07/27/21

A Regulated Kratom Policy

On August 31, 2016, the DEA announced its intent to temporarily place kratom into Schedule I. This meant that in the DEA’s view, there was no currently accepted medical use for kratom and a high potential for abuse. This led to an immediate and aggressive public backlash. There was a demonstration near the White House, phone calls to Congress, a petition protesting the proposed scheduling with over 100,000 signatures. On October 13, 2016, the DEA announced it would withdraw its intent to temporarily Schedule kratom because of “numerous comments from the public,” but the debate over kratom scheduling was not over just yet.

Natural Products Insider reported that in 2018 the U.S. Department of Health and Human Services, (HHS) officially rescinded the DEA’s request to classify two constituents in kratom, mitragynine and 7-hydroxymitragynine, as controlled substances. But this letter from HHS to DEA was not released to the public until January 2021, when it was made public by The American Kratom Association (AKA). The letter said, “HHS is instead recommending that mitragynine and 7-hydroxymitragynine not be controlled at this time, either temporarily or permanently, until scientific research can sufficiently support such an action.” However, the FDA is still concerned about kratom, as kratom products have been associated with significant safety concerns.

An FDA spokesman said, “While it is important to gather more evidence, data suggest that certain substances in kratom have opioid properties that expose users to the risks of addiction, abuse and dependence.” While the HHS letter did recommend against scheduling kratom, it also stated it was possible that new data and evidence could support scheduling the chemicals in kratom at some future time. “Kratom may have harmful effects, particularly when used with other drugs.” Mitragynine and 7-hydroxymitragynine have many of the properties of an opioid; and enhancing public awareness “that kratom contains molecules that may be potentially dangerous” was encouraged by the HHS.

NPR broadcasted “The Kratom Debate” on its program, Morning Edition. Linda Kline, the owner of Bumble Bee Botanicals, credited kratom with helping her with her mental health. “I went from feeling desperate and hopeless to finding an alternative where I had full control over how I felt.” She couldn’t always find a high-quality supply of kratom, so she began selling kratom herself and now has several stores in California, Idaho and Nevada.

There also was the story of Marco, who struggled with an opioid addiction in high school. He became hooked on painkillers after his dentist pulled his wisdom teeth. Eventually, when he wanted to kick his opioid addiction, he tried kratom and was eventually using multiple kratom capsules daily. During his freshman year at college, he started hyperventilating regularly. The incidents worsened, and led to seizure-like episodes and trips to the emergency room. The doctors were stumped; no one thought to test for kratom.

Marco died in his UC Davis dorm in February 2018, late on a Sunday night. The toxicology report listed “acute mitragynine intoxication” — a chemical constituent of kratom — as the cause of death.

Michael White, of the Department of Pharmacy Practice at the University of Connecticut said, “The data to support either the benefits or the harms for kratom is really, really poor.” He went on to say much of the information available comes from single-case reports. White thought scientists needed to conduct more research before the appropriate level of regulation become clear. He suggested placing it behind the pharmacy counter as with pseudoephedrine.

McLain Haddow, a spokesperson for the American Kratom association thought kratom should only be sold to adults. Haddow added that some manufacturers were adding fentanyl, heroin or morphine to their products to give users a high. “We would like vendors to register their product with the FDA and get a chemical analysis from a certified lab to ensure the only ingredient is the naturally occurring alkaloid in the kratom plant.”

Dr. Scott Steiger, the deputy medical director for an opiate treatment outpatient program said he did not know how to advise patients who wanted to try kratom. “I tell them I just don’t know enough on the basis of science to tell them whether it’s a great idea or not.” He added he’d seen people who use kratom and end up having a very hard time stopping. He doesn’t recommend self-medicating with kratom until more research is available. “We just don’t know enough about this chemical and the long-term use of it to know whether experimenting would lead to complications.”

A Wired article, “Release the Kratom,” said, “They are using the drug for everything from chronic pain relief to replacement for their morning coffee.” People also use it to improve their eye sight, clear up their skin boost their immune systems, or just get high. Some addicts use it to manage or help them get away from their addiction. Faith Day, a kratom business owner in Portland and former addict, said a third of her clientele were looking for a caffeine-free alternative to get through the day: “I’m talking soccer moms.”

