Mitragynine is the most abundant alkaloid in the leaf of Mitragyna speciosa, and on the published record it is a low efficacy partial agonist at the human mu-opioid receptor, a competitive antagonist at kappa and delta receptors, and a weak ligand at adrenergic alpha-2 receptors. It is also a substrate for CYP3A4, which converts a small fraction of an oral dose into 7-hydroxymitragynine (7-OH), a far more potent mu agonist.123
That metabolic relationship is why the two alkaloids are now treated differently in law. On 6 July 2026 the Drug Enforcement Administration published a notice of intent to temporarily place 7-OH above a specified threshold into Schedule I, at 91 FR 40917. The threshold is more than 0.050 percent of 7-OH on a dry weight basis in botanical kratom, or more than 0.050 percent by weight or more than 1.00 milligram of 7-OH in a concentrated or synthesized article.7 Mitragynine itself is not named in that action, and it is not a federally controlled substance.
What follows is what the peer-reviewed literature establishes about mitragynine’s receptor pharmacology, its metabolism, and its behavior in human plasma, followed by where the federal line sits as of mid-September 2026 and what it does not yet settle.
What mitragynine is and how much of it is in the leaf
Mitragynine is a corynanthe-type indole alkaloid. It is the major alkaloid in dried kratom leaf, while 7-OH is a minor one. The DEA notice states that in natural botanical form 7-OH makes up less than two percent of total alkaloid content or occurs only in trace amounts, and that it can be made from mitragynine in a single chemical step.7 The FDA describes 7-OH as having substantially greater mu-opioid receptor potency than mitragynine and than classical opioids including morphine.8
Those two facts together explain most of the confusion in this area. The alkaloid that dominates the plant is not the alkaloid that dominates the opioid signal, a point covered in more detail in our comparison of mitragynine and 7-hydroxymitragynine. Concentrated 7-OH products, by contrast, invert the natural ratio deliberately.
How mitragynine behaves at opioid receptors
The first receptor-level functional characterization of the Mitragyna alkaloids at cloned human receptors was published by Kruegel and colleagues in 2016. They reported that mitragynine and 7-OH are partial agonists of the human mu-opioid receptor and competitive antagonists at the kappa and delta receptors. Both compounds activated G protein signaling without recruiting beta-arrestin after receptor activation, which the authors described as G-protein-biased agonism. Molecular docking combined with the observed structure-activity relationships suggested that these alkaloids adopt a binding pose at the mu receptor distinct from that of classical opioids. The unnatural enantiomer, (+)-mitragynine, was much weaker.1
Two qualifications matter when reading that result. First, absence of measurable beta-arrestin recruitment is hard to separate from simple low efficacy: a ligand that only weakly activates the receptor may fail to produce a detectable arrestin signal for that reason alone, and later work routinely describes mitragynine as a low efficacy mu agonist rather than a strongly biased one.4 Second, the practical significance of bias at the mu receptor for side effect profiles remains contested across the wider opioid literature, and no clinical trial has tested that hypothesis with kratom alkaloids in people.
More recent screens of indole and oxindole kratom alkaloids at human mu, kappa and delta receptors have extended rather than overturned this picture, and a fuller account of that receptor work is in our overview of what researchers have found at the opioid receptor.
Receptors beyond the opioid family
Mitragynine’s effects are not purely opioid, and the adrenergic component has been examined directly. Obeng and colleagues reported in 2024 that mitragynine displaced a radiolabeled antagonist from human alpha-2A adrenergic receptors with relatively low affinity, a Ki of 1260 nanomolar, compared with 263 nanomolar for epinephrine and 7.42 nanomolar for lofexidine. Mitragynine did not significantly stimulate GTPgammaS binding at alpha-2A receptors in vitro. In rats trained to discriminate mitragynine, however, both alpha-2 antagonists and mu antagonists shifted the dose-effect curve rightward, while alpha-2 agonists shifted it leftward. The authors concluded that mitragynine acts as a low efficacy alpha-2 receptor agonist in vivo.4
Broader reviews of kratom alkaloid pharmacology also describe interactions with serotonergic and dopaminergic systems, and note that stereochemistry at C-20 influences serotonin receptor affinity across the alkaloid series.3 The FDA’s own summary lists effects on serotonin and dopamine systems alongside mu-opioid binding.8 None of this amounts to a mapped mechanism for any particular reported effect in humans, and the in vitro concentrations used in these assays are not always relatable to plasma levels reached after oral use.
