Understanding Kratom Use: A Guide for Healthcare Providers

       Marc T. Swogger¹*, Kirsten E. Smith², Albert Garcia-Romeu³, Oliver Grundmann^4,5, 

       Charles A. Veltri⁴, Jack E. Henningfield^3,6 and Lorna Y. Busch¹

• ¹Department of Psychiatry, University of Rochester Medical Center, Rochester, NY, United States
• ²Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, United States
• ³Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
• ⁴Department of Pharmaceutical Sciences, Midwestern University College of Pharmacy, Glendale, AZ, United States
• ⁵College of Pharmacy, Department of Medicinal Chemistry, University of Florida, Gainesville, FL, United States
• ⁶Pinney Associates, Bethesda, MD, United States

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.

Introduction

Kratom (Mitragyna speciosa Korth., Rubiaceae; also known as ketum) is made from the leaves of a tropical tree in the coffee family indigenous to Southeast (SE) Asia, where it has been used for centuries as medicine for various ailments, including hypertension, diarrhea, cough, and fever (Tanguay, 2011; Cinosi et al., 2015; Singh et al., 2016). Despite such traditional medicinal use, it is important to recognize that neither kratom, nor its constituents (e.g., “alkaloids”), nor metabolites have been approved as safe and effective medicines for any therapeutic use. Nonetheless, widespread use for health and well-being include diverse uses reported by consumers as reasons for their use. For example, at low doses, kratom has long been consumed orally as a stimulant to enhance stamina and productivity, making it particularly popular among field laborers working long days in arduous conditions (Tanguay, 2011; Prozialeck et al., 2012; Hassan et al., 2013; Warner et al., 2016). Consumption remains widespread in kratom’s native lands, where people commonly chew raw kratom leaves or boil leaves to make tea (Swogger and Walsh, 2018). Kratom can also be smoked, vaporized, or consumed as a powder. Because of its purported analgesic properties, kratom is used to treat pain and, notably, as a means to alleviate opioid withdrawal or as an opioid replacement among people with opioid use disorder (OUD) (Smith and Lawson, 2017; Henningfield et al., 2018; Bath et al., 2020). In addition to analgesia produced at higher doses, kratom is reported to have relaxing, anxiolytic effects. Over the past 2 decades, kratom has gained popularity beyond Asian borders, particularly in North America and Europe (Boyer et al., 2007; Grundmann, 2017).

An estimated 10–16 million people in the United States take kratom, though current prevalence ranges of 1.3%–6.1% from national representative surveys may underestimate regular kratom users (Henningfield et al., 2019; Covvey et al., 2020). Whereas in Southeast Asia users typically buy kratom leaves directly from a grower, Westerners often purchase capsules, powders, or extracts via the internet, specialty smoke shops, and gas stations (Prozialeck et al., 2012; Singh et al., 2016). Kratom is currently not recognized as a dietary supplement in the United States, and the Food and Drug Administration (FDA) has not issued guidance or regulatory standards on kratom regarding allowable product contents, alkaloid concentrations, packaging, labeling, or marketing of kratom products that is usually provided for dietary ingredients (Coe et al., 2019). This gap in regulatory policy prompted the American Kratom Association (AKA) to develop voluntary industry guidelines through a Good Manufacturing Practice (GMP) Standards Program that tests for purity and contaminants (American Kratom Association, 2019). Due to the potential for adulteration of kratom products the unregulated status of kratom in most United States remains a concern.

