Pharmakokinetik: Was mit Mitragynin im Körper passiert - Kratoein

Pharmacokinetics: What Happens to Mitragynine in the Body

Very different figures circulate about mitragynine, the main constituent of the leaves of Mitragyna speciosa, and the half-life is the worst offender. This article answers what has actually been measured about the uptake, conversion and excretion of the substance, in which experimental systems that happened, and why the published values differ by more than a factor of ten. At the center of it stands a finding that for a long time appeared only as a subordinate clause and is by now regarded as the most interesting one in the whole field: metabolic saturation.

What pharmacokinetics describes and what it does not

Pharmacology separates two questions that are easily confused in everyday discussion. Pharmacodynamics asks: what does a substance do to the body, which target molecules does it bind to, and what happens inside the cell afterwards? Pharmacokinetics asks the reverse: what does the body do with the substance?

This second question breaks down into four steps, abbreviated in the technical vocabulary as ADME: absorption, distribution, metabolism and excretion. This article deals exclusively with those; it describes routes and time spans, not effects.

The evidence base has improved considerably in a short time. Until 2020 the field relied almost entirely on animal experiments and a single small human study. Since then several controlled investigations in healthy volunteers have been added, among them a randomized, double-blind, placebo-controlled dose escalation study. Much of what follows here was simply not measurable five years ago.

Enteral uptake and the first liver passage

A substance taken up through the gastrointestinal tract takes a detour. Blood from the intestine does not flow directly into the circulation but first through the portal vein into the liver. That is where the enzymes sit which convert compounds foreign to the body. Only what survives this passage reaches the rest of the body. This process is called the first-pass effect.

The fraction that makes it into the circulation unchanged is called oral bioavailability. For mitragynine this fraction turns out very low in animal experiments: in rats it was measured in the low single-digit percentage range, so the overwhelming majority never arrives as mitragynine at all but is converted beforehand or not absorbed in the first place. A systematic review from 2019 in the Asian Journal of Psychiatry collected these and further animal data (Ya et al. 2019).

A second point comes on top of that: mitragynine is not stable in an acidic environment. In stability experiments it decomposes over time at low pH, while it remains stable at neutral and slightly basic pH. The stomach is therefore already part of the calculation.

The conversion: which enzymes are involved

The best-investigated conversion step is the formation of 7-hydroxymitragynine. A paper from 2019 in ACS Central Science showed in liver preparations from mouse and human that mitragynine is converted into this substance and that enzymes of the cytochrome P450 3A family are chiefly responsible for it, CYP3A4 in particular (Kruegel et al. 2019). In the experiment, almost nothing of the mitragynine was left after one hour in the presence of CYP3A4; with the other enzymes tested, hardly anything happened. A CYP3A4 blocker suppressed both the breakdown and the formation of the metabolite.

In 2024 the same pathway was documented directly in humans for the first time. A paper in ACS Pharmacology & Translational Science gave healthy volunteers a freshly prepared infusion containing 23.6 mg of mitragynine, once on its own and once after four days of pretreatment with the CYP3A inhibitor itraconazole. Under itraconazole the peak concentration of 7-hydroxymitragynine fell by 56 percent and the total exposure by 43 percent, while the peak concentration of mitragynine itself rose by a factor of one and a half (Mongar et al. 2024). The CYP3A4 route is therefore no longer merely an extrapolation from the liver preparation but has been shown in humans.

Besides the CYP route, conjugation reactions via UDP-glucuronosyltransferases have also been investigated in liver preparations, that is, enzymes which make substances water-soluble for excretion. Little has been published about excretion itself: in the first human study the fraction recovered unchanged in urine was stated as well below one percent, so the substance practically does not leave the body in the form in which it entered.

Metabolic saturation: why the conversion has an upper limit

At this point pharmacokinetics becomes the actual subject rather than a marginal note. For 7-hydroxymitragynine is considerably more potent at the µ-opioid receptor than the parent compound, and how much of it is formed is decided not by a receptor but by an enzyme.

Enzymes do not work at arbitrary speed. Each has a maximum velocity; once that is reached, more starting material no longer changes the turnover. In the technical vocabulary this state is called saturation.

