned physical security of the workplace area and where the drugs are going to be stored.
“Many institutions just can't afford the infrastructure that is needed for that type of work,” Prozialeck explains. “For a drug to be Schedule I in the DEA 's opinion, there is high potential for abuse or some other problems from toxicity. As a result, many institutions feel that researching the material might be unethical or put patients at undue risks.”
And the FDA does not seem optimistic that kratom will be determined to be risk-free. A spokesperson writes in an email, “To date, the FDA is not aware of any evidence of safety establishing that kratom (or any compounds derived from kratom) will reasonably be expected to be safe as a dietary ingredient.”
It’s a catch-22, Prozialeck says. In order to determine if a Schedule I substance isn’t dangerous or medically beneficial, you first need to study it. So what if kratom were to become Schedule II, III, or IV, designations that are less restrictive, research-wise? For example, the hallucinogenic analgesic ketamine is Schedule III, which is how it can be prescribed for off-label use, such as depression. But in order to fit into these categories, there needs to already be established therapeutic use. Again, a catch-22.
“Somebody would have to do the research study and take the data to the FDA to get it approved for a clinical use, show that it is reasonably safe, and that the benefits outweigh the risk,” Prozialeck says. “And then the DEA and FDA would schedule it based on the abuse potential of the drug. So they're not going to schedule something in II to IV until somebody shows that it's clinically effective for a specific condition.”
Until then, multiple researchers Tonic spoke with argued that better regulation—not increased prohibition—would be more effective at keeping harmful or low-grade substances out of people's hands.
“Rather than scheduling it, what I'd like to see is dietary supplements actually be managed for what they are, and that's medications,” says Edward Boyer, an associate professor of emergency medicine at Harvard Medical School. Boyer and McCurdy worked on a 2008 case study of a man who mixed kratom and the narcolepsy drug modafinil and experienced seizures. They also filed a now-abandoned patent in 2009 for using kratom to treat opioid withdrawal symptoms. “At the time, it seemed like intellectual property worth protecting,” Boyer says.
“Kratom, by itself, in its natural form, is a reasonably safe compound,” he says. “There are no reports of respiratory depression in unadulterated kratom. If you had to come up with a medication that was safe and could serve as a bridge from someone to go from compulsive opioid use to effective drug treatment, kratom might actually be a reasonable alternative—if we could guarantee that the supply of kratom was not adulterated. And that's kind of difficult.”
Boyer was going to do pharmacokinetic research on kratom, which would describe how the body metabolizes the substance. But the FDA wanted to him to treat kratom like a prescription medicine, which requires following much more stringent regulations, even though in the past they’ve treated it as a dietary supplement. (You can’t actually get kratom by prescription, a point to which Boyer responds, “Yeah, the world is full of mystery, isn’t it?”)
“Does the FDA make life more difficult for me? Yes, because it's harder to do research now,” he says. “Are they wrong for doing that? It's hard for me to get my head around that totally because I understand both sides of the issue.”
McCurdy, for his part, isn’t giving up. The day I called him, he’d just submitted two grants to the National Institute on Drug Abuse and is waiting for peer review on a rat study showing that mitragynine has low abuse potential, while 7-hydroxymitragynine has significant abuse potential. Even though the FDA has made research more difficult, McCurdy says for him and other researchers like him, it’s also been a motivating factor.
“It’s a little paradoxical,” he admits. “Everybody kind of panicked and thought that research was going to be stopped, halted, and shut down. And it was initially for a little while. [But] after the dust settled … I think it actually has cranked up the research efforts.”
Now everyone’s trying to get out as much kratom data as quickly as they can, McCurdy says, almost as if it’s their last chance to make the argument that the plant has scientific potential.
“I would think it would be hard for anybody in this time to turn away something that has potential in the crisis that our country is facing,” he says. “At least from my local perspective, it's really cranked up the efforts of research and part of that is just because we don't know when that hammer is gonna drop. We want to get as much done as we can.”
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