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Kratom

Scientific Name(s): Mitragyna speciosa Korth.
Common Name(s): Biak, Biak-biak, Herbal speedball, Ithang, Kahuam, Kakuam, Ketum, Krathom, Maeng da kratom, Mambog, Thang, Thom

Medically reviewed by Drugs.com. Last updated on Dec 4, 2018.

Clinical Overview

Use

In 2017, an FDA statement noted that there are no approved uses for this product and advised against its use based on significant safety risk. A mandatory recall of kratom-containing products associated with Triangle Pharmanaturals, LLC, occurred in 2018.

Historically, the dried leaves have been chewed by manual laborers in Southeast Asia to reduce fatigue and increase tolerance to heat. In Malaysian folk medicine the leaves have been used to treat diarrhea, fever, asthma, cough, pain, and stomach ailments, and for deworming and to prolong sexual intercourse. Though kratom has been proposed to manage opioid withdrawal symptoms, there are no clinical data to support this use.

Dosing

Clinical studies are lacking. Use is not recommended.

Contraindications

An FDA Statement has been published that advises against the use of this product based on significant safety risk.

Pregnancy/Lactation

Do not use. Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

A 2017 FDA statement alerted consumers and clinicians to significant safety risks associated with the use of kratom, including but not limited to risks of addiction, and abuse and dependence; in some cases, these events may be fatal. Sensitivity to sunlight, nausea, itching, sweating, dry mouth, constipation, increased urination, loss of appetite, psychotic symptoms, and tolerance and dependence have occurred. Long-term use can result in anorexia, weight loss, insomnia, skin darkening, tremors, seizures, dry mouth, polyuria, and constipation; with long-term use at high doses, hallucination and paranoia can occur. Cases of intrahepatic cholestasis have also been reported. Serious and even fatal adverse effects have been reported when kratom is mixed with other specific drugs.

Toxicology

Data regarding kratom toxicity are limited. This agent is currently under review by the FDA for safety and toxicity risk. In March 2018, the US FDA and CDC announced multistate investigation regarding outbreak of Salmonella infections related to kratom use. Consumers have been advised to avoid the use of kratom and kratom-containing products.

Scientific Family

  • Rubiaceae

Botany

M. speciosa is a deciduous tree indigenous to tropical and subtropical regions of Southeast Asia (ie, Thailand, Malaysia, Philippines, Myanmar, New Guinea) and parts of Africa.National Institute on Drug Abuse 2016 It has relatively large dark green leaves that are broad, glossy, and oval shaped. The flowers are deep yellow spherical clusters of approximately 120 florets each. The harvested leaves and small stems of the plant are primarily used for consumption.Warner 2016

History

The genus Mitragyna was named by the Dutch botanist Pieter Willem Korthals because of the similarities between kratom leaves and stigmas and a bishop's miter. Kratom plays a key role in culture and tradition, especially in the southern peninsula of Thailand. The leaves are bitter and contain psychoactive opioid compounds that have been consumed for mood enhancement and pain relief, and as an aphrodisiac. Kratom leaves can be chewed, dried and brewed as a tea, smoked, or eaten in food. The dried leaves can also be crushed into a powder that is used to fill capsules, prepared in a hot tea, or cooked with sugar or honey to yield a syrup-like formulation that is compressed into tablets. It is also available as a liquid and gum.National Institute on Drug Abuse 2016, Warner 2016, National Institute on Drug Abuse 2016 Historically, the dried leaves have been chewed by manual laborers, known as "chewers," to reduce fatigue and increase tolerance to heat, thereby aiding working conditions in plantation fields; daily consumption usually ranges from 10 to 60 leaves a day.Warner 2016 Kratom is also used in cultural performances and teashops.Warner 2016 In Malaysian folk medicine, the leaves are used for diarrhea, fever, asthma, cough, pain, deworming, and stomach ailments, and to prolong sexual intercourse.Shaik Mossadeq 2009

