7-Hydroxymitragynine is an Active Metabolite of Mitragynine and a Key Mediator of its Analgesic Effects

Abstract

<p><i>Mitragynina speciosa</i>, 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 <i>in vitro</i> 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 <i>in vitro </i>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.</p>

Pharmacological Comparison of Mitragynine and 7-Hydroxymitragynine: In Vitro Affinity and Efficacy forμ-Opioid Receptor and Opioid-Like Behavioral Effects in Rats

“…The vast majority of morphine discrimination assays are selectively mediated by MOR agonism (Picker et al, 1990;Walker and Young, 2001), and it appears MOR agonism is the predominant mechanism by which mitragynine produces discriminativestimulus effects. The qualitatively distinct effects of mitragynine in vitro (no agonism in our study) and in vivo (agonism) might be due to metabolism of mitragynine to 7-hydroxymitragynine in vivo (Kruegel et al, 2019;Hiranita et al, 2020;Kamble et al, 2020).…”

“…Mitragynine was also previously ineffective against acutely applied noxious heat in rats (see also Hiranita et al, 2019). In contrast, mitragynine produced antinociceptive effects in mice (Matsumoto et al, 1996a;1996b;Shamima et al, 2012;Kruegel et al, 2019).…”

“…In mice, mitragynine was 2.6-fold less potent than codeine, a prodrug of the MOR agonist morphine, at producing antinociception using a hotplate test (Macko et al, 1972). The antinociceptive effects of mitragynine were blocked by the non-selective opioid antagonist naloxone in mice and were absent in mice lacking MORs and with δ-and κ-opioid receptors intact (Matsumoto et al, 1996b;Kruegel et al, 2019). Results from additional ex vivo and in vivo studies indicate that the activity of mitragynine may extend beyond MOR.…”

Acute mitragynine administration suppresses cortical oscillatory power and systems theta coherence in rats

“…One such potential alternative is Mitragyna speciosa , most often referred to as kratom, a plant that is reported to induce opiate-like effects, including analgesia, antinociception and psychoactive effects at higher doses (Kruegel and Grundmann, 2018). This activity is commonly attributed to the major alkaloid present in kratom, mitragynine, as well as its derivative 7-hydroxymitragynine (7-HMG) (Idayu et al, 2011; Kruegel et al, 2019). Although both alkaloids have been shown to act via the opioid receptors, with the greatest binding affinity for the mu opioid receptor (MOR) subtype, they are considered to be ‘atypical opioids’ due to the fact that their agonism of the MOR is β-arrestin sparing (Ismail et al, 2019; Kruegel et al, 2016; Takayama et al, 2002).…”

“…The potential role for mitragynine as a therapeutic for pain management is supported by several preclinical studies demonstrating that kratom (Sabetghadam et al, 2010; Takayama et al, 2002) or mitragynine (Hiranita et al, 2019; Kruegel et al, 2019; Matsumoto et al, 1996) systemically administered to rats displayed analgesic efficacy similar or less to that of morphine-exposed rats. However, the addictive potential of mitragynine has been less clear.…”