Kratom, Mitragynine, and 7-Hydroxymitragynine (7-OH)

"Kratom is a plant known as Mitragyna Speciosa (Rubiaceae Family), naturally growing in Africa, South-East Asia (e.g., Malaysia and Thailand), and New Guinea. Since the 19th century, its leaves and extracts have been used as a folk remedy in these countries to deal with common health problems (e.g., pain, fever, diabetes), to replace opiates, and to boost energy and reduce fatigue (Cinosi et al. 2015; Hassan et al. 2013; Kruegel and Grundmann 2018; Swogger et al. 2022). Kratom use has also expanded to Western countries, leading to a wide availability of kratom products (e.g., powder, capsules, tablets) online and in specialty shops (Hillebrand et al. 2010; Prevete et al. 2024; Prozialeck et al. 2012; Williams and Nikitin 2020). The main motivations for using kratom include recreational purposes and self-treatment of various mental and physical health conditions (Bath et al. 2020; Coe et al. 2019; Grundmann et al. 2022, 2023; Smith et al. 2024a). A small amount (< 5 g) of raw plant material has been reported to produce stimulatory effects such as increasing talkativeness, alertness, or physical energy (Henningfield et al. 2024; Kruegel and Grundmann 2018; Prozialeck et al. 2012; Singh et al. 2019a; Swogger et al. 2022). Doses above 5 g have been reported to produce inhibitory-analgesic and sedative properties like opioids (Henningfield et al. 2024; Kruegel and Grundmann 2018; Prozialeck et al. 2012; Singh et al. 2019a; Swogger et al. 2022). Moreover, it has been shown that kratom’s stimulant and sedative effects can co-exist (Smith et al. 2023a), often at higher doses (Peran et al. 2023)."

"Kratom is a plant-derived from a species of plant native to Southeast Asia called Mitragyna speciosa [1]. It is generally prepared through boiling leaves derived from Mitragyna speciosa to produce kratom tea. Additionally, kratom can be crushed in order to produce a powder that is then able to be ingested [2]. Kratom comprises numerous alkaloids, which are organic compounds that contain nitrogen. Two of these alkaloids are mitragynine and 7-hydroxy mitragynine. Both are believed to be crucial in kratom's physiological effect on humans [3]. Though the mechanism of action of these compounds is still not fully understood, it is believed they work primarily via acting as agonists at certain subtypes of opioid receptors expressed on neurons, with mitragynine acting at the μ and δ receptors while 7-hydroxy mitragynine acts at the μ and κ receptors. These receptor-ligand interactions may then stimulate signal transduction mechanisms involving the activation of G proteins. In addition, these metabolites are also believed to act on various monoaminergic and opioid receptors [4,5].

"Kratom has been shown to cause both a stimulant-like effect and a sedative effect in humans. The physiological effects vary based on the dose that is taken as well as the particular strain of kratom that is consumed [3]. For example, the red vein strain of Mitragyna speciosa tends to induce a sedated state when ingested, whereas the green vein strain tends to cause a stimulating effect [6]. The use of kratom has historically been by people living in Southeast Asia [7]. However, in recent years, the use of kratom has increased significantly among people living in the United States [8]. In the United States, kratom can now be bought online or at certain drug shops [9]. As kratom has only recently gained popularity in the United States, much is still unknown regarding the potential adverse effects of the drug. However, some negative side effects that have been documented include nausea, vomiting, hypertension, tachycardia, and elevated levels of creatine phosphokinase [10].

"Additionally, there have been several instances where kratom intake caused severe liver damage that was eliminated once patients stopped consuming kratom [11]. Further compounding issues with kratom are evidence showing that individuals taking kratom develop a physiological dependence, especially when taking other drugs of abuse, which can result in withdrawal symptoms. These withdrawal symptoms include extreme pain, muscle spasms, and difficulty sleeping [12,13]."

"Kratom (Mitragyna speciosa) is a tropical evergreen tree from the Rubiaceae family, native to Southeast Asia, and its leaves have been used as herbal remedies since at least the mid-19th century [6]. The bioactive alkaloids in kratom may have favorable interactions with neurotransmitter receptors in the central nervous system (D2 dopamine, 5-hydroxytryptamine 2A {HT2A}, and 5-HT2C receptors), which could confer potential benefits for anxiety and other mental health conditions [7,8]. Mitragynine stands as the primary alkaloid in kratom leaves, metabolized to form the active metabolite 7-hydroxymitragynine. A cross-sectional study compared hematology and clinical chemistry parameters between regular kratom users (daily dosages ranging from 76.3 to 114.8 mg of mitragynine) and healthy nonuser controls, demonstrating no significant differences [9]."

