On February 06, 2018, the United States Food and Drug Administration (US-FDA) intensified its warnings about Kratom, stating that new research provides strong evidence that the unregulated botanical substance has 'opioid properties'43.
A new analysis by scientists at the US -FDA shows that compounds in Kratom act like prescription-strength opioids. The agency also said that Kratom has now been linked to 44 deaths. The agency said that over the past several months, many questions have been raised about the botanical substance known as Kratom. FDA has taken some significant steps to advance the scientific understanding of this product and how it works in the body. The agency provided details of some of the important scientific tools, data and research that have contributed to the FDA's concerns about Kratom's potential for abuse, addiction, and serious health consequences including death.
The agency recently conducted a novel scientific analysis using a computational model developed by agency scientists, which provided even stronger evidence of Kratom compounds' opioid properties. These kinds of models have become an advanced, common and reliable tool for understanding the behavior of drugs in the body. The agency also learnt more about deaths that involved Kratom use and have identified additional adverse events related to this product. This new data adds to the substantial scientific evidence supporting agency's concern about the safety and abuse potential of Kratom.
The agency has been especially concerned about its use to treat opioid withdrawal symptoms, as there is no reliable evidence to support the use of Kratom as a treatment for opioid use disorder and significant safety issues also exist. The agency further said that it recognizes the need and desire for alternative treatments for both the treatment of opioid addiction, as well as the treatment of chronic pain, and stands ready to evaluate evidence that could demonstrate a medicinal purpose for Kratom. However, to date, the agency has not received any such submissions and is not aware of any evidence that would meet the agency's standards for approval.
About Kratom
Mitragyna speciosa (commonly known as Kratom also ketum) is a tropical evergreen tree in the coffee family (Rubiaceae) native to Southeast Asia in the Indochina and Malaysia phytochoria (botanical regions). M. speciosa is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea44.
The FDA's PHASE model used to assess Kratom
The FDA developed the Public Health Assessment via Structural Evaluation (PHASE) methodology – a tool to help simulate, using 3-D computer technology, how the chemical constituents of a substance (such as the compounds/ alkaloids found in Kratom) are structured at a molecular level, how they may behave inside the body, and how they can potentially affect the brain. In effect, PHASE uses the molecular structure of a substance to predict its biological function in the body.
Using this computational model, scientists at the FDA first analyzed the chemical structures of the 25 most prevalent compounds in Kratom. From this analysis, the agency concluded that all compounds share the most structural similarities with controlled opioid analgesics, such as morphine derivatives. Next, the scientists analyzed the chemical structure of these Kratom compounds against the software to determine its likely biologic targets.
The model predicted that 22 (including mitragynine) of the 25 compounds in Kratom bind to mu-opioid receptors. This model, together with previously available experimental data, confirmed that two of the top five most prevalent compounds (including mitragynine) are known to activate opioid receptors ("opioid agonists").
The new data provides even stronger evidence of Kratom compounds' opioid properties.
The computational model also predicted that some of the Kratom compounds may bind to the receptors in the brain that may contribute to stress responses that impact neurologic and cardiovascular function. The agency has previously warned of the serious side effects associated with Kratom including seizures and respiratory depression.
The third aspect of the model is the 3-D image, the agency generated to look at, not just where these compounds bind, but how strongly they bind to their biological targets. The agency found out that Kratom has a strong bind to mu-opioid receptors, comparable to scheduled opioid drugs.
Learnings from reports of death associated with Kratom
US-FDA has been carefully monitoring the use of Kratom for several years and have placed Kratom products on import alert to prevent them from entering the country illegally. The agency has also conducted several product seizures. These actions were based, in part, on a body of academic research, as well as reports the agency has received, suggesting harm associated with its use. Numerous countries, states and cities have banned Kratom from entering their jurisdictions.
The agency also shared more information about the tragic reports it has received of additional deaths involving the use of Kratom. Looking at the information the agency has received from sources like academic research, poison control data, medical examiner reports, social science research and adverse event reports – it is reported that 44 deaths are associated with the use of Kratom.
