Learning Overview: Attendees will be able to better compare the respiratory depressant effects and relative toxicity of oral mitragynine and oxycodone. Impact on the Forensic Science Community: Lack of respiratory depression following highdose mitragynine in rats questions the appropriateness of designating kratom as cause of death in postmortem cases.

The sole authority for scheduling of dangerous substances is held by the DEA. The FDA can only make recommendations for scheduling, and even then, the Agency is required to provide documentation on 8 specific factors specified by the CSA. The DEA has, over the past 4 years, taken no action on two separate scheduling recommendations clearly because the FDA has failed to meet its burden to conclusively justify the scheduling of kratom.

The internet is full of bad actors who regularly peddle false information to promote their own agendas. With kratom, the FDA has joined the ranks of the grifters, tricksters, and outright liars who play on the trust of the American people, particularly in an institution of government that people should be able to trust. The FDA desperately wants to ban consumer access to natural kratom with the transparent purpose of creating an opportunity for an enterprising Big Pharma company to create a synthetic kratom drug that would mimic the benefits of the natural plant. The FDA knows that will never happen if consumers can purchase the natural plant because the Big Pharma company would not be able to charge exorbitant prices when kratom is legal to be sold as the food that it is. The FDA’s attempt to expand its regulatory reach over kratom is a typical Washington power play by an Agency that transparently attempting to expand its budget and staff to impose one more unjustified restriction on Americans who should be able to make their own informed decisions on the products they use to maintain their health and well-being.

INTRODUCTION: This is an update to the Henningfield et al. (2018) assessment of the abuse potential of kratom based on the eight factors of the United States Controlled Substances Act (US CSA) (Henningfield et al., 2018a) and summarizes new scientific findings from January 2018 through August 2021. The CSA eight factors evaluate pharmacological actions in the brain or central nervous system (CNS) that may lead to dependence, substance use disorders, or addictions (American Psychiatric Association, 2013; National Institute on Drug Abuse, 2019; World Health Organization, 1994; O’Brien et al., 2011). Abuse potential assessments determine whether substances and medicinal products should be controlled by the CSA (scheduled), and if so the restrictiveness or level of control.

ABSTRACT Kratom use appears to be increasing across the United States, increasing attention to deaths in which kratom use was detected. Most such deaths have been ascribed to fentanyl, heroin, benzodiazepines, prescription opioids, cocaine and other causes (e.g., homicide, suicide and various preexisting diseases). Because kratom has certain opioid-like effects (e.g., pain relief), and is used by some people as a substitute for opioids for pain or addiction, kratom has been compared to “narcotic-like opioids” (e.g., morphine) with respect to risk of death despite evidence that its primary alkaloid, mitragynine, carries little of the signature respiratory depressing effects of morphine-like opioids. This commentary summarizes animal toxicology data, surveys and mortality data associated with opioids and kratom to provide a basis for estimating relative mortality risk. Population-level mortality estimates attributed to opioids as compared to kratom, and the per user mortality risks of opioids as compared to kratom are provided. By any of our assessments, it appears that the risk of overdose death is > 1000 times greater for opioids than for kratom. The limitations of the mortality risk estimate warrants caution in individuals with unknown factors such as use of other substances and medications, or other preexisting conditions. More research on kratom safety and risks is needed, as is regulation of commercial kratom products to ensure that consumers are informed by FDA labeling and that kratom products are not contaminated or adulterated with other substances.

Abstract Rationale Substantial use of the plant kratom for psychoactive effects has driven interest in its abuse liability. Several place conditioning studies suggest abuse liability of the active ingredient mitragynine, though studies of its self-administration have not been published.Conclusions These results suggest a limited abuse liability of mitragynine and potential for mitragynine treatment to specifically reduce opioid abuse. With the current prevalence of opioid abuse and misuse, it appears currently that mitragynine is deserving of more extensive exploration for its development or that of an analog as a medical treatment for opioid abuse.

