Kratom, a derivative of an Asian evergreen tree, that contains the stimulant mitragynine and narcotic 7-hydroxymitraginine, is used by as many as 5 million people in the United States. The substance has been touted as an alternative approach to pain management.
However, some have suggested it shares many of the harmful effects associated with opioid use and that some products made from kratom are contaminated with salmonella.
The latter of these concerns culminated in the historical development of April 3, when the FDA issued a mandatory recall for all food products containing powdered kratom manufactured, processed, packed, or held by Triangle Pharmanaturals LLC. The agency said it was the first-ever mandatory recall because a company failed to comply with the agency’s request to conduct a voluntary recall.
“We … have serious concerns about the safety of any kratom-containing product and we are pursuing these concerns separately,” FDA Commissioner Scott Gottlieb, MD, said in announcing the recall.
Gottlieb’s comments alluded to the alarm the FDA sounded well before the April 3 announcement.
“At a time when we have hit a critical point in the opioid epidemic, the increasing use of kratom as an alternative or adjunct to opioid use is extremely concerning,” he said in a November statement, citing 36 deaths and a 10-fold increase in calls to the nation’s poison control centers from 2010 to 2015 that were linked to kratom-containing products.
The discussion about kratom grew louder earlier this year, when Gottlieb announced on Feb. 6 that a computational model produced “stronger evidence of kratom compounds’ opioid properties.”
A few weeks later, he announced that a large number of kratom-containing dietary substances were recalled by a Missouri-based manufacturer and destroyed. He encouraged other companies who make products with kratom to remove them from the market and have them go through the FDA regulatory process. The agency has also accused a California-based company that produces kratom products of making “misleading statements about its compliance with FDA regulations.”
“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,” the FDA stated in a press release.
“Additionally, kratom should not be used to treat any medical conditions, nor should it be used as an alternative to prescription opioids. There are currently no FDA-approved therapeutic uses of kratom and importantly, the FDA has evidence to show that there are significant safety issues associated with its use,” the FDA added.
The CDC has also expressed concerns about kratom, advising that it not be consumed in any form due to the substance being the “likely source” of at least 132 cases of salmonella across 38 states.
“People should talk to their health care provider before taking any supplement, especially if they are in a group more likely to get a severe Salmonella infection,” the agency said.
The concerns raised by the FDA and CDC are being borne out in practice.
Aside from the potential for infectious agents in the commercial compound, the entity itself may have serious organ toxicities.
“I saw a patient with very abnormal liver function that had been taking kratom to deal with the stress from his law school exams and had very serious liver injury as a result,” Bruce Chabner, MD, clinical director emeritus and professor of medicine at Massachusetts General Hospital Cancer Center, told Healio Family Medicine. “This patient recovered, thank goodness, but it could have been devastating.”
According to Chabner, who also reported on the case in The Oncologist, the 23-year-old man had taken 85 g of a powdered form of kratom for 6 weeks. The patient experienced dark urine, painless jaundice and light stools for 4 days, 1 week after he stopped using the substance. A few other cases of liver toxicity due to kratom have been reported.
“Kratom is not a well-studied compound and it is thus dangerous to take,” Chabner said. “If patients buy it directly off the shelf, there is no guarantee it’s going to be safe.”
A report in the American Journal of Emergency Medicine found tachycardia, altered mental status, seizure, agitation and central nervous system depression were the clinical effects reported in kratom-related calls to a regional poison center from Jan. 1, 2002 to Nov. 30, 2016.
CDC researchers looked at calls made to poison centers nationwide and determined that 660 were made from January 2010 to December 2015. “Isolated” kratom exposure was linked to 428 of the calls, with the others reporting the kratom had been combined with acetaminophen, benzodiazepines, other botanicals, and narcotics. The report, which appeared in MMWR, also indicated that 49 of the calls were linked to patients that had resulted in life-threatening signs or symptoms and one person who took kratom along with paroxetine and lamotrigine died. CDC researchers also found kratom exposure linked to signs of agitation or irritability, drowsiness, nausea, hypertension and tachycardia.
Other research shows that even patients who use kratom in an attempt to break themselves of their opioid addiction face potential medical problems.