In Southeast Asian regions, the first reports of kratom use for treatment of opioid addiction date back to 1836, with mitragynine, the active alkaloid of kratom, first isolated in 1907.Pantano 2016 In Thailand, its use to manage opioid withdrawal dates back to the 1940s, when opium costs were increasing as a result of the Greater East Asia War. Opium users sought to obtain kratom, which was a low-cost option to help with opium withdrawal symptoms. Thai officials began to control kratom in 1943 under the Kratom Act; it remains controlled or banned in many regions of Southeast Asia and is increasingly controlled in other countries (eg, Australia, New Zealand, Denmark, Germany, Poland, Romania, South Korea, Sweden) where recreational use is gaining popularity. A tea-based cocktail of kratom leaves, cough syrup, Coca-Cola, and ice (known as "4x100") has become popular in Thailand.Warner 2016

An emerging market for kratom is developing in the West (ie, Europe, North America), driven by ease of availability via the internet, head shops, and kava bars, and is leading to increased misuse and abuse. Poison control centers report incidences of kratom use in the United States as early as 2008. It is touted as a legal and more economical alternative to other sedative and stimulant drugs, which adds to its popularity. Kratom and its active constituents remain predominantly uncontrolled in the United States, although some states are considering bans on the plant and/or have added labeling and manufacturing requirements, while other states have listed kratom and/or mitragynine and 7-hydroxymitragynine (7-HMG) as schedule I substances.Warner 2016, Alabama Senate Bill 226 2016, Anwar 2016, Denver Department of Environmental Health 2016

Chemistry

More than 25 alkaloids have been identified in the leaves of kratom, with a total alkaloid content of 0.5% to 1.5%. Mitragynine and 7-HMG are considered the primary active alkaloids comprising 60% and up to 2%, respectively, of the total alkaloid content. Paynantheine, speciociliatine, and speciogynine are present at concentrations of 10%, 9%, and 7%, respectively. Other alkaloids that individually comprise less than 1% of the total alkaloid content are mitraphylline, rhynchophylline, mitralactonal, raubasine, and mitragynaline. Various physiological effects are suggested to occur through obstruction of neuronal calcium channels, stimulation of postsynaptic alpha-2 adrenergic receptors, serotonergic 5-HT2A receptor blocking, and binding at delta- and kappa-opioid central receptors.Warner 2016

Mitragynine, an indole alkaloid, is structurally similar to yohimbine, voacangine, and Uncaria alkaloids, and has a reported opioid-like potency of approximately 13 times that of morphine. However, 7-HMG has CNS stimulant and depressant effects that are 4 times that of mitragynine, and about 14 times that of morphine when orally consumed.Warner 2016, Pantano 2016, Matsumoto 2014 Mitragynine and 7-HMG are selective and full agonists of mu-opioid receptors in the brain that produce sedation, pleasure, and antinociception (decreased pain), especially when large amounts are consumed. Mitragynine is also a central stimulant. At low doses, it is reported to increase energy, sociability, and alertness.National Institute on Drug Abuse 2016, Warner 2016 In addition to dose, the desired stimulant or sedative effect can be controlled by the strain of kratom, which is likely due to varying concentrations of inherent alkaloids. The red vein variety (Bali) tends to exert more powerful analgesic effects, whereas the white or green vein varieties (Malaysia) provide more CNS stimulation and mood-enhancing effects. The green vein tends to be a less potent stimulant. The abuse potential of kratom stems from its psychoactive effects, which are dose dependent.Warner 2016

There is a considerable variability in pharmacokinetics among species of kratom. Noticeable effects are often observed within 10 to 20 minutes, while full effects are experienced within approximately 30 to 60 minutes after ingestion and typically last 5 to 7 hours, with peak effect occurring at 2 to 4 hours. Weak effects may continue the day after consumption. Taking kratom after eating can delay the initial response, as can consuming it in capsule form. Mitragynine and 7-HMG half-lives are about 3.5 and 2.5 hours, respectively. Elimination is primarily via urine.Warner 2016

Uses and Pharmacology

Research reveals no clinical data regarding use of kratom in humans. Use is not recommended by the FDA and kratom is currently under review for significant safety concerns.FDA Statement 2017, FDA News Release 2017 A mandatory recall of kratom-containing products associated with Triangle Pharmanaturals, LLC, occurred in 2018.FDA Safety Recall 2018

