July CE Article

july CPE Article

Kratom: An Emerging Herbal Supplement with Opioidlike Properties

Authors: Anisa Moore, PharmD and Karen Blumenschein, PharmD, MS

The authors declare that there are no financial relationships that could be perceived as real or apparent conflicts of interest.

Universal Activity #0143-0000-21-007-H08-P &T Contact Hour 1.0 KPERF offers all CE articles to members online at Expires:8/05/2024 www.kphanet.org

Learning Objectives: At the conclusion of this knowledge-based article, the reader should be able to: 1. Describe kratom and its origins of use 2. Identify kratom use patterns in the United States 3. List adverse health effects that may result from kratom use 4. Review the current regulatory challenges posed by kratom 5. Identify the pharmacist’s role in caring for patients who use kratom

Introduction

Kratom is an herbal supplement with growing popularity in the United States due to its unique pharmacologic activity with both stimulant and opioid-like properties. The broad range of activity for this natural product is largely due to the compound mitragynine and the analog 7-hydroxymitragynine[1]. These compounds are indole alkaloids that are partial agonists for mu-opioid receptors, competitive antagonists at kappa- and delta-opioid receptors, and have activity on the adrenergic, serotonergic, and dopaminergic receptors [2,3,4]. Kratom comes from leaves of Mitragyna speciosa, a tree a native to Southeast Asia [1]. It has been consumed medicinally in Indonesia, Malaysia, and Thailand for hundreds of years, where kratom leaves were chewed by labor workers for the stimulant effects to combat fatigue and brewed into tea for the relaxing effects [1]. There is also documented use of this herbal product in Malaysia and Thailand as an opioid alternative [2]. Given the current opioid epidemic, the opioid-like activity of kratom creates a valid concern for the potential of abuse liability.

In addition to its stimulant and analgesic properties, kratom is thought to have antidepressant, antidiarrheal, euphoriant, antispasmodic, and muscle relaxant activity [2,3]. The effects of kratom largely depend on the dose that is ingested and can vary from one person to another. At low to moderate doses of 1-5 grams, kratom produces mild stimulant effects [1]. At higher doses of 5-15 grams, kratom produces opioid-like effects including analgesia, constipation, euphoria, and sedation [1].

In the United States, kratom is used for selftreatment of pain, mood disorders, fatigue, and mitigation of opioid withdrawal symptoms, despite the fact that there is minimal empiric evidence to support such use, and growing concern about the safety of this product. While kratom is currently legal in most of the United States, there is great debate around whether or not this product should be controlled due to its opioid-like properties.

Kratom Use in the U.S. In the United States, kratom is sold in a variety of products including raw leaves, powders, capsules, tablets, and concentrated extracts [1]. These products can easily be purchased via the Internet, in herbal stores, or in specialty stores known as “head shops” or “smoke shops” [1,2]. Kratom is most commonly consumed as a liquid, by brewing as a tea or mixing in juice, but the use of tablets and capsules is growing [3]. Over the last two decades, kratom has become widely available in America and its use has increased significantly as well. It is estimated that the number of individuals using kratom in America ranges from 3 to 5 million people [2]. Voluntary surveys have been conducted to collect demographic and kratom-surveys had a mean age of around 40 years old, usually more than half were male, and a majority were Caucasian and non-Hispanic with varying education and income levels [4,5]. These surveys indicate that current kratom users commonly ingest muluse information from current and previous users with over 11,000 total responses [4,5]. Overall, respondents for these tiple doses on a daily basis [4,5]. In a voluntary survey done by Nicewonder et al., a majority of kratom users consumed between 1 to 5 grams up to three times per day [6]. Kratom is primarily used in America to self-manage chronic pain, mood disorders, and opioid, alcohol, or other drug withdrawal symptoms [2]. Kratom use has also been promoted as a “legal” or “natural” high, but few survey respondents indicated that this was their reason for use [2].

Common Reasons for Kratom Self-Administration Kratom is not classified as a prescription or overthe-counter medication so there are no Food and Drug Administration (FDA) approved indications for its use. However, anecdotal reports indicate that kratom is used as a natural alternative for selftreatment of a wide variety of maladies. The most common reported reason for selftreatment using kratom is chronic pain [4]. While there is limited clinical data supporting the use of kratom products for pain management, various animal models have shown evidence for pain alleviation with this compound [1]. Kratom’s opioid-like analgesic effects can be explained by the partial agonist activity on the mu-opioid receptor by mitragynine and 7-hydroxymitragynine [1, 7]. The most commonly reported reasons for using kratom for pain include relief of spine or back pain, fibromyalgia, injury-related pain, and osteoarthritis [4]. A majority of current and previous users state that kratom is “very” or “somewhat” useful in their pain management [4], and that prior to kratom use, other pain relief therapies were unsuccessful, including prescription medications, over-the-counter medications, physical therapy, and chiropractic adjustments [4]. Anecdotal data combined with evidence from animal models suggest that kratom could potentially be an alternative for pain relief, but further research is necessary before this product can be recommended for managing painful conditions.

