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Trust at the U.S. Food and Drug Administration (FDA) declined after it approved the controversial Alzheimer’s disease drug, aducanumab. Three experts resigned amid allegations the FDA had bowed to industry pressure. Some argue that his credibility has hit a new low.
These events should have prompted the FDA to pause, think, and work to repair its reputation. Instead, the agency is forging ahead with actions that could further erode its credibility. A fitting example is its position on Mitragyna speciosa, commonly known as kratom, a tree related to coffee trees.
Kratom has long been consumed in Southeast Asia as a pain reliever and mild stimulant. Millions of Americans also use it, claiming that it relieves symptoms of chronic pain and addiction, significant effects as drug overdose deaths continue to rise.
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Last year, the Centers for Disease Control and Prevention (CDC) recorded a record number of overdose deaths, two-thirds of which are due to opioids. Meanwhile, restrictions on legitimate opioid prescriptions leave few alternatives for people with chronic pain. Some turn to illicit opioids. Others commit suicide. But many rely on kratom, which occupies an important niche in the public health ecosystem.
Kratom has dose dependent effects. In low doses, it can act as a mild stimulant. In Southeast Asia, people chew the leaves of Mitragyna speciosa to stay focused, just like drinking a cup of coffee to stay alert. At higher doses, kratom acts as a sedative and pain reliever. While this dose-dependent relationship is not well understood, what is understood is that the active ingredients in kratom, mitragynine and 7-hydroxymitragynine, exhibit an affinity for what is called the mu- receptor. opioid, which binds to a variety of substances, including morphine and other opioids.
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Through a phenomenon called biased agonism, the mu-opioid receptor causes different intracellular effects when it binds to different molecules, allowing opioids and mitragynines to have different physical effects. Specifically, opioids activate an intracellular signaling protein called beta-arrestin, unlike mitragynines. This distinction is important because the activity of beta-arrestin is linked to the dangerous side effects of opioids, including slow, shallow breathing that cannot sustain life.
The FDA analysis lacks that level of detail.
Federal agencies have tried to ban kratom for years. In 2016, the U.S. Drug Enforcement Administration (DEA) announced its intention to classify kratom as a Schedule I controlled substance. Compounds in this class are said to have no currently accepted medical uses and present a high potential for abuse.
A year after the DEA announced its intention to ban kratom, the Federal Department of Health and Human Services (HHS) responded with a letter supporting the proposed ban. These developments have sparked a public outcry from scientists, kratom advocates, and state and federal lawmakers. More than 130,000 Americans have signed a petition to the White House opposing the ban, and 51 members of Congress have sent a letter to the DEA urging it to listen to the public. Meanwhile, experts analyzed the potential for abuse of kratom and concluded that the ban was inappropriate.
In response, HHS rescinded its programming recommendation. But instead of following suit and turning the tide of kratom policy, the FDA has doubled down. Having failed to ban kratom nationally, the agency may soon recommend that the World Health Organization ban it internationally.
If the FDA gets a worldwide ban on kratom, countless people could die from suicide and unintentional overdose. Many Americans say that kratom reduces cravings for opioids, which are frequently obtained on the illicit market and are often combined with synthetic opioids like fentanyl. According to the CDC, synthetic opioids are “the number one killer of drug overdose,” responsible for nearly three-quarters of opioid-related overdoses. A ban would criminalize people who use kratom, eliminate legitimate sources of the plant, and push many users to resort to more harmful substances.
The ban would also prevent researchers from studying the effects of kratom, which would be a costly mistake reminiscent of what happened when research on psychedelics was banned in the 1970s and 1980s. controlled substances in Schedule I, it has become illegal for scientists to produce and study them, and promising research into their therapeutic potential has been halted. Today, decades later, there is a revival of research on psychedelics.
Results from Phase 1 and 2 clinical trials reflect the promise of psychedelics for treating mental illness. But their Schedule 1 status continues to hamper research: authorization from the DEA is required but not always granted, the agency imposes annual limits on production, and it is almost impossible to obtain a federal funding for research on psychedelics. As suicide and overdose rates rise and innovative treatments for mental illnesses are scarce, the damage caused by the prohibition of psychedelics is untold.
The FDA is about to make the same mistake with kratom.
A review of the FDA’s arguments against kratom reveals many weaknesses. The agency is relying on calls to poison control centers as proof of kratom risks. However, there are many reasons people call poison control, not all of them serious, and calls for kratom are pale compared to calls for common household products.
According to the CDC, there were 1,807 kratom calls from early 2011 to late 2017, an average of 258 calls per year. For comparison, over the same period, single-use laundry pods generated 12,157 calls per year. Using annual reports from the American Association of Poison Control Centers, I calculated that antihistamines caused 94,977 annual calls and pain relievers caused 294,812.
Some people have died while the kratom was in their bodies. 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 these cases testing 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 excluded.”
Most kratom-associated deaths are attributable to other substances, including opioids and alcohol, which are each responsible for nearly 100,000 deaths per year. Yet the FDA acts as if people who have died with kratom in their system are harmed by kratom alone. The data do not support this conclusion. Instead of banning kratom, the FDA should encourage manufacturers to label it with contraindications such as active use of opioids or alcohol.
A 2011 report describes nine people injured by kratom products adulterated with a drug called O-desmethyltramadol. Others can be harmed 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 foreign suppliers who may not follow good manufacturing practices.
Instead of using this type of information to fit its narrative that kratom is harmful, the FDA should regulate kratom to ensure it is produced safely. The American Kratom Association has established good practices for the production, labeling, and safety verification of kratom. Although 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 the use of the plant, the FDA used what is known as the Public Health Assessment Methodology Via Structural Assessment (PHASE), an experimental computer model, to predict the effects of kratom, concluding that it contains harmful opioids. Experts argue that the FDA is wrong to rely on this simplistic model. PHASE ignores how quickly substances are absorbed from the gastrointestinal tract, how easily they cross the blood-brain barrier, and what happens inside cells once the drugs bind to the receptors on them. area. The system does not take into account the biased agonism of the mu-opioid receptor and the lack of activation of beta-arrestin by mitragynines. These factors influence the physical effects of kratom, but they are not taken into account by the PHASE model, and the FDA ignores its limitations.
Why is the FDA defaming kratom when so many stakeholders identify flaws in its arguments? Could it be that drug companies are marketing synthetic versions of kratom and that banning the plant would protect their interests? Companies with a financial interest in substances listed in Annex I have benefited from their ban. When drug makers get clearance from the DEA and the FDA to market drugs that are otherwise illegal, the ban protects them from potential competition. It strengthens government-granted monopolies provided by patents and marketing exclusivity.
In July, the FDA asked for comment on the proposed global kratom ban, leaving people just two weeks to respond. The American Kratom Association has sued the agency and the HHS in federal court, and the deadline has been extended to August 24, 2021. I urge the FDA to listen to scientists and advocates who say kratom works differently opioids. A ban will only encourage people to use more harmful illicit substances like heroin or fentanyl, and many will die from suicide or from an unintentional overdose. The regulation of kratom is preferable to a ban because it creates a more secure supply and will not hamper research.
Kratom may not be the safest substance. But it’s probably no more dangerous than many household products or over-the-counter drugs, and there’s no data to support an outright ban. Banning substances without solid evidence can be just as harmful as approving them without it.
Mason Marks is Professor of Law at the Franklin Pierce School of Law at the University of New Hampshire and Principal Investigator at the Petrie-Flom Center at Harvard Law School where he leads the Psychedelic Law and Regulation project.
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