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