The FDA has a long-standing bias against any dietary ingredient, botanical supplement, or dietary supplement that is not a chemical formulation subject to regulatory approval as a new drug. In 1994, Congress passed the Dietary Supplement Health and Education Act (DHEA) to reign in the FDA’s overregulation of dietary supplements FDA wanted banned on the premise they were highly addictive, being used to self-medicate without physician supervision, or were so poorly formulated these products posed a threat to public health requiring them to be banned.
What is clearly needed is balanced regulation to ensure that kratom products purchased by consumers are pure and unadulterated, in other words meeting the same types of standards that apply to other food products, and even bottled water. Steps toward such standards were taken in states that passed their own versions of kratom consumer protection act laws. Ultimately, the Food and Drug Administration (FDA) needs to develop national performance standards for kratom as it does for other products. Such standards will help ensure access to kratom products that are appropriately marketed and are without contaminants and adulterants that might pose safety risks.
Specific regulatory and policy approaches supported by new evidence
The DHHS request to schedule kratom and mitragynine was reversed by its lead official charged with Controlled Substances Act recommendations to the DEA, namely, the Assistant Secretary of Health, Dr. Brett Giroir. Dr. Giroir requested a review of the evidence pertaining to kratom scheduling and safety, and concluded in August 2018, that the evidence did not support Schedule I placement. See a summary of the findings of the review in Dr. Giroir’s formal 2018 scheduling rescission letter to the DEA here.
As discussed in the scheduling rescission letter, the evidence was not sufficient to support scheduling, but was sufficient to support the conclusion that many thousands of kratom consumers use kratom as a path away from opioids. This led to the public health concern that “[Scheduling would lead to] … kratom users switching to highly lethal opioids… risking thousands of deaths…”. Dr. Giroir raised other concerns including that placing kratom and mitragynine in Schedule I would discourage pregnant women and others from talking to their health care providers about their kratom use, discourage research, and more.
The conclusions of the Assistant Secretary of Health were consistent with those of the National Institute on Drug Abuse (NIDA), which states on its Kratom Facts webpage that “While there are no uses for kratom approved by the FDA, people report using kratom to manage drug withdrawal symptoms and cravings (especially related to opioid use), pain, fatigue and mental health problems. NIDA supports and conducts research to evaluate potential medicinal uses for kratom and related chemical compounds.” NIDA substantially expanded its kratom research support since 2017 and this research portfolio is rapidly expanding the evidence base for kratom regulation and possibly new kratom derived medicines in the years to come.
Similarly, at the international level, the large evidence base was reviewed in 2021 by the World Health Organization Expert Committee on Drug Dependence (WHO ECDD) to determine if kratom met criteria for being placed on a critical review pathway for international scheduling. The WHO ECDD came to essentially the same conclusions as had the Assistant Secretary of Health and NIDA. After conducting a thorough pre-review and a public hearing with input from leading international experts, the ECDD reported to the United Nations Office of Drug Control that there was insufficient evidence to recommend kratom for critical review but that it should be kept under surveillance. It also stated, “(k)ratom is used for self-medication for a variety of disorders but there is limited evidence of abuse liability in humans…”
Addressing overdose risks, the ECDD noted: “Although mitragynine has been analytically confirmed in a number of deaths, almost all involve use of other substances, so the degree to which kratom use has been a contributory factor to fatalities is unclear.” Both the Assistant Secretary, and the WHO ECDD also acknowledge beneficial uses to abstain from opioids. Without labeling this as “therapeutic use”, the Assistant Secretary clearly acknowledges such use and the public health risks of banning kratom. This nuanced recognition of benefits of use, along with risks of banning access to use by Assistant Secretary Giroir, was absent in the 2017 and early 2018 position of FDA, but was since recognized by the Secretary of Health Becerra in a letter to Senator Mike Lee and Congressman Mark Pocan on March 16, 2022.1
People also read: Kratom Legality Map and information. States, Cities and Counties where Kratom products are prohibited
What is the current state of kratom science and evidence?
Kratom has been studied for decades, primarily in Southeast Asia (SEA), where kratom trees grow in abundance, but research escalated substantially in the US and globally with support by NIDA, SEA countries, and philanthropies. New science over the past 5-10 years includes investigations on kratom/mitragynine chemistry and medicinal development, neuropharmacology, brain imaging, preclinical and clinical studies, and surveys in the US and SEA. The rate of published kratom research continues to increase, along with presentations and symposia at national and international scientific meetings, such as the College on Problems of Drug Dependence in June 2022 that included a kratom symposium and a clinical study report in the late breaking hot topics research sessions.