CYP3A4 metabolism and the route to 7-OH
Kamble and colleagues profiled mitragynine metabolism in human liver microsomes and S9 fractions in 2019 and identified thirteen metabolites, with four oxidative metabolites and a 9-O-demethylated metabolite as the major products. Using selective chemical inhibitors and recombinant enzymes, they found that metabolism proceeds predominantly through CYP3A4, with minor contributions from CYP2D6 and CYP2C9. CYP3A4 catalyzed formation of five oxidative metabolites, including 7-OH.2
The functional consequence was established the same year. Kruegel and colleagues showed in ACS Central Science that hepatic conversion of mitragynine to 7-OH is mediated by cytochrome P450 3A isoforms in both mouse and human liver preparations, and that human microsomes performed the conversion more efficiently than mouse microsomes. In mice given equianalgesic doses of either compound, mean brain concentrations of 7-OH did not differ significantly, even though mitragynine itself reached brain levels roughly 170-fold higher. The authors concluded that 7-OH formed as a metabolite is sufficient to explain the opioid-mediated analgesic activity of mitragynine.5
Two further points follow from CYP3A4 involvement. Mitragynine is not only a substrate but also an inhibitor: reviews describe it as a competitive inhibitor of CYP2D6 with a Ki of 1.17 micromolar and a mechanism-based inhibitor of CYP3A4, which is the basis for concern about kratom and drug interactions.3 And because 7-OH exposure depends on enzyme activity that varies between people and can be altered by co-administered drugs, the same oral dose of leaf will not produce the same metabolite exposure in everyone. Transport at the blood-brain barrier adds another layer, discussed in our 7-OH and the blood-brain barrier overview.
What human pharmacokinetics show
Three human datasets carry most of the weight. Trakulsrichai and colleagues published the first human pharmacokinetic study in 2015, in ten chronic Thai kratom users given standardized tea at steady state. In the nine subjects analyzed, time to maximum plasma concentration was 0.83 plus or minus 0.35 hours, terminal half-life 23.24 plus or minus 16.07 hours, and apparent volume of distribution 38.04 plus or minus 24.32 liters per kilogram. Only 0.14 percent of the dose was excreted unchanged in urine, and the data fit an oral two-compartment model with approximately linear kinetics over the doses tested.6
A randomized, double-blind, placebo-controlled dose-escalation study published in 2024 dosed healthy adults with encapsulated dried leaf powder from 500 to 4000 milligrams, containing 6.65 to 53.2 milligrams of mitragynine. Median mitragynine time to peak was 1.0 to 1.3 hours after single doses, terminal half-life reached 43.4 hours at the highest single dose and 67.9 hours with repeated daily dosing, and steady state was reached within seven to nine days. The plasma ratio of 7-OH to mitragynine was 0.20 to 0.31 after single doses and fell to 0.15 to 0.21 with repeated dosing.9
A 2026 study extended this to concentrated extract, at 9.9, 29.6 and 59.2 milligrams of mitragynine. Mean mitragynine peak concentrations rose dose-dependently to 196 nanograms per milliliter after the highest single dose, with 7-OH peaks of 6.8 to 30.5 nanograms per milliliter at a median peak time of 1.3 to 1.7 hours. Exposure increased slightly more than strict dose proportionality would predict, which the authors noted may indicate enzyme saturation, and concentrated extracts produced greater overall mitragynine exposure than leaf powder or tea at comparable doses.10
| Parameter | Chronic users, kratom tea (2015) | Healthy adults, dried leaf powder (2024) | Healthy adults, concentrated extract (2026) |
|---|---|---|---|
| Participants | 10 enrolled, 9 analyzed | 12 per dose group, 13 at top dose | Single and 15 daily doses, escalating |
| Mitragynine dose range | Standardized tea at steady state | 6.65 to 53.2 mg | 9.9 to 59.2 mg |
| Median or mean time to peak | 0.83 hours | 1.0 to 1.3 hours | 1.3 hours |
| Terminal half-life | 23.24 hours | Up to 43.4 hours single dose, 67.9 hours repeated | Best characterized at higher doses |
| 7-OH relative to mitragynine | Not reported | Ratio 0.20 to 0.31 single, 0.15 to 0.21 repeated | Higher ratios after repeated and lower doses |
The practical reading of these numbers is that mitragynine is absorbed quickly, clears slowly, accumulates modestly with daily use, and yields circulating 7-OH at a fraction of parent concentrations. Half-life estimates differ widely between studies because of assay sensitivity, dose, and whether subjects were chronic users, so a single figure for how long mitragynine stays in the body is not well supported.