Kratom is the common term for Mitragyna speciosa, a tree native to Southeast Asia. The kratom leaf contains more than 50 alkaloids. The two main known psychoactive compounds in kratom leaf are the indole alkaloids mitragynine, comprising up to two-thirds of the alkaloid content, and 7-hydroxymitragynine, which comprises about 1% of alkaloid content and is also formed by metabolism of mitragynine in vivo. Several total synthesis of mitragynine have been developed, but require too many steps and provide the final product in very low yields. Hence, extraction of the compound seems to be more convenient. 7- Hydroxymitragynine can also be obtained from mitragynine by a single step chemical reaction. M. speciosa can be identified macroscopically by examining the leaf, although this analysis can be misleading as the leaves from plants of the same tribe or genus are very similar. Numerous analytical methods have been reported in the literature for the identification and quantification of kratom alkaloids, particularly mitragynine, in a wide range of samples, including commercial samples, raw plant material and biological specimens. The most applied methods include chromatographic techniques coupled to either spectrophotometric or mass spectrometric detectors.

Kratom can be lawfully marketed and sold as a food. FDA does not preapprove food products. Although FDA has taken enforcement action against kratom manufacturers and vendors whose products are intended to be used for other purposes such as an unapproved new drug, the Agency has never found that all kratom is adulterated. To the contrary, kratom has been lawfully and safely consumed as a food by American consumers for decades. The FDA can and should enforce all labeling laws that restrict the sale of kratom where a marketer makes an illegal therapeutic claim. The AKA maintains a “Truth in Labeling” program to support the responsible sale of kratom products and the referral of any non-compliant violators to the FDA for enforcement actions. Millions of Americans eat or drink kratom every day to improve their well-being. Kratom can be legally sold under existing FDA laws, rules, and guidance.

Kratom (Mitragyna speciosa Korth., Rubiaceae) is a plant native to Southeast Asia, where it has been used for centuries as a mild stimulant and as medicine for various ailments. More recently, as kratom has gained popularity in the West, United States federal agencies have raised concerns over its safety leading to criminalization in some states and cities. Some of these safety concerns have echoed across media and broad-based health websites and, in the absence of clinical trials to test kratom’s efficacy and safety, considerable confusion has arisen among healthcare providers. There is, however, a growing literature of peer- reviewed science that can inform healthcare providers so that they are better equipped to discuss kratom use with consumers and people considering kratom use within the context of their overall health and safety, while recognizing that neither kratom nor any of its constituent substances or metabolites have been approved as safe and effective for any disease. An especially important gap in safety-related science is the use of kratom in combination with physiologically active substances and medicines. With these caveats in mind we provide a comprehensive overview of the available science on kratom that has the potential to i clarity for healthcare providers and patients. We conclude by making recommendations for best practices in working with people who use kratom.

ABSTRACT Background: Made as a tea, the Thai traditional drug “kratom” reportedly possesses pharmacological actions that include both a coca-like stimulant effect and opium-like depressant effect. Kratom has been used as a substitute for opium in physically-dependent subjects. The objective of this study was to evaluate the antinociception, somatic and physical dependence produced by kratom tea, and then assess if the tea ameliorated withdrawal in opioid physically-dependent subjects. Methods: Lyophilized kratom tea (LKT) was evaluated in C57BL/6J and opioid receptor knockout mice after oral administration. Antinociceptive activity was measured in the 55 ◦C warm-water tail-withdrawal assay. Potential locomotor impairment, respiratory depression and locomotor hyperlocomotion, and place preference induced by oral LKT were assessed in the rotarod, Comprehensive Lab Animal Monitoring System, and conditioned place preference assays, respectively. Naloxone-precipitated withdrawal was used to determine potential physical dependence in mice repeatedly treated with saline or escalating doses of morphine or LKT, and LKT amelioration of morphine withdrawal. Data were analyzed using one- and two-way ANOVA. Results: Oral administration of LKT resulted in dose-dependent antinociception (≥1 g/kg, p.o.) absent in mice lacking the mu-opioid receptor (MOR) and reduced in mice lacking the kappa-opioid receptor. These doses of LKT did not alter coordinated locomotion or induce conditioned place preference, and only briefly reduced respiration. Repeated administration of LKT did not produce physical dependence, but significantly decreased naloxone-precipitated withdrawal in morphine dependent mice. Conclusions: The present study confirms the MOR agonist activity and therapeutic effect of LKT for the treatment of pain and opioid physical dependence.