"Studies have detailed what demographic in the US displays the highest rate of kratom consumption. These studies have shown that use is highest among White, middle-class men living in suburban areas. Additionally, individuals who have a history of opioid misuse are also more likely to take kratom [18]. Another risk factor for kratom use that has been found is the use of e-cigarettes. A study found that individuals who reported using e-cigarettes within the past year had 4.8 higher odds of using kratom within that same interval than those who did not [19]. This is important to note as the use of e-cigarettes has skyrocketed in recent years, especially among teenagers and young adults [20].

"Kratom is used by many different people in the US for numerous other reasons. Some of the most often cited reasons include to treat chronic pain conditions, depression, and anxiety. Individuals who used kratom for these reasons consumed kratom daily at a typical dose of 1-3 grams, with the kratom converted into a powder so that it could be consumed in a capsule [21]. Kratom may also be used by people due to its stimulant-like effects, causing increased feelings of motivation, higher levels of energy, a stronger desire to work, and an overall increase in productivity [22]. Additionally, there have been reports of kratom being used to treat opioid withdrawal symptoms, as kratom can bind to some of the same receptors as opioids [14,23]."

"The primary psychoactive alkaloid in kratom is mitragynine. This compound and its metabolite 7α-hydroxy-7 H-mitragynine are partial µ-opioid receptor agonist and competitive antagonist at κ- and δ-opioid receptors. In contrasts to classical opioids, mitragynine and 7-hydroxymitragynine also bind to adrenergic (α1 and α2) and serotonergic (5-HT1A and 5-HT2B) receptors (Henningfield et al. 2024; Hiranita et al. 2022; Kruegel et al. 2016; Kruegel and Grundmann 2018; Obeng et al. 2020, 2022; Raffa et al. 2018). In regular kratom users, the estimated, daily dose of mitragynine can typically range between 75 and 435 mg divided over 3 to 4 glasses of kratom juice (Leong Abdullah et al. 2021; Singh et al. 2018). In Western countries, kratom users typically consume between three and eight grams of raw plant material (Smith et al. 2022). However, kratom products might have variable mitragynine concentrations, making it hard to estimate a typical mitragynine dose. Mitragynine’s pharmacokinetic profile has been studied in preclinical research (Ramachandram et al. 2019; Ya et al. 2019) and in humans (Huestis et al. 2024). In the latter study, 12 participants received dried kratom leaf powder capsules (500–4000 mg) containing between 6.65 and 53.2 mg of mitragynine. The median mitragynine Tmax was 1.0–1.3 h after single and 1.0–1.7 h after multiple doses; for 7-hydroxymitragynine Tmax, it was 1.2–1.8 h and 1.3–2.0 h. Steady-state mitragynine concentrations were reached in 8–9 days and 7-hydroxymitragynine within 7 days. Clinical data consistently indicate that mitragynine fits a two-compartment model when orally administered (Tanna et al. 2022; Trakulsrichai et al. 2015). Following 10–20 min, individuals may experience initial euphoric effects, which are reported to reach their peak intensity within 0.5–1 h, and can last 5 to 7 h (Prozialeck et al. 2012; Rosenbaum et al. 2012; Scott et al. 2014; Warner et al. 2016). Knowledge of adverse effects of kratom is scarce and mainly comes from user reports on drug fora and case reports that have suggested risks of dependence, withdrawal, cardiorespiratory problems, and kidney and liver injury (Alsarraf et al. 2019; Corkery et al. 2019; Peran et al. 2023; Schimmel and Dart 2020). However case reports often lack thoroughness because they may not provide a full assessment of the patient’s kratom use (Feldman et al. 2023). Systematic reviews of case reports (Smith et al. 2023b) and in-depth interviews (Smith et al. 2023a) with chronic kratom users confirmed risk of dependence, while the latter also identified feelings of jitter at high doses.

"To our knowledge, little comprehensive research has been conducted to evaluate the acute effects of mitragynine on measures of safety and neurocognition in healthy volunteers. A recent observational study in 10 chronic kratom users revealed only minor changes in vital signs and mild increments of euphoria after self-administration of 5.16 g (on average) of kratom leave powder (Smith et al. 2024b). Self-reported (n = 357) and simulated driving reports (n = 10) have suggested that kratom effects at self-selected doses among regular kratom consumers do not produce significant changes in subjective and objective measures of driving impairment (Zamarripa et al. 2024). However, systematic, controlled studies with mitragynine are presently missing."