New evidence
What is the new evidence that is so compelling to result in the Assistant Secretary’s withdrawal of an earlier scheduling recommendation, and support the WHO ECDD findings accepted by the United Nations Office of Drug Control? In short, more than 100 new studies since early 2018 addressing kratom safety, abuse potential, mechanisms of action, and reasons for use, with most kratom users reporting that use is primarily motivated by health and well-being related benefits and not for recreational purposes. Much of this research was supported by NIDA and conducted in the US, but extensive additional research was conducted internationally with generally similar findings.
The following summary and conclusions are based on peer-reviewed scientific publications, many conducted by international leaders in kratom research and supported by NIDA. A bibliography with links to the articles is provided.
What is kratom?
Kratom is a tree in the coffee family. Not surprisingly, its diverse effects include coffee-like alerting, stimulating, and mood enhancing effects, which are quite distinct from the effects of morphine-type opioids. It also has some opioidlike effects that include pain relief, possible opioid withdrawal symptoms after chronic frequent use and unpleasant side effects like constipation, but without the potentially lethal respiratory depressing or highly addictive brain rewarding effects that are driving the opioid epidemic.
People also read: What Is Kratom – National Institute of Health Overview of Kratom.
Is kratom an opioid?
While some naturally occurring substances in kratom act on opioid receptors, kratom is not a prototypical opioid based on its chemical structure, botanical origins, or law – nationally or internationally. Like many natural products it has diverse effects and mechanisms of action that contribute to these effects and the reasons people use kratom. Some kratom constituents bind to opioid receptors and relieve pain whereas others do not. Unlike opioids which sedate and can impair mental functioning, kratom is used by many people in place of coffee for its alerting, mental focusing, and occupational performance enhancing effects. Animal and human studies, as well as neuropharmacology mechanisms of action studies, show that kratom does not carry the substantial opioid-like risks of deadly respiratory depression or powerfully addictive euphoria. A misunderstanding of one of kratom’s self-reported beneficial uses, recognized by researchers and NIDA, providing relief of opioid withdrawal, is sometimes interpreted as evidence that it must be an opioid. In fact, the nonopioid adrenergic blocking drugs developed for treating high blood pressure, clonidine and lofexidine, were prescribed for decades to treat opioid withdrawal. FDA approved lofexidine (Lucemyra) for treating opioid withdrawal in 2018. Mitragynine and other kratom constituents also produce adrenergic effects.
People also read: Kratom Can Reduce Opioid Withdrawal – McCurdy Studies
Who uses kratom and why?
According to surveys in the US, most consumers report are White adults, aged 35-55, with jobs and health care insurance, who report that their consumption is primarily for health and wellbeing. This includes consumption as an alternative to caffeinated products for alertness and increased focus, for the self-management of pain, and to improve mood. Many consumers state that kratom worked better for them, had fewer side-effects than the FDA-approved medicines that had been taken, and/or that they preferred natural products. A smaller but especially important fraction of consumers are people who consider kratom as a “life-line” or a path away from opioids. They use kratom to manage opioid withdrawal and reduce or eliminate opioid use.
What led to increased kratom use in the United States?
Although kratom has been taken as a natural traditional medicine in SEA for centuries, its use in the US was largely limited to Asian immigrants from the early 1970s through the 1990s. In the early 2000s, with a rising general interest in natural products as alternatives to conventional medicines and growing public access to information via the Internet, kratom use began to increase. Reasons for use appear generally similar from the US to SEA; as an alternative to coffee and tea for its alerting and mild stimulant effects, to improve mood and relieve pain, and to manage withdrawal and help people to reduce or discontinue use of opioids, alcohol and other addictive substances. Many survey respondents report that kratom was eithermore effective, carried fewer side effects of concern such as the sedating effects of opioid painrelivers, and/or that they prefer natural products over conventional medicine. Estimates of the present market vary widely. By 2014, there were an estimated 3-5 million kratom consumers, and marketing and SEA export estimates suggest that the present market is 15 million or more in the US. One federal survey estimated between 2-3 million kratom consumers, which might reflect its panel of respondents. The federal survey is designed to track substance abuse and might underrepresent middle aged and older people with lower rates of recreational substance use who might use kratom for other reasons.
Does kratom contain dangerous substances?
Like its botanical cousin coffee, kratom contains many substances referred to as alkaloids, which tend to be somewhat alkaline and bitter in flavor. More than 40 alkaloids are identified in kratom to date, with most having little or no known pharmacological effect, or occurring at such low levels as to be of little cause for harm or benefit. However, as is the case with other natural products, the naturally occurring mixture of substances likely contributes to the overall effects and natural variations in alkaloid composition may lead to varying pharmacological effects. The main ingredient currently thought to account for most of the effects reported by kratom consumers is mitragynine, which does not have strong rewarding and addictive effects, nor respiratory depressant effects like opioids and conventional stimulants.
