Mitragynine is an indole-based alkaloid and is one of the main psychoactive constituents in the Southeast Asian plant Mitragyna speciosa, commonly known as kratom. It has also been researched for its use to potentially manage symptoms of opioid withdrawal. It is a partial agonist of the μ-opioid receptors; and as such can produce effects similar to those of classic opioids such as morphine. Mitragynine is the most abundant active alkaloid in kratom. In Thai varieties of kratom, mitragynine is the most abundant component (up to 66% of total alkaloids), while 7-hydroxymitragynine (7-OH) is a minor constituent (up to 2% of total alkaloid content). In Malaysian kratom varieties, mitragynine is present at lower concentration (12% of total alkaloids). Total alkaloid concentration in dried leaves ranges from 0.5 to 1.5%. Such preparations are orally consumed and typically involve dried kratom leaves which are brewed into tea or ground and placed into capsules.
Uses
Medical As of April 2019, the US Food and Drug Administration (FDA) had stated that there were no approved clinical uses for kratom, and that there was no evidence that kratom was safe or effective for treating any condition. This reiterated the conclusion of an earlier report by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA): As of 2023, mitragynine had not been approved for any medical use. As of 2018, the FDA had noted, in particular, that there had been no clinical trials to study safety and efficacy of kratom in the treatment of opioid addiction.
Pain Mitragynine-containing kratom extracts, with their accompanying array of alkaloids and other natural products, have been used for their pain-mitigation properties for at least a century. In Southeast Asia, the consumption of mitragynine from whole leaf kratom preparations is common among laborers who report utilizing kratom's mild stimulant and analgesic properties to increase endurance and ease pain while working. In one laboratory study in a rat model in 2016, alkaloid-containing extracts of kratom gave evidence of inducing naloxone-reversible antinociceptive effects in hotplate and tail-flick tests to a level comparable to oxycodone.
Chronic pain Kratom is commonly used in the United States as self-medication for pain. A 2019 review of existing literature suggested the potential of kratom as substitution therapy for chronic pain.
Opioid withdrawal As early as the 19th century, kratom was in use for the treatment of opioid addiction and withdrawal. As of 2018, a review of mental health aspects of kratom use mentioned opioid replacement and withdrawal as primary motivations for kratom use: almost 50% of the approximately 8,000 kratom users surveyed indicated kratom use that resulted in reduced or discontinued use of opioids. Some animal models of opioid withdrawal suggest mitragynine can suppress and ameliorate withdrawal from other opioid agonists (e.g., after chronic administration of morphine in zebra fish).
Recreational Mitragynine and its metabolite 7-hydroxymitragynine (7-OH) are thought to underlie the effects of kratom. Consumption of dried kratom leaves yields different responses depending on the dose consumed. At low doses, kratom is reported to induce a mild stimulating effect, while larger doses are reported to produce sedation and analgesia typical of opioids. The concentration of mitragynine and other alkaloids in kratom has been found to vary between particular "strains" of the plant, thus indicating "strain-specific" effects from consumption, as well. Effects of mitragynine-containing preparations from M. speciosa include analgesic, anti-inflammatory, antidepressant, and muscle relaxant properties; adverse effects include a negative impact on cognition; in animal studies the potential for misuse has been found, including through the use of the conditioned place preference (CPP) test, which indicated a distinct reward effect for 7-OH.
Adverse effects
Dependence and withdrawal In one study, symptoms of withdrawal lasted less than three days for most subjects. In an animal study, mitragynine withdrawal symptoms were observed following 14 days of mitragynine intraperitoneal injections in mice and included displays of anxiety, teeth chattering, and piloerection, all of which are characteristic signs of opioid withdrawal in mice and are comparable to morphine withdrawal symptoms in character.
Chemistry
Solubility The solubility of mitragynine from kratom in neutral-pH and alkaline water is very low (0.0187 mg/ml at pH 9). The solubility of mitragynine in acidic water is higher (3.5 mg/ml at pH 4), however, this alkaloid can become unstable, so certain products, such as low-pH beverages, have a very short shelf life. Many vendors offer concentrated kratom products with claims of improved mitragynine solubility, however, those products are often formulated with solvents such as propylene glycol, which can make products unpleasant.
Pharmacology
Pharmacodynamics Mitragynine acts on a variety of receptors in the central nervous system (CNS), most notably the μ-, δ-, and κ-opioid receptors. The nature of mitragynine's interaction with opioid receptors has yet to be fully classified, with some reports suggesting partial agonist activity at the μ-opioid receptor and others suggesting full agonist activity. Additionally, mitragynine is known to interact with δ- and κ-opioid receptors as well, but these interactions remain ambiguous, with some reports indicating mitragynine as a delta and κ-opioid receptor competitive antagonist and others as a full agonist of these receptors. In either case, mitragynine is reported to have lower affinity to delta and κ-opioid receptors compared to μ-opioid receptors. Mitragynine is also known to interact with dopamine D2, adenosine, serotonin, and alpha-2 adrenergic receptors, though the significance of these interactions is not fully understood. Additionally, several reports of mitragynine pharmacology indicate potential biased agonism activity favoring G protein signaling pathways independent of β-arrestin recruitment, which was originally thought to be a primary component in reducing opioid-induced respiratory depression. However, recent evidence suggests that low intrinsic efficacy at the μ-opioid receptor is responsible for the improved side effect profile of mitragynine, as opposed to G protein bias.
Pharmacokinetics
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