"The present study aimed to evaluate the safety (i.e. vital signs and adverse events) and impact on neurocognitive performance of single acute doses of mitragynine. Mitragynine did not have a significant effect on the majority of outcome measures at any dosage level and was well-tolerated. Still, the lowest dose (5 mg) increased subjective ratings of amphetamine-like arousal and attention. Further, the 5 mg dose increased accuracy in a sustained attention task and increased errors in the stop-signal task as compared to placebo. The highest dose (40 mg) of mitragynine increased subjective ratings of amnesia and produced some mild symptoms of psychological distress. Moreover, vital signs were not significantly affected by mitragynine, and only mild, transient side effects were reported."

"Mitragyna speciosa (i.e., kratom) is a psychoactive plant indigenous to Southeast Asia that has increased in popularity across the US in recent years (Grundmann, 2017, Prozialeck et al., 2012). Evidence from the National Survey on Drug Use and Health suggests that nearly 2 million Americans reported kratom use in 2022 (Substance abuse and mental health services administration., 2023), yet industry reports place estimates between 5 and 15 million US adults (American Kratom Association, 2019). Marketed as a dietary supplement, rising rates of kratom use may be attributable to the botanical’s various purported effects, with motivations for use that include increased focus, nonmedical self-management of physical pain and psychiatric symptoms (e.g., anxiety), and use of kratom to self-manage substance use disorders (SUDs) (Grundmann et al., 2022, Smith et al., 2024a, Smith et al., 2022b, Smith et al., 2021b, Smith and Lawson, 2017). Notably, however, there have also been some reports of toxicity and overdose fatalities involving kratom exposure, typically involving complicated health history and polydrug use (Corkery et al., 2019, Eggleston et al., 2019, Olsen et al., 2019). Development of kratom physical dependence (e.g., tolerance, withdrawal) and DSM-5-derived SUD for kratom (i.e., kratom use disorder; [KUD]) have also been documented among some people who use kratom regularly (Hill et al., 2024, Smith et al., 2022a, Weiss et al., 2024).

"Currently, kratom is unscheduled at the federal level and legal in most US states, with some states adopting legislation to regulate kratom (Ellis et al., 2023). Despite kratom’s lack of federal regulation, proliferating product formulations, and increasing popularity, human data on kratom remains limited in comparison to other commonly used substances. Current scientific gaps, while narrowing, hinder individuals' ability to make informed decisions about their use, while leaving policy makers and clinicians without the data necessary to develop appropriate regulations and health recommendations."

"In the United States, anecdotal reports suggest that kratom commerce and use began in the last quarter of the 20th century but was largely limited to Southeast Asia immigrants and returning United States veterans with no published estimates of kratom use prevalence until the 21st century. In 2015, the Botanical Education Alliance (BEA) survey of kratom vendors estimated three to five million kratom consumers in the United States (BEA, 2016). The major United States surveillance systems tracking trends in recreational substance use and treatment-seeking for 'addiction' or substance use disorder (SUD) did not include kratom on their annual reports until 2020 3 . The National Survey on Drug Use and Health (NSDUH) prevalence data suggested approximately 1.7–1.8 million past-year kratom consumers from 2019–2021 (Palamar, 2021; SAMHSA, 2022; 2023a; b;c), while the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) system estimated 2.03 million, with lifetime prevalence at 3.4 million based on 2018–2019 data (Schimmel and Dart, 2020). Covvey et al. estimated lifetime prevalence of kratom use at 6.1% based on a 2019 survey (Covvey et al., 2020). Other approaches to estimating kratom use prevalence based on kratom import volume and market data projected more than 10 million current users in 2019 (American Kratom Association, 2019). Together, evidence suggests that the NSDUH and RADARS systems likely underestimate kratom use prevalence, indicating that better methods for estimation of novel product use are needed (Henningfield et al., 2022b; Palamar, 2022)."

