Updated 8 Factor Analysis
Leading Edge Kratom Science
Addressing Abuse Potential, Safety, Patterns of Use, Reasons for Use, and New Studies of Mitragynine, 7- hydroxymitragynine, and Other Kratom Alkaloids
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An annotated update of the 2018 published review article:
The Abuse Potential of Kratom According to the 8 Factors of the Controlled Substances Act:
Implications for Regulation and Research
By
Jack Henningfield, Reginald Fant & Daniel Wang
This report was developed by
Dr. Jack Henningfield and colleagues at PinneyAssociates
For the American Kratom Association to inform and update policy makers, health and regulatory officials, and public health and medical experts on kratom safety and abuse potential
August 6, 2021
Preface and Main Findings
Background: The 2018 Henningfield, Fant & Wang kratom abuse potential assessment was based on a 2016 assessment developed by Dr. Henningfield and colleagues at PinneyAssociates to inform the United States (US) Drug Enforcement Administration (DEA) and Food and Drug Administration (FDA) in their assessment as to the most appropriate regulatory approach to kratom and whether listing kratom (specifically, its alkaloids mitragynine [MG] and 7-hydroxymitragynine [7-OH-MG]) in Schedule I of the Controlled Substances Act (CSA) was warranted and in the interests of public health.
In brief, we concluded there was no evidence of an imminent threat to public health (a requirement for temporary or emergency scheduling) and that kratom was not like opioids in its safety and addiction risks. Furthermore, there was evidence that millions of people were using kratom for reasons associated with health and well-being, including in place of opioids they had been using for pain and/or addiction, and that thousands of people would be at risk of relapse to opioids and overdose if sale of kratom were banned and possession considered a narcotic criminal offense. We also concluded that banning kratom would foreseeably lead to the emergence of a deadly illicit market that would worsen what appeared to be the main problems with kratom, namely contaminated, adulterated, and inappropriately marketed products. We concluded that these problems could be addressed by continuing to allow legal sale of kratom but with FDA oversight providing standards for product quality, labeling, and other issues that FDA routinely addresses.
Overview of main findings: This update reaffirms all of the conclusions of the 2018 report. The more than 100 new peer-reviewed published studies by researchers worldwide and many laboratory studies in the US with funding from the National Institute on Drug Abuse (NIDA), sustain those earlier findings. These studies provide a much fuller characterization of how kratom works and how it provides the benefits that many people report as their reason for use, but without narcotic-like addiction and overdose risks. The studies include the state-of-the-art types of animal abuse and physical dependence/withdrawal studies that FDA requires for new medicines and which DEA relies on for drug scheduling decisions. New clinical studies in humans provide initial assessments of kratom’s physiological health and safety related effects on liver, kidney, and cardiovascular function, as well as brain function, using magnetic resonance imaging techniques.
Conclusions based on new studies since January 1, 2018
Since the Henningfield, Fant & Wang (2018) 8-FA, there have been over 100 new published scientific studies, reviews, and commentaries by leading kratom experts, and an accelerating research pipeline funded in part by the US National Institutes of Health (NIH), National Institute on Drug Abuse (NIDA). These studies provide an increasingly strong evidence base for regulation and policy.
Nature got it right. There is a convergence of studies showing that the main natural constituent of kratom that accounts for the reasons people use kratom is MG, which carries relatively low abuse and health risks (See below). 7-OH-MG naturally occurs at very low levels and product standards should prevent marketing of products with levels higher than those that appear to carry little risk.
Evidence does not support the conclusion that kratom is an imminent public health threat or that it is fueling the opioid and drug overdose epidemic that led to more than 93,000 deaths in 2020. Rather, the evidence supports the conclusion that for many people kratom is a path away from opioids and other drugs to help self-manage craving and withdrawal for people who find kratom more effective, accessible, acceptable, tolerable, and/or prefer natural products.
Animal drug self-administration, physical dependence, and withdrawal studies show low abuse potential and withdrawal risks of kratom relative to opioids. Furthermore, these studies also show that MG administration can reduce self-administration of morphine and heroin as well as withdrawal from morphine. These findings are consistent with human surveys and studies showing that addiction risks for kratom are overall low as compared to opioids.
Numerous surveys and field studies of kratom users have been conducted in the US and Malaysia. These new studies largely confirm the earlier large US survey on kratom consumer usage patterns published by Dr. Grundmann (2017). Most US kratom users are 30-50 years old, employed, have some college education, and have health insurance. Leading reasons for use are to self-manage pain, depression, anxiety, to increase focus and alertness analogous to caffeinated beverage use, and to self- manage opioid and other substance use disorders to relieve craving and withdrawal and often the pain that motivates such drug use.