Where regulation stands as of September 2026
Kratom is not approved by the FDA for any use, and the agency states that kratom is not lawfully marketed in the United States as a drug product, a dietary supplement or a food additive in conventional food.8 Mitragynine is not a scheduled controlled substance at the federal level, and state law varies, as set out in our state by state guide.
The 2026 federal activity concerns 7-OH and related compounds, not mitragynine. The DEA notice records that HHS provided its scientific and medical evaluation recommending control of 7-OH above a threshold in a letter dated 28 July 2025, and that the Assistant Secretary for Health had no objection to temporary placement, in a letter dated 6 March 2026.7 On 6 July 2026 the DEA published its notice of intent for 7-OH above the threshold described above, stating that such an order would take effect on publication and run for two years with a possible one-year extension, and that the order would be published on or after 5 August 2026. The notice reasons that isolated or semi-synthetic formulations deliver unattenuated effects of the target alkaloid, whereas the raw plant matrix may produce a modified or attenuated effect because of competing co-occurring alkaloids.7
As of 17 September 2026, no temporary scheduling order for 7-OH itself appears in the Federal Register; the 6 July document remains listed as a proposed action. What has been finalized is a separate temporary order, published 26 August 2026 at 91 FR 54948, placing three 7-OH-related substances, mitragynine pseudoindoxyl, MGM-15 and MGM-16, into Schedule I on an imminent hazard finding.11 In parallel, the HHS Office of the Assistant Secretary for Health extended the comment period on its request for information about the proposed 7-OH threshold to 10 September 2026.12 Anyone tracking this should check the Federal Register directly rather than rely on secondary summaries, since the threshold order could be published at any time.
| Item | Mitragynine | 7-OH above the specified threshold |
|---|---|---|
| Federal control status | Not scheduled | Notice of intent published; temporary Schedule I order pending |
| Named in 91 FR 40917 | Referenced as the parent alkaloid and precursor | Yes, as the substance to be scheduled |
| Threshold that triggers control | None | More than 0.050 percent dry weight, or more than 1.00 mg per article |
| FDA marketing position | Not lawfully marketed as a drug, supplement or food additive | Same, plus warning letters and seizures of 7-OH products |
What this body of evidence cannot settle
The receptor work is in cells and rodents. The metabolism work is in liver preparations and mice. The human work is pharmacokinetic, in small samples, and says nothing about efficacy or long-term safety. No adequately powered randomized trial has tested mitragynine for any clinical indication, and no dosing standard exists. Product composition also varies widely between vendors and formats, so the alkaloid content of what someone actually consumes may not resemble what any study administered. Those limits are worth holding in mind when a mechanistic finding gets described as if it were a clinical result.
Frequently asked questions
Is mitragynine an opioid?
It binds and partially activates the mu-opioid receptor, so it acts on the opioid system, but it is chemically an indole alkaloid rather than a morphinan and it antagonizes kappa and delta receptors.1 Regulators treat it as an opioid-acting substance without it being a scheduled opioid drug.
Does the body turn mitragynine into 7-OH?
Yes, through CYP3A4 oxidation. Human plasma studies found 7-OH present at roughly 0.15 to 0.31 of mitragynine concentrations depending on dose and repetition.29 How much forms depends on individual enzyme activity and co-administered drugs.
Is mitragynine illegal in the United States?
It is not federally scheduled as of September 2026, and the pending DEA action addresses 7-OH above a threshold rather than mitragynine.7 Several states and municipalities restrict kratom independently, so local rules decide the answer.