On August 31, 2016, the Drug Enforcement Administration (DEA) published in the Federal Register a notice of intent to temporarily place mitragynine and 7-hydroxymitragynine, which are the main psychoactive constituents of the plant Mitragyna speciosa, also referred to as kratom, into schedule I pursuant to the temporary scheduling provisions of the Controlled Substances Act. Since publishing that notice, DEA has received numerous comments from members of the public challenging the scheduling action and requesting that the agency consider those comments and accompanying information before taking further action. In addition, DEA will receive from the Food and Drug Administration (FDA) a scientific and medical evaluation and scheduling recommendation for these substances, which DEA previously requested

While options for scheduling have been discussed, we believe that additional data and information are needed to understand the public health impact of kratom in terms of therapeutic benefits as well as safety risk. Discussions continue within HHS on mitigating actions to best address the various public health concerns presented, including potential unintended consequences that may arise from transitioning to riskier alternatives (for example fentanyl) if kratom were to be scheduled.

Pure kratom used responsibly, like thousands of other dietary supplements and over-the-counter drugs, is safe for use. It is estimated that about a third of kratom consumers use it to manage acute and chronic pain as an alternative to dangerous opioids or to reduce or wean off opioids entirely. Some unscrupulous bad actors in the kratom marketplace have found a lucrative market for dangerously adulterated kratom products spiked with fentanyl, heroin, morphine, and other opioids to deceive consumers by giving the kratom product an “opioid kick” when they think they are purchasing pure kratom. These spiked kratom products should be banned from the marketplace just like any other adulterated or misbranded drug. NIDA conducted its own review of the deaths reported by the FDA to be associated with kratom and concluded that all resulted from polydrug use or adulterated kratom products, and even the FDA now concurs with that assessmentxvi. Consumers currently are put at unacceptable risk by an unregulated kratom marketplace where it is the “wild west” and no appropriate regulatory scheme is in place to ensure kratom products are pure and unadulterated. The Kratom Consumer Protection Act requires kratom be pure, not adulterated or synthesized to alter the alkaloids in the natural plant, be labeled properly, and be subject to an appropriate age restriction.

The American Kratom Association advocates for states to stand up against overregulation by the FDA; stand up to the exploitation of some opportunistic PhRMA company in the pain relief market; and support consumers having the freedom to make informed decisions on safe kratom products to manage their own health and well-being.

ABSTRACT Kratom, derived from the plant Mitragyna speciosa, is receiving increased attention as an alternative to traditional opiates and as a replacement therapy for opiate dependence. Mitragynine (MG) and 7-hydroxymitragynine (7-HMG) are major psychoactive constituents of kratom. While MG and 7-HMG share behavioral and analgesic properties with morphine, their reinforcing effects have not been examined to date. 7-HMG, but not MG, substituted for morphine selfadministration in a dose-dependent manner in the rat self-administration paradigm. Following the substitution procedure, re-assessment of morphine self-administration revealed a significant increase following 7-HMG and a significant decrease following MG substitution. In a separate cohort, 7-HMG, but not MG, engendered and maintained intravenous self-administration in a dose-dependent manner. The effects of pretreatment with nalxonaxine (NLXZ), a μ1 opiate receptor antagonist, and naltrindole (NTI), a δ opiate receptor antagonist, on 7-HMG and morphine selfadministration were also examined. Both NLXZ and NTI reduced 7-HMG self-administration, whereas only NLXZ decreased morphine intake. The present results are the first to demonstrate that 7-HMG is readily self-administered, and the reinforcing effects of 7-HMG are mediated in part by μ and δ opiate receptors. In addition, prior exposure to 7-HMG increased subsequent morphine intake whereas prior exposure to MG decreased morphine intake. The present findings indicate that MG does not have abuse potential and reduces morphine intake, desired characteristics of candidate pharmacotherapies for opiate addiction and withdrawal, whereas 7-HMG should be considered a kratom constituent with high abuse potential that may also increase the intake of other opiates.

