Kratom Abuse Potential 2021: An Updated Eight Factor Analysis

Abstract

Drugs are regulated in the United States (US) by the Controlled Substances Act (CSA) if 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 not 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.

Respiratory effects of oral mitragynine and oxycodone in a rodent model

“…Self-report data posted on internet websites were summarized in several kratom use reviews (e.g., Cinosi et al 2015;Henningfield et al 2018Henningfield et al , 2022Swogger and Walsh 2018;Veltri and Grundmann 2019). These data suggest that kratom intake is typically limited by non-life-threatening but discomfort-producing gastrointestinal symptoms and/ or undesirable lethargy.…”

“…Kratom products are used globally for health and well-being, improved mood, sleep, attention, and coffee-caffeine-like alerting effects (Grundmann, 2017;Henningfield et al 2018Henningfield et al , 2022Swogger et al 2022). There is recreational use; however, many people who use opioids recreationally report kratom as a poor substitute for producing opioid-like euphoria but do find it useful to self-manage withdrawal and discontinue opioid use (Coe et al 2019;Garcia-Romeu et al 2020;Prozialeck et al 2019;Swogger et al 2022).…”

“…Many products have low or nondetectable concentrations of other alkaloids that may contribute to respiratory and other effects (Chakraborty et al 2021;Sharma et al 2019;Sharma and McCurdy 2021). Furthermore, unlike opioids and other substances widely used recreationally that are taken intravenously, insufflated, or inhaled (e.g., O'Brien 2015), kratom is taken almost exclusively by the oral route as dried kratom leaf powder teas, foods, or beverages to mask its bitter unpleasant taste, or leaf powder-filled capsules (Cinosi et al 2015;Henningfield et al 2018Henningfield et al , 2022Ramanathan and McCurdy 2020;Singh et al 2016).…”

Understanding Kratom Use: A Guide for Healthcare Providers

“…Studies aimed to establish lethal kratom doses have not induced any acute deaths with symptoms similar to morphine. Instead, at doses of mitragynine equivalent to hundreds or more times the typical human dose range, some animals died within days or weeks from a variety of causes unrelated to respiratory depression ( Henningfield et al, 2018 ; Prozialeck et al, 2019 ; Henningfield et al, 2022 ). Kratom doses of up to 807 mg/kg in rats or 920 mg/kg in dogs did not indicate signs of toxicity ( Macko et al, 1972 ).…”

“…Mitragynine was also found to reduce rodent morphine ( Hemby et al, 2018 ) and heroin self-administration ( Yue et al, 2018 ). See Henningfield et al (2022) in this special issue for an update of many more studies related to the abuse potential of kratom. Furthermore, administration of 7-hydroxymitragynine takes the equivalent of 100 times more than what humans consume to display reinforcing effects ( Hemby et al, 2018 ).…”