Kratom Fact Sheet for Healthcare Professionals

1. Introduction

Kratom is both the whole tree Mitragyna speciosa in the family

Rubiaceae as well as the leaves and extracts of the leaves that

are used for medicinal and recreational purposes [1]. The tree

is native to Southeast Asia and primarily grown in Malaysia,

Thailand, and Indonesia. It is occasionally cultivated in other

countries including the US. It is also known as ketum, biak-

biak, Maeng Da, thang, thom, and kakuam, among others [2].

2. History of use outside and in the US

Traditional use of Kratom in Southeast Asia was first reported

in 1836 but likely dates back further primarily for two reasons:

as an opium substitute in Malaysia and as a stimulant to

increase work efficiency in Thailand [3]. Kratom is used alone

or brewed in combination with cough syrup (often codeine) and

Coca Cola, then referred to as 4x100 as a drug of abuse, in

Southeast Asia [4]. Its first use in the US remains unknown but

cases emerged in the early 2000s describing Kratom for self-

treatment of opioid withdrawal symptoms, pain, and mental

conditions [5]. The CDC reported an increase in calls to Poison

Control Centers involving Kratom and the FDA has warned

consumers to avoid taking Kratom [6, 7]. As of February 2019,

the FDA recommends placing Kratom’s active compounds,

mitragynine and 7-hydroxymitragynine, in DEA schedule 1

because of their opioid-like effects and potential for

dependence without any current medical indication in the US.

3. Traditional uses

In Southeast Asia, fresh Kratom leaves were chewed to

increase work efficiency and relieve fatigue for manual

laborers. Fresh and dried leaves were also brewed into teas in

Malaysia and Thailand for a range of ailments including

diabetes, diarrhea, fever, pain, and for use as a wound poultice

[8]. It was and remains used as a substitute for opium and to

reduce opioid withdrawal symptoms both in Asian countries

and in the West. There is no scientific information on traditional

uses of Kratom preparations before the 2000s outside of Asia.

4. Dosage forms, dose range; differentiation between pure

Kratom and adulterated products

Kratom is primarily consumed orally. It is available in the US as

powder, tablets, capsules, raw leaves (mostly dried), and

concentrated extracts (most containing varying amounts of

ethanol). The doses range widely based on the dosage form

with powders usually suggesting a dose of 3-5 g while

concentrated liquid extracts may only require 1-2 drops to be

added to a beverage according to manufacturer

recommendations. Users may administer the extracts several

times per day to achieve improvement of their condition

although a majority appear to use the extract 3 times/day in

doses of 3-5 g [9]. Self-dosing in combination with currently

unregulated Kratom product quality results in highly variable

concentrations of the active ingredients mitragynine and 7-

hydroxymitragynine. Pure Kratom products should contain no

more than 66% of mitragynine as the main alkaloid and 2% of

7-hydroxymitragynine in the alkaloid fraction of the extract or a

total of approximately 2% of alkaloids (1.8-2% mitragynine and

0.02-0.03% 7-hydroxymitragynine) in the whole leaf extract

[10, 11]. Kratom preparations are known to be adulterated in

Western countries with various synthetic compounds including

7-hydroxymitragynine, O-desmethyltramadol (then referred to

as “Krypton”), fentanyl, hydrocodone and other prescription

opioids [10, 12].

5. Potential uses, what consumers and patients may use it for

Because of its many traditional uses as both a dose-dependent

stimulant and analgesic, Kratom preparations may be used for

a wide range of self-treatment options by patients. Surveys and

case reports describe the use for acute and/or chronic pain,

mitigation of opioid, prescription and other drug dependency

withdrawal symptoms, substitution of opioid medication or illicit

opioid drugs, harm reduction measures in opioid withdrawal,

depressive or anxiety disorders, attention deficit and

hyperactivity disorders (ADHD/ADD), bipolar disorder, post-

traumatic stress disorder (PTSD), and other conditions [5, 9,

13]. In addition, a person may use Kratom recreationally to

obtain relaxation, improved mood, increased energy, or an

altered state of consciousness (“high”) especially if used in

combination with other drugs such as alcohol,

benzodiazepines, opioids, cocaine, or amphetamines [13].