Alcohol withdrawal

Animal data

Because the usefulness of antidepressants for the management of alcohol withdrawal can be limited by an accompanying reduction in rapid eye movement (REM) sleep, the effects of an M. speciosa alkaloid extract and fluoxetine (a standard antidepressant used as a reference drug) on ethanol withdrawal symptoms and acute sleep parameters were evaluated in rats. Significant reductions in REM sleep were observed with fluoxetine administration, with 4 of 8 rats never entering the REM stage, while the alkaloid extract produced limited impact on REM sleep with results similar to those of controls. Compared with controls, fluoxetine 10 mg/kg significantly reduced the number of REM episodes (P<0.001), average time in REM (P<0.05), and total time in REM (P<0.01), whereas effects of the M. speciosa 60 mg/kg alkaloid extract on REM sleep were not statistically significant. Both fluoxetine and the alkaloid extract produced similar but insignificant effects on electroencephalogram (EEG) patterns in the parietal and frontal cortices. Additionally, both treatments almost completely prevented the increase in EEG gamma power that was induced by ethanol withdrawal to a level comparable with controls.Cheaha 2015

Antinociception/Analgesia

Animal data

The effects of M. speciosa extract, alkaloids fraction, and mitragynine on thermal nociception in rats were compared with the known effects of morphine and oxycodone. Additionally, differences between intraperitoneal and oral administration were documented. A significant latency in hot plate response was observed with intraperitoneal administration of morphine 10 mg/kg, oxycodone 3 mg/kg, and mitragynine 30 mg/kg (P=0.0001, P=0.039, and P=0.022, respectively), but not with M. speciosa 300 mg/kg extract or M. speciosa alkaloids fraction 75 mg/kg. However, with oral administration, significant hot plate latency was noted only at 60 minutes after administration (not at 30 minutes) for only oxycodone 6 mg/kg and mitragynine 100 mg/kg (P=0.048 and P=0.037, respectively) and not for M. speciosa 300 mg/kg extract.Carpenter 2016 Similarly, the methanolic extract of M. speciosa produced an antinociceptive effect in mice via several pain models. Hot plate latency was increased by morphine and M. speciosa extract. In the writhing test, a comparable effect to aspirin 100 mg/kg was produced by M. speciosa extract doses of 100 and 200 mg/kg given intraperitoneally. The extract at a dose of 200 mg/kg yielded an inhibitory effect on pain comparable to morphine in both the early and late phases of the formalin test, whereas aspirin produced an inhibitory effect only in the second phase.Shaik Mossadeq 2009

Because cannabinoid receptor type 1 (CB1) is thought to be involved in the regulation of cognition, memory, motor activity, and pain management, the antinociceptive actions of mitragynine within the opioid and cannabinoid systems were investigated in mice. A dose-dependent antinociceptive hot plate response was observed with mitragynine 3 to 35 mg/kg given intraperitoneally. The best antinociceptive effect was observed at 35 mg/kg, which resulted in a significant increase (P<0.05) in latency time compared with vehicle and morphine (3 mg/kg). However, compared with tetrahydrocannabinol (THC) as the positive control, mitragynine did not appear to exert antinociceptive actions via the CB1 receptor. The effects of mitragynine were completely reversed with the administration of the nonselective opioid receptor antagonist naloxone and the delta-opioid antagonist naltrindole, were only partially blocked by the kappa-opioid antagonist norbinaltorpimine, and were not affected by the mu1-opioid antagonist naloxonazine.Shamima 2012

Because chronic pain and acute pain are moderated by different opioid receptors (delta- and mu-opioid receptors, respectively), a dual-acting mu- and delta-opioid agonist was developed from 7-HMG in an effort to create a novel opioid analgesic useful for both acute and allodynic pain, which is a common attribute of neuropathic pain. Two novel derivatives from 7-HMG were developed: MGM-15 and MGM-16. MGM-16 administered subcutaneously and orally to mice exhibited antinociceptive effects approximately 71 and 240 times more potent than that of morphine, respectively. These effects were completely blocked by an irreversible mu-opioid receptor selective antagonist and partially blocked by a delta-opioid receptor selective antagonist; a kappa-opioid receptor antagonist had no effect. Additionally, MGM-16 showed potent mu- and delta-opioid dual agonist action with a dose-dependent antihyperanalgesic effect after both oral (0.5, 1, and 2 mg/kg) and subcutaneous (0.1, 0.2, and 0.4 mg/kg) administration.Matsumoto 2014

