A look at the ‘Wild West’ of synthetic kratom, which doctors are calling ‘more potent than fentanyl’

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Philadelphia emergency room physician Dr. Jeanmarie Perrone was on duty on a recent Sunday, when a man came in suffering from a host of symptoms — nausea, stomach pain, sweating, restlessness and flu-like body aches.

Perrone, who directs the Penn Center for Addiction Medicine and Policy, clocked the cause immediately.

“It looked really like fulminant opioid withdrawal,” she said, “had all the components of opioid withdrawal.”

The patient did have a history of opioid use disorder, but he was in recovery. This time, the culprit was something different: a drug called 7-Hydroxymitragynine, better known as 7-OH, a synthetic version of kratom.

Kratom is usually advertised as a safe herbal supplement that’s used as an energy booster, pain reliever and, crucially, an aid for quitting opioids. But addiction specialists and researchers say that 7-OH is a different, more potent and much more dangerous beast.

“Kratom was one problem, but that was a lower dose of exposure of the compound that binds to the mu-opioid receptor,” Perrone said. The mu-opioid receptor is the primary target for our bodies’ own endorphins and also opioids like morphine and fentanyl.

“Once they started concentrating it in these 7-OH products, it was really replicating a full opioid,” she said.

For Perrone, this came into clear focus when she saw how her ER patient reacted to the treatment she administered.

“I gave him one dose of buprenorphine, or suboxone, in the emergency department and all of his symptoms went away,” she said. “So, you know, to be able to use an opioid use disorder treatment on somebody with 7-OH use really solidifies for me — eyes open — that this is really the same problem.”

From kratom to 7-OH: how a traditional herbal remedy evolved into lab-made drugs

When addiction psychiatrist Corneliu Stanciu first started looking into kratom in 2013, it was, he said, “a very different landscape compared to now.”

“I tried to put out some public education alerts and nobody was interested,” said Stanciu, an assistant professor of psychiatry at the Geisel School of Medicine at Dartmouth. “They’re like, ‘Who cares about this?'”

Back then, we were still in what Stanciu characterizes as the “first wave” of kratom use here in the U.S.

Kratom originally hails from southeast Asia, where, Stanciu says, people have used it for centuries as a kind of herbal remedy for the ailments of every life.

“It’s something that’s been embedded in their culture,” Stanciu said. “They smoke it, chew it, maybe brew it as a tea, to a lesser extent smoke it. It gives them energy, helps with pain. A very natural modality.”

And, importantly, he said that kind of usage has led to few-to-no fatalities or significant side effects.

It was in a similar form that kratom first arrived in the U.S. in the early 2000s — as a powder made from the dried leaves that people could take with water, or brew into a tea.

It quickly gained traction as a way of helping people get off of heroin or other opioids.

In lower doses, kratom functions like a stimulant — but in larger doses, it has an opioid-like effect that can help ease withdrawal symptoms, without the same risk profile of traditional opioids, making it an attractive option for people struggling with opioid addiction.

“And it was effective,” Stanciu said. “It’s pretty challenging to overdose on it or to have any type of toxicity when used that way.”

That all changed around 2015, with the introduction of a second wave of “enhanced” kratom products.

“Vendors got smarter and they noticed, ‘OK, maybe we can enhance kratom,'” Stanciu said. “So what they did is they increased the amount of a very potent ingredient in kratom, which is 7-OH.”

Although only present in small amounts in the leaves of kratom, 7-OH is produced by the body as a byproduct of mitragynine, the primary psychoactive alkaloid in kratom. Mitragynine itself has an opioid-like effect, but 7-OH took that effect to the next level.

Since that time, kratom poisonings have surged by 1,200%, according to a recent Centers for Disease Control and Prevention report, aided by the third wave of kratom products, which Stanciu characterizes as “products that look absolutely nothing like kratom.”

“You have things like mitragynine pseudoindoxyl, which is not found in the kratom leaf,” he said.

Like 7-OH, mitragynine pseudoindoxyl is produced by the body in small quantities — 7-OH as a metabolite of mitragynine, and mitragynine pseudoindoxyl as a metabolite of 7-OH.

In the forms they’re sold as, however — which are partially, if not totally, synthetic — both are leagues more potent than what’s produced in the body as metabolites.

And just as 7-OH is like kratom on steroids, mitragynine pseudoindoxyl is like 7-OH on steroids.

“It’s highly potent — more potent than fentanyl,” Stanciu said of mitragynine pseudoindoxyl. “And they sell it as kratom, even though it has nothing to do with the kratom plant itself — doesn’t resemble the composition, doesn’t resemble anything.”

Both 7-OH and mitragynine pseudoindoxyl are sold in multiple, sometimes even kid-friendly forms, including as tablets, capsules, liquid shots, tinctures, drinks and candy — all unregulated.

“Currently, the market is basically a Wild West,” Stanciu said. “You have everything out there being called kratom, even though it’s not kratom.”

Not all users are understanding that fact, however — while others may seek synthetic products out intentionally.

Stanciu saw one patient who advanced from kratom to 7-OH to mitragynine pseudoindoxyl, in search of greater potency.

“And then when he came to me, he experienced very, very distressing withdrawal symptoms that occurred very suddenly and definitely required some aggressive intervention,” he said. “More than, say, someone that was withdrawing from fentanyl.”

A growing problem

When kratom first started gaining traction in the U.S. two decades ago, its popularity was largely fueled by people trying to quit opioids. Many either wanted a more natural way of combating cravings and withdrawal symptoms, or found kratom, which exists in a legal gray zone, to be more accessible than medication-assisted treatments, like methadone.

But in the years since, the popularity of kratom — and its synthetic derivatives — has spread.

“Now we’re seeing individuals who have never used anything in the past get into [these products],” Stanciu said. “You have people who don’t have any substance use issues gravitating towards them.”

Perrone said that part of that may be simple curiosity — and accessibility.

“People see the shops on almost every corner around Philadelphia or anywhere,” she said. “It’s like bubble tea.”

Others seek out kratom or its derivatives to help deal with mental health symptoms, or for energy.

“There is an activating component to opioids, and that’s what people talk about with kratom,” Perrone said. “It helped them at work. It helped them with long hours. It helped them work two jobs. In the beginning, that’s a very enticing aspect of using a drug.”

Over time though, dependence can form, which means users require more or stronger doses to get the same effect. And that’s led a growing number of people to move on to 7-OH and the stronger, but less prevalent, mitragynine pseudoindoxyl.

“What concerns us and me most is that, particularly with the 7-OH, there has been such a surge in access to it and use of it,” Perrone said, citing the recent spike in calls to national poison centers, and reports from her colleagues of increasing numbers of patients seeking treatment for kratom and 7-OH addiction. “And this is really almost like in the beginning of the prescription opioid epidemic, except you don’t need a prescription. These drugs are addictive like an opioid.”