Human Mitragynine and 7-Hydroxymitragynine Pharmacokinetics after Single and Multiple Daily Doses of Oral Encapsulated Dried Kratom Leaf Powder
Kratom leaves, consumed by millions worldwide as tea or ground leaf powder, contain multiple alkaloids, with mitragynine being the most abundant and responsible for most effects. Mitragynine is a partial µ-opioid receptor agonist and competitive antagonist at κ- and δ-opioid receptors; however, unli...
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| Format: | Article |
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MDPI AG
2024-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/29/5/984 |
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| author | Marilyn A. Huestis Martin A. Brett John Bothmer Ramsey Atallah |
| author_facet | Marilyn A. Huestis Martin A. Brett John Bothmer Ramsey Atallah |
| author_sort | Marilyn A. Huestis |
| collection | DOAJ |
| description | Kratom leaves, consumed by millions worldwide as tea or ground leaf powder, contain multiple alkaloids, with mitragynine being the most abundant and responsible for most effects. Mitragynine is a partial µ-opioid receptor agonist and competitive antagonist at κ- and δ-opioid receptors; however, unlike morphine, it does not activate the β-arrestin-2 respiratory depression pathway. Due to few human mitragynine data, the largest randomized, between-subject, double-blind, placebo-controlled, dose-escalation study of 500–4000 mg dried kratom leaf powder (6.65–53.2 mg mitragynine) was conducted. LC-MS/MS mitragynine and 7-hydroxymitragynine plasma concentrations were obtained after single and 15 daily doses. Mitragynine and 7-hydroxymitragynine C<sub>max</sub> increased dose proportionally, and AUC was slightly more than dose proportional. The median mitragynine T<sub>max</sub> was 1.0–1.3 h after single and 1.0–1.7 h after multiple doses; for 7-hydroxymitragynine T<sub>max</sub>, it was 1.2–1.8 h and 1.3–2.0 h. Steady-state mitragynine concentrations were reached in 8–9 days and 7-hydroxymitragynine within 7 days. The highest mean mitragynine T<sub>1/2</sub> was 43.4 h after one and 67.9 h after multiple doses, and, for 7-hydroxymitragynine, it was 4.7 and 24.7 h. The mean 7-hydroxy-mitragynine/mitragynine concentration ratios were 0.20–0.31 after a single dose and decreased (0.15–0.21) after multiple doses. These mitragynine and 7-hydroxymitragynine data provide guidance for future clinical kratom dosing studies and an interpretation of clinical and forensic mitragynine and 7-hydroxymitragynine concentrations. |
| first_indexed | 2024-04-25T00:25:00Z |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-25T00:25:00Z |
| publishDate | 2024-02-01 |
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| spelling | doaj.art-f7497e1fcd4a4a9187a4741fbc9beb212024-03-12T16:50:38ZengMDPI AGMolecules1420-30492024-02-0129598410.3390/molecules29050984Human Mitragynine and 7-Hydroxymitragynine Pharmacokinetics after Single and Multiple Daily Doses of Oral Encapsulated Dried Kratom Leaf PowderMarilyn A. Huestis0Martin A. Brett1John Bothmer2Ramsey Atallah3Institute of Emerging Health Professions, Thomas Jefferson University, Philadelphia, PA 19107, USAPK Consultant, 50259 Pulheim, GermanyJB Pharma Consulting, 6418PR Heerlen, The NetherlandsDella Terra Pharmaceuticals, Atlanta, GA 30309, USAKratom leaves, consumed by millions worldwide as tea or ground leaf powder, contain multiple alkaloids, with mitragynine being the most abundant and responsible for most effects. Mitragynine is a partial µ-opioid receptor agonist and competitive antagonist at κ- and δ-opioid receptors; however, unlike morphine, it does not activate the β-arrestin-2 respiratory depression pathway. Due to few human mitragynine data, the largest randomized, between-subject, double-blind, placebo-controlled, dose-escalation study of 500–4000 mg dried kratom leaf powder (6.65–53.2 mg mitragynine) was conducted. LC-MS/MS mitragynine and 7-hydroxymitragynine plasma concentrations were obtained after single and 15 daily doses. Mitragynine and 7-hydroxymitragynine C<sub>max</sub> increased dose proportionally, and AUC was slightly more than dose proportional. The median mitragynine T<sub>max</sub> was 1.0–1.3 h after single and 1.0–1.7 h after multiple doses; for 7-hydroxymitragynine T<sub>max</sub>, it was 1.2–1.8 h and 1.3–2.0 h. Steady-state mitragynine concentrations were reached in 8–9 days and 7-hydroxymitragynine within 7 days. The highest mean mitragynine T<sub>1/2</sub> was 43.4 h after one and 67.9 h after multiple doses, and, for 7-hydroxymitragynine, it was 4.7 and 24.7 h. The mean 7-hydroxy-mitragynine/mitragynine concentration ratios were 0.20–0.31 after a single dose and decreased (0.15–0.21) after multiple doses. These mitragynine and 7-hydroxymitragynine data provide guidance for future clinical kratom dosing studies and an interpretation of clinical and forensic mitragynine and 7-hydroxymitragynine concentrations.https://www.mdpi.com/1420-3049/29/5/984mass spectrometrymetabolismanalytical toxicologymitragyninekratom7-hydroxymitragynine |
| spellingShingle | Marilyn A. Huestis Martin A. Brett John Bothmer Ramsey Atallah Human Mitragynine and 7-Hydroxymitragynine Pharmacokinetics after Single and Multiple Daily Doses of Oral Encapsulated Dried Kratom Leaf Powder Molecules mass spectrometry metabolism analytical toxicology mitragynine kratom 7-hydroxymitragynine |
| title | Human Mitragynine and 7-Hydroxymitragynine Pharmacokinetics after Single and Multiple Daily Doses of Oral Encapsulated Dried Kratom Leaf Powder |
| title_full | Human Mitragynine and 7-Hydroxymitragynine Pharmacokinetics after Single and Multiple Daily Doses of Oral Encapsulated Dried Kratom Leaf Powder |
| title_fullStr | Human Mitragynine and 7-Hydroxymitragynine Pharmacokinetics after Single and Multiple Daily Doses of Oral Encapsulated Dried Kratom Leaf Powder |
| title_full_unstemmed | Human Mitragynine and 7-Hydroxymitragynine Pharmacokinetics after Single and Multiple Daily Doses of Oral Encapsulated Dried Kratom Leaf Powder |
| title_short | Human Mitragynine and 7-Hydroxymitragynine Pharmacokinetics after Single and Multiple Daily Doses of Oral Encapsulated Dried Kratom Leaf Powder |
| title_sort | human mitragynine and 7 hydroxymitragynine pharmacokinetics after single and multiple daily doses of oral encapsulated dried kratom leaf powder |
| topic | mass spectrometry metabolism analytical toxicology mitragynine kratom 7-hydroxymitragynine |
| url | https://www.mdpi.com/1420-3049/29/5/984 |
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