6. Current known pharmacology, active pharmacological

principles

Early investigations of whole Kratom extracts indicated that the

extract exerted a stimulant effect in both humans and animals

“comparable to cocaine” but only a weak analgesic effect

equivalent “in potency to that of codeine” [3]. Following

isolation of the indole alkaloids mitragynine and 7-

hydroxymitragynine from enriched extracts, both were found to

be partial agonists at the μ-opioid receptor [11]. Mitragynine

binds with much lower affinity to the receptor compared to

morphine (EC

=339 nM for mitragynine vs. EC

=3 nM for

morphine) while 7-hydroxymitragynine is about 10 times more

potent than mitragynine at the receptor with an EC

=35 nM in

vitro. Other alkaloids from Kratom bind as competitive

antagonists to the μ-opioid receptor thus resulting in a

potentially complex overall pharmacological response of the

whole extract depending on the amount of alkaloids present.

The binding affinities for mitragynine and 7-hydroxymitragynine

at κ- and δ-opioid receptors as partial competitive antagonists

has been reported in functional assays as much weaker (κ-

opioid receptor: K

=772 nM for mitragynine and K

=188 nM for

7-hydroxymitragynine; δ-opioid receptor: K

>10 μM for

mitragynine and K

=219 nM for 7-hydroxymitragynine).

Mitragynine has been investigated in non-opioid receptor

binding studies and has shown affinity for α

-adrenergic,

adenosine A

, dopamine D

, serotonin 5-HT

, and 5-HT

receptors although it remains unclear if this activity is agonistic

or antagonistic [11, 14]. Both in vitro and in vivo studies

confirmed that the analgesic effects of mitragynine are

reversible with the administration of naloxone, an opioid-

receptor antagonist [15].

7. Known/reported adverse effects, toxicology (both general

and specific to organ systems as applicable)

The most common adverse effects with the use of Kratom are

nausea, vomiting, constipation, stomach upset, and either

drowsiness/dizziness or irritability/agitation [6, 9]. Dry mouth,

sweating, sedation, and tachycardia have been reported in

doses above 8g. Intrahepatic cholestasis and hepatic liver

enzyme elevation has been reported with chronic and frequent

use (one month or longer) of Kratom [16]. Liver function

returned to normal after cessation of Kratom use. Withdrawal

symptoms associated with Kratom cessation are dose-

dependent and may include decreased appetite, diarrhea,

agitation, sedation, insomnia, hallucination, changes in heart

rate and blood pressure, and seizures [2, 17]. Respiratory

depression and hemorrhagic stroke which were reported in

fatalities involving Kratom could not be casually linked to the

ingestion since they also involved other drugs and/or

medications.

8. Known and suspected drug interactions

To date several case studies of drug interactions with Kratom

have been reported that relate to its CNS depressant effects.

Both additive and synergistic effects are observed if Kratom is

used with benzodiazepines, barbiturates, alcohol, opioids,

antidepressants, anxiolytics, and other CNS-active drugs [18].

Because of unknown routes of metabolism, specific CYP

enzyme interactions remain unknown but caution is advised if

Kratom is used in combination with drugs that are substrates of

CYP isoforms 1A2, 2C19, 2D6, and 3A4. For a list of general

known clinically relevant CYP substrates (not specific to

Kratom interactions) see

https://www.fda.gov/drugs/developmentapprovalprocess/

developmentresources/druginteractionslabeling/ucm093664.ht

m#table3-1. Few case reports indicate that some drugs

(quetiapine, modafinil) may interact with Kratom although it

remains unknown if this can be attributed to a CYP interaction

[2, 19]. In vitro studies have shown that Kratom and

mitragynine are inhibitors of the multi-drug transporter P-gp

that may lead to increased concentrations of a range of drugs

that are substrates for this transporter [20]. It is not known to

what degree these metabolic interactions are clinically

relevant.

9. Risks for misuse, abuse, and dependence to Kratom;

withdrawal symptoms

Kratom poses a risk for dependence development if consumed

in higher doses (more than 5g/dose and more than 3

times/day) on a frequent basis and does present with

withdrawal symptoms. The risk of dependence development

appears to be higher if the extract is used for harm reduction to

mitigate opioid and illicit drug withdrawal or for self-treatment of

pain [5, 12, 21]. Case reports of pregnant mothers who used

Kratom giving birth to newborns presenting with signs of

neonatal abstinence syndrome (NAS) similar to opioids

warrants advising against the use of the supplement in this

population [22]. Withdrawal symptoms are mild compared to

opioids with anxiety, diarrhea, pain, insomnia, restlessness,

mood changes, tension, anger, and nervousness presenting.