A case report in a 2008 issue of Addiction authored by Edward W. Boyer, MD, of the division of medical toxicology at the University of Massachusetts Medical School, and colleagues, detailed how a 43-year-old man admitted for evaluation of a generalized tonic-clonic seizure who had also said he would inject 10 mg hydromorphone a day from crushed pills subcutaneously to manage the pain caused by his thoracic outlet syndrome. When that treatment was not available, these authors wrote, he managed opioid withdrawal with kratom purchased from internet vendors, eventually spending $15,000 a year on the substance.
According to Boyer, during the patient’s care following the tonic-clonic seizure, a physician noticed that rhinorrhea, insomnia, poor concentration, constricted affect and myalgias persisted for 10 days following the patient’s last kratom dose.
Kratom’s advocates cite those who use it to treat opioid use disorder, the epidemic that the CDC has said claims an estimated 115 lives a day and is responsible for 30% of overdoses in EDs across the country.
“Recent studies indicate that kratom users are reporting pain relief, mood elevation and anxiety reduction. Some individuals who wish to abstain from opioids are reporting that kratom has enabled them to do so by easing opioid withdrawal symptoms and decreasing cravings for opioids,” Marc T. Swogger, PhD, associate professor, department of psychiatry at the University of Rochester Medical Center and co-author of a Drug and Alcohol Dependence article last year about kratom’s risks and benefits. He acknowledged in an interview that kratom research is still in its infancy, but said he thinks there are many positives surrounding its use.
“As a social scientist I can merely summarize the existing data. I see no good evidence that kratom is ‘deadly’ and the overall data suggest that kratom is a relatively mild plant that is helping people … and is an important tool for fighting the opioid problem. An estimated three to five million people in the U.S. are using kratom, and if access is restricted people may return to opioids and some will die. It is insane to restrict access based on what we know right now.”
Kratom has been linked with withdrawal syndrome, but Swogger said this is typically only found in those who take doses of more than 5 g, and 21 doses a week.
“This syndrome is physically uncomfortable and significantly affects mood, but it is not generally harmful and is mild relative to classical opioid withdrawal.”
Swogger also commented on the FDA’s announcements on kratom.
“From a scientific standpoint, these announcements make little sense unless one is trying to conjure hysteria. The model that the FDA has used to call kratom an opioid has been heavily criticized by top scientists,” he told Healio Family Medicine.
Others outside of the FDA raised questions with how that agency has attempted to restrict access to kratom.
Jack E. Henningfield, PhD, is an adjunct professor at Johns Hopkins University and vice president for research, health policy and abuse liability at Pinney Associates. He is currently a consultant to the American Kratom Association and had previously provided pro bono support to the same group in their efforts to prevent the Drug Enforcement Administration from banning kratom. Henningfield also worked on dietary supplement notifications for kratom products in an effort to get FDA to regulate kratom as a dietary supplement.
He told Healio Family Medicine FDA regulation on kratom is “vital” and that regulation of the substance as a dietary supplement was a viable approach to keep kratom available with some regulatory oversite.
“The FDA and DEA received more than 20,000 testimonials in 2016 alone from a cross-section of America that said kratom is working for them,” Henningfield said in an interview. “Four different surveys show that some fraction of respondents use kratom to stop using opioids.”
“For the FDA to deny people the chance to use kratom in spite of the evidence is flat out ignoring the reality and very scary. When someone has a lifeline away from addiction, whether it’s an approved treatment or not, if it’s working you don’t take it away, because if you do, then the risk of slipping back into addiction starts all over again,” he continued. “If someone fell into the lake with a life preserver and said they couldn’t swim, are you going to take away their life preserver?”
Another scientist who questions the FDA’s approach to its classification is Walter C. Prozialeck, PhD, professor and chair of the department of pharmacology, Chicago College of Osteopathic Medicine at Midwestern University, who told Healio Family Medicine he has a problem with what the FDA calls its “sound science,” and compared it to “a game of semantics.”
“The FDA has taken the position that since the compounds in kratom can bind to opioid receptors, kratom is an opioid. I’m not sure that is a correct assumption. For example, Narcan, which is used to treat opioid poisoning binds to opioid receptors, but no one calls Narcan an opioid.”
Prozialeck was one of the first to recognize that interest in kratom was growing. He co-authored a 2012 paper in the Journal of the American Osteopathic Association on kratom. The article also provided an overview of usage for the substance such as fatigue, diarrhea and cough. He also provided information on its legal status and additional potential medical uses of kratom including fighting off fatigue and managing coughs.