Although the rise of kratom use in the West has been an opportunity for increased scientific study, the resultant publication of a great deal of research of limited rigor has created confusion for health practitioners attempting to understand the benefits and risks of the plant and the heterogeneity of kratom products. Case studies, poison control center briefings, and tallied coroner and medical examiners’ reports have disproportionately emphasized, as these forms of inquiry often do, extreme and rare events, including seizure, liver damage, and death (e.g., Nelsen et al., 2010; Sheleg and Collins, 2011; Kapp et al., 2011; Neerman et al., 2013; Anwar et al., 2016; Wang and Walker, 2018; Post et al., 2019; Afzal et al., 2020), even as some have elucidated that adverse health outcomes from kratom exposure have been mild to moderate and resolved quickly (Anwar et al., 2016). Still, there remains considerable ambiguity on the potential harms from kratom use. In February 2018, the FDA cited 44 cases of kratom-associated deaths based upon coroner or forensic toxicologist reports. However, at the current level of scientific knowledge, several factors make it impossible to determine whether kratom contributed to lethal outcomes. Almost all of the cases cited involved adulterated kratom products and/or the co-ingestion of substances with fatal overdose potential, including heroin and synthetic opioids (Babin, 2018). For instance, nine deaths were from an herbal mix, Krypton, containing a metabolite of the opioid tramadol (Bäckstrom et al., 2010). Additionally, the mere presence of mitragynine (one of kratom’s primary alkaloids believed to be responsible for analgesia) in decedents’ plasma or evidence of presumed kratom consumption (e.g., kratom product packages) does not implicate the plant’s role in toxicity, especially given the large variability of mitragynine serum levels of decedents, ranging from 5.6 to 29,000 ng/ml (Papsun et al., 2019). Finally, there is no clear mechanism by which kratom alone and taken even at high doses would directly cause death. Unlike classical opioids, which act as full agonists at mu opioid receptors, kratom’s two primary and best understood bioactive alkaloids, mitragynine and 7-hydroxymitragynine, act at mu opioid receptors as partial putatively “biased” agonists, meaning that they do not contribute to significant respiratory depression in pre-clinical animal studies (as discussed more below), making “poisoning”, when kratom alone is used, a highly questionable cause of death. Importantly, there are no reports of deaths due to kratom use in SE Asia for over a century (Veltri and Grundmann, 2019). Despite insufficient evidence for kratom’s role in harm, media headlines misleadingly insinuate that kratom has been established as a cause of death (e.g., “kratom deaths” and “kratom overdose deaths; ” Galvin, 2019; Kaur, 2019; Miller, 2019).

Conclusions by many negative, sensationalized, or otherwise decontextualized media reports on kratom have been questionably drawn from case studies and toxicology reports which, at best, provide low levels of evidence due to unknown internal validity and generalizability and over-representation of extreme events (Merriam, 2009). Unfortunately, warnings regarding kratom exhibit features of drug hysteria (Hart, 2013), which involves the promulgation of sensational and biased information and the pursuit of legislative approaches that are disproportionate to apparent public health risks. At the public health level, drug hysteria is not only scientifically unfounded, but dangerous. In the case of kratom, misinformation can lead to dehumanization of kratom users, disinclination for people with OUD to try kratom as a substitute for opioids that are causing them harm, and the continued promotion of ineffective, draconian, and punitive policies with the potential to contribute to mass incarceration, a serious public health threat in its own right. Simultaneously, drug hysteria can contribute to the inhibition of rigorous scientific study and thereby deprive the public of scientifically-informed pharmacotherapeutic interventions (PR Newswire, 2016). Banning or criminalizing kratom, as six United States have done at the time of this writing, has the potential to create a new illicit market for kratom products, increasing the likelihood of adulteration and the use of dangerous substances as kratom substitutes. All of this results in harm to people who regularly use kratom to address pain, psychiatric problems, and SUD symptoms (Grundmann, 2017; Swogger and Walsh, 2018; Coe et al., 2019; Smith et al., 2021a; Smith et al., 2021b). Moreover, sensationalized and negative reports lead some patients to fear revealing kratom use to their healthcare providers (Smith et al., 2021b) and misinform those providers about the risks of kratom use.