The symptoms may last from 3-10 days following the last dose

and withdrawal symptoms can be treated with short-term

buprenorphine-naloxone substitution therapy [23, 24].

10. Potential lab values in diagnostic and differential evaluation

There are currently no standard laboratory procedures for the

measurement of Kratom or its metabolites in a clinical setting.

Methods for the measurement of mitragynine have been

described in the scientific literature and a few forensic

laboratories have implemented them as part of their screening

and confirmatory testing [25, 26]. It has been difficult to link

blood concentrations of mitragynine to impairment or toxicity

given the wide range of variability with the ingestion of Kratom

preparations and undetermined mitragynine levels. Reports of

mitragynine blood levels vary from 0.02 to 0.24 μg/g in fatalities

(often in combination with other drugs) but also 0.0194 to

0.158 μg/g in subjects who did not experience any serious side

effects [12]. Hepatotoxicity indicated through elevated levels of

bilirubin, alkaline phosphatase (ALP), and alanine

aminotransferase (ALT) have been reported with chronic high

doses of Kratom in individuals who take other medications that

are potentially hepatotoxic indicating a potential drug

interaction [16]. This has not been observed if unadulterated

Kratom is taken alone.

11. Treatment approaches, triage, intermittent, and long-term

intervention

Presentation of Kratom overdoses can be varied and should be

treated symptomatically. In general, patients may be

tachycardic and may present with respiratory depression. If

seizures are present, a benzodiazepine such as lorazepam

(Ativan®) is likely going to be effective. A trial dose of naloxone

(Narcan®) has shown to be effective in reversing respiratory

depression [27]. Fluid resuscitation is advised in cases of

gastrointestinal symptoms such as vomiting, diarrhea, or

constipation. In an acute overdose with suspected

polysubstance exposure, laboratory values for CBC,

electrolytes, ethanol, and a drug screen should be drawn. If

possible, the patient should be asked about any other co-

ingested substances, licit or illicit, that can cause a complex

presentation and require appropriate intervention.

12. Literature

1. Singh, D., S. Narayanan, and B. Vicknasingam, Traditional and non-traditional uses of Mitragynine

(Kratom): A survey of the literature. Brain Res Bull, 2016. 126(Pt 1): p. 41-46.

2. 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.

3. Jansen, K.L. and C.J. Prast, Ethnopharmacology of kratom and the Mitragyna alkaloids. J

Ethnopharmacol, 1988. 23(1): p. 115-9.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

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.

10. Lydecker, A.G., et al., Suspected Adulteration of Commercial Kratom Products with 7-

Hydroxymitragynine. J Med Toxicol, 2016. 12(4): p. 341-349.

11. 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.

12. 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),

2018. 235(2): p. 573-589.

13. Swogger, M.T., et al., Experiences of Kratom Users: A Qualitative Analysis. J Psychoactive Drugs, 2015.

47(5): p. 360-7.

14. 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.

15. 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.

16. Kapp, F.G., et al., Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa). J

Med Toxicol, 2011. 7(3): p. 227-31.

17. Stanciu, C.N., et al., Kratom Withdrawal: A Systematic Review with Case Series. J Psychoactive Drugs,

2019. 51(1): p. 12-18.

18. Gershman, K., et al., Deaths in Colorado Attributed to Kratom. N Engl J Med, 2019. 380(1): p. 97-98.

19. 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.

20. Rusli, N., et al., The inhibitory effects of mitragynine on P-glycoprotein in vitro. Naunyn Schmiedebergs

Arch Pharmacol, 2019.

21. 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.

22. Eldridge, W.B., C. Foster, and L. Wyble, Neonatal Abstinence Syndrome Due to Maternal Kratom Use.

Pediatrics, 2018. 142(6).

23. Singh, D., et al., Severity of Kratom (Mitragyna speciosa Korth.) Psychological Withdrawal Symptoms. J

Psychoactive Drugs, 2018: p. 1-6.

24. 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.

25. 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,

2018. 101(4): p. 964-965.

26. 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.

27. 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.

Authors: Oliver Grundmann, PhD

Charles A. Veltri, PhD

Mohammad Salari, RPh

Reviewers: Edward W. Boyer, MD, PhD

Walter C. Prozialeck, PhD

Revision: March 2019