Kratom, scientifically known as Mitragyna speciosa and belonging to the Rubiaceae family, encompasses not just the plant itself but also its leaves and extracts, all of which find applications in both medical and recreational domains . Originating from Southeast Asia, Kratom primarily thrives in Malaysia, Thailand, and Indonesia, and is occasionally cultivated in other regions, including the United States. This versatile plant goes by various names such as ketum, biak-biak, Maeng Da, thang, thom, and kakuam .
History of use, both within and outside the United States
The history of Kratom usage in Southeast Asia dates back to 1836, although its precursors likely extend further. Its historical significance has two facets: as a substitute for opium in Malaysia and as a performance-enhancing stimulant in Thailand . In Southeast Asia, Kratom is often used individually or combined with cough syrup containing codeine and Coca-Cola, creating a concoction known as "4x100," which unfortunately has been abused as an addictive substance . While its exact introduction date in the United States remains unclear, cases of individuals using Kratom for self-treatment of opioid withdrawal symptoms, pain management, and mental health issues began to emerge in the early 2000s . The CDC reported an increase in calls to poison control centers related to Kratom, prompting the FDA to issue warnings about its consumption [6, 7]. By February 2019, the FDA had proposed placing Kratom's active compounds, mitragynine and 7-hydroxymitragynine, in the DEA's Schedule 1 list of controlled substances due to their opioid-like effects and lack of recognized medical efficacy in the United States.
In Southeast Asia, fresh Kratom leaves are often chewed to boost productivity and alleviate fatigue for manual laborers. Additionally, these leaves, whether fresh or dried, are brewed into tea in Malaysia and Thailand to treat various health issues, including diabetes, diarrhea, fever, pain, and wound care . Kratom also serves as a substitute for opium and a method for alleviating opioid withdrawal symptoms, both in Asian regions and abroad. Prior to the early 2000s, there was limited scientific information on the traditional uses of Kratom outside of Asia.
Varieties, dosages, and concerns about purity
Kratom is primarily consumed orally and is available in various forms in the United States, including powder, capsules, pills, fresh leaves (often dried), and concentrated extracts, which may contain varying levels of ethanol. Dosages can vary widely depending on the form of use, with powder typically recommended at 3-5 grams per dose, while concentrated liquid extracts may require just 1-2 drops, as per the manufacturer's instructions. Users often take multiple extracts throughout the day to address their specific needs, though a common regimen consists of three doses of 3-5 grams each day . The lack of standardized quality control for Kratom products has led to significant variations in the levels of active compounds, mitragynine and 7-hydroxymitragynine. Authentic Kratom should ideally contain no more than 66% mitragynine as the primary alkaloid and 2% 7-hydroxymitragynine in concentrated alkaloid extract, or a total alkaloid content around 2% (1.8-2% mitragynine and 0.02-0.03% 7-hydroxymitragynine) in whole leaf extract [10, 11]. Unfortunately, Kratom products in Western countries are often adulterated with synthetic compounds, including 7-hydroxymitragynine, O-desmethyltramadol (known as Krypton), fentanyl, hydrocodone, and various other opioid pharmaceuticals [10, 12].
Potential applications and consumer use
The extensive historical use of Kratom as both a stimulant and a pain reliever opens doors to numerous self-treatment possibilities for consumers. Surveys and case reports indicate that Kratom has been used to manage acute and chronic pain, alleviate withdrawal symptoms from opioids, prescription drugs, and other substances, as well as to minimize harm during opioid withdrawal. Furthermore, it has been used in the treatment of conditions such as depression, anxiety, attention-deficit/hyperactivity disorder (ADHD/ADD), bipolar disorder, post-traumatic stress disorder (PTSD), and many other conditions [5, 9, 13]. In addition to therapeutic applications, Kratom can also be used recreationally for relaxation, mood enhancement, increased energy, or altered consciousness, especially when combined with other substances like alcohol, benzodiazepines, opioids, cocaine, or amphetamines .
Initial research on Kratom extracts revealed stimulating effects similar to cocaine and pain-relieving properties akin to codeine . The extraction of indole alkaloids mitragynine and 7-hydroxymitragynine from high-content extracts has unveiled their partial agonistic activity at μ-opioid receptors . Notably, mitragynine exhibits lower receptor binding affinity than morphine. Conversely, 7-hydroxymitragynine is approximately ten times stronger than mitragynine at μ-opioid receptors. Other Kratom alkaloids also play roles as competitive inhibitors at μ-opioid receptors, leading to a complex pharmacological response that may depend on total alkaloid content. Furthermore, mitragynine interacts with other receptors such as α2-adrenergic, adenosine A2a, dopamine D2, serotonin 5-HT2C, and 5-HT7, with unclear agonistic or antagonistic effects [11, 14]. Both in vitro and in vivo research has shown that naloxone, an opioid receptor antagonist, can reverse the analgesic effects of mitragynine .