Antidepressant

Animal data

In a study in mice, 2 classical behavioral models of antidepressant screening (forced swim test and tail suspension test) were used in combination with the open field test to evaluate the antidepressant-like effects of mitragynine. The effect on the hypothalamic-pituitary axis via serum corticosterone measurements was also noted. The mice were randomly assigned to control (vehicle treated) or one of 6 experimental groups: mitragynine (prepared from fresh M. speciosa leaves) 5, 10, or 30 mg/kg intraperitoneally 30 minutes before testing, fluoxetine 20 mg/kg, amitriptyline 10 mg/kg, or amphetamine 1 mg/kg. The mitragynine 10 and 30 mg/kg doses significantly reduced the duration of immobility in the forced swim and tail suspension tests (P<0.05) compared with the control (vehicle), as did the fluoxetine and amitriptyline groups. In contrast to the psychostimulant amphetamine, neither mitragynine nor the antidepressants fluoxetine and amitriptyline significantly affected locomotor activity in the open field test. Serum corticosterone levels in mice exposed to the forced swim and tail suspension tests were reduced in the mitragynine, fluoxetine, and amitriptyline groups compared with the vehicle control group (P<0.05).Idayu 2011

Anti-inflammatory

Animal data

A study in rodents investigated the antinociceptive and anti-inflammatory activity of M. speciosa. Local edema, induced by a subplantar injection of carrageenan in control mice, was reduced with administration of 100 mg/kg and 200 mg/kg of M. speciosa methanolic extract. This effect was more pronounced than that produced by aspirin 100 mg/kg and was greater with the higher M. speciosa dose. Additionally, the M. speciosa extract (200 mg/kg dose) inhibited growth of granuloma tissue, provoking an inhibitory effect (44.9%) greater than that observed with aspirin (25.4%) when compared with control.Shaik Mossadeq 2009 The cellular mechanisms involved in this response were explored. Macrophage cells were pretreated with mitragynine (0.5 to 20 mcg/mL) and the effects on mRNA gene expression and protein expression of cyclooxygenase-1 (COX-1) were evaluated. Additionally, bacterial lipopolysaccharide (LPS) was used to induce COX-2 and the effect on prostaglandin E2 production was measured. Celecoxib, aspirin, and indomethacin were used as positive controls. Mitragynine at higher doses of 10 and 20 mcg/mL reduced expression of COX-1 protein expression, as did aspirin and indomethacin. Similar to the COX-2–selective control celecoxib, lower doses of mitragynine showed little effect on COX-1 protein expression. None of the treatments (mitragynine and controls) suppressed COX-1 mRNA expression. In contrast, COX-2 mRNA expression was reduced in a dose-dependent manner with various mitragynine doses, with protein expression minimally impacted. In another study, mitragynine similarly suppressed prostaglandin E2 production in LPS-stimulated cells, with inhibition similar to that observed with the positive controls.Utar 2011

Opioid tolerance prevention

Animal data

Because previous studies have indicated that opioid combinations may improve analgesia, reduce toxicity, and delay the development of tolerance, the analgesic action of mitragynine combined with morphine was investigated in mice. Mitragynine 15 mg/kg, mitragynine 25 mg/kg, and morphine 5 mg/kg were administered intraperitoneally alone and in combination (mitragynine 15 mg/kg plus morphine 5 mg; mitragynine 25 mg/kg plus morphine 5 mg/kg) 15 minutes prior to subjecting mice to the hot plate test. The combination of mitragynine plus morphine resulted in a significant antinociceptive effect compared with morphine alone and with controls (P<0.05). Analyses of relevant gene expressions that reflect development of morphine tolerance also demonstrated a significant reduction in protein expression (cyclic adenosine monophosphate and its response element binding protein) with the combination compared with morphine alone (P<0.05). Additionally, no significant changes were noted in liver or kidney function tests with the combination of mitragynine plus morphine.Fakurazi 2013

