Trust in the U.S. Food and Drug Administration (FDA) declined after its approval of the controversial Alzheimer’s drug aducanumab. Three experts resigned amid allegations that the FDA had caved to industry pressure. Some argue that its credibility has reached a new low.
These events should have prompted the FDA to pause, reflect, and work to repair its reputation. Instead, the agency is forging ahead with actions that may further erode its credibility. A timely example is its position on Mitragyna speciosa, commonly called kratom, a tree related to coffee plants.
Kratom has long been consumed in Southeast Asia as a pain reliever and mild stimulant. Millions of Americans also use it, claiming it eases symptoms of chronic pain and addiction, important effects as drug overdose deaths continue to rise.
Last year, the Centers for Disease Control and Prevention (CDC) recorded a record number of overdose deaths, two-thirds of them caused by opioids. Meanwhile, restrictions on legitimate opioid prescriptions leave few alternatives for people with chronic pain. Some turn to illicit opioids. Others turn to suicide. But many rely on kratom, which fills an important niche in the public health ecosystem.
Kratom has dose-dependent effects. At low doses, it can act as a mild stimulant. In Southeast Asia, people chew the leaves of Mitragyna speciosa to maintain focus, much as one might drink a cup of coffee to remain alert. At higher doses, kratom acts as a sedative and pain reliever. Although this dose-dependent relationship is not well understood, what is well understood is that kratom’s active ingredients, mitragynine and 7-hydroxymitragynine, show affinity for what’s known as the mu-opioid receptor, which binds a variety of substances, including morphine and other opioids.
Through a phenomenon called biased agonism, the mu-opioid receptor causes different intracellular effects when it binds different molecules, allowing opioids and the mitragynines to have different physical effects. Specifically, opioids activate an intracellular signaling protein called beta-arrestin, while the mitragynines do not. This distinction is important because beta-arrestin activity is linked to dangerous side effects of opioids, including slowed, shallow breathing that cannot sustain life.
The FDA’s analysis lacks this level of detail.
Federal agencies have attempted to ban kratom for years. In 2016, the U.S. Drug Enforcement Administration (DEA) announced plans to classify kratom as a Schedule I controlled substance. Compounds in this category are said to have no currently accepted medical use and a high potential for abuse.
One year after the DEA announced its intention to prohibit kratom, the federal Department of Health and Human Services (HHS) responded with a letter supporting the proposed ban. These developments provoked public outcry from scientists, kratom advocates, and state and federal lawmakers. More than 130,000 Americans signed a White House petition opposing the ban, and 51 members of Congress sent a letter to the DEA urging it to listen to the public. Meanwhile, experts analyzed the abuse potential of kratom and concluded that prohibition was inappropriate.
In response, HHS rescinded its scheduling recommendation. But instead of following suit and reversing course on kratom policy, the FDA doubled down. Having failed to ban kratom domestically, the agency may soon recommend to the World Health Organization that it be prohibited internationally.
If the FDA secures a global kratom ban, countless people could die by suicide and unintentional overdose. Many Americans say kratom curbs cravings for opioids, which are frequently obtained on the illicit market and are often laced with synthetic opioids like fentanyl. According to the CDC, synthetic opioids are “the main driver of drug overdose deaths,” responsible for nearly three-quarters of opioid-related overdoses. A ban would criminalize people who use kratom, eliminate legitimate sources of the plant, and cause many users to resort to using more harmful substances.
Prohibition would also prevent researchers from studying the effects of kratom, which would be a costly mistake reminiscent of what happened when psychedelics research was banned in the 1970s and 1980s. When psychedelics became Schedule I controlled substances, it became illegal for scientists to produce and study them, and promising research on their therapeutic potential came to a halt. Now, decades later, there is a revival of psychedelics research.
The results of Phase 1 and 2 clinical trials reflect the promise of psychedelics to treat mental illness. But their Schedule 1 status continues to impede research: DEA permission is required but is not always granted, the agency imposes annual limits on production, and it is nearly impossible to obtain federal funding for psychedelics research. When suicide and overdose rates are rising, and innovative treatments for mental illness are few and far between, the harm caused by psychedelics prohibition is incalculable.