Notable adverse effects and toxicities
Common side effects associated with Kratom use include nausea, vomiting, constipation, stomach discomfort, and feelings of drowsiness or irritability [6, 9]. High doses, often exceeding 8 grams, can lead to dry mouth, sweating, dizziness, and rapid heartbeat. Long-term and frequent Kratom use (over one month) has been linked to intrahepatic cholestasis and elevated liver enzymes, but these symptoms typically resolve upon discontinuation of Kratom use . Withdrawal symptoms from Kratom, depending on dosage, may include reduced appetite, diarrhea, anxiety, insomnia, hallucinations, changes in heart rate and blood pressure, and seizures [2, 17]. Importantly, respiratory failure and hemorrhagic stroke, reported in Kratom-related deaths, cannot be conclusively linked to Kratom use, as there is often concurrent use of medications or other substances.
Drug interactions: known and suspected
Some research studies have pointed to potential drug interactions with Kratom, primarily related to CNS depressant effects. When combined with benzodiazepines, barbiturates, alcohol, opioids, antidepressants, anxiolytics, and other CNS-active drugs, Kratom may have synergistic or additive effects . Due to unknown metabolic pathways, caution is warranted when combining Kratom with drugs that are substrates of CYP enzymes, including CYP 1A2, 2C19, 2D6, and 3A4 isoforms. While some case reports suggest interactions with drugs like quetiapine and modafinil, it remains unclear whether these interactions are linked to CYP interactions [2, 19]. In vitro studies have shown that Kratom and mitragynine can inhibit the multi-drug transporter protein P-glycoprotein (P-gp), leading to increased levels of other drugs that are P-gp substrates . However, the clinical significance of these metabolic interactions remains unclear.
Risks of abuse, dependence, and addiction
The use of Kratom carries the risk of dependence when consumed at high doses (exceeding 5 grams per dose and more than three times per day), especially when used to mitigate harm during opioid withdrawal or self-treat pain [5, 12, 21]. Pregnant individuals using Kratom have reported giving birth to infants with symptoms of neonatal abstinence syndrome (NAS), similar to the effects of opioids, emphasizing the importance of discouraging Kratom use during pregnancy . Withdrawal symptoms from discontinuing Kratom use, although milder than opioids, may include anxiety, diarrhea, pain, insomnia, restlessness, mood swings, tension, anger, and anxiety. These symptoms typically last from 3-10 days after the last dose, and managing withdrawal symptoms may involve short-term buprenorphine-naloxone replacement therapy [23, 24].
Diagnosis and distinctions
Currently, there are no standardized testing procedures for measuring Kratom or its metabolites in clinical settings. While scientific literature has described methods for measuring mitragynine, only a few scientific investigative methods have incorporated these tests into their testing and confirmation protocols [25, 26]. Establishing a direct correlation between blood mitragynine levels and impairment or toxicity is challenging due to significant variations in Kratom consumption and undetermined mitragynine levels. Mitragynine blood levels in fatal cases, often associated with other substances, range from 0.02 to 0.24 μg/g. Interestingly, individuals who did not experience severe adverse effects had mitragynine blood levels ranging from 0.0194 to 0.158 μg/g . Furthermore, hepatotoxicity, indicated by elevated bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT), has been reported with prolonged high-dose Kratom consumption, especially when used with potentially hepatotoxic medications . Remarkably, Kratom does not appear to cause liver damage under isolated conditions.
Treatment approaches and interventions
The presentation of Kratom overdose cases can manifest in various ways and should be symptom-driven in terms of treatment. Patients may experience rapid heartbeat and respiratory distress, requiring immediate attention. In cases of seizures, the use of benzodiazepines such as lorazepam (Ativan®) may be effective. Naloxone (Narcan®) has also demonstrated the ability to reverse respiratory depression in cases of Kratom overdose . For gastrointestinal symptoms like nausea, diarrhea, or constipation, nutritional support is recommended. In situations of acute overdose involving suspected exposure to multiple substances, blood testing for a complete blood count (CBC), electrolyte levels, ethanol, and drugs should be performed. When possible, patients should be questioned about substances used, both legal and illicit, as this information is crucial for determining the appropriate course of action in complex cases.
Kratom, with its diverse traditional applications and complex pharmacology, offers both therapeutic potential and significant risks. Healthcare experts must remain vigilant in understanding the effects of Kratom, potential drug interactions, and adverse effects to provide comprehensive care for individuals who may use this substance.
- Ulbricht, C., et al., An evidence-based systematic review of kratom (Mitragyna speciosa) by the Natural Standard Research Collaboration. J Diet Suppl, 2013. 10(2): p. 152-70.