Prozialeck published another paper in the same journal in 2016, which included what he called the “most controversial development” between the publishing of his two papers: the DEA’s announcement in December 2016 of its intention to make kratom a Schedule 1 controlled substance. In so doing, kratom would be put in the same category as substances such as marijuana, LSD and heroin. However, The Washington Post reported that the DEA yielded to protests from the public and lawmakers and withdrew the plan.
“Many advocates of kratom … have argued that kratom should be regulated under the Dietary Supplement Health and Education Act of 1994 rather than the Controlled Substances Act. The DEA has backed off for the time being, but I do not know how long the FDA will,” O. Hayden Griffin, III, PhD, JD, associate professor of criminal justice at the University of Alabama at Birmingham, told Healio Family Medicine.
“Kratom has operated in a grey area of the law and since there are no regulations for sellers of the drug, it is hard to tell which sellers of kratom are reputable and which are not. That is the real problem,” he continued. “There is evidence that kratom is effective, but there are no companies lining up to go through the approval process because not only is it expensive, but how do you market and patent a naturally growing plant that has been around for hundreds if not thousands of years?”
Griffin added he was not in favor of placing kratom in Schedule 1, saying that doing so would effectively ends research into the substance.
Prozialeck agreed with much of Griffin’s comments, saying it is hard for him to agree with the DEA’s proposal.
“Just the number of deaths the DEA is attributing to kratom — 44 deaths in 5 years — seems disproportionate. All but one of those kratom deaths had other factors such as existing diseases or conditions like CVD, epilepsy or multiple drug use such as stimulants and alcohol. To me, kratom just doesn’t seem as dangerous as the DEA is saying,” he said.
FDA and DEA’s stances keep more patients and medical professionals from seeing kratom’s potential, Prozialeck added.
“There is overwhelming anecdotal evidence from humans that something in kratom can alleviate pain, can suppress symptoms of opioid withdrawals. Though those are only anecdotal, it is difficult to ignore that volume of information. Secondly, there are animal studies that show the chemicals isolated from kratom can alleviate pain and the symptoms of opioid withdrawal. Those studies, even though there are not a lot of them, should not be completely ignored.”
Other clinicians and professionals who have researched kratom told Healio Family Medicine the polar opposite views being expressed in the debate pose their own set of dangers to people, and that a common ground must be found.
“We currently have unfettered access to a product with addiction potential, an unknown safety profile, and potential for serious drug interactions (including access to children). This is madness. We clearly need a better system,” C. Michael White, PharmD, FCP, FCCP, of the department of pharmacy practice at the University of Connecticut, said in an interview.
“The FDA and DEA want to replace this poor paradigm with a complete ban. This is also dangerous because it denies a therapy that many people are currently using for opioid maintenance therapy or chronic pain that they rely on or to which they are addicted. Making it illegal or shutting off the legal supply by forcing recalls will push some law abiding citizens to use illegally smuggled kratom or even worse, use heroin or illicit fentanyl.”
White authored a paper that appeared in the American Journal of Health System Pharmacy that underscored the need for more research on kratom, saying the existing clinical, pharmacokinetic, and pharmacologic data is inadequate.
“Kratom is a unique drug with opioid and nonopioid mechanisms of action and in animal studies has a low risk of stopping breathing, the main mechanism of death for other opioids. There has to be a middle road that allows kratom to be available while the serious research that needs to be done can be completed. Access should be restricted for recreational use and to children but allowed for chronic pain and opioid addicted people. Pending those study results, the availability is maintained, eased, or lessened,” he told Healio Family Medicine.
“We have to have the courage to find a compromise solution that gives us reasonable safety and reasonable access. I have not heard much support from either entrenched parties for a compromise and that means to me that either way, innocent people are going to get hurt,” White added.
Others, such as Kirk L. Cumpston, DO, FACEP, FACMT, of the department of emergency medicine at the Virginia Commonwealth University’s Medical Center and co-author of the study that looked at the calls to the regional poison center, also noted the medical limbo that lack of research on kratom presents.
“The problem is not whether kratom is good or bad, but that it is an unregulated, unresearched, herbal substance. We don’t really know if it is effective or about its side effects like we know about drugs that are FDA-approved,” he told Healio Family Medicine. “Because of this knowledge gap, people are exposing themselves to risk when trying to self-treat with kratom.”
FDA, DEA respond
A FDA official told Healio Family Medicine established federal and scientific processes mean the door has not completely closed on kratom use.