Opioid withdrawal management

Animal data

Measurement of several behavioral indices of anxiety as well as cortisol production during morphine withdrawal was used in a zebrafish model for addiction. Strong anxiogenic behaviors were observed during morphine withdrawal that were attenuated with administration of mitragynine to a level comparable with controls. Additionally, the increase in cortisol levels during morphine withdrawal was reduced when the zebrafish were exposed to mitragynine.Khor 2011

Dosing

Use is not recommended. Kratom is under FDA review for safety concerns.

Pregnancy / Lactation

Do not use. Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

Mitragynine undergoes phase 1 and 2 metabolism. Hydrolysis of the parent compound is followed by O-desmethylation, with oxidative and reductive transformations proceeding to the intermediate aldehydes; phase 2 glucuronidation and sulfate conjugation is the final step prior to urinary excretion. Experimental studies have revealed that kratom inhibits cytochrome 450 (CYP-450) enzymes, specifically CYP3A4, 2D6, and 1A2.Warner 2016

Serious and even fatal adverse effects have been reported when kratom is mixed with carisoprodol, modafinil, propylhexedrine, Datura stramonium, fentanyl, diphenhydramine, caffeine, morphine, and/or O-desmethyltramadol.Warner 2016, Holler 2011, Nelsen 2010

Drugs that undergo N-demethylation by the CYP-450 system (ie, cocaine, codeine, heroine, methadone, morphine) and/or glucuronidation (ie, morphine, acetaminophen, diazepam) have been known to be used and/or mixed with kratom. In vitro studies documented an increase in the amount of CYP-450 microsomal protein that ranged from 1.2 to 1.9 times higher in rats treated with M. speciosa methanolic, aqueous, or total alkaloid leaf extracts compared with controls. In vivo, N-demethylation enzyme activities were significantly induced by all tested doses of the various extracts except for the 50 mg/kg methanolic extract, which produced slight inhibition. Glucuronidation was significantly inhibited with the methanolic extract and mitragynine (P<0.05 each). The degree of inhibition of the CYP-450 enzymes was directly proportional to the total flavonoid content.Azizi 2013

Adverse Reactions

A 2017 FDA statement alerted consumers and clinicians to significant safety risks associated with the use of kratom, including but not limited to risks of addiction, and abuse and dependence; in some cases, these events may be fatal. The FDA is aware of 36 deaths associated with the use of kratom-containing products. Additional adverse events noted in the FDA statement and news release included seizures, liver damage, withdrawal symptoms, respiratory depression, vomiting, nervousness, weight loss, and constipation. Kratom may have both narcotic and stimulant-like effects, and withdrawal symptoms may include hostility, aggression, excessive tearing, aching of muscles and bones, and jerky limb movements. The FDA statement noted that there are no approved uses and that all available scientific data is under review by the FDA.FDA Statement 2017, FDA News Release 2017

Sensitivity to sunlight, nausea, itching, sweating, dry mouth, constipation, increased urination, loss of appetite, psychotic symptoms, and tolerance and dependence have occurred. Low doses (1 to 5 g of dried leaves) can cause slightly contracted pupils, blushing, anxiety, and agitation, while high doses (5 to 15 g of dried leaves) can result in diarrhea. Unlike opioids, the initial sweating, dizziness, nausea, and dysphoric effects of high kratom doses (more than 15 g of dried leaves) subside quickly and are followed by calmness and a dream-like state. Long-term use can result in anorexia, weight loss, insomnia, skin darkening (especially of the cheeks), tremors, seizures, dry mouth, polyuria, constipation; long-term use with high doses can produce hallucinations and paranoia.National Institute on Drug Abuse 2016, Warner 2016, National Institute on Drug Abuse 2016