According to Oliver Grundmann, who studies the effects of herbal products on the central nervous system, interest in kratom didn’t become widespread in the US and Europe until the mid 2000s. Grundmann has authored or coauthored several studies of kratom (see here and here), including “Kratom policy, The challenge of balancing therapeutic potential with public safety.” All the article’s authors are engaged in various aspects of kratom research “and it is our intention to provide a fair and balanced overview that can form the basis for informed decision on kratom policy.”

Citing data from the American Kratom Association, the authors said there were more than 1 million kratom users in the US. Given the widespread use of kratom and the extensive media attention it is receiving, the authors said policy makers need to be knowledgeable about the science of kratom. In their article, they sought to answers questions such as: should kratom be classified as an opioid; was it safe; is it effective for pain and OUD management; how serous are the abuse and addiction potentials?

Because of its ability to interact with opioid receptors, mitragynine is often referred to as an “opioid.” Yet it produces physiological, biochemical and behavioral effects that differ from classical opioids. “In light of this evidence, mitraginine and its analogs can best be described as ‘atypical opioids.’”

The authors reported that when used in its traditional context, pure kratom was unlikely to produce serious adverse effects in most users. “In fact, there have been no reported deaths attributed to kratom in Southeast Asia when used in the traditional setting as unadulterated, pure kratom leaf.” At low to moderate doses of 5 g of raw kratom leaves or less, the adverse effects generally seem mild, but can vary between persons. More troubling and serious toxicities are often associated with high dose usage or using concentrated extracts.

The lack of regulation and standardization related to the production and sale of “kratom” products are compounded by unscrupulous vendors selling kratom products adulterated with potentially toxic drugs. “Probably the most notorious example of such adulteration involved a product known as ‘Krypton’, which was touted as a very potent form of kratom.” Sold mainly in Europe, it was a factor in at least nine deaths. Detailed forensic analysis revealed that Krypton was adulterated with the synthetic opioid, O-desmethyltramadol. See “Krypton Can Kill You.”

The unregulated sale of kratom via the internet and deceitful marketing practices may have prompted some individuals to use kratom as a recreational drug. This poorly regulated market, wide distribution, and reported risks of toxicity associated with kratom use, are all likely to have encouraged regulatory agencies to suggest the removal of this product from the market.

While kratom has not been evaluated in the typical controlled clinical trials required by the FDA, many individuals believe it to be a safe and effective alternative to prescription or illicit opioids. “Nonetheless, kratom has a long history of such use that is widely accepted in the general population in Southeast Asia, where it is commonly used as an affordable substitute for street heroin or other opioids.” More than 23,000 comments to the DEA and FDA indicate many Americans have used kratom to relieve withdrawal symptoms and eliminate addictions to licit and illicit opioids.

Thus, even though we do not make the claim that kratom should be viewed as a medically proven effective and safe therapy for OUD, we believe it is warranted to take seriously the extensive user reports and analytical surveillance indicating many people are self-managing their OUD using kratom.

Regular use of kratom, especially at higher doses, can lead to tolerance and dependence. But it seems that abstinence from kratom is typically associated with milder symptomatology than abstinence from classical opioids. Even at high doses, kratom does not seem to severely depress respiration as do classic opioids. “Thus, even though kratom has some potential for abuse and dependence, several investigators have concluded that kratom has both less abuse liability and much lower risk of fatal overdose than traditional opioids.” The study authors said the potential benefits may outweigh the risks.

Kratom is widely used in the West and Southeast Asia as a relatively safe herbal supplement (traditional medicine) for the self-treatment of medical disorders, including pain and OUD. Extensive reports from kratom users, considered alongside limited basic science and clinical research studies, suggest that kratom and its constituent compounds (especially mitragynine) may in fact have beneficial pharmacological and therapeutic properties. Unfortunately, no well-controlled clinical trials have been performed to date to determine the true risks and benefits of kratom use in humans. The high monetary costs of such clinical trials greatly complicate this issue, given that sufficient intellectual property protection to justify the large capital investments necessary for formal drug approval is often challenging to obtain for natural products like kratom.

The conclusions of the authors from their analyses are: (a) kratom and its main constituent alkaloid, mitragynine may be useful for alleviating pain and managing symptoms of opioid withdrawal; (b) while kratom lacks many of the toxicities of classical opioids, there are legitimate concerns about the safety and lack of quality control over “kratom” products being sold in the US; and (c) the issues regarding the safety and efficacy of kratom and mitragynine can only be resolved by further research.