The number of individuals who were trapped in opioid addictions and found kratom to be the pathway to reduce or eliminate opioid use is powerful evidence that kratom is part of the solution, and not the problem. If kratom saved only one life, that would be enough. But based on the reports of kratom users who have successfully used kratom to escape addictions, it clearly has saved many lives. Kratom needs to be freed from the bias of the FDA against all non-drug substances used to manage acute and chronic pain; the special interest anti-kratom hysteria driven in part by fears of financial losses; and kratom should be allowed to take its place as a legitimate player in the substance abuse treatment community.

On August 31, 2016, the Drug Enforcement Administration issued a Notice of Intent to temporarily schedule the chemicals mitragynine and 7-hydroxymitragynine into Schedule I pursuant to the temporary scheduling provisions of the CA, 21 USC. In response to the Notice of Intent, the dEA received numerous comments from the public on mitragynine and 7-hydroxymitragynine, including comments offering their opinions regarding the pharmalogical effects of these substances.

ABSTRACT Background: Kratom, a Southeast Asian plant with opioid-receptor mediated effects, has emerged as a potential substance of abuse, with limited data on its use and effects. This study characterized kratom user demographics, use patterns, and perceived drug effects. Methods: A cross-sectional, anonymous online survey was conducted between January and December 2017. Results: 2,798 kratom users – mean age 40 (SD = 12); predominantly White (90 %), female (61 %), and located in the US (97 %) – completed the survey. Kratom was primarily taken orally in doses of 1−3 g (49 %), with daily use (59 %) being most common. Kratom was used for pain (91 %), anxiety (67 %), and depression (65 %), with high ratings of effectiveness. 1,144 (41 %) used kratom to stop or reduce prescription or illicit opioid use, citing decreased opioid withdrawal and craving related to kratom use, with 411 reporting > 1-year continuous abstinence from opioids attributed to kratom use. Roughly one-third of respondents reported adverse effects of kratom, largely rated as mild in severity and lasting ≤24 h. Seventeen participants (0.6 %) sought treatment for adverse effects. Fifty-six individuals (2 %) met DSM-5 criteria for a past-year moderate or severe kratom-related substance use disorder (SUD). When asked how troubled they felt regarding their kratom use, the mean (SD) rating was 3.2 (9.8) on a scale from 0 to 100. Conclusion: Kratom is used among White, middle-aged Americans for symptoms of pain, anxiety, depression, and opioid withdrawal. Although regular use was typical, kratom-related SUD and serious adverse effects were uncommon. Additional research on kratom epidemiology and pharmacology is imperative in light of the present opioid epidemic.

While the FDA attempts to ban consumer access to kratom products, it is saving lives. In the midst of the pandemic, where social isolation, increased depression, and spiking opioid overdoses plague us, the FDA should be doing everything it can to encourage products that reduce harm. It is critically important for states to enact the Kratom Consumer Protection Act that stops dangerous adulteration, bans synthesizing kratom’s alkaloids; requires labeling so consumers know what is in a kratom product; and sets an appropriate age limit to purchase kratom products.

Kratom (mitragyna speciosa) is an evergreen tree found in the tropical and subtropical regions of Southeast Asia. A member of the Rubiaceae or coffee family, it has been used for hundreds of years in parts of Southeast Asia and Africa for its energy boosting effects, increased focus, improved mood, and to alleviate pain or as a replacement for more harmful pain medications.