Kratom Abuse Potential 2021: An Updated Eight Factor Analysis

This review used the 8 factors of the Controlled Substance Act (CSA) to assess recently published literature involving kratom. It was found that public health would be better served by assuring continued access to kratom and that placing kratom in the CSA would criminalize consumers, impede research and have dangerous public health consequences. Regulation to minimize risks of contaminated, adulterated, and inappropriately marketed products is recommended.

Abstract

“Drugs are regulated in the United States (US) by the Controlled Substances Act (CSA) if the assessment of their abuse potential, including public health risks, show such control is warranted. An evaluation via the 8 factors of the CSA provides the comprehensive assessment required for permanent listing of new chemical entities and previously uncontrolled substances. Such an assessment was published for two kratom alkaloids in 2018 that the Food and Drug Administration (FDA) have identified as candidates for CSA listing: mitragynine (MG) and 7-hydroxymitragynine (7-OH-MG) (Henningfield et al., 2018a). That assessment concluded the abuse potential of MG was within the range of many other uncontrolled substances, that there was no evidence of an imminent risk to public health, and that a Schedule I listing (the only option for substances that are not FDA approved for therapeutic use such as kratom) carried public health risks including drug overdoses by people using kratom to abstain from opioids. The purpose of this review is to provide an updated abuse potential assessment reviewing greater than 100 studies published since January 1, 2018. These include studies of abuse potential and physical dependence/withdrawal in animals; in-vitro receptor binding; assessments of potential efficacy treating pain and substance use disorders; pharmacokinetic/pharmacodynamic studies with safety-related findings; clinical studies of long-term users with various physiological endpoints; and surveys of patterns and reasons for use and associated effects including dependence and withdrawal. Findings from these studies suggest that public health is better served by assuring continued access to kratom products by consumers and researchers. Currently, Kratom alkaloids and derivatives are in development as safer and/or more effective medicines for treating pain, substances use disorders and mood disorders. Placing kratom in the CSA via scheduling would criminalize consumers and possession, seriously impede research, and can be predicted to have serious adverse public health consequences, including potentially thousands of drug overdose deaths. Therefore, CSA listing is not recommended. Regulation to minimize risks of contaminated, adulterated, and inappropriately marketed products is recommended.”

Authors: Jack E. Henningfield, Daniel W. Wang & Marilyn A. Huestis

Summary

1 INTRODUCTION

This assessment of the abuse potential of kratom focuses on its primary alkaloid, mitragynine (MG), and summarizes new scientific findings from January 2018 through August 2021. It uses the eight factors of the US Controlled Substances Act to determine whether kratom should be controlled by the CSA.

Kratom and its alkaloids are not approved by the FDA for any therapeutic use, and are not federally controlled in the US, nor in the International Drug Control Conventions. However, some countries do control kratom and/or its two primary alkaloids, MG and 7-OH-MG.

In August 2016, the DEA proposed scheduling kratom on a temporary “emergency” basis, but withdrew the proposal after receiving thousands of comments from kratom consumers and bipartisan members of Congress. The FDA then completed an 8-FA and made a recommendation to the DEA in November 2017.

The US Department of Health and Human Services (DHHS) issued a scheduling rescission order for kratom on August 18, 2018, stating that it did not satisfy the first of the three statutory requisites for Schedule I and that there was a significant risk of immediate adverse public health consequences.

The National Institute on Drug Abuse (NIDA) increased its research on kratom in 2017 and included more than 100 new studies on the abuse potential of kratom.

2 METHODS

We searched for new studies published in English relevant to kratom abuse potential, safety and mechanisms of action since January 1, 2018 and included some essential earlier studies mentioned and referenced to our 2018 review.

3.1.1 Summary of 2018 Findings

There were no animal studies on kratom’s alkaloids, but other data suggested relatively low abuse potential as compared to opioids and other drugs of abuse. Survey data showed most kratom use was for health-related benefits, and to facilitate occupational performance.

