The History of Kratom: A Summary of the Uses, Pharmacology, and Health Effects of a Traditional and Modern Herb

The History of Kratom: A Summary of the Uses, Pharmacology, and Health Effects of a Traditional and Modern Herb

Kratom, scientifically named Mitragyna speciosa, is a tree found primarily in South Asia, particularly Malaysia, Thailand and Indonesia. This tree reaches a maximum height of 25 centimeters (cm) at maturity and produces a characteristic oval-lanceolate leaf shape. The leaves of this tree have pinnate venation that can be white, green, or red. Kratom belongs to the coffee family and has similar dose-dependent stimulant properties to caffeine, but does not contain theophylline or caffeine.

Kratom has gained traction in the last two decades due to its opiate-like effects as well as dose-dependent stimulant properties imparted by the indole alkaloids contained in the leaves. Kratom has historically been used for medicinal and recreational purposes in many Southeast Asian countries for centuries. Typically, kratom is given a common name in the region where it is grown. Only the fresh leaves of the Kratom plant are chewed to provide stimulating effects and reduce fatigue caused by hard work in fishermen, farmers or workers. Additionally, kratom has been used to treat symptoms of substance use disorders, particularly opium withdrawal. Rarely, the dried leaves are used either to prepare a water concoction or for smoking.

Kratom use is now banned in Malaysia and Indonesia, while Thailand allows legal growth and consumption of the plant. However, Indonesia exports kratom as a cash crop to the United States and several other countries. In Europe and the US, kratom is sold alongside cannabidiol, cannabis and kava products, all of which have medicinal and recreational uses. Kratom is sold in Western countries primarily as a loose powder, tablet, or capsule. These kratom products typically contain around 2% mitragynine. In comparison, kratom products containing 7% and 40% mitragynine are sold as semi-solid resins, gummies, or soft capsules. Traditionally, Kratom has been used for anti-diarrheal, analgesic, antipyretic, anti-diabetic and muscle relaxant purposes. For the past decade, kratom has been used among young adults in Thailand in a homemade concoction called “4 x 100.” This plant has also been heated and used for oral ingestion with cough syrups containing diphenhydramine or codeine and with soft drinks containing caffeine.

Some of the adverse effects of kratom consumption include dehydration, weight loss, hyperpigmentation, and constipation. Higher doses of kratom can cause lethargy and fatigue, associated with a higher risk of developing dependence and tolerance. Rare cases of death from 4 x 100 mixtures have also been reported in Thailand.

Previous research has shown that mitragynine and other kratom indole alkaloids may serve as patented opioid agonist precursors and thus could be developed into medications. Several in vitro and in vivo studies have also shown that mitragynine is a partial agonist of the μ-opioid receptor, along with antagonists of the δ-opioid receptor and κ-opioid receptor. Some studies have also shown that mitragynine can be converted to 7-hydroxy-mitragynine by some cytochrome P450 enzymes, which may explain some of its analgesic effects. Mitragynine has also been shown to bind with α-adrenergic receptors, having the highest affinity for the α1A receptor and the lowest affinity for the α2B receptor. This compound can also bind to serotonin receptors 5-HT1A and 5-HT2B with low affinity, while two of its enantiomers can bind to these receptors with high affinity.

Mitragynine, which makes up 66% of kratom and is a main active ingredient of this plant, can be quickly absorbed by the small intestine and produce effects within minutes. This compound has a terminal half-life of 23 hours and its concentration decreases within about four hours. Mitragynine is usually protein-bound in the serum and is converted into at least seven different phase I metabolites in the liver. In addition to mitragynine, 25 other alkaloids have been found in lower concentrations in kratom.

Previous in vitro studies in rats showed that mitragynine is the main alkaloid compound in kratom extract that can reduce electroencephalography (EEG) activity in the parietal and frontal cortices. However, a recent study showed that not only mitragynine but also other kratom alkaloids are essential for kratom's analgesic effects and pain management. Clinical trials on kratom are currently restricted in many countries because this agent is not classified as a drug, food or dietary supplement. For example, the US Food and Drug Administration (FDA) has reported that kratom and its alkaloids are opioids. The FDA has banned the import of kratom and warned the public against its consumption.

Multiple self-reported kratom surveys have shown that kratom users are predominantly male, non-Hispanic white, employed full-time or self-employed, and with middle incomes. Many of these individuals use kratom to treat a mental health disorder or chronic pain.

Small doses of kratom rarely have health effects, while larger doses can affect health. Restlessness, seizures, vomiting, tachycardia, or sedative/opioid-like effects occur during acute overdose. Seizures were reported in 9% of cases to poison centers in the United States and in 16-18% of cases to a poison center in Thailand. Kratom use is also associated with monomorphic or polymorphic ventricular arrhythmias. Polymorphic ventricular tachycardias could be due to kratom's effect on the QTc interval. In addition, several deaths have been reported due to pulmonary congestion secondary to respiratory depression following ingestion of high concentrations of mitragynine. Several cases of liver-related injuries from kratom have also been reported. Most patient