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A brief overview of Kratom (Mitragyna speciosa Korth.)

Kratom, scientifically referred to as Mitragyna speciosa Korth., is a tree native to Southeast Asia in the coffee (Rubiaceae) family. The subtropical
climate of Thailand, Malaysia, Indonesia and a few other Southeast Asian countries has provided natives with a range of medical applications from using
the fresh leaves from the tree. Traditional medicine has used kratom leaves for at least the past two centuries to treat ailments such as fever,
gastrointestinal disorders, pain, and mitigation of withdrawal effects from “drugs with abuse potential”, most prominently opium and heroin. The fresh leaves may also be chewed to increase work performance and endurance.

In the past two decades, kratom has been increasingly used by Western cultures, particular in Europe and North America.
All products are derived from the leaves of the tree which are harvested, dried, and primarily exported in powder or cut leaf form. Further processing of the leaves by distributors may involve extraction to increase the concentration of indole alkaloids. The main indole alkaloid present in many kratom products is mitragynine which is accompanied by more than 40 indole and oxindole alkaloids that have been identified in the leaves.

Mitragynine was the first alkaloid isolated from kratom in 1921 and found to possess both stimulant and analgesic effects.
It was determined later that mitragynine and some of its metabolites bind to opioid receptors as partial agonists, potentially exerting a distinguished
pharmacological effect from classical opioids like morphine or heroin. In both animal experiments and initial human case studies, neither mitragynine nor kratom have led to fatal respiratory depression which has been in part related to its adrenergic, dopaminergic, and serotonergic activities.

Kratom contains other alkaloids that are also associated with pharmacological effects, such as paynantheine, speciocilliatine, mitraphylline, and isorhynchophilline. These lesser-known alkaloids have shown to bind to dopaminergic and serotonergic receptors as well
as exert effects on the immune system. This may explain the complex pharmacology observed after kratom administration to animals. In low doses,
kratom does exert primarily stimulant effects which have been linked to be at least in part mediated through adrenergic, dopaminergic, and serotonergic pathways. This activity may also explain the observed antidepressant and anxiolytic effects of kratom in animals. Higher doses of kratom can cause sedation and analgesia and are likely mediated through opioid receptor interactions of alkaloids and their metabolites.

The presence of 7-hydroxymitragynine, a close structural analogue to mitragynine, in fresh leaf material has not been confirmed to date but its presence in dried products appears to be variable, at times appearing in amounts as high as 1% of the total plant material while
being undetectable in other instances. It therefore appears to be an artifact as the result of processing of fresh leaf material. But it has also been shown
that 7-hydroxymitragynine and its tautomer mitragynine pseudoindoxyl are active metabolites generated in the human body from mitragynine. While mitragynine has shown no abuse liability or substitution for morphine in animals, 7-hydroxymitragynine and mitragynine pseudoindoxyl do possess abuse liability and can lead to tolerance and use disorders. Products that are low in or do not contain 7-hydroxymitragynine should therefore be preferred over those that are either not tested for its content or contain more than 0.1% of 7-hydroxymitragynine by weight.

Studies in humans remain sparse to date given the ambiguous regulatory status of kratom in most countries. Surveys
conducted since 2017 among people who use kratom have identified that kratom is primarily used for self-treatment of chronic pain (arthritis, lower back pain, neuropathic pain), mood disorders (anxiety, depression, attention deficit and hyperactivity disorder, and post-traumatic stress disorder), and withdrawal symptoms from illicit and prescription drugs (primarily opioids). A majority of users ingest kratom leaf material in powder form either as a suspension in water or in capsule form. In this form, a majority of users consume between 1-5 g/dose and 1-3 times/day but there is variability in the frequency of use depending on the health condition and intended use.

While kratom is perceived by many people who use kratom to be safe, reports of tolerance and use disorders have been reported in the scientific literature. The symptoms of a kratom use disorder seem to often align with opioid use disorder and may require medication-assisted treatment, e.g. with buprenorphine or methadone. A person is more likely to develop a kratom use disorder if they have a history of a substance
use or mental disorder.