Subsequent to increased kratom use in the United States, an eight-factor analysis (8 FA) normally required prior to scheduling decisions was performed by the FDA, and another by an independent agency (Pinney Associates). The former has been criticized by kratom researchers for omission of important scientific studies and pertinent data, as well as inappropriate use of a computer simulation model (PHASE) that provided data that the FDA used to deem kratom an “opioid” (Grundmann et al., 2018), linking it to more dangerous classical opioids without providing information on differences between kratom and these drugs. Meanwhile, Pinney Associates concluded that kratom is distinct from classical opioids and poses no more of a public health risk than many commonly-used substances, thereby warranting product oversight rather than a ban. Nonetheless, recent publications in medical journals espouse kratom use as “highly problematic” and its effects “contributors to the growing opioid crisis” (e.g., Goldin et al., 2019), without adequate supporting data. This rhetoric can stigmatize users and mislead well-intentioned healthcare professionals into an anti-kratom stance that could negatively impact their patients and the patient-provider relationship.

A balanced examination of what can be drawn from the existing literature directed to healthcare providers and clinicians is warranted. This is particularly true given that the study of kratom is in its infancy: there is only one published clinical trial of kratom’s effects in humans. There is, however, a growing body of observational literature that represents a higher level of evidence than case reports or forensic toxicologists’ and medical examiners’ reports. Here, we first review research on the pharmacology of kratom and then summarize the available observational science on human kratom use in order to provide the most nuanced, accurate, and comprehensive review of kratom’s potential benefits and risks possible at this early stage of kratom research. We acknowledge that information provided here will inevitably change as more data are collected on kratom and kratom use. Like all things in science, our understanding of this plant and its use is provisional. Here we provide the most up-to-date information in an accessible manner. Based on the review, we conclude with recommendations to health practitioners for conceptualizing kratom use and working with patients who use kratom.

Pharmacology and Animal Studies

Of the dozens of alkaloids identified in kratom, mitragynine is the most prominent (comprising approximately 60 percent; Hassan et al., 2013) and appears, along with 7-hydroxymitragynine, to be primarily responsible for the plant’s unique psychoactive properties, which include opioid and non-opioid activities (Adkins et al., 2011; Kruegel and Grundmann, 2018; Raffa et al., 2018) that are dose dependent. In relatively low doses (<5 g), kratom has stimulant properties similar to its coffee relative, while larger quantities may produce sedating and analgesic effects (Kruegel and Grundmann, 2018; Coe et al., 2019; Kruegel et al., 2019; Todd et al., 2020). 7-hydroxymitragynine, while more potent than mitragynine, is unlikely to contribute to pharmacological effects due to its low natural presence in kratom leaves (Kruegel and Grundmann, 2018; Todd, et al., 2020; Obeng et al., 2021). Mitragynine is metabolized by humans via CYP enzymes into 7-hydroxymitragynine but the amount generated via metabolism is not sufficient to explain the analgesic effects of kratom products as a whole (Kamble et al., 2019; Maxwell et al., 2021).

In vitro studies reveal that biochemical pathways responsible for the analgesic and sedating effects of kratom do not carry risk of overdose comparable to classical opioids. Specifically, mitragynine and 7-hydroxymitragynine have partial affinity for the mu opioid receptor (Kapp et al., 2011; Prozialeck et al., 2012), whereas morphine is a full agonist. Binding of kratom alkaloids to this receptor largely activate G-protein coupled pathways, as opposed to the beta-arrestin pathway responsible for classical opioids’ common deadly side effect of respiratory depression (Kruegel et al., 2016; Váradi et al., 2016; White, 2018; Kruegel et al., 2019; Basiliere and Kerrigan, 2020; Behnood-Rod et al., 2020). Mitragynine also exerts non-opioid receptor pain-relieving effects by stimulating alpha-2 adrenoceptors and inhibiting cyclooxygenase-2 messenger RNA (mRNA) and protein expression (Matsumoto et al., 1996).

