7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects

Summary & key facts

Researchers tested how kratom’s main chemical, mitragynine, works in the body. They found that liver enzymes turn mitragynine into a much stronger breakdown product called 7-hydroxymitragynine. In mice and in lab tests with mouse and human liver, the brain levels of that breakdown product were high enough to explain most of the pain relief. The parent chemical, mitragynine, showed up in the brain at high amounts but probably does not directly activate the brain’s opioid sites. The study says the way the body changes mitragynine — and how the drug is taken — matters a lot, and that more research in humans is needed.

Key facts:

• Kratom’s main alkaloid is mitragynine, and people have used kratom leaves for pain relief and other effects.
• In lab tests with mouse and human liver tissue, enzymes called CYP3A changed mitragynine into 7-hydroxymitragynine, a different chemical.
• 7-hydroxymitragynine is a much stronger activator of the brain’s mu-opioid sites, which are the same places classical opioids act to relieve pain.
• In mice, mitragynine was actually converted into 7-hydroxymitragynine in the body, and the amount of that breakdown product in the brain could explain most or all of the pain relief seen.
• Mitragynine itself was found in the mouse brain at high concentrations but at levels that make it unlikely to directly turn on opioid sites.
• Because mitragynine’s effects depend on being converted in the body, the way someone takes kratom (the route of administration) can change how it works.
• The experiments were done in mice and in lab liver samples, so the authors say more studies in humans are needed before we can be sure how this works in people.

Abstract

, more commonly known as kratom, is a plant native to Southeast Asia, the leaves of which have been used traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently, growing use of the plant in the United States and concerns that kratom represents an uncontrolled drug with potential abuse liability, have highlighted the need for more careful study of its pharmacological activity. The major active alkaloid found in kratom, mitragynine, has been reported to have opioid agonist and analgesic activity in vitro and in animal models, consistent with the purported effects of kratom leaf in humans. However, preliminary research has provided some evidence that mitragynine and related compounds may act as atypical opioid agonists, inducing therapeutic effects such as analgesia, while limiting the negative side effects typical of classical opioids. Here we report evidence that an active metabolite plays an important role in mediating the analgesic effects of mitragynine. We find that mitragynine is converted in vitro in both mouse and human liver preparations to the much more potent mu-opioid receptor agonist 7-hydroxymitragynine and that this conversion is mediated by cytochrome P450 3A isoforms. Further, we show that 7-hydroxymitragynine is formed from mitragynine in mice and that brain concentrations of this metabolite are sufficient to explain most or all of the opioid-receptor-mediated analgesic activity of mitragynine. At the same time, mitragynine is found in the brains of mice at very high concentrations relative to its opioid receptor binding affinity, suggesting that it does not directly activate opioid receptors. The results presented here provide a metabolism-dependent mechanism for the analgesic effects of mitragynine and clarify the importance of route of administration for determining the activity of this compound. Further, they raise important questions about the interpretation of existing data on mitragynine and highlight critical areas for further research in animals and humans.

Topics

Alkaloids: synthesis and pharmacology Chemical synthesis and alkaloids Traditional and Medicinal Uses of Annonaceae

Categories

Life Sciences Pharmacology Pharmacology, Toxicology and Pharmaceutics

Tags

Active metabolite Agonist Alkaloid Analgesic Biochemistry Chemistry Medicine Metabolite Opioid Pharmacokinetics Pharmacology Receptor Stereochemistry Stimulant

Substances

Other

Conditions & symptoms

Addiction Chronic Pain Addiction or harmful habbits Chronic pain