The poorly regulated market, the growing use and reported risks with kratom call for greater oversight or regulation. The suggestions noted above by McLain Haddow of the American Kratom Association are a good start. Both sides of the kratom debate agree that more scientific research is needed and the publication of “Kratom policy” described and linked above is a good start in that direction. Listing kratom as a Schedule I substance at this time will limit the ability to do quality research into the benefits and risks with kratom as it has with marijuana. The abuse and dependence liability with kratom and so-called “kratom” products is real and needs to be investigated with open eyes and not simply minimized.

It’s time for a regulated kratom policy. Let’s not repeat the mistake we made with marijuana by scheduling it before the scientific research supporting its listing can be done.

07/16/19

Noose Tightening On Kratom

The “Noose Tightens Around Kratom” as the DEA and FDA continues to underscore concerns with the herbal product. The FDA warned consumers not to use kratom, as it effects mu receptors, the same receptors as opioids, and seems to have properties “that expose users to the risks of addiction, abuse, and dependence.” The DEA listed kratom as a “drug of concern” several years ago, but it continues to be unregulated and sold as an herbal supplement after the agency backed away from Scheduling it and limiting its ability to police it. See “Kratom: Part of the Problem or a Solution?” The FDA’s ability to regulate herbal products is limited to concerns with the safety of kratom and preventing vendors from making overt, unapproved health claims.

As a dietary supplement kratom is not subject to the same safety regulations as other drugs. However, the FDA has persisted in doing what it can to monitor companies that sell this herbal product and so-called “dietary supplement.” The FDA ordered a recall of some kratom products because of Salmonella contamination in April of 2018. In May of 2018 the agency accused three sellers of kratom products of making unapproved health claims.

The FDA continues to warn consumers not to use Mitragyna speciosa, commonly known as kratom, a plant which grows naturally in Thailand, Malaysia, Indonesia and Papua New Guinea. The 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 dependence. There are no FDA-approved uses for kratom, and the agency has received concerning reports about the safety of kratom.The FDA is actively evaluating all available scientific information on this issue and continues to warn consumers not to use any products labeled as containing the botanical substance kratom or its psychoactive compounds, mitragynine and 7-hydroxymitragynine. The FDA encourages more research to better understand kratom’s safety profile, including the use of kratom combined with other drugs.

MedPage Today noted the FDA included kratom on “import alerts” in 2012 and 2014, which allowed it to seize kratom and kratom products worth over $5.5 million in 2014 and 2016. Several suppliers reported having tons of kratom seized during that time. There were no further seizures for a while, but they seem to be sporadically occurring again as kratom companies adjusted their marketing strategies. A Denver company, Kratom Café USA, reported recently that its order of kratom was seized by the FDA. When the FDA began tightening its restrictions, the company revised its website. Kratom Café USA now claimed it sold kratom for aromatherapy and making candles. Despite the benefits section of their website having the following disclaimer, the FDA detained 540 kilos of kratom on November 30, 2018:

We make no claims that kratom cures, prevents or treats any disease or ailment. Keep this product out of the reach of children. Kratom is not a dietary supplement, but a precise amount of an ingredient sold as a raw materials and/or bulk herbs. All information provided has not been evaluated by the FDA, and all kratom products on this site are sold for horticultural, educational and scientific use.

But what is the real story? Nicolas Moodley, the owner of Kratom Café USA, said he thought the FDA’s action was “government overreach” and a violation of his rights. Besides, he added, it was taking a toll on his business. Moodley himself became dependent on opioids as the result of chronic pain from his work as a roofer. He credited kratom with relieving his pain and helping him kick the opioid habit. Now take a look at some of the Testimonials on Kratom Café USA:

Gabe T. said: “I love to use kratom for working out and for chilling out. Your powder is off the hook! I don’t mind paying a little more to get 5 time the potency and nearly lasts twice as long.” Richard G. said: “I have been using kratom for a few years now for anxiety and mood swings. It has worked okay from some head shops I buy from. The first time I used your product I was amazed how much more effective & smooth it is. Your kratom is the best I have EVER used.” This does not sound like Moodley’s customers are using kratom bought from him for aromatherapy and candle making.