Surveys also show that users fear a kratom ban and the risks of resumption of opioid and other drug use, and/or turning to illicitly marketed kratom. This makes it foreseeable that thousands of people would be at risk of opioid overdose and other mortality risks associated with illicit drug use, injection drug use, and adulterated kratom products.
Studies of kratom’s alkaloids support the conclusion that that MG and other alkaloids are not appropriately categorized as opioids, as they are diverse in their activity, effects, and mechanisms of action. Moreover, the primary active constituent of kratom, MG, does not produce the signature powerfully rewarding and lethal respiratory depressant effects that characterize morphine-like opioids.
Kratom PK and safety studies include examination of the pharmacokinetics (PK) and pharmacodynamics (PD) in rats and dogs by oral and intravenous administration of many kratom alkaloids in addition to MG. MG, at human dose equivalents many times higher than humans take, are without acute serious adverse effects and there is little evidence of a respiratory depressant effect.
Six clinical studies evaluated the effects of long term kratom use on a variety of physiological parameters including kidney and liver function, hematological parameters, cognition, and brain function by magnetic resonance imaging. Although these were relatively small studies, none suggest serious adverse consequences of long term kratom use. It is important to note that these are not definitive safety studies and cannot be used to claim that kratom has no adverse effects on any of the studied physiological domains and limitations of each study were noted in the publications. Nonetheless, the findings are encouraging and should facilitate the conduct of more comprehensive follow-up studies.
New medicine innovation efforts are developing new molecules as analogs of MG and other kratom alkaloids as possible safer and/or more effective treatments for pain, addiction, depression, and other disorders, due to the promising findings with kratom and its naturally occurring alkaloids. These efforts are also contributing to knowledge about kratom safety and effects; however, New Drug Applications (NDAs) typically require a decade or more of research at costs often exceeding one billion dollars before they can be submitted for review and potential approval by the FDA.
The pipeline of research and new science has been enhanced in quantity and quality not only by funding from the US National Institutes of Health (NIH) and other organizations but as well by regular scientific conferences that are fostering global collaboration and cooperation in an exciting new frontier in search of safer and more effective ways to manage health and well-being. Such efforts are working and should be expanded.
These scientific findings taken together have implications for consideration of kratom regulation by the Controlled Substances Act (CSA). The CSA is intended to protect the public health from substances that pose as imminent threat to public health, and in the case of medicines with a potential for abuse to ensure that they are appropriately regulated if the science supports placement in the CSA. Kratom is not a new drug but rather is a naturally occurring substance with decades of history of use in the US and much longer in Southeast Asia where it grows in abundance and is used by many more people. The scientific evidence does not indicate a profile of meaningful abuse potential or physiological dependence potential of its primary active constituent, mitragynine. This review supports the key findings and action by Assistant Secretary of Health, Dr. Brett Giroir (Giroir, 2018) to rescind the 2017 recommendation (FDA, 2017a) to place MG and 7-OH-MG in Schedule I of the CSA. Specifically, it supports the conclusions that “mitragynine does not satisfy the first of the three statutory requisites for Schedule I”, and that “there is a significant risk of immediate adverse public health consequences for potentially millions of users if kratom or its components are included in Schedule I” and that the very research that all parties agree is needed would be severely stifled by CSA scheduling.
Kratom regulation would be better informed by scientific and public health information exchange and active collaboration among CDC, DEA, FDA, NIDA, and the Substance Abuse and Mental Health Services Administration. Kratom science should be accelerated by increased kratom research funding to NIDA, as well as to support increased surveillance that is specific to kratom. As in other areas of science and public health, progress and process would likely be improved if federally funded kratom research had input and possibly oversight by a multi-agency task force and with an annual report developed with updates on the state of kratom science and annual surveillance, perhaps led by NIDA.
An important development that relates to overall safety, health benefits and risks of kratom use is a regulatory and policy update and is not included in the science updates: at the time of this writing, five states, Arizona, Georgia, Nevada, Utah, and Oklahoma, have enacted laws referenced as the Kratom Consumer Protection Act (KCPA). The KCPA establishes a regulatory framework to protect consumers from unsafe and adulterated kratom products that by requiring manufacturers strict adherence to good manufacturing standards (GMP) to ensure purity; requires testing for contaminants; prohibits adding any dangerous substances to kratom products; forbids boosting the alkaloid levels of MG and 7-OH-MG over those present in the natural kratom plant; bars synthesizing any of the alkaloids; requires registration and product testing; prohibits any therapeutic health claims; and forbids sales to minors. These KCPA laws provide needed consumer protections for consumers. To illustrate the kratom regulatory framework for the Utah KCPA, the Utah Department of Agriculture rule on kratom can be found at https://ag.utah.gov/businesses/regulatory-services/kratom/ . For updates on the status of KCPA legislation in other states, visit the American Kratom Association website at https://www.americankratom.org/advocacy/aka-in-your-state.html .
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