MG self-administration rates were similar to saline, and MG pretreatment decreased heroin self-administration with little effect on methamphetamine self-administration. These results suggest that MG does not have abuse potential and reduces morphine intake, desired characteristics of candidate pharmacotherapies for opiate addiction and withdrawal.

Intracranial Self-Stimulation

In the ICSS model, rats equipped with brain electrodes self-deliver rewarding electrical brain stimulation. No evidence of brain rewarding effects of MG was found, whereas morphine robustly decreased the stimulation threshold.

Drug Discrimination Studies

The discriminative stimulus effects of MG were evaluated in studies designed to assess generalization to morphine, SNC80, U69593, alpha adrenergic agonists, alpha adrenergic antagonists, and the cannabinoid agonist -9-tetrahydrocannabinol.

MG and 7-OH-MG partially generalized to morphine in rats, whereas 7-OH-MG fully generalized to morphine in rats.

3.1.2.4 Conditioned Place Preference

Various MG preparations produced mixed CPP effects in mice, with some suggesting abuse potential at high doses. Baclofen pretreatment prevented the acquisition and expression of MG-induced CPP.

3.1.2.5 Physical Dependence and Withdrawal

Morphine withdrawal symptoms were stronger in morphine treated rats than in MG treated rats, and MG treatment attenuated withdrawal symptoms significantly, similar to methadone and buprenorphine, and potentially with less undesired effects.

Although the withdrawal signs of kratom are weak compared to those of morphine withdrawal, there is evidence of physical dependence. Kratom withdrawal was not associated with anxiogenic-like subjective symptoms, further supporting kratom as a novel pharmacotherapeutic intervention for managing opioid use disorder.

Although surveys and anecdotal reports indicate that some kratom users report “addiction”, kratom use “to get high” is relatively low as compared to opioids and other recreational drugs of abuse, and use by smoking, injecting, and/or insufflating is rare.

Kratom is used to self-manage opioid withdrawal. Two published US surveys confirm that the overwhelming majority of kratom consumers report using it for health benefits and not for recreational purposes.

3.1.3 Factor 1 Updated Conclusion

Diverse scientific approaches were used to profile kratom’s abuse potential, and the results suggest that kratom has a relatively low abuse potential as compared to morphine-like opioids, stimulants, and other drugs of abuse that demonstrate robust rewarding effects across all such abuse potential models.

3.2 Factor 2—Scientific Evidence of its Pharmacological Effects 3.2.1 Summary of 2018 Findings

MG and 7-OH-MG have some MOR mediated effects, but their mechanisms of action are diverse and mediated by non-opioid transmitters and pathways. Therefore, MG and 7-OH-MG are not opioid “analogs” or “narcotic like opioids”.

3.2.2.1 Potential Therapeutic Effects

Although kratom is not approved for therapeutic use for any disorder, surveys show that individuals in the US and around the world describe using kratom for its health benefits. Research has advanced since 2018 that has provided objectively measured evidence of kratom’s pain relieving properties.

After testing several minor indole and oxindole alkaloids, the authors concluded that mitragynine had low affinity and was an antagonist at the human m-opioid receptor (MOR) and had no therapeutic effect for treating pain or opioid physical dependence.

3.2.2.2 Mechanisms of Action

Although kratom produces some effects in common with opioids, it also has several non-opioid mechanisms of action, including serotonergic effects potentially mediated by their metabolites.

Kratom contains 1 – 2% MG by weight, as well as other alkaloids that are present at such low levels in kratom leaf material that it is uncertain if they contribute to kratom effects. 7-OH-MG is present in low concentrations in natural kratom products, but gradually emerges in vivo as a MG metabolite.

Kratom is commonly consumed to enhance occupational performance and as a coffee substitute for energy at low doses, but high doses impaired memory in an animal model.

In a study by Gutridge et al. (2020), kratom alkaloids did not recruit beta-arrestin at mu, delta and kappa opioid receptors, and reduced alcohol intake in male and female mice. This may explain why some find kratom useful to self-medicate for alcohol use disorder.

