FDA Seeks Schedule I Status for ‘Legal Morphine’

The FDA is recommending that 7-hydroxymitragynine (7-OH), a synthetic, concentrated substance derived from kratom leaves, be classified as a Schedule I substance under the Controlled Substances Act.

The recommendation is the latest effort by the agency to raise awareness of and limit access to 7-OH, which acts on opioid receptors in the brain and is available as gummies, tablets, and drinkable shots sold at gas stations, smoke shops, and online.

The FDA also issued a “Dear Colleague” letter to all US physicians, warning about the risks of 7-OH, and published two reports designed to raise awareness among clinicians and consumers. These actions come on the heels of warning letters issued by the FDA to seven companies for illegal marketing of the substance as kratom, as reported byMedscape Medical News. 

“7-OH is not just like an opioid. It does not just have opioid-binding properties. 7-OH binds to the mu opioid receptor, which means scientifically, by definition, it is an opioid. And yet it is sold in vape stores, in smoke shops, in convenience stores and gas stations that are popping up all over the United States, and nobody knows what it is,” Marty Makary, MD, MPH, FDA commissioner, said in announcing the scheduling recommendation at a press conference on Tuesday. 

Although trace amounts of 7-OH are found in the kratom leaf, kratom products would not be affected by the scheduling recommendation, said Makary, who added that scheduling would apply only to concentrated 7-OH. 

The Drug Enforcement Administration (DEA) will now review the recommendation and launch a public rule-making process, which includes a public comment period and can take months to conclude. If the DEA follows the FDA’s guidance, 7-OH would be in the same class as opioids, morphine, heroin, and other psychoactive drugs.

Limited Data

Also known as “7-hydroxy,” “7-OHMG,” “7,” or “legal morphine,” 7-OH makes up less than 1% of dried leaves of the kratom tree, which is native to Southeast Asia. The predominant alkaloid in kratom is mitragynine, which makes up about 60%-65% of dried leaves.

Although mitragynine also acts on opioid receptors, s tudies suggest concentrated 7-OH formulations are 13 times more potent than morphine. Research has shown that 7-OH has high abuse potential and may also increase the intake of other opiates. 

“7-OH carries a high risk for addiction — on purpose,” Jim O’Neill, deputy secretary of Department of Health and Human Services, said at the press conference. “Young people, veterans, and people who suffer from chronic pain or addiction are being misled into thinking that these are safe alternatives. They are not.”

A kratom trade association estimates as many as 12 million people use kratom, but as the new FDA report notes, data on 7-OH use is scarce. 

The National Survey on Drug Use and Health collects information on kratom use, but not 7-OH. The National Poison Data System only added 7-OH specific codes in February, limiting data collection. The FDA’s Adverse Event Reporting System does include some documented cases of adverse events thought to involve 7-OH, but investigators are unable to confirm whether other substances may have been involved in those cases. 

Although biological testing can identify the presence of mitragynine in a toxicology report, it’s impossible to discern whether the alkaloid came from kratom or 7-OH.

Although the sale of 7-OH products and anecdotal evidence suggest that misuse of the substance is occurring, “the current epidemiologic data on 7-OH exposures often lack sufficient detail to distinguish with confidence involvement of botanical kratom products from 7-OH enhanced products,” report authors wrote.

The decision to act now, even with limited evidence on misuse, is an effort to head off “another wave of the opioid epidemic,” Makary said.

“Public health is supposed to prevent disasters, not just clean them up after they’ve killed thousands and thousands of people,” he added.

No Focus on Kratom

This is not the first time the FDA has moved to restrict access to kratom products. In 2016, the agency recommended the DEA classify kratom as a Schedule I controlled substance. But within months, the agency withdrew its recommendation amid pushback from the public, industry, and even some clinicians.

This time, the FDA is focusing only on 7-OH, not kratom. 

“We’re not prepared to say anything is 100% safe, especially when it has psychoactive substances in it,” Makary said.

“There have been physicians who have had concerns about some claims around natural kratom,” he continued. “We have to prioritize what we work on so we are going after the killer first, which is the synthetic concentrated kratom, and then we can look into that other question. We think it is night and day in terms of the public health risk.”

The American Kratom Association praised the announcement from the FDA. 

“These 7-OH products are not kratom. They are chemically altered substances that carry potent opioid-like effects and pose an imminent threat to consumers,” Mac Haddow, senior fellow on public policy for the association, said in a statement. “This move sends a clear and long-overdue message: the safety of the American public comes first.”

Commenting on the announcement for Medscape Medical News, Lief Fenno, MD, PhD, chair of the American Psychiatric Association’s Council on Addiction Psychiatry, said that although banning 7-OH is a good first step, he hopes it’s not the last step when it comes to regulating kratom. 

“Kratom has been on our list for a long time,” said Fenno, who also is assistant professor of psychiatry at Dell Medical School and assistant professor of neuroscience at the University of Texas at Austin. 

“Past FDA approaches to enforcement around kratom and their long-standing policy that there can be no kratom-containing beverages or supplements really hasn’t stopped the evolution of these products,” he said. “I think it’s a really great step to take today to try to put a dent in the continued evolution and what is a growing problem with kratom dependence and 7-hydroxymitraginine dependence.”

As a clinician in an opioid addiction clinic, Fenno has treated patients who use kratom. 

“The experience the patients have with kratom is very similar to addiction to any other opioid,” he said.

Fenno has yet to see patients who report using 7-OH, but said that may change given the wide availability of product containing the concentrated substance. 

“The pressed high concentration 7-OH tablets are fairly new and I do appreciate that the intervention is happening quite quickly after they have appeared on the market,” he said. “Waiting until the cat’s out of the bag to say we want to step back seems like an approach we tried before with opioids, and it hasn’t gone very well. So I think it’s a very reasonable step to take even without a documented epidemic.”

Kelli Whitlock Burton is assistant managing editor for Medscape Medical News, covering psychiatry and neurology.