The agency also released the reports of the 36 deaths it had referenced to in November last year. These reports underscore the serious and sometimes deadly risks of using Kratom and the potential interactions associated with this drug. Overall, many of the cases received could not be fully assessed because of limited information provided; however, one new report of death was of particular concern. This individual had no known historical or toxicologic evidence of opioid use, except for Kratom. The FDA is continuing to investigate this report, but the information it has received so far reinforces its concerns about the use of Kratom. In addition, a few assessable cases with fatal outcomes raise concern that Kratom is being used in combination with other drugs that affect the brain, including illicit drugs, prescription opioids, benzodiazepines and over-the-counter medications, like the anti-diarrheal medicine, loperamide. Cases of mixing Kratom, other opioids, and other types of medication is extremely troubling because the activity of Kratom at opioid receptors indicates there may be similar risks of combining Kratom with certain drugs, just as there are with FDA-approved opioids.
However, unlike Kratom, FDA-approved drugs have undergone extensive review for safety and efficacy, and the agency continuously tracks safety data for emerging safety risks that were previously unknown. So the agency now has better information about the risks associated with these products; and can better inform the public of new safety concerns. For example, in August 2016, the FDA required a class-wide change to drug labeling to help inform health care providers and patients of the serious risks (including respiratory depression, coma and death) associated with the combined use of certain opioid medications and benzodiazepines. In June 2016, the agency also issued a warning that taking significantly high doses of loperamide, including through abuse or misuse of the product to achieve euphoria or self-treat opioid withdrawal, can cause serious heart problems that can lead to death. The FDA also recently took steps to help reduce abuse of loperamide by requesting packaging restrictions for these products sold "over-the-counter45."
Overall, the scientific evidence of the agency provides a clear picture of the biological effect of this substance. Kratom should not be used to treat medical conditions, nor should it be used as an alternative to prescription opioids. There is no evidence to indicate that Kratom is safe or effective for any medical use. The agency further said that claiming that Kratom is benign because its "just a plant" is shortsighted and dangerous. After all, even heroin, which is derived from the seed pod of various opium poppy plants, is an illegal, dangerous, and highlyaddictive substance containing the opioid morphine. Further, as the scientific data and adverse event reports have clearly revealed, compounds in Kratom make it, even though a plant, an opioid. And this opioid is associated with novel risks because of the variability in how it is being formulated, sold and used recreationally and by those who are seeking to self-medicate for pain or who use Kratom to treat opioid withdrawal symptoms.
USFDA added that individuals seeking treatment for opioid addiction, who are being advised that Kratom can be an effective treatment, should seek help from a health care provider. There are safe and effective, FDA-approved medical therapies available for the treatment of opioid addiction. Combined with psychosocial support, these treatments are effective. Importantly, there are three drugs (buprenorphine, methadone, and naltrexone) approved by the FDA for the treatment of opioid addiction. Also, there are safer, non-opioid options to treat pain.
FDA to oversee destruction and recall of Kratom products
Further, the agency on February 21, 2018, announced the voluntary destruction and recall of a large volume of Kratom-containing dietary supplements manufactured and distributed nationwide under various brand names. The FDA said all companies currently involved in the sale of products containing Kratom intended for human consumption should take similar steps to take their products off the market and submit any necessary evidence, as appropriate, to the FDA to evaluate them based on the applicable regulatory pathway. Additionally, the FDA and the U.S. Centers for Disease Control and Prevention were also monitoring an active nationwide outbreak across 20 states of a rare type of salmonella associated with Kratom products46. This outbreak associated with Kratom-containing capsules, teas and powders, underscores the risk that harmful bacteria may contaminate these products when not subjected to manufacturing controls to eliminate that risk, in addition to the overall safety concerns regarding Kratom itself.
Conclusion:
The U.S. Food and Drug Administration is warning consumers not to use Mitragyna speciosa, commonly known as Kratom. FDA is concerned that Kratom, which affects the same opioid brain receptors as morphine, appears to have properties that expose users to the risks of addiction, abuse, and dependency. Further, the agency has reiterated that currently there are no FDA-approved uses for Kratom.
Footnotes
43. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm595622.htm
44. https://en.wikipedia.org/wiki/Mitragyna_speciosa
45. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm594443.htm
46. https://www.fda.gov/Food/RecallsOutbreaksEmergencies/Outbreaks/ucm597265.htm
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