Hiranita et al. (2019) found that mitragynine did not appear to be mediated by opioid receptors in behavioral and antinociception assays in rat models.

3.2.2.3 Studies of Kratom Minor Alkaloids and Their Metabolites, and Analogs

Advances in analytical methods are accelerating our understanding of the effects of numerous kratom alkaloids, including MG, but it is possible that one or more minor alkaloids may also play a minor role in the biological actions of kratom consumed by humans.

Kratom alkaloids are of interest as templates for novel synthesized molecules for new medicines. These molecules have strong analgesic effects but low respiratory depressant, locomotor, and conditioned place preference suggesting lower adverse effects including abuse potential.

3.2.3 Factor 2 Updated Conclusion

Kratom’s main effects are due to the consumption of MG, but other minor alkaloids and metabolites may also contribute to effects reported by consumers. Science is improving our understanding of how these alkaloids and metabolites interact.

3.3 Factor 3—The State of Current Scientific Knowledge Regarding the Drug 3.3.1 Summary of 2018 Findings

Kratom’s anti-nociceptive effects were mediated by MOR receptors, and long-term use in humans was based on anecdotal reports, case histories, and preliminary field studies.

3.3.2.1 Pharmacokinetics and Pharmacodynamics Findings Related to MG and 7-OH-MG Safety

Oral MG at doses of 20 mg/kg, 40 mg/kg, and 80 mg/kg produced no adverse events and no major abnormalities in clinical parameters. The metabolic formation of 7-OH-MG contributed to the antinociception of oral MG.

3.3.2.2 Pharmacokinetic and Pharmacodynamic Findings With Kratom’s Minor Alkaloids

Kratom’s pharmacokinetics were characterized following IV and oral dosing to rats, and its anti-nociceptive effects in the cold pressor test were described in Factor 2. Six new clinical studies were conducted to assess health and safety endpoints.

Leong Bin Abdullah et al. (2020) studied 100 chronic kratom users and 100 healthy nonusers in Malaysia and found that kratom users had lower serum total cholesterol and LDL levels than healthy subjects.

Singh, Muller, Murugaiyah et al. (2018) studied various hematological and clinical-chemistry parameters of kratom users in Malaysia and found that long-term and heavy kratom consumption did not alter the hematological and clinical-chemistry parameters of kratom users.

Singh, Narayanan, Grundmann et al. (2020) studied 13 people who used kratom longer than 20 years and found that long-term use was not associated with altered biochemical levels, although prolonged and chronic, frequent use (>3 glasses per day) may result in cardiovascular risks.

Singh, Chye, Suo et al. (2018) conducted a preliminary study of kratom users’ brain function using brain magnetic resonance imaging. They found no significant differences between kratom users and controls.

Singh, Narayanan, Muller et al. (2019) studied potential long-term cognitive effects associated with kratom use in Malaysia, finding that higher consumption was associated with impaired performance on the Paired Associates Learning task.

Leong Bin Abdullah, Tan,etal., found that kratom users had higher prevalence of ECG abnormalities and prolonged QTc intervals, and daily kratom consumption was associated with borderline QTc intervals.

3.3.3 Factor 3 Updated Conclusion

Data from multiple species, kratom preparations, alkaloids, and metabolites confirm that there are no serious adverse or life-threatening effects over a broad range of doses, dosage forms, and in four species.

Kratom science has made major advances with the publication of six clinical studies of long term kratom use effects and safety. These studies suggest that kratom has no serious adverse effects on any of the studied physiological domains.

3.4 Factors 4, 5, and 6—History and Current Patterns of Abuse; the Scope, Significance and Duration of Abuse; what, if Any, Risk is There to the Public Health 3.4.1 Summary of 2018 Findings

The Henningfield et al., 2018 8-FA reviewed all major relevant federal surveys, as well as data from internet monitoring, and more than 20,200 comments to the DEA, and concluded that there was no evidence of an imminent public health threat associated with kratom.