- Jansen, K.L. and C.J. Prast, Ethnopharmacology of kratom and the Mitragyna alkaloids. J Ethnopharmacol, 1988. 23(1): p. 115-9.
- Warner, M.L., N.C. Kaufman, and O. Grundmann, The pharmacology and toxicology of kratom: from traditional herb to drug of abuse. Int J Legal Med, 2016. 130(1): p. 127-38.
- Smith, K.E. and T. Lawson, Prevalence and motivations for kratom use in a sample of substance users enrolled in a residential treatment program. Drug Alcohol Depend, 2017. 180: p. 340-348.
- Anwar, M., R. Law, and J. Schier, Notes from the Field: Kratom (Mitragyna speciosa) Exposures Reported to Poison Centers - United States, 2010-2015. MMWR Morb Mortal Wkly Rep, 2016. 65(29): p. 748-9.
- FDA, Statement from FDA Commissioner Scott Gottlieb, M.D., on the agency's scientific evidence of the presence of opioid compounds in kratom, underscoring its potential for abuse. 2018, United States Food and Drug Administration: Silver Spring, MD.
- Prozialeck, W.C., J.K. Jivan, and S.V. Andurkar, Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am Osteopath Assoc, 2012. 112(12): p. 792-9.
- Grundmann, O., Patterns of Kratom use and health impact in the US-Results from an online survey. Drug Alcohol Depend, 2017. 176: p. 63-70.
- Lydecker, A.G., et al., Suspected Adulteration of Commercial Kratom Products with 7- Hydroxymitragynine. J Med Toxicol, 2016. 12(4): p. 341-349.
- Kruegel, A.C. and O. Grundmann, The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse. Neuropharmacology, 2017.
- Henningfield, J.E., R.V. Fant, and D.W. Wang, The abuse potential of kratom according the 8 factors of the controlled substances act: implications for regulation and research. Psychopharmacology (Berl),
- 235(2): p. 573-589.
- Swogger, M.T., et al., Experiences of Kratom Users: A Qualitative Analysis. J Psychoactive Drugs, 2015. 47(5): p. 360-7.
- Matsumoto, K., et al., Antinociceptive action of mitragynine in mice: evidence for the involvement of supraspinal opioid receptors. Life Sci, 1996. 59(14): p. 1149-55.
- Shamima, A.R., et al., Antinociceptive action of isolated mitragynine from Mitragyna Speciosa through activation of opioid receptor system. Int J Mol Sci, 2012. 13(9): p. 11427-42.
- Kapp, F.G., et al., Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa). J Med Toxicol, 2011. 7(3): p. 227-31.
- Stanciu, C.N., et al., Kratom Withdrawal: A Systematic Review with Case Series. J Psychoactive Drugs,
- 51(1): p. 12-18.
- Gershman, K., et al., Deaths in Colorado Attributed to Kratom. N Engl J Med, 2019. 380(1): p. 97-98.
- Kong, W.M., et al., Evaluation of the effects of Mitragyna speciosa alkaloid extract on cytochrome P450 enzymes using a high throughput assay. Molecules, 2011. 16(9): p. 7344-56.
- Rusli, N., et al., The inhibitory effects of mitragynine on P-glycoprotein in vitro. Naunyn Schmiedebergs Arch Pharmacol, 2019.
- Singh, D., C.P. Muller, and B.K. Vicknasingam, Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users. Drug Alcohol Depend, 2014. 139: p. 132-7.
- Eldridge, W.B., C. Foster, and L. Wyble, Neonatal Abstinence Syndrome Due to Maternal Kratom Use. Pediatrics, 2018. 142(6).
- Singh, D., et al., Severity of Kratom (Mitragyna speciosa Korth.) Psychological Withdrawal Symptoms. J Psychoactive Drugs, 2018: p. 1-6.
- Khazaeli, A., J.M. Jerry, and M. Vazirian, Treatment of Kratom Withdrawal and Addiction With Buprenorphine. J Addict Med, 2018. 12(6): p. 493-495.
- Mudge, E.M. and P.N. Brown, Determination of Alkaloids in Mitragyna speciosa (Kratom) Raw Materials and Dietary Supplements by HPLC-UV: Single-Laboratory Validation, First Action 2017.14. J AOAC Int,
- 101(4): p. 964-965.
- Kowalczuk, A.P., A. Lozak, and J.K. Zjawiony, Comprehensive methodology for identification of Kratom in police laboratories. Forensic Sci Int, 2013. 233(1-3): p. 238-43.
- Overbeek, D.L., J. Abraham, and B.W. Munzer, Kratom (Mitragynine) Ingestion Requiring Naloxone Reversal, in Clin Pract Cases Emerg Med. 2019: United States. p. 24-26.