The second most widely recognized substance is 7-hydroxymitragynine that has stronger opioid effects but occurs at non-detectable levels in fresh kratom leaves. However, 7-hydroxymitragynine is also a product of mitragynine metabolism. In the absence of kratom regulation, some kratom makers boosted 7-hydroxymitragynine content far higher than that found in the native plant material. States passing kratom consumer protection act laws ensure that legally marketed kratom does not contain boosted 7-hydroxymitragine levels, contaminants, or other adulterants, thereby reducing public health risks. Additionally, dangerous substances like fentanyl, heroin, and morphine were found in adulterated kratom products, and these can be harmful. Regulation is needed from FDA to ensure that all US consumers are protected from risky exposure to contaminated or adulterated products.
Respiratory effects of kratom
It is well understood that kratom’s respiratory effects are not like those of morphine-like opioids; however, studies since 2018 support the conclusion that kratom is not simply weaker than opioids with respect to respiratory depression. Specifically, mitragynine and other alkaloids in kratom act as partial agonists at opioid receptors, meaning that their maximal effects reach a ceiling beyond which higher doses produce little additional effect. This was demonstrated in several animal species (including cats, dogs, mice, and rats) with mitragynine doses increased to levels far beyond what is or can be consumed by even high intake chronic kratom consumers. The most recent study employed a sophisticated rodent model developed by FDA to compare a broad range of mitragynine doses to therapeutic and toxic oxycodone doses across blood gases and other parameters. Whereas oxycodone produced the signature dose-related plummeting blood oxygen levels and deaths, mitragynine produced no evidence of respiratory depression at any dose, and no life-threatening effects.
Can you overdose on kratom?
It is possible that kratom contributed to some deaths occurring in kratom consumers but the overall risk appears at least 1,000 times lower for kratom as compared to opioids. There were no deaths in which either the FDA or CDC confirmed as appropriately categorized as due to kratom consumption, though the possibility cannot be ruled out. Kratom consumers should not assume that kratom is without risk. Nonetheless, the CDC did not list kratom as a cause of any of the more than one hundred and eight thousand drug overdose deaths in 2021, or in any other year of which we are aware. In contrast, opioids were concluded by the CDC and NIDA to account for more than 80,000 overdose deaths in 2021. Overdose is possible with many readily available consumer substances, including caffeine, but kratom’s most common side-effect, transient stomach upset and nausea, also limits intake and is discomforting but not seriously harmful. In February 2018, after announcing that kratom carried opioid-like death risk, the FDA noted that only one of 44 deaths occurring in kratom consumers did not involve other respiratory depressing substances. Further investigation found that the final cause was a motor vehicle fatality involving a kratom consumer.
In fact, NIDA, FDA, US DHHS, and WHO ECDD all concluded that most kratom-associated deaths involved other substances. This is also true in SEA where scientists’ conclusions were similar to those of the US Assistant Secretary of Health, Dr. Brett Giroir. As summarized by Dr. Giroir in the previously mentioned 2018 DHHS scheduling rescission letter, “There is still debate among reputable scientists over whether kratom by itself is associated with fatal overdoses.”
People also read: Kratom effects; Can You Overdose On Kratom?
Is kratom fueling the opioid overdose epidemic?
The US has the world’s most sophisticated and multi-pronged substance abuse and product safety monitoring network detecting signals of gateway drug use and ways in which one substance may contribute to the abuse and risks of another. US monitoring systems include the National Survey on Drug Use and Health (NSDUH), Monitoring the Future (MTF), Treatment Episodes Data Set, and the DEA’s National Forensic Laboratory Information System (NFLIS). It also includes the Drug Abuse Warning Network (DAWN) which reported a variety of potential signals of emerging substance threats while kratom use was rapidly increasing from the 1990s through its pre-2012 reports, as well as the “new” DAWN system that reported on 2021 data in its 2022 report. None of these systems, nor more than 20,000 comments to the DEA, suggested that kratom contributed to the opioid epidemic. Kratom was also never listed in DEA’s annual National Drug Threat Assessment, though DEA routinely monitors kratom as a “chemical of concern” Despite over 10 years of monitoring, DEA has not listed kratom or mitragynine or 7-hydroxymitragynine as a national drug threat.
Read More at: The Truth About Kratom: Facts, Science and Safety