Fatalities have been reported with the consumption of kratom although it is unclear whether kratom was causative in nearly all cases due to concomitant consumption of other substances. Kratom may interact with other medications and should not be taken with impairing drugs
such as alcohol, opioids, benzodiazepines, or antidepressants.

Variability in the composition and quality of kratom products available to consumers require a cautionary approach to its
consumption, especially if pre-existing health conditions exist and other medications are taken. Certain products may have established quality control
measures such as Good Manufacturing Practices (GMP) which allows for consistent quality of the product, often limiting the amount of 7-hydroxymitragynine. Products with adequate labeling to warn consumers of potential drug interactions, providing information on how to take the product, and any limitations of use should be preferred for consumption.

If you are thinking of consuming kratom, please consult with your healthcare professional (physician, pharmacist, or nurse practitioner) or apply “safer use” principles, such as starting with a low dose (1-2 g) and not exceeding 5 g/dose no more than 3 times/day.

 Written by:

Oliver Grundmann, Ph.D

Fabian Steinmetz, Ph.D

Further resources:

American Kratom Association:

Evaluation of Kratom Opioid Derivatives as
Potential Treatment Option for Alcohol Use Disorder, Front Pharmacol. 2021 Nov

Kratom Use Within the Context of the
Evolving Opioid Crisis and the COVID-19 Pandemic in the United States, Front
Pharmacol. 2021 Aug 26;12:729220.

Kratom-Induced Liver Injury: A Case Series
and Clinical Implications, Cureus. 2021 Apr 25;13(4):e14679.

Pharmacotherapy for Management of ‘Kratom
Use Disorder’: A Systematic Literature Review With Survey of Experts, WMJ. 2021

Evaluation of the rewarding effects of
mitragynine and 7-hydroxymitragynine in an intracranial self-stimulation
procedure in male and female rats, Drug Alcohol Depend. 2020 Oct 1;215:108235.

The Potential for Kratom as an Antidepressant
and Antipsychotic, Yale J Biol Med. 2020 Jun 29;93(2):283-289.

Kratom and Pain Tolerance: A Randomized,
Placebo-Controlled, Double-Blind Study, Yale J Biol Med. 2020 Jun

Mitragynine Attenuates Morphine Withdrawal
Effects in Rats-A Comparison With Methadone and Buprenorphine, Front Psychiatry.
2020 May 7;11:411.

Kratom (Mitragyna speciosa): User
demographics, use patterns, and implications for the opioid epidemic, Drug
Alcohol Depend. 2020 Mar 1;208:107849.

Exploration of cytochrome P450 inhibition
mediated drug-drug interaction potential of kratom alkaloids, Toxicol Lett.
2020 Feb 1;319:148-154.

Current perspectives on the impact of
Kratom use, Subst Abuse Rehabil. 2019 Jul 1;10:23-31.

Mitragyna speciosa: Clinical, Toxicological
Aspects and Analysis in Biological and Non-Biological Samples, Medicines
(Basel). 2019 Mar 4;6(1):35.

The abuse potential of kratom according the
8 factors of the controlled substances act: implications for regulation and
research, Psychopharmacology (Berl). 2018 Feb;235(2):573-589.

Synthetic and Receptor Signaling
Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular
Framework for Opioid Receptor Modulators, J Am Chem Soc. 2016 Jun

Mitragynine/Corynantheidine Pseudoindoxyls
As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit
β-Arrestin-2, J Med Chem. 2016 Sep 22;59(18):8381-97.

Following “the Roots” of Kratom
(Mitragyna speciosa): The Evolution of an Enhancer from a Traditional Use to
Increase Work and Productivity in Southeast Asia to a Recreational Psychoactive
Drug in Western Countries, Biomed Res Int. 2015;2015:968786.

Anti-inflammatory and antinociceptive
effects of Mitragyna speciosa Korth methanolic extract, Med Princ Pract.

Chemistry and pharmacology of analgesic
indole alkaloids from the rubiaceous plant, Mitragyna speciosa, Chem Pharm Bull
(Tokyo). 2004 Aug;52(8):916-28.