The FDA is poised to make the same mistake with kratom.
Scrutinizing the FDA’s arguments against kratom reveals many weaknesses. The agency relies on calls to poison control centers as evidence of kratom’s risks. However, people call poison control for many reasons, not all of them serious, and the calls regarding kratom pale in comparison to calls regarding common household products.
According to the CDC, there were 1,807 calls regarding kratom from the start of 2011 to the end of 2017, an average of 258 calls per year. By comparison, during the same period, single-use laundry pods generated 12,157 calls per year. Using annual reports of the American Association of Poison Control Centers, I calculated that antihistamines caused 94,977 annual calls and pain relievers generated 294,812.
Some people have died while kratom was in their systems. But a causal link between kratom and death has not been established. In 2019, the CDC analyzed 27,338 overdose deaths that occurred over an 18-month period. Kratom was detected in 152 (less than 1%) of these deaths, but in most of those cases tests also revealed the presence of drugs known to cause overdoses. Only seven tested positive for kratom alone, and the researchers concluded that “the presence of additional substances cannot be ruled out.”
Most kratom-associated deaths are attributable to other substances, including opioids and alcohol, which are each responsible for nearly 100,000 deaths a year. Yet the FDA acts as though people who died with kratom in their systems were harmed by kratom alone. The data don’t support that conclusion. Instead of prohibiting kratom, the FDA should encourage manufacturers to label it with contraindications such as active opioid or alcohol use.
A 2011 report describes nine people harmed by kratom products adulterated with a drug called O-desmethyltramadol. Others may be injured by contaminants such as heavy metals, which the FDA has identified in some kratom products. But these problems are associated with kratom production, rather than the plant itself. Consumers are often forced to buy from overseas suppliers who may not follow good manufacturing practices.
Instead of using this kind of information to fit its narrative that kratom is harmful, the FDA should regulate kratom to ensure that it is safely produced. The American Kratom Association has established good practices for kratom production, labeling, and safety verification. Though some states have banned kratom, it remains legal in most states, and four states have even passed a Kratom Consumer Protection Act to regulate its domestic production and sale. Others are considering similar legislation.
To further condemn use of the plant, the FDA has used what’s known as the Public Health Assessment via Structural Evaluation (PHASE) methodology, an experimental computer model, to predict kratom’s effects, concluding that it contains harmful opioids. Experts argue the FDA is wrong to rely on this oversimplified model. PHASE ignores the rate at which substances are absorbed in the gastrointestinal tract, how easily they cross the blood-brain barrier, and what happens inside cells after drugs bind to receptors on their surface. The system fails to account for biased agonism of the mu-opioid receptor and the lack of beta-arrestin activation by mitragynines. These factors influence kratom’s physical effects but they are not considered by the PHASE model, and the FDA ignores its limitations.
Why does the FDA vilify kratom when so many stakeholders identify deficiencies in its arguments? Could it be that drug companies are commercializing synthetic versions of kratom and banning the plant would protect their interests? Companies with a financial stake in Schedule I substances have benefitted from their prohibition. When drug makers gain DEA and FDA permission to commercialize drugs that are otherwise illegal, prohibition shields them from potential competition. It strengthens government-granted monopolies provided by patents and marketing exclusivity.
In July, the FDA sought comments on the proposed global kratom ban, leaving only two weeks for people to respond. The American Kratom Association sued the agency and HHS in federal court, and the deadline has been extended until August 24, 2021. I urge the FDA to listen to scientists and advocates who explain that kratom acts differently than opioids. A ban will only encourage people to consume more harmful illicit substances like heroin or fentanyl, and many will die by suicide or from unintentional overdose. Regulating kratom is preferable to prohibition because it creates a safer supply and will not impede research.
Kratom may not be the safest substance. But it is likely no more dangerous than many household products or over-the-counter medicines, and there are no data to support an outright ban. Prohibiting substances without good evidence can be just as harmful as approving them without it.
This article was first published in STAT on August 23, 2021.