"In our study, mitragynine doses between 10 and 40 mg caused a slight decrease in blood pressure and respiratory rate. These variations were within the normal range, and therefore not considered clinically relevant. Such findings contrast with cardiorespiratory toxicities described in the literature (Brogdon et al. 2022; Sheikh et al. 2021) and cardiological alterations, including sinus tachycardia (Leong Abdullah et al. 2021), prolonged QTc interval (Leong Bin Abdullah and Singh 2021), and increased blood pressure/pulse rate in regular kratom users after drinking kratom tea containing up to 20 mg of mitragynine (Trakulsrichai et al. 2015). This suggests that the cardiovascular effects of mitragynine might be different in chronic kratom users who use higher doses or products containing other substances/contaminants, often considered responsible for health hazards. At the same time, lab safety data (clinical chemistry, hematology, and urinalysis) in the present study did not show significant deviations from normal ranges. These results are in line with findings showing that kratom did not cause alterations in blood exams of kratom users (La-Up et al. 2021, 2022; Ramachandram and Sangarran Chia Siang 2023; Singh et al. 2018; Vicknasingam et al. 2020). Further, no significant adverse events were described and only mild, transient side effects (e.g., dizziness, headache, sleepiness) were reported from participants which were related to the highest (40 mg) dose of mitragynine. In the literature (Cinosi et al. 2015; Grundmann 2017; Grundmann et al. 2023; Kruegel and Grundmann 2018), these adverse events have been reported and are often linked to chronic use. However, they did not have any clinical relevance and resolved spontaneously without treatment.

"We also found that the lowest dose (5 mg) of mitragynine increased subjective ratings of amphetamine-like arousal, subjective feelings of attention, improved accuracy in a sustained attention task and decreased inhibition in the stop signal task. Additionally, amphetamine-like arousal was also increased by mitragynine 10 mg. Such findings would suggest that low doses of mitragynine exert stimulant effects. Further, mitragynine might increase euphoria, as shown by the ratings in the Morphine Benzedrine Group scale, and selectively ameliorate cognitive performance. Increments in euphoria as assessed with the ARCI rating scale have been reported before in daily kratom users (Smith et al. 2024b). Taken together, these results suggest that mitragynine might induce some stimulatory effects on attention and arousal, supporting some previous claims that kratom products can enhance cognition (Cinosi et al. 2015; Prevete et al. 2021; Swogger et al. 2022). These data are also in line with reports from kratom users claiming that kratom does not cause cognitive impairment (Singh et al. 2019b).

"Mitragynine also exhibited stimulant effects at higher doses, as a single dose of 40 mg also led to an increase in subjective ratings of impulsivity symptoms. However, the 40 mg dose of mitragynine also increased subjective ratings of amnesia and symptoms of obsessive-compulsive behaviour, suggesting a potential sedative effect on cognition and a potential to induce symptoms of psychological distress. Overall, the stimulant and inhibitory effects of mitragynine shown in our study support earlier claims of kratom’s double action, which has been described as psychostimulant at low doses, and sedative at high doses (Kruegel and Grundmann 2018; Prozialeck et al. 2012; Singh et al. 2019b; Swogger et al. 2022) or both (Peran et al. 2023; Smith et al. 2023a)."

"Over the past decade, kratom use has become increasingly popular in the United States (US). Many thousands of US users have reported that consumption of kratom preparations (most often in the form of dried, powdered leaf material) is an efficacious treatment not only for physical pain, but also for mood and anxiety disorders, particularly in cases where other available treatments have either failed or elicited intolerable side effects.9−13 A significant portion of users have also reported use of kratom as a tool to stop or reduce consumption of prescription or illicit opioids, a potential application that is presently of high interest given the ongoing opioid abuse epidemic in the US. Unfortunately, there have been no controlled clinical studies either examining these alleged therapeutic effects or quantifying any potential risks of kratom use. At the same time, kratom is primarily distributed through unregulated Internet sales and used outside medical supervision. Considering these factors, as well as the reported opioid-like effects and adverse health effects of the plant, the US Drug Enforcement Administration (DEA) and the US Food and Drug Administration (FDA) have both raised concerns that kratom represents a potential drug of abuse and public health threat.14−16 In September 2016, the DEA announced its intent to place the active compounds found in kratom into Schedule I of the Controlled Substances Act but ultimately decided not to proceed with this action following a large public outcry from the kratom user community, including over 23 000 comments logged in the federal register docket for this issue.13,17−19 Despite this turn of events, kratom at this time remains in regulatory limbo, with an uncertain future in the US. Accordingly, our laboratories have been working to develop a preclinical profile of kratom’s biological effects, with the hope that such knowledge will prove useful for the development of future therapeutics based on kratom, as well as guide regulatory decision making on the plant itself.