Intrahepatic cholestasis accompanied by abnormal liver tests, jaundice, dark urine, and/or pruritus have been reported in 2 cases. In the first case, a 25-year-old male without a medical or medication history who ingested kratom powder for 2 weeks (starting at 1 to 2 teaspoons twice daily [1 teaspoon = 2.3 to 3.5 g, corresponding to 5 to 8 dried leaves] and increasing the dose over the course of 2 weeks to 4 to 6 teaspoons daily) experienced hepatotoxicity.Kapp 2011 The second case was a 58-year-old man receiving psychotropic medications (quetiapine, sertraline) for schizoaffective disorder who developed liver toxicity after taking 1 tablespoon of kratom powder daily for 3 months.Dorman 2015

Toxicology

The FDA is aware of 36 deaths associated with the use of kratom-containing products. In March 2018, the US FDA and CDC announced multistate investigation regarding outbreak of Salmonella infections related to kratom use. Consumers have been advised to avoid the use of kratom and kratom-containing products.FDA Statement 2018

Calls to US poison control centers related to kratom exposure increased 10-fold from 2010 to 2015 (from 26 to 263 calls); ethanol, other botanicals, benzodiazepines, narcotics, and acetaminophen were the most commonly reported substances used in combination with kratom. The reported adverse reactions associated with kratom use for the majority of exposures (41.7%) required treatment but resulted in no residual disability and were non–life-threatening; 24.5% of exposures were associated with mild signs or symptoms that resolved rapidly, and 7.4% were associated with major life-threatening reactions with some residual disability.Anwar 2016

Kratom products may often contain artificially elevated concentrations of 7-HMG. By switching to a different kratom formulation, patients who use a certain amount of dried leaves could unintentionally get a higher dose than intended.Lydecker 2016

Tolerance and cross-tolerance with CNS stimulants or depressants may occur.Warner 2016 Kratom may cause dependence; withdrawal symptoms include muscle aches, insomnia, irritability, hostility, aggression, dysphoria, emotional changes, yawning, runny nose, jerky movements, hypertension, and diarrhea. Withdrawal symptoms similar to those with opioids may occur.National Institute on Drug Abuse 2016, Warner 2016, National Institute on Drug Abuse 2016

In a 44-year-old male patient with a 3-year kratom habit and a positive history of multidrug abuse, dihydrocodeine (60 mg given 4 times daily) and lofexidine (0.2 mg twice daily) were titrated according to withdrawal symptom severity over 4 days to facilitate kratom detoxification. At the time of admission, he was taking approximately 40 g/day (10 g every 6 hours) and was experiencing cravings and other symptoms between doses, despite regular dosing intervals.McWhirter 2010 In another case, an opioid withdrawal protocol using clonidine and hydroxyzine was used to effectively manage a case of kratom addiction that developed over 2 years in a 37-year-old woman. Six months after starting kratom for pain relief from carpal tunnel surgery, the patient attempted to reduce her consumption and experienced cravings and withdrawal symptoms (ie, severe abdominal cramps, sweats, blurred vision, nausea, vomiting, diarrhea). Attempts to detoxify with low-dose clonidine were ineffective, and she continued to use kratom despite effects on her health (weight loss, insomnia, cravings, and decreased energy level). The patient was ultimately admitted to an addiction unit. Within a few hours of starting symptom-triggered clonidine 0.1 to 0.2 mg every 2 hours and hydroxyzine 50 mg every 6 hours, her symptoms worsened and she required up to 2 mg of clonidine over 36 hours. Symptoms subsequently rapidly improved over the next 2 to 3 days and she was discharged home with a prescription to start naltrexone 7 days after discharge to avoid precipitating additional withdrawal symptoms.Galbis-Reig 2016

In the clinical and forensic toxicology settings, mitragynine and 7-HMG are not routinely detected in most drug testing or screening procedures. However, a range of analytical methods have been developed in recent years to detect kratom and its constituents in plant, urine, blood, and commercial preparations. Focusing on kratom alkaloid metabolites as targets in urine samples provides a suitable screening approach and, in the absence of tramadol or its metabolite, "Krypton" (kratom-tramadol mixture) intake can be assumed if O-demethyltramadol is detected.Warner 2016, Philipp 2011

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