Kratom for Mental Health and Focus The second most common reason for kratom use relates to its psychoactive properties that may aid in anxiety, post-traumatic stress disorder, depression, and combatting fatigue [4, 8]. Mitragynine and its analogs have activity on the serotonin and dopamine signaling pathways which suggest kratom could potentially help with depression or mood disorders [9]. There is little clinical data regarding the use of kratom for mood disorders, but several animal studies have demonstrated that mitragynine administration produces similar results when compared to atypical antipsychotics and antidepressants [9]. In addition to the potential antidepressant and antipsychotic properties, kratom has also been reported to alleviate anxiety and post-traumatic stress disorder (PTSD), as well as boost energy [9]. Several surveys highlight that a number of kratom users experienced an enhanced sense of wellbeing, relaxation, reduced anxiety, and increased energy following kratom administration [8]. One study also noted that a portion of respondents experienced enhanced sociability and/or empathy after kratom ingestion [8]. A majority of kratom users who use it for increased energy, focus, and motivation state that the stimulant effect is not as intense as other amphetamine-like substances [1]. Although anecdotal reports suggests that kratom’s psychoactive properties may enhance mood and combat fatigue, empiric evidence from randomized controlled trials

to support these claims is lacking [8]. Kratom for Opioid and Other Substance Use Disorders Kratom formulations are also used to decrease or discontinue the use of opioids, alcohol, and other drugs, combat withdrawal symptoms, and sustain opioid abstinence [4, 8]. This activity can be explained by mitragynine being a partial mu-opioid receptor agonist and a kappa- and delta-opioid receptor antagonist [4]. Animal models have shown that pretreatment with mitragynine resulted in decreased self-administration of heroin and morphine suggesting that kratom may reduce cravings for these substances[4]. Survey respondents currently using kratom reported significantly less opioid use and an overwhelming majority of current and previous kratom users reported that this supplement was either “very” or “somewhat” helpful in decreasing or stopping prescription opioid or heroin use [4]. Kratom has also been reported to relieve withdrawal symptoms associated with excessive opioid and alcohol use [4]. Most survey respondents who report using kratom to reduce withdrawal symptoms indicated that the supplement was “very” or “somewhat” helpful [4]. Anecdotal and animal data suggest that kratom could be used as a potential opioid alternative or to relieve opioid withdrawal symptoms, but once again, additional data from robust clinical trials is needed before kratom is considered safe and effective for these conditions.

Risks of Kratom Use While kratom-use has been promoted for the selftreatment of several maladies as described above, this herbal supplement is associated with several risks.

Kratom Adverse Reactions Survey responses from current and previous kratom users document adverse effects associated with kratom exposure. The most common adverse effects include agitation, tachycardia, hypertension, sedation, gastrointestinal problems, headaches, sweating, and confusion [4,10]. The online survey conducted by Coe and colleagues (2019) found that 13% of respondents reported experiencing “bad reactions” while using kratom [4]. As Kratom use has increased over the last decade, so have kratom-related calls to Poison Control Centers [10]. When looking at exposures reported from 2011 to 2018, there is a considerable increase in cases over time with 18 exposures reported in 2011 and 357 exposures reported during the first 7 months of 2018 [10]. A 2016 report evaluated 660 kratomrelated calls made to United States Poison Control Centers from 2010-2015 [11]. The authors found that most calls were from health care providers, with about 25% of cases classified as minor (symptoms resolved rapidly with no residual disability), and roughly 42% of cases classified as moderate (some form of treatment was required but there was no residual disability) [11]. Reports that were classified as major and life-threatening consisted of about 7% of exposures, with one death in a person who was exposed to paroxetine and lamotrigine in addition to kratom [11]. The remaining reports either had no effects reported or the Poison Control Center staff members were unable to follow-up on the report [11]. Many of these reports included the use of multiple substances in addition to kratom so it is difficult to determine if kratom was the sole cause of these reactions [11]. Serious adverse effects associated with kratom use, including seizures, hallucinations, respiratory depression, coma, and cardiac or respiratory arrest, have been documented [10]. In a small sample of case studies, kratom was determined to be the cause of hepatotoxicity and death, but these instances were rare and further research is needed to determine if kratom was the primary reason for these outcomes [12]. Despite kratom’s opioid receptor activity, it does not appear to result in significant respiratory depression and is far less likely to cause fatal overdose when compared to opioids [7].