An article published in Clinical Toxicology analyzed exposures to kratom reported to poison control centers (PCCs) in the U.S. from 2011-2017. Kratom exposure increased over fifty-fold, from 13 exposures in 2011 to 682 exposures in 2017. “Almost two-thirds (65%) of these exposures occurred during 2016-2017.” Most exposures were with adults 20 years old and above (65%) and most were with males (70.8%). Exposure rates by state were highest in Idaho and Oregon and lowest in Delaware and Wisconsin. “There were seven neonatal exposures reported during the study period and five were attributed to kratom withdrawal.”

Clinical effects observed for single-substance kratom exposures among the neonates included agitation/irritability, diarrhea, and hyperventilation/tachypnea. These neonatal withdrawal cases suggest that transplacental transfer is possible and that healthcare providers should educate pregnant women on the risks of kratom use during pregnancy. Notably, although not in a neonate, one exposure was documented as having occurred through breast milk. Thus, the possibility of exposure via breast milk should also be communicated to new mothers who use kratom.

The authors said the clinical effects observed during the study highlighted the fact kratom can have serious physiologic effects. Common non-opioid effects included tachycardia (21.4%), agitation/irritability (22.9%), seizures, and hypertension. More than one-third of exposures resulted in admission to a health care facility and more than half resulted in a serious medical outcome. “These high percentages reflect the potential toxicity of the active compounds found in kratom leaves.” And they highlight the need for kratom regulation by the FDA “to ensure quality and safety.”

Despite the perception that kratom is safe because it is classified as an herbal supplement, a variety of serious medical outcomes following exposure to kratom have been documented, especially when kratom is used in combination with other substances. More research is needed to define the human response to kratom. At a minimum, kratom products should be free of potentially harmful contaminants, provide a uniform strength of active ingredients, and have appropriate labeling. Increased regulation of kratom products would help guarantee product quality and safety. Individuals who choose to use kratom should be educated about its potential risks, including the dangers of using it in combination with other substances.

While there is no federal ban yet for kratom, a number of states and some smaller jurisdictions have banned its use. Currently there are six states where kratom is a controlled substance and thus illegal to sell, possess, use and grow: Alabama, Arkansas, Indiana, Rhode Island, Vermont, and Wisconsin. Several additional states have banned kratom in certain counties or cities. Others like Illinois and New Hampshire have set a legal age limit for its use.

Then on June 25, 2019, the FDA again issued warning letters to two additional marketers and distributers of kratom products, Cali Botanical and Kratom NC for illegally selling unapproved and misbranded kratom products. The companies claimed their products could treat or cure opioid addiction, withdrawal symptoms, depression, anxiety and even cancer. The FDA has also found high levels of heavy metals in kratom products. The Acting FDA Commissioner said “Despite our warnings, companies continue to sell this dangerous product and make deceptive medical claims that are not backed by science or any reliable scientific evidence.” Some examples of the claims being made by these companies include:

Kratom is frequently used as a natural alternative to treat depression, anxiety, addiction, diabetes, chronic pain and fatigue…Kratom has been reported to have taken the place of brand name drugs like Hydrocodone or Oxycodone for individuals, all the way to weaning people off of Heroin.Some researchers have even claimed that kratom can protect you against cancer!Kratom is used for energy, to increase attention/focus, to relax, and also to treat pain and addiction. Here is just some of what our customers have used kratom to treat . . . Chronic Pain, Migraines, Opiate Addiction, ADHD/ADD, Anxiety, Depression, Arthritis, Insomnia and much more!

There is an ongoing dispute about kratom-positive overdose deaths, with kratom advocates pointing to how the herbal supplement was not the only substance found in most decedents. In the Morbidity and Mortality Weekly Report (MMWR) for April 12, 2019 the CDC analyzed data from the State Unintentional Drug Overdose Reporting System (SUDORS) for July 2016 through December 2017. SUDORS records all substances detected on postmortem toxicology testing. The CDC analyzed overdose death where kratom was detected on postmortem toxicology testing and deaths where the medical examiner or coroner determined kratom to be a cause of death.

Kratom-positive deaths occurred in only 152 of 27,338 overdose deaths (.56%) for the time period of the study. “Kratom was determined to be a cause of death (i.e., kratom-involved) by a medical examiner or coroner for 91 (59.9%) of the 152 kratom-positive decedents, including seven for whom kratom was the only substance to test positive on postmortem toxicology.” However, the presence of additional substances could not be ruled out. And here is the rub: “Postmortem toxicology testing detected multiple substances for almost all decedents.” About 80% of the decedents with a kratom-positive and kratom-involved death had a history of substance misuse.