The distinct affinity for and activation of opioid receptors, as well as non-opioid analgesic effects that clearly distinguish kratom from classical opioids (Raffa et al., 2018), may explain why there are relatively few kratom-related safety issues given its widespread use. It is likewise important to keep in mind that while many effects of kratom are mediated by opioid receptors, kratom’s pharmacology indicates additional non-opioid mechanisms of action, including for mitragynine, again underscoring the complexity of the plant and our limited knowledge of its pharmacology (Hiranita et al., 2019). In addition to limitations in understanding the mechanisms of action and toxicity of kratom, is the limitation in data addressing use of kratom in combination with approved medicines, illicit drugs, and other herbal products. By way of example, the partial opioid agonist buprenorphine, which is approved by many regulatory agencies globally for the treatment of opioid withdrawal and use disorder, as well as pain, carries a far lower risk of lethal respiratory depression when used alone, but has been identified as contributing to overdose deaths when used in combination with benzodiazepines and other sedatives (Kumar et al., 2021). There has not been sufficient study to determine if kratom in combination with benzodiazepines and other sedatives, carries similar, greater, or lessor risks as compared to buprenorphine, so it would seem prudent for health care providers and kratom consumers to be aware of such limitations in the evidence and avoid such combinations and to minimize intake levels when combination consumption occurs because risks with most substances tend to be dose-related. The same cautions apply to use in combination with other substances.

The pharmacokinetics of mitragynine have been established in rodents, primarily rats, following oral administration (Ramachandram et al., 2019). Depending on the vehicle preparation, maximum plasma concentration, c_max (0.42–0.70 μg/ml), time to reach c_max, t_max (1.26–4.50 h), and elimination half-life, t_1/2, (3.85–9.43 h) indicated that mitragynine was highly variable in its absorption and/or metabolism. A study using traditionally prepared kratom tea and a hydroalcoholic kratom extract given orally to rats resulted in a c_max of 63.8 and 111.9 ng/ml and t_max of 1.3 and 3.1 h, respectively, while the t_1/2 was not determined (Kamble et al., 2021). This supports the conclusion that the absorption of mitragynine is influenced by the presence of other kratom leaf compounds. Only one human study to date evaluated the pharmacokinetics of mitragynine following oral administration of a traditionally prepared kratom tea in 10 male volunteers (Trakulsrichai et al., 2015). The pharmacokinetic parameters for mitragynine were an average t_max of 0.83 h, c_max ranging from 0.0185 to 0.105 μg/ml, and an average terminal t_1/2 of 23.2 h. The maximum plasma concentration depends largely on the dose administered and thus needs to be interpreted within that context. However, both the time to reach maximum plasma concentration and half-life are usually comparable, at least within the same species. Because there is only one human study reporting mitragynine pharmacokinetics and substantial variability was found in rat studies, it is too early to conclude how well animal data can predict mitragynine pharmacokinetics in humans. Furthermore, the kratom preparation may impact the absorption and pre-systemic metabolism of mitragynine and other active principles.

Animal research provides further evidence of kratom’s relative safety compared to classical opioids. 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). Animal studies evaluating reinforcing effects through intravenous self-administration reveal that, unlike morphine, mitragynine does not serve as a reinforcer in rats (Hemby et al., 2018; Yue et al., 2018) and therefore has lower abuse potential. 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). Rodent studies also demonstrate that prodigious amounts of mitragynine (not ingestible at a human equivalent) may be needed to produce severe and sustained withdrawal effects that rival those produced by classical opioids (Harun et al., 2015; Henningfield et al., 2018). Rather, kratom has been found to attenuate opioid withdrawal symptoms in animals, albeit with its own milder withdrawal effects after cessation of long-term use (Hassan et al., 2013; Sabetghadam et al., 2013; Yusoff et al., 2016). Rodent studies confirm physical withdrawal from kratom that occurs after injection with the opioid inhibitor naloxone (e.g., Matsumoto et al., 2005), as well as with cessation of repeated mitragynine administration (Yusoff et al., 2016). Symptoms include somatic withdrawal within 12 h and increased anxiety, evident after 24 h. Across studies, dose-dependent indicators of both toxicity and withdrawal related to isolated kratom alkaloids have been found to resolve after discontinuation or a short duration of time has passed, respectively. (Source: www.frontiersin.org)

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