© Noppharat Manakul | 123rf.com; close up of a mitragyna speciosa (kratom) leaf
February of 2018 was not a good month if you are pro-kratom. The FDA released information on adverse events and “even stronger evidence of kratom compounds’ opioid properties.” Then the CDC announced a multistate outbreak of Salmonella infections related to kratom. Then FDA announced the destruction and recall of kratom products. And the icing on the kratom cake was the FDA stating the agency has seen their death count related to kratom increase from 36 to 44.
The February 6th statement regarding additional adverse events associated with kratom said the agency used the PHASE (Public Health assessment via Structural Evaluation) methodology to simulate how the chemical elements of kratom are structured at a molecular level, how they behave inside the body and what they potentially do to the brain. In other words, PHASE used the molecular structure of a kratom to predict how it could biologically function in the body. “The new data provides even stronger evidence of kratom compounds’ opioid properties.” The 25 most prevalent compounds in kratom all share structural similarities with controlled opioid substances such as morphine derivatives.
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”).
Additionally, the computational model predicted some kratom compounds may bind to receptors in the brain thought to contribute stress responses contributing to neurologic function in seizures and cardiovascular function in respiratory depression. And the FDA “found that kratom has a strong bind to mu-opioid receptors, comparable to scheduled opioid drugs.” What all this means is that:
The data from the PHASE model shows us that kratom compounds are predicted to affect the body just like opioids. Based on the scientific information in the literature and further supported by our computational modeling and the reports of its adverse effects in humans, we feel confident in calling compounds found in kratom, opioids.
Kratom-related deaths have increased to 44, according to the FDA. The agency said they could not fully assess many of the cases because of limited information. Additionally, some of the cases with fatal outcomes indicate kratom was not the only substance used. “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.” Particularly troubling was a new report of death where the individual had no known history of toxicologic evidence of opioid use except kratom.
Taken in total, the scientific evidence we’ve evaluated about kratom provides a clear picture of the biologic 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. And claiming that kratom is benign because it’s “just a plant” is shortsighted and dangerous.
Writing for the HuffPost, Nick Wing questioned the reliability of the FDA’s conclusions on kratom-related deaths. He stated that almost all the FDA cases involved subjects using multiple substances at the time of death, “with the vast majority including either illicit or prescription drugs that carry well-known fatal risks.” He concluded when taken together, the case reports fail to provide a clear picture of the deadly risks claimed by the agency with kratom. He gave examples from FDA case studies to illustrate his conclusions, but there was not a link in his article or the FDA press release to the case reports. And the given link in the FDA press release did not connect to the reports of the “36 deaths.”
Wing commented on the irony that many of the deaths the FDA associates with kratom also involved prescription drugs. But that seems to be part of the FDA concern, since “kratom has a strong bind to mu-opioid receptors,” meaning that when used in conjunction with other drugs, the combined adverse effects could be serious and even fatal.
Wing also said: “most of the emerging science on kratom has found it to be largely benign, especially when taken in low or moderate doses.” Andrew Kruegel, a chemist who has authored a number of studies on kratom, thought it was better to say kratom is an “atypical opioid,” given the differences between kratom and classical opioids. Kratom used alone may be less likely to lead to adverse events, but consumers need to be aware that it is an opioid. Even if it does have a better side-effect profile than classical opioids, the potential for adverse events when it’s mixed with other drugs seems to be a clear danger.
There was an FDA report, “CAERS: Kratom Deaths,” released on December 13, 2017. The case reports corresponding to the examples given in the HuffPost article could not be readily identified. But you can review the CAERS report for several examples of the dangers of kratom’s primary opioid agonist, mitragynine. Here are a few examples.
The cause of an accidental death for case # 10698706 was: mixed drug toxicity primarily mitragynine. “Despite the detection of the other compounds at therapeutic concentrations, they were considered to have additive toxic central nervous system effects in the presence of mitragynine and were therefore felt to have contributed toward the death.”
Case # 10708286 was a 17 year-old male who was self-medicating with kratom to treat a history of heroin abuse and chronic back pain. No other compelling cause of death beside mitragynine was evident. He had “a well-established history of opioid abuse, including Kratom abuse.” Kratom was present at the scene “and the active compound of this substance was identified in the decedent’s blood. Other drugs found were not felt to be significantly related to death.”
Case # 12569892 was a middle-aged man with a history of substance abuse and psychiatric problems for which he was taking medication, including Celexa, Lamictal, and zopiclone. He was being drug tested at work, so in order to avoid testing positive for a mind altering substance, he ordered kratom from the internet. He commented that his most recent batch seemed more potent than what he had previously. The concentrations of his prescription medications were within therapeutic levels and were felt to be of little significance in causing his death. There was a high concentration of mitragynine in his blood. “Mitragynine intoxication was assumed to be the main cause of death.” However, it could be that the other medications present may have enhanced the effects of the mitragynine.
When it’s used as a dietary supplement, kratom is considered to be a new dietary ingredient by the FDA. Dietary supplements typically require a New Dietary Ingredient Notification indicating the product is reasonably expected to be safe. “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.” Some individuals use it to treat pain or other medical conditions, but there are no FDA-approved therapeutic uses of kratom, while there is evidence of significant safety issues. “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.”
Some individuals use it to treat their opioid dependency. But again, there is no reliable evidence to support kratom’s effectiveness for this use.
The CDC announced on February 20, 2018 that it was investigating a multistate outbreak of Salmonella infections. “Epidemiologic evidence indicates that kratom is a likely source of this multistate outbreak.” Eight of 11 people interviewed reported consuming kratom. There were no common brands, or suppliers identified at the time of the announcement. “At this time, CDC recommends that people not consume kratom in any form. The investigation indicates that kratom products could be contaminated with Salmonella and could make people sick.” The investigation is ongoing and will be updated as more information becomes available.
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 for kratom itself.
In a February 21, 2018 FDA News Release, the agency announced the voluntary destruction and recall of a large volume of kratom-containing products manufactured and distributed by Divinity Products Distribution of Grain Valley Missouri under the names: “Botany Bay, Enhance Your Life and Divinity.” The company has also agreed to stop selling all products containing kratom. The FDA encouraged all companies involved in the sale of products containing kratom for human consumption to take similar steps to take their products off the market. FDA Commissioner, Scott Gottlieb said that some individuals use kratom believing it can help them treat their opioid dependency, “but there’s no reliable evidence to support kratom’s effectiveness for this use.” He added:
To protect the public health, we’ll continue to affirm the risks associated with kratom, warn consumers against its use and take aggressive enforcement action against kratom-containing products. We appreciate the cooperation of companies currently marketing any kratom product for human consumption to take swift action to remove these products from circulation to protect the public.
Kratom then is an unregulated substance with 23 compounds that qualify as opioids—atypical opioids if you prefer. In high enough doses it can be abused and lead to all the adverse effects common with opioids—withdrawal, cravings, anxiety, sleep disturbance, etc. In combination with other substances it can lead to overdose and death. Marketed and sold as a dietary supplement for human consumption, it varies in strength with no real way for consumers to know the strength of what they are ingesting. Sounds like something the FDA would want to regulate.
For more on kratom, see: “The Secret of Kratom,” “Kratom: Part of the Problem or a Solution?” or “What is the Future of Kratom?”