"Kratom contains a number of indole alkaloids that are believed to be the primary contributors to its psychoactive effects. Chief among these is mitragynine (Figure 1), which typically constitutes 1–2% of the dry leaf mass and up to approximately two-thirds of the total alkaloid content.1,5 This compound is joined by 7-hydroxymitragynine (7-OH, Figure 1) in much lower concentrations, typically less than 0.05% of the dried leaf mass.1,20 The other predominant alkaloids found in kratom leaf are speciogynine, speciociliatine, and paynantheine (each ∼0.2–0.5% of dry leaf mass), but at this time little is known about their pharmacology.1,5"

"Kratom (Mitragyna speciosa Korth.) refers to herbal products derived from the leaves of a tropical tree in the Rubiaceae family that grow throughout Southeast Asia and regions of Africa, China, and India (Brown et al., 2017). Domestic cultivation in Florida and Hawaii was also reported. Kratom products marketed in the United States (US) and globally are diverse. These include dried leaf powder that is used in tea-like decoctions, pressed into pellets or encapsulated, as well as more concentrated extracts that range widely in their content of kratom’s major alkaloid, mitragynine (MG), and other minor alkaloids or metabolites, including 7-hydroxymitragynine (7OHMG) (Prozialeck et al., 2020; Todd et al., 2020; Manwill et al., 2022; Sengnon et al., 2023; Grundmann et al., 2024).

"In the United States, kratom products are marketed as dietary ingredients and meet criteria under the Food, Drug and Cosmetic Act for regulation by the United States Food and Drug Administration’s (FDA’s) Office of Dietary Supplements but have yet to be accepted for regulation or provided with any regulatory standards for product purity, ingredients, labeling or warnings (FDA, 2024a). At least six kratom products were submitted to FDA by kratom product manufacturers as new dietary ingredient notifications; all were rejected by FDA (Johnson, 2022). 1 At this writing, we are not aware of any submissions to FDA of new drug applications containing kratom or kratom derivatives. The FDA regulatory position on kratom evolved over the past decade and as of 22 February 2024, it included the following statement on its kratom website: “kratom is not lawfully marketed as a dietary supplement and cannot be lawfully added to conventional foods” (FDA, 2024)."

"Kratom leaves are typically crushed, smoked, brewed in tea, or eaten [41]. The half-life of mitragynine is around 3.5 hours. The onset of effects of kratom alkaloids is about 10-20 minutes, with peak effects occurring around two to four hours after ingestion [4]. The clinical effects of kratom can vary by dose, producing stimulant-like effects at lower doses and opioid-like effects at higher doses [53,54].

"The kratom alkaloids are primarily metabolized hepatically by cytochrome P450 enzymes through linear pharmacokinetics and have a biphasic elimination pattern [55,56]. Mitragynine is metabolized to the more active form 7-OH-mitragynine through four CYP 450 isoenzymes: 2C19, 3A4, 2D6, and 2C18 [56-58]. The CYP3A4-mediated dehydrogenation process is believed to activate mitragynine, not the trace concentrations of 7-OH-mitragynine found in kratom extracts that lead to its analgesic effects [40].

"Kratom use is associated with various toxicities and organ dysfunction through studies on cell lines and animal models [43,59]. Studies have found evidence of cardiotoxic and cytotoxic effects of mitragynine and its diastereomers [47,60]. Indole alkaloids have also been shown to inhibit CYP450 isoforms (including CYP3A4 and CYP2D6), resulting in drug-drug interactions with CYP450-mediated compounds [61,62]. Studies also showed that the kratom alkaloids have activity against glutathione transferases, including UGT1A1 and UGT2B7, suggesting interactions with other UGT substrate drugs [63-65]. These interactions can contribute to various presentations associated with kratom toxicity in the form of the airway, antipsychotic toxicities, and organ injury [41]."

"To date, 7-hydroxymitragynine product marketing fails to distinguish itself from kratom. Kratom-naïve consumers purchasing 7-hydroxymitragynine products may erroneously believe that they are relatively safe ‘natural’ products similar or identical to kratom products that have been used in the United States for at least two decades. Consumers of these novel products are unwittingly exposing themselves to high-dose, MOR-binding formulations that have never undergone human or animal testing. Apart from toxicity risks from acute exposure, chronic 7-hydroxymitragynine product use could result in opioid-like physical dependence and possibly addiction. Scale and severity may be distinct from kratom leaf-based and extract products, which have not produced widespread severe addiction, but rather mild–moderate physical dependence [12-14].