Focusing attention on the kratom-positive decedents who only used kratom appears to be a misdirection tactic. The problem seems to be individuals with a history of substance misuse who miscalculated on the strength or influence of the kratom they used—along with the other substances they ingested—and overdosed as a result of their mistake. Remember that in the Clinical Toxicology article, Post et al. concluded: “Despite the perception that kratom is safe because it is classified as an herbal supplement, a variety of serious medical outcomes following exposure to kratom have been documented, especially when kratom is used in combination with other substances.” The noose of regulation needs to get tighter around kratom and needs to occur sooner rather than later.

11/20/18

Kratom Ping-Pong

A 25 year-old man was driving to work on the Pennsylvania Turnpike in Chester County PA on June 27, 2018 when his car veered into the right lane, struck a curb and flipped over. The West Chester County coroner ruled he died of “acute mitragynine intoxication.” With the exception of the equivalent amount of caffeine in a cup of coffee, there were no other drugs in his system. A Montgomery County Pennsylvania woman died in May of 2018 from multiple drug intoxication. She had cocaine, heroin, fentanyl and mitragynine (kratom) in her system.

According to The Inquirer in “Deaths from kratom,” there have been at least four kratom-related overdose deaths reported in the Philadelphia area since 2016. Two of those deaths in Chester County occurred in 2018 and listed kratom as the sole cause of death. The website OverdoseFreePA, which tracks overdose fatalities, reported there have been 27 deaths in 2017 where kratom was present. NMS Labs, a nationally known forensic lab in Willow Grove PA, reported that from January to June in 2018 they found kratom in the postmortem toxicology cases of 303 deaths. Often the kratom was in combination with other opioids.

Kratom activists and the federal government have been playing “scheduling ping-pong” since August of 2016 when the DEA announced its intention to temporarily schedule kratom as a Schedule I controlled substance. Public and political outcry at this proposed action resulted in the DEA reversing itself, saying it would await the FDA’s “scientific and medical evaluation” of the proposed scheduling. Since then the FDA has released information on the adverse events when using kratom and its opioid properties. The agency took actions to address a multistate salmonella outbreak related to kratom. And there were FDA reports on kratom-related deaths. See: “Kratom Regulation Is Coming,” “Kratom: Part of the Problem or a Solution?” and “What Is the Future of Kratom?” on this website.

Then in May of 2018 the FDA announced it was warning three marketers and distributers of kratom products for illegally selling unapproved kratom products with unproven claims the products could treat opioid addiction and withdrawal. “The companies also make claims about treating pain, as well as other medical conditions like lowering blood pressure, treating cancer and reducing neuron damage caused by strokes.” The FDA Commissioner Scott Gottlieb said the agency had determined kratom is an opioid analogue that “may actually contribute to the opioid epidemic and puts patients at risk of serious side effects.” He added the FDA was open to review data on the benefits of kratom through its new drug approval process. “In the meantime, I promised earlier this year that the FDA would step up our actions against unapproved and unsafe products that are being deceptively marketed for the treatment of opioid addiction and withdrawal symptoms.”

The 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 dependence. There are no FDA-approved uses for kratom, and the agency has received concerning reports about the safety of kratom.

Similar to the days of patent medicines, the companies receiving the warning letters said kratom could be used to lower blood pressure, relieve pain, boost a person’s metabolism, increase their sexual energy, improve the immune system, prevent diabetes, ease anxiety, eliminate stress, and help you get a good night’s sleep.

At the beginning of September of 2018 the FDA sent warning letters to two additional companies selling kratom because of their illegal claims that kratom treats or cures opioid addiction and withdrawal. The two companies receiving FDA warning letters, Mitra Distributing and Chillin Mix Kratom, were reported by MarketWatch to be selling kratom at cheap wholesale prices. The FDA letters indicate both companies claimed their kratom products could be used to “treat or cure” opioid addiction and withdrawal symptoms. The FDA warning letters also cited specific examples from the company websites they reviewed, including the following:

“Kratom can render both mildly stimulating effects and mildly relaxing effects depending upon the measurement used. At smaller amounts, the effects tend to be slightly more stimulating; and at larger amounts, the effects tend to be more relaxing.”
“Some [kratom users] have reported an increase in focus, attentiveness, and social confidence resulting from the responsible use of kratom.”
“Due to the rise in opium costs and the discovery that kratom could relieve opium withdrawals, many users turned to kratom as a means to cure their addiction.”
“It has been long reported that kratom has been used to treat a myriad of ailments including but not limited to: diarrhea, depression, diabetes, obesity, high blood pressure, stomach parasites, diverticulitis, anxiety, alcoholism, and opiate withdrawal.”