Kratom Dependence and Withdrawal Although kratom use has been reported to ease opioid-withdrawal symptoms, current literature and case reports suggest that kratom use can also cause dependence and withdrawal [13]. Kratom users who consume larger doses multiple times a day for an extended period of time are more likely to become dependent [1]. Several case reports have documented withdrawal symptoms upon abrupt discontinuation of kratom [10,13]. Withdrawal symptoms typically present within 12-24 hours of kratom cessation and can last up to seven days [13]. The physical symptoms of kratom withdrawal manifest as muscle spasms, diarrhea, nausea, tremors, anorexia, fever, pain, and lacrimation [1,10,13]. The psychological symptoms of kratom withdrawal include insomnia, restlessness, irritability, fatigue, anxiety, and mood disturbances [1,10,13]. When compared to opioids, kratom’s dependence syndrome appears to be mild in its psychosocial and physiological effects [8]. There are no specific guidelines on how to manage kratom withdrawal, but it is commonly treated using similar strategies that are used with opioid withdrawal [13].

Kratom-Drug Interactions As with any medication or herbal supplement, kratom has the potential to interact with other medications or products that are concurrently administered. In vitro, kratom demonstrated inhibition of cytochrome P-450 (CYP) isozymes 2C9, 2D6, 1A2, and 3A4 which can impact the metabolism, efficacy, and safety of commonly prescribed medications, including warfarin, phenytoin, and several antiarrhythmics, and opioids [10]. This is especially important to consider because kratom may be used concurrently with illicit substances that are also substrates for these enzymes, including opioids, methylenedioxymethamphetamine (MDMA), and synthetic cannabinoids. Thus, coadministration of kratom with both licit medications and illicit substances can increase the risk of serious adverse effects [10].

Inconsistent Dosing and Impurities Kratom is currently classified as a dietary supplement, thus, there is potential for inconsistent dosing and impurities because supplements do not undergo extensive testing for purity and safety. Furthermore, the amount of psychoactive compounds in different kratom plants can vary depending on where the plants were grown [14]. Inconsistent dosing among kratom products can put users at risk for adverse effects because they may unintentionally consume larger quantities than anticipated. The potential for contamination is also a concern relating to the use of natural products. A major Salmonella outbreak related to kratom products occurred in 2018 with 41 states reporting a total of 199 cases and 50 hospitalizations [15]. The product was recalled but the investigation was not able to identify a single, common source of contaminated kratom, potentially resulting in contaminated products still being available for distribution and infecting more kratom-users [15].

Kratom Regulation Overview Kratom is banned in several countries including Australia, Malaysia, New Zealand, Romania, South Korea, and the United Kingdom due to its activity on the opioid receptor [6]. In the United States, kratom is currently classified as a dietary supplement but there is great debate about whether or not this natural product should be controlled because of its opioid-like effects. In August 2016, the Drug Enforcement Administration (DEA) proposed to make mitragynine and 7-hydroxymitragynine Schedule I compounds, but this action was delayed due to an outcry from the public, researchers, and legislators [10]. Kratom advocates filed comments to the DEA protesting the Scheduling of this compound and on October 13th 2016 the DEA announced its intent to withdraw the Scheduling of kratom components and instead placed kratom on the “Drugs of Concern” list [16]. While kratom is not federally controlled in the United States, it is currently classified as a Schedule 1 narcotic in Alabama, Arkansas, Indiana, Tennessee, Vermont, and Wisconsin, as well as a few municipalities [10]. Florida attempted to move kratom’s classification to a Schedule I narcotic, but this proposal was rejected in May of 2017 [17]. Further research regarding kratom’s pharmacologic effects and potential for abuse could help create a better understanding of whether or not this product should be classified as a controlled substance

Pharmacist’s Role With the growing availability and popularity of kratom in the United States, it is imperative that pharmacists and other healthcare providers are aware of the reasons that patients may be selfmedicating with this supplement, as well as the risks associated with its use. When conducting a patient medication review, pharmacists need to thoroughly investigate dietary supplementation in addition to prescribed and over-the-counter medications. Pharmacists should ensure that patients who use kratom are knowledgeable about adverse reactions that may accompany kratom use, and that they are aware of the potential risk of dependence and withdrawal symptoms when kratom use is discontinued. Patients taking warfarin, celecoxib, or glipizide should be especially cautious when using kratom because of the drug-drug interactions caused by CYP 2C9 inhibition. Kratom is not detected in a urine drug screen so healthcare professionals must be cognizant of the potential involvement of kratom in overdose situations, including events of multi-substance exposure. Healthcare providers should also be familiar with how to identify and manage kratom withdrawal.

Conclusion The use of kratom products is increasing throughout the United States as a method of selfmedication for a variety of maladies including chronic pain, mood disorders, opioid mitigation, and opioid withdrawal. While a majority of kratom respondents in voluntary online surveys suggest that this supplement is a natural alternative to current medical treatments, further research is need-

ed before it can be considered a safe and effective form of treatment for any condition. The similarities between kratom and opioids raise valid concern for potentially inappropriate kratom use. Pharmacists and other healthcare providers should stay up-todate with federal and state regulations pertaining to kratom. Pharmacists can play a crucial role in enhancing the safety of patients who use kratom by performing thorough medication reviews and counseling patients on the adverse effects, potential herb-drug interactions, withdrawal symptoms, impurities, and inconsistent dosing associated with kratom.

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