"As forensic laboratories use mitragynine as a surrogate marker for kratom use, 7-hydroxymitragynine-related fatalities would incorrectly implicate kratom, as the presence of mitragynine in these products arises from incomplete conversion of mitragynine into 7-hydroxymitragynine [15]. Currently, 7-hydroxymitragynine products contain trace amounts of mitragynine and ‘new’ chemicals yet to be identified. The safety of these unknown chemicals, and of 7-hydroxymitragynine at high doses, has not been evaluated in living subjects. Accordingly, they pose an eminent public health concern until they have been identified and proven to be safe."

"The alkaloid composition of Mitragyna speciosa (kratom) is dominated by mitragynine, which constitutes approximately 66.2% of the total alkaloid content in commercial kratom products. In contrast, 7-hydroxymitragynine, despite its higher potency at opioid receptors, is a minor component, accounting for only 0.01–0.03% of the total alkaloids. Other significant alkaloids include speciociliatine (8.6–16.6%), paynantheine (9.0–16.0%), and speciogynine (6.6–8.6%), with trace amounts of additional alkaloids such as corynoxeine, isocorynoxeine, and speciophylline. These secondary alkaloids may also contribute to kratom’s pharmacological profile but in a less pronounced manner. The variability in alkaloid composition across kratom products is influenced by factors such as genetic differences, environmental conditions, and processing methods, resulting in inconsistencies that affect their pharmacological effects and safety profiles.

"Among these compounds, mitragynine and corynoxeine, derived from the Southeast Asian plant Mitragyna speciosa (Figure 1), commonly known as kratom, stand out as potentially safer alternatives to traditional opioids. While kratom contains a range of bioactive alkaloids, the oxindoles, including corynoxeine and its stereoisomer isocorynoxeine, are minor yet significant tetracyclic oxindole alkaloids. Kratom also contains other active compounds, such as flavonoids, polyphenols, and terpenoids, which contribute to the pharmacological effects of the raw plant products and crude plant extract. These oxindoles also occur in higher concentrations in other plants, such as species within the Uncaria genus, further highlighting their pharmacological importance [3]. Mitragynine, an indole alkaloid, is recognized as a partial agonist of the mu-opioid receptor (MOR), whereas corynoxeine demonstrates notable anti-inflammatory and neuroprotective properties. Unlike conventional opioids, both mitragynine and corynoxeine lack β-arrestin recruitment, which reduces risks of adverse effects such as respiratory depression, constipation, and tolerance development [4]. This unique pharmacological profile positions them as promising candidates for managing various types of pain—including neuropathic, inflammatory, nociceptive, visceral, and central pain syndromes—with a particular focus on cancer-related pain."

"In our online convenience sample, we observed significantly greater odds of lifetime kratom use among White men, and greater odds of past-year kratom use among men only. When examining combined factor(s) through which we operationalized “White and middle-class,” we found that men in the White, middle-class group were nearly twice as likely to report lifetime kratom use as other men. Further, we observed much stronger and consistent associations between this indicator and both lifetime and past-year kratom use in NSDUH data. Lifetime kratom use was 3.10 times more likely to be reported by White, middle-class men and 1.86 times as likely to be reported by White, middle-class women. With respect to past-year kratom use, White, middle-class men and women were 2.30 times and 2.05 times as likely to report use, respectively. We suspect that these kratom users are not only of people with SUD histories, but also people who represent far more socially normative substance-use sub-groups who are using kratom for wellness purposes or enhancement (e.g., to boost cognitive and physical performance), as these motivations have been expressed by kratom-using people in prior investigations (Smith et al., 2021a; Smith et al., 2021b). Given the cross-sectional nature of these data and that these analyses are the first to use a “White, middle-class” indicator variable to represent a specific demographic of kratom users, we cannot claim that kratom use is increasing among this demographic. Rather, we can only assert that kratom use prevalence is significantly higher with this demographic intersection, seemingly among those with suburban residence, when compared with the rest of the US population (using NSDUH data), or when compared to other survey respondents with normative and illicit substance use (in our crowdsourced convenience sample). That kratom use has been associated with similar “middle class” attributes in kratom-specific online surveys in the US suggests that at least a sizeable proportion of people using kratom can be characterized in this way, even though we do not dismiss the heterogeneity that likely exists within this group. For instance, there are people who use kratom to address anxiety, chronic pain, fatigue, or SUD who are also among such a demographic group, but this does not suggest that there are no other motivations within this demographic groups, or other demographic groups for whom kratom use will become more prevalent for these or other reasons. With respect to the former, the lack of greater understanding of heterogeneity of kratom-using people may be an artifact of the questions that have been typically asked in surveys."