Beginning in February of 2018 the FDA began an investigation into the link of several kratom-containing products contaminated with salmonella. “Interviews conducted by state and local health departments in coordination with the CDC found that a high proportion of the ill people reported recent consumption of kratom, either as capsules, powders or herbal remedies.” One of the three companies receiving warning letters from the FDA was also implicated in an FDA investigation of kratom products tainted with salmonella. This led to multiple recalls, with most marketers being cooperative. In one case, a marketer failed to conduct a voluntary recall and the FDA was forced to issue a first-ever mandatory recall order. On July 2, 2018 the agency announced the results of their investigation, saying it appears the salmonella problem has probably been occurring for some time, and was even still happening.

As of the end of May 2018, a total of 199 cases of salmonellosis in 41 states have been linked to kratom consumption; 38 percent of those illnesses led to hospitalizations. Fortunately, there have been no known deaths related to these illnesses. In addition to Salmonella I 4, [5],12:b:-, illnesses have been linked to Salmonella Heidelberg, Salmonella Javiana, Salmonella Okatie, Salmonella Thompson and Salmonella Weltevreden. A total of 81 samples of kratom were collected and tested as a direct result of the outbreak investigation, and 42 (52 percent) were found to be contaminated with salmonella. This means that users of these products had essentially a one in two chance of being exposed to this pathogen.

While kratom hasn’t been scheduled as a controlled substance yet, the DEA does list it as a “Drug of Concern.” At low doses, it produces stimulant effects like increased alertness, physical energy and talkativeness. At higher doses, it has sedative effects and can lead to addiction. “Several cases of psychosis resulting from use of kratom have been reported, where individuals addicted to kratom exhibited psychotic symptoms, including hallucinations, delusion, and confusion.”

Kratom’s effects on the body include nausea, itching, sweating, dry mouth, constipation, increased urination, tachycardia, vomiting, drowsiness, and loss of appetite. Users of kratom have also experienced anorexia, weight loss, insomnia, hepatotoxicity, seizure, and hallucinations.

At the end of July 2018 the National Institute of Drug Abuse (NIDA) released an official position on kratom that was quoted as saying: “Kratom by itself is not associated with fatal overdose.” The American Kratom Association said this clarified that it was “only when the natural ingredient is contaminated or “laced with other compounds” has it been associated with death.” The AKA then repeated its previous claim that the original data used by the FDA to warn the public about using kratom was tainted by “adulterated or contaminated kratom.” The president of the AKA said:

NIDA’s statement was consistent with these findings, and we call upon the two agencies to work together to remove the FDA’s scheduling recommendation for natural kratom and focus on protecting the rights of Americans who rely on it by removing adulterated and dangerous counterfeit products from the market.

But the AKA celebration was short-lived. According to The Washington Times, when NIDA was alerted to the AKA statement, it quickly edited the information cited by the AKA. For the FAQ, “Can a person overdose on kratom?” the website now reads: “There have been multiple reported deaths in people who had ingested kratom, but most have involved other substances.” An email inquiry to NIDA from The Washington Times said the AKA’s statement was inaccurate. “Currently, no Government agency views Kratom as a safe drug. Just because a drug is not routinely fatal does not mean it is safe.” In response to the revisions to the NIDA website, the AKA sent a letter to the NIDA director, claiming it bowed to political pressure from the FDA.

We are concerned that NIDA may be under pressure from purely political requests or demands being made by the FDA related to kratom that are not supported by the science, including research done by NIDA and its research contractors.

The science supporting adverse effects from kratom use and its scheduling as a controlled substance is not as weak or corrupted as the AKA claims. See discussions in the above linked articles on this website. It seems we might soon see the “kill shot” in the ping-pong match on kratom if the FDA recommends for the DEA to schedule it.

03/27/18

Kratom Regulation is Coming

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 6^th 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?”