3.4.2 Factors 4, 5, and 6 Science Updates 3.4.2.1 U.S. National and Federal Survey Data

The main findings from the major national and federal surveys and other data sources are summarized in Table 2. The prevalence of kratom use is substantially underestimated by the NSDUH and RADARS surveys, and kratom use is not listed in the most recent DEA National Drug Threat Assessment. Kratom is not contributing to the opioid epidemic, but may help some users reduce or discontinue their opioid use.

3.4.2.2 Kratom Use Prevalence

The NSDUH and RADARS surveys may greatly underestimate the US prevalence and incidence of kratom use, with estimates of past year kratom use of 1,790,00 – 2,040,000.3

3.4.2.3 Kratom Use Associated Mortality

The two most widely cited estimates of kratom associated mortality are based on world-wide reports over nearly 10 years. Most kratom positive or “involved” deaths were caused by other substances, and kratom was not a primary cause of death in any of the 93,000 drug overdoses estimated for 2020.

The risk of kratom associated death is at least a thousand times lower than for morphine-like opioids, according to a 2019 assessment by Henningfield et al.

3.4.2.4 Mortality Risks Projected as a Result of Banning Licit Kratom

Kratom users fear resumption of opioid use and the need to resort to illicit kratom markets. The DEA withdrew its 2016 kratom scheduling proposal and the US DHHS kratom scheduling recission letter.

3.4.2.5 Public Health and Individual Benefits of Kratom

In 2018, a systematic review of kratom use and mental health concluded that kratom may have several important mental health benefits. More and better research, including well-controlled, prospective studies, is necessary to further elucidate kratom’s potential for good and harm.

The most important public health benefits of kratom use are its use to self-manage opioid and other drug addiction and withdrawal symptoms, and thereby reduce use and overdose from far deadlier substances.

While the opioid epidemic is highly visible and deadly in its own right, many millions use kratom to manage other life-threatening disorders.

3.4.2.6 Kratom Use for Managing Opioid Use/Withdrawal and Other Health Reasons

Kratom was not affected by the COVID-19 pandemic, and the main reasons for use were pain relief, anxiety, “PTSD” or depression, increase energy or focus, and “help cut down on opioid use and/or relieve withdrawal”.

Field studies in Malaysia with face-to-face interviews provide complementary evidence to US Internet surveys regarding reasons for use and potential benefits. The majority of kratom users report using kratom to enhance sexual performance.

In a study of 142 current and 62 former opioid polydrug users, kratom was used to ameliorate opioid withdrawal, but former opioid polydrug users were more likely to use kratom for mood elevating effects.

3.4.2.7 Comment on Therapeutic Use in Context of FDA Standards

The FDA has not approved any kratom product for therapeutic use in the US, despite evidence that millions of people in the US and many more in SEA use kratom primarily for therapeutic, beneficial use.

None of this research meets FDA’s standard for therapeutic efficacy, which is determined by evaluation of a New Drug Application (NDA). Only two botanical substances were developed as drug products consistent with FDA’s Botanical Drug Guidance.

3.4.3 Factor 4, 5, and 6 Updated Conclusions

New US survey evidence shows that kratom products do not pose a serious imminent threat to public health, and that scheduling them in Schedule I of the CSA would create serious public health problems.

For those using kratom products in place of opioids, including potent and deadly prescription opioids, heroin, and fentanyl, removing kratom from the legal marketplace would put many at risk of returning to opioid use and risking opioid overdose death.

3.5.1 Summary of 2018 Findings

Psychic dependence is often referred to as “dependence” or “substance use disorder” and more commonly as “addiction”, though definitions of addiction vary widely.

Henningfield, Fant and Wang (2018) concluded that there have not been laboratory studies of physical dependence or abuse potential in humans caused by kratom, but that real-world evidence supported the following conclusions: abrupt discontinuation of kratom use may be accompanied by withdrawal symptoms.

3.5.2 Factor 7 Science Updates

There are several new studies, surveys, and expert reviews addressing the risk and factors associated with dependence and withdrawal. Kratom may be used as a harm reduction alternative to opioids, alcohol, methamphetamine, and other drugs.