“While we remain open to the potential medicinal uses of kratom, those uses must be backed by sound science and weighed appropriately against the potential for abuse. They must be put through a proper evaluative process that involves the DEA and the FDA. For those who believe in the proposed medicinal uses of kratom, the agency encourages research that will help us better understand kratom’s risk and benefit profile, so that well studied and potentially beneficial products can be considered,” a FDA spokesperson said.
“What’s important to remember is that there are no scientific data from studies of kratom in humans. Kratom should not be used to treat any medical conditions, nor should it be used as an alternative to prescription opioids,” the official continued. “There are currently no FDA-approved therapeutic uses of kratom and importantly, the FDA has evidence to show that there are significant safety issues associated with its use. Before it can be legally marketed for therapeutic uses in the U.S., kratom’s risks and benefits must be evaluated as part of the regulatory process for drugs established by Congress.”
For its’ part, a DEA spokesperson acknowledged the “continuing debate within the scientific community” on kratom in an interview with Healio Family Medicine and also noted that its evaluation of kratom is still ongoing.
“We do not have a timetable to share on when a scheduling decision will be made,” the official added. “DEA continues to consider kratom to be harmful and dangerous and has included kratom on its list of drugs of concern since 2011. Both mitragynine and 7-hydroxymitraginine are substances with opioid effects whose use may result in serious negative outcomes and accordingly, DEA would advise anyone against using this substance for its psychoactive properties.”
The FDA spokesperson said patients needing treatment for opioid use disorder already have viable legal options, and more such therapies could be forthcoming.
“There are three FDA-approved products [buprenorphine, methadone, naltrexone] that are safe and effective for the treatment of opioid use disorder and we encourage patients to seek advice from their health care professional and pursue treatment for addiction,” the spokesperson said in the interview.
“Additionally, the FDA is taking new steps to bring new, safe and effective, FDA-approved therapies to the market for treatment of opioid use disorder. We understand that patients suffering from opioid addiction need access to effective treatment options. Creating an efficient pathway for the development of these treatments is a very high priority for Commissioner Gottlieb.”
Advice for patients
Primary care providers must help their patients make informed decisions when it comes to kratom, Cumpston said, and even then, may want to encourage patients to think twice about recommending it, especially when it comes to opioid addiction.
“If a patient is using or wants to use kratom, providers need to educate them about the risks and benefits, just like any other herbal product. In my opinion, the combination of FDA-approved drugs to treat addiction and therapy from addiction specialists is known to be safe and effective, so kratom users are taking unnecessary risks.”
White said that despite the benefits of kratom, there are many things to be considered before suggesting it to patients.
“First ask them why they want to use it. If it is for recreational use I would advise against it because the benefits are very low and the risks are not well established but preliminary evidence suggests it could be serious injury or death,” he told Healio Family Medicine.
“If the patient wants to take kratom for chronic pain find out what other medications he or she has previously tried before and what kind of pain they have. If a person has had bad experiences with prescription opioids before and its either opioids or kratom as treatment options, then I would bring kratom into the discussion.”
“However, keep in mind that those who are on kratom cannot fall off the wagon and use other opioids because of the drug interaction potential. So recommend the lowest dose of kratom you can and use it as sparingly as possible,” he added.
Griffin, the associate professor of criminal justice, co-authored a study that was published in the Journal of Psychoactive Drugs that conducted laboratory tests on 15 different products that were advertised on the internet as kratom or came up when the term ‘kratom’ was searched.
He and his colleagues found all of the products contained the stimulant mitragynine on their label, but the narcotic 7-hydroxymitraginine was not found. However, these authors also pointed out that previous studies have shown the small quantities of this chemical in kratom can make it difficult to identify.
“Keeping this in mind, our results suggest that a user of any of the products purchased for the current study would be unlikely to significantly harm themselves,” Griffin and colleagues wrote.
Despite his skepticism about the FDA’s approach to kratom and lack of clear evidence of its potential for harm, Prozialeck said he would not encourage primary care physicians to recommend kratom to their patients.
“It is the wild west out there when it comes to some types of kratom and kratom-related products. There is a lack of standardization and quality control surrounding the manufacturing these items. People who buy kratom, and what’s reported to be kratom, don’t always know what they are getting. “If you have a patient who is going to insist on taking kratom, advise the patient to be careful and use a reputable brand,” he said. – by Janel Miller