What does G-protein bias mean here?
It describes a ligand that activates G protein signaling with little or no beta-arrestin recruitment. Kruegel and colleagues reported that pattern for mitragynine and 7-OH in 2016.1 Low agonist efficacy can produce a similar assay result, and the clinical relevance of bias remains unproven.
Why did the DEA pick 0.050 percent as the line?
The threshold is intended to separate naturally occurring trace 7-OH in leaf material from concentrated, isolated or semi-synthetic articles. The notice explains that 7-OH normally accounts for less than two percent of total alkaloid content in the plant and can be synthesized from mitragynine in one step.7
Sources
- Kruegel AC, Gassaway MM, Kapoor A, et al. Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. Journal of the American Chemical Society, 2016. https://pubmed.ncbi.nlm.nih.gov/27192616/
- Kamble SH, Sharma A, King TI, Leon F, McCurdy CR, Avery BA. Metabolite profiling and identification of enzymes responsible for the metabolism of mitragynine, the major alkaloid of Mitragyna speciosa (kratom). Xenobiotica, 2019. https://pubmed.ncbi.nlm.nih.gov/30547698/
- Hanapi NA, Chear NJ, Azizi J, Yusof SR. Kratom Alkaloids: Interactions With Enzymes, Receptors, and Cellular Barriers. Frontiers in Pharmacology, 2021. https://pmc.ncbi.nlm.nih.gov/articles/PMC8637859/
- Obeng S, Crowley ML, Mottinelli M, et al. The Mitragyna speciosa (kratom) alkaloid mitragynine: Analysis of adrenergic alpha-2 receptor activity in vitro and in vivo. European Journal of Pharmacology, 2024. https://pubmed.ncbi.nlm.nih.gov/39068978/
- Kruegel AC, Uprety R, Grinnell SG, et al. 7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects. ACS Central Science, 2019. https://pubs.acs.org/doi/10.1021/acscentsci.9b00141
- Trakulsrichai S, Sathirakul K, Auparakkitanon S, et al. Pharmacokinetics of mitragynine in man. Drug Design, Development and Therapy, 2015. https://pubmed.ncbi.nlm.nih.gov/25995615/
- Drug Enforcement Administration. Schedules of Controlled Substance: Temporary Placement of 7-Hydroxymitragynine Above a Specified Threshold in Schedule I. 91 FR 40917, 6 July 2026. https://www.federalregister.gov/documents/2026/07/06/2026-13580/
- US Food and Drug Administration. FDA and Kratom. Updated 2025. https://www.fda.gov/news-events/public-health-focus/fda-and-kratom
- Atallah E, Huestis MA, Brett MA, Bothmer J. Human Mitragynine and 7-Hydroxymitragynine Pharmacokinetics after Single and Multiple Daily Doses of Oral Encapsulated Dried Kratom Leaf Powder. Molecules, 2024. https://www.mdpi.com/1420-3049/29/5/984
- Huestis MA, Brett MA, Bothmer J, Henningfield JE, Swift S. Mitragynine and 7-hydroxy-mitragynine plasma pharmacokinetics in humans after single and 15 multiple oral kratom extract doses. Journal of Analytical Toxicology, 2026. https://pubmed.ncbi.nlm.nih.gov/42266029/
- Drug Enforcement Administration. Schedules of Controlled Substances: Temporary Placement of Mitragynine Pseudoindoxyl, MGM-15, and MGM-16 in Schedule I. 91 FR 54948, 26 August 2026. https://www.federalregister.gov/documents/2026/08/26/2026-17429/
- Department of Health and Human Services, Office of the Assistant Secretary for Health. Hydroxymitragynine Above a Specified Threshold in Schedule I; Extension of Comment Period. 91 FR 55104, 26 August 2026. https://www.federalregister.gov/documents/2026/08/26/2026-17409/
Editorial note: This article is for general information only and is not medical or legal advice. Mitragynine has not been evaluated by the FDA to diagnose, treat, cure or prevent any disease. Laws vary by location and change often, so verify the rules that apply where you are. Always talk to a licensed healthcare provider before use, especially if you are under 21, pregnant or nursing, taking medication, or managing a health condition.