"Over the past decade, kratom has been reported as a source for naturally occurring, G-protein–biased opioidergic alkaloids, and has been investigated for its effects on pain management (Matsumoto et al., 2004; Kruegel et al., 2019; Chakraborty et al., 2021b; Chakraborty and Majumdar, 2021), opioid withdrawal (Wilson et al., 2020, 2021), and alcohol abuse (Gutridge et al., 2020) as well as its decreased reward profile relative to traditional opioids (Hemby et al., 2019; Wilson et al., 2021). Here, we further probed the effects of kratom alkaloids and synthetic kratom alkaloid derivatives to obtain a better understanding of its in vivo pharmacology and in search of novel treatment options for alcohol use disorder. We report 7-hydroxyspeciogynine as an effective lead compound to reduce alcohol with an MTD of at least 10 mg∙kg−1.

"We previously demonstrated that 7-hydroxymitragynine as well as paynantheine could decrease alcohol consumption (Gutridge et al., 2020). However, we were unable to obtain a MTD for 7-hydroxymitragyinine as it caused both hyperlocomotion and CPP at a 3 mg∙kg−1 dose, which was the minimal effective dose to reduce alcohol intake (Gutridge et al., 2020). It has been well-established that µOR agonism can cause CPP, and that these rewarding effects can be blocked by μOR antagonists (Negus et al., 1993; Piepponen et al., 1997) as well as μOR KO (Matthes et al., 1996). Here, we show that 7-hydroxymitragynine–induced hyperlocomotion also appears to be μOR-mediated as it is completely blocked by a dose of naloxone considered to be μOR-selective (Takemori and Portoghese, 1984; Pastor et al., 2005). Since the alcohol-reducing effect of 7-hydroxymitragynine was dependent on δORs (Gutridge et al., 2020), μOR potency may be a liability when exploring kratom alkaloids as treatment option for AUD. Paynantheine has much lower μOR potency, while retaining δOR potency and decreases alcohol intake in mice at a 10 mg∙kg−1 dose without causing hyperlocomotion (Gutridge et al., 2020). In line with the lower μOR potency, we find that 10 mg∙kg−1 paynantheine does not produce place preference in an extended CPP paradigm. In a brief CPP paradigm, however, the same dose of paynantheine induces conditioned place aversion (CPA). Kratom use can lead to seizures (Coonan and Tatum, 2021) and we noticed that at 30 mg∙kg−1, paynantheine induced minor seizure activity. It is possible that mice administered a dose of 10 mg∙kg−1 paynantheine did not feel well despite not showing overt tonic-clonic seizure activity that could contribute to the observed CPA at this dose. δOR agonism can cause seizures (Hong et al., 1998; Broom et al., 2002; Jutkiewicz et al., 2006); however, it is reported mostly for δOR agonists that are strong recruiters of β-arrestin, such as SNC80 and BW373U86 (O’Neill et al., 1997; Hong et al., 1998; Jutkiewicz et al., 2005). As such, we were not surprised that the G-protein–biased paynantheine-induced seizures were still present in δOR KO mice, indicating the seizures may be caused by an off-target interaction. Paynantheine can decrease alcohol consumption in wild-type mice (Gutridge et al., 2020); however, it also decreases alcohol consumption in δOR KO mice (Supplementary Figure S5; RM two-way ANOVA, dose: F (4, 32) = 6.407, p = 0.0007, time: F (1, 8) = 16.46, p = 0.0036, dose × time: F (4, 32) = 1.851, p = 0.1435, with Sidak’s MC (T-R vs F), p < 0.0001). This analysis provides further evidence that many of paynantheine’s in vivo effects are not mediated by δOR."