A systematic review of kratom use for mental health reasons concluded that kratom dependence is a risk for some people, though the dependence syndrome appears to be mild in its psychosocial and physiological effects relative to that of opioids.

The Vicknasingam et al. (2021) study included in Factor 2 assessed potential withdrawal signs using the Clinical Opiate Withdrawal Scale, and concluded that despite long histories of daily kratom consumption and substantial amounts consumed, no participant reported or displayed discomfort, symptoms, or signs of potential withdrawal symptoms.

100 long term kratom users and 100 non-users in Malaysia were interviewed to assess potential symptoms related to kratom dependence and withdrawal. Kratom use was associated with dependence, reduced quality of life and/or withdrawal symptoms when kratom use is discontinued.

In an internet survey, 2.798 present and past kratom users reported kratom-related withdrawal symptoms, and another 17.5% reported possible kratom-related withdrawal. This supports results of previous studies that suggest kratom has a relatively benign risk profile compared to typical opioids.

In an internet survey, 2,867 current, 157 former kratom users reported that kratom was less likely to interfere with social, family, and occupational functioning compared to conventional opioids, and was generally considered “very effective” for managing opioid withdrawal.

Singh, Narayanan, Muller et al. (2018) used widely used psychiatric instruments to assess potential symptoms of anxiety and depression that may accompany abrupt discontinuation of kratom use in apparently frequent chronic kratom consumers in Malaysia.

3.5.3 Factor 7 Updated Conclusion

Kratom can produce psychic dependence and physiological dependence, but it is less likely to interfere with occupational, social and family activities and responsibilities compared to dependencies to opioids, alcohol, stimulants and other drugs of abuse.

Some people do experience strong addiction and withdrawal to kratom, and those people should have the same access to treatment as anyone with a substance use disorder. However, treating with buprenorphine or methadone may introduce people to opioids and may not be the best option.

4 DISCUSSION AND CONCLUSION

In 2018, there was sufficient evidence to conclude that kratom did not pose an imminent public health threat or a high degree of pharmacological abuse potential. The US DHHS rescinded its 2017 recommendation to place kratom on Schedule I of the CSA.

Four studies showed that MG did not carry morphine-like physical dependence or withdrawal potential, and that MG pretreatment of animals reduced spontaneous morphine withdrawal.

New US survey data shows that kratom use is generally non-addictive, with withdrawal being less severe than with opioids.

In vitro and in vivo animal neuropharmacology studies indicate that kratom alkaloids are not opioids, opioid analogs, or “atypical opioids”, though 7-OH-MG produces stronger MOR mediated opioid effects on abuse potential related measures and antinociception.

Kratom based extracts and individual alkaloids do not appear to carry substantial mortality risk, with one analysis suggesting a mortality risk at least 1000 times less than illicit opioids.

No analysis of factors 4 – 6 of the 8 CSA factors revealed kratom to pose an imminent public health threat, and none of the major surveillance systems identified such a public health threat.

Millions of US citizens use kratom for health and well-being, and many self-manage opioid and other drug withdrawal and use disorders as their preferred approach. There are problems with kratom product purity and adulteration in the consumer marketplace.

There has yet to emerge a generally accepted estimate of the number of current US kratom consumers, and surveys are needed before any action to ban consumer kratom sales and possession is contemplated.

Additional analysis and public input regarding kratom and its chemical components are needed before any scheduling should be undertaken. This includes a scientific assessment of how many Americans utilize kratom and the geographic and demographic distribution of these users.

This review provides stronger evidence than was available to Henningfield et al. or the US DHHS in 2018 to recommend against CSA scheduling of kratom, which carries a substantial foreseeable risk of thousands of opioid overdose deaths.

In conclusion, we do not recommend scheduling kratom or any of its alkaloids in the CSA, but do recommend accelerated research into new medicines.

ACKNOWLEDGMENTS

This report is an update of the Henningfield et al., 2018 kratom abuse potential assessment review and comprises an annotated bibliography and review of kratom-related scientific studies published since January 1, 2018. The AKA did not support the preparation of this review article.