"These latter two opioid-related motivations for use indicate that kratom use in the US may vary by region. Kratom’s relevance to people’s needs (and thus its prevalence of use) may be greater in rural communities that experienced higher per capita rates of opioid prescribing during the early 2000s and subsequently experienced changes in the licit and illicit prescription opioid market (Thomas et al., 2020). Findings consistently indicate high opioid-related risk for those living in rural settings: opioid prescribing is up to 33% higher in rural counties than elsewhere; rural-residing adolescents are more likely than those in urban-metro counties to initiate nonmedical use of opioids; rural justice-involvement carries a five-fold greater likelihood of nonmedical use of opioids; and overdose death rates for nonmedical use of opioids are 20–30% higher in rural counties (Havens et al., 2007; Paulozzi and Xi, 2008; Havens et al., 2011; Mack et al., 2017; Mosher et al., 2017; Ayres and Jalal, 2018; Luu et al., 2019). These outcomes are compounded by the practical and social difficulties of accessing treatment for opioid use disorder (OUD) in rural counties, including stigma surrounding medication for OUD (MOUD) (Bunting et al., 2018; Jones, 2018; Jacobson et al., 2020; Lister et al., 2020; Cole et al., 2021; Franz et al., 2021). Recent findings suggest that only half of physicians authorized to prescribe MOUD had the availability to accept new patients (Andrilla et al., 2018), and though MOUD access is increasing nationally and gains have been made to increase prescriber capacity in underserved areas (Barnett et al., 2019), more than half of small and rural counties lack a physician waivered by the Drug Enforcement Administration to prescribe MOUD (Andrilla and Patterson, 2021). Given the high prevalence of prescription opioid misuse, poor psychiatric (Snell-Rood and Carpenter-Song, 2018) and physical health (including high rates of chronic pain) (Meit et al., 2017), and the difficulty in obtaining MOUD in rural areas (Sexton et al., 2008; Prunuske et al., 2014; Woolf et al., 2019; Monnat, 2020), it is possible that kratom use might be more prevalent in rural counties than in urban-metro counties. Although heroin use is increasing in many rural communities that had elevated rates of opioid prescribing (Nolte et al., 2020; Schnell et al., 2020; Hedegaard and Spencer, 2021; Strickland et al., 2021), kratom might be more accessible or more attractive than heroin to people whose sole prior opioid use had involved prescribable pills. To date, kratom use has not been well characterized in terms of rural/suburban/urban differences. Only two large US survey studies have noted the geographic region of kratom users in their sample, both finding that a slightly greater proportion resided in the US South (Coe et al., 2019; Garcia-Romeu et al., 2020). However, in separate analyses, Nicewonder et al. (2019) found that kratom use was more widely distributed across the US, with higher rates in Florida, as well as Oregon, California, and Idaho, and still noteworthy use in the Northeast. These findings were from data collected in 2017; given the relatively recency of kratom’s emergence in the US, an update would probably be informative."

"Street names for kratom include ‘thang’, ‘kakuam’, ‘thom’, ‘ketum’ and ‘biak’. Kratom leaves are usually consumed fresh, although dried leaves in powder form are also available. The fresh leaves are chewed while the powder form is often either swallowed or brewed into tea. Dried leaves are rarely smoked."

"In spite of the increasing use of this substance, scientific literature about the effects and toxicity of kratom alone remains very scarce.

"Kratom is a central nervous system stimulant, from which over 40 alkaloids have been isolated. In low doses it is reported to have stimulant effects (used to combat fatigue during long hours of work), while at high doses, it can have sedative-narcotic effects.⁸⁷ In 1921, the major alkaloid found in this plant, ‘Mitragynine’, was first isolated. Mitragynine has an opioid agonistic activity and its derivative 7-hydroxymitragynine (7-OH-mitragynine) is reported to be more potent than mitragynine or morphine.⁸⁸

"Nine fatal cases of intoxication associated with the use of ‘krypton’, a mixture of mitragynine and O-desmethyltramadol, have been described in scientific literature. However, these fatalities have been attributed to the addition of O-desmethyltramadol to the dried kratom leaves.⁸⁹"

"Mitragyna speciosa Korth (of the Rubiaceae family) is a large tree found in tropical and sub-tropical regions of South-East Asia. In Thailand, the tree known as ‘Kratom’ is found throughout the country but predominantly in the southern region, although the growing and harvesting is prohibited.

"Kratom contains many alkaloids including mitragynine, mitraphylline, and 7-hydroxymitragynine. Traditionally, kratom had been used in Malaysia and Thailand by labourers and farmers to enhance productivity, but also as a substitute to opium and in traditional medicine, allegedly due to its morphine-like pharmacological effects. However, its use as a new psychoactive substance in the global market has been recently reported.

"In the early 2000s, products labelled as ‘kratom acetate’ or ‘mitragynine acetate’ became available in Europe, although it was found that neither of them contained mitragynine. Caffeine and synthetic O-desmethyltramadol (an active metabolite of tramadol) were found in products under the name ‘krypton’.⁸⁴ More recently, products containing kratom have been sold as ‘incense’ for their psychoactive effects, but concentrations of the active components mitragynine and 7-hydroxymitragynine in these products differ depending on the variety of the plant used, the environment and the time of harvesting."