In 2022 a group around Hill examined in the British Journal of Pharmacology what this means in the animal model. Breathing was measured in awake, freely moving mice by whole-body plethysmography after administration through the gastrointestinal tract. The central finding: the respiratory depressant effect of mitragynine showed a ceiling effect. Above 10 mg per kilogram of body weight, higher doses no longer produced any stronger depression. 7-hydroxymitragynine itself behaved differently; there the effect continued to rise with the dose. And after CYP3A was blocked, the respiratory depressant effect of mitragynine came out smaller, while that of 7-hydroxymitragynine remained unchanged (Hill et al., British Journal of Pharmacology 2022).

The authors trace the ceiling back to the limited speed of the conversion: because the step to the more potent metabolite is metabolically limited, more parent compound stops yielding more metabolite beyond a certain point. The conclusion states that this "metabolic saturation" at high doses may underlie the more favorable safety profile the authors discuss for mitragynine as a possible drug candidate.

The finding comes from a mouse model using male animals; whether and in what dose range something corresponding appears in humans has not been investigated. It is remarkable nonetheless, because it names a mechanism that has nothing to do with the disputed receptor hypotheses: it is about the speed of an enzyme, not about the signaling bias of a receptor. Precisely for that reason the prodrug property of mitragynine is not only a methodological complication but at the same time a structural peculiarity of the substance.

How much 7-hydroxymitragynine is formed in the process

The measured proportions are small but not negligible, and on repeated administration they tend to fall rather than rise.

Experimental system	Share of 7-OH relative to mitragynine
Rat, repeated administration (2024)	around 8 percent (male) and 14 percent (female)
Human, single dose of infusion (2024)	around 9 percent (peak value), around 20 percent (total exposure)
Human, single dose of leaf powder (2024)	around 20 to 31 percent (concentration ratio)
Human, 15 daily doses of leaf powder (2024)	around 15 to 21 percent

The rat figures come from a repeated-dose study in ACS Pharmacology & Translational Science (2024), the infusion values from the itraconazole study mentioned above, and the leaf powder values from a randomized, double-blind, placebo-controlled dose escalation study in Molecules using 500 to 4000 mg of dried leaf powder, corresponding to 6.65 to 53.2 mg of mitragynine (Huestis et al. 2024).

The rat study is striking in a second respect: the rate of elimination differed between male and female animals by roughly a factor of three. Sex differences in this class of compounds are therefore measurable, an observation worth keeping in mind when reading older studies with exclusively male experimental groups.

The half-life, and why the numbers diverge

The half-life is the time in which the concentration in the blood falls to one half. The published figures for mitragynine cover a range that is unusually wide for a single substance.

Rat: a few hours after administration into the vein, somewhat longer after administration through the gastrointestinal tract.
Human, first study (2015): about one day on average, with a scatter almost as large as the mean value itself, measured in ten regular users after a run-in phase (Trakulsrichai et al. 2015).
Human, controlled study (2022): after a single low dose, the terminal half-lives of the alkaloids with 3S configuration, mitragynine among them, had medians of roughly 24 to 45 hours (Tanna et al. 2022).
Human, dose escalation study (2024): the highest mean value was 43.4 hours after a single administration and 67.9 hours after repeated administration; steady state was reached after eight to nine days.

These numbers are not suitable for extrapolation. They come from different species, different study protocols and different analytical methods; the scatter within a single study is in places larger than the difference between two studies.

The reason for the divergence is nevertheless well understood, and that is itself a result: the half-life rises with the length of the observation window. Whoever measures long enough and sensitively enough finds a slowly declining remainder, the so-called terminal phase. Older studies with a shorter observation period were unable to capture it at all and therefore reported systematically shorter values. The higher numbers in the more recent work are thus not a correction of the older ones but a consequence of better measurement technique.

Linear or non-linear?

Linear kinetics means that twice the intake yields twice the concentration in the blood. Non-linear kinetics means that this simple relationship does not hold, for instance because an enzyme is working at capacity at higher concentrations. The blood level then rises disproportionately.

For mitragynine there are by now robust data on this from a defined range. The dose escalation study of 2024 found a dose-proportional rise in the peak concentration across the investigated range of 500 to 4000 mg of leaf powder; the total exposure rose somewhat more than proportionally. The first human study of 2015 had likewise reported linearity.

Proportionality is therefore documented for a defined, investigated section. What happens outside it has not been measured, and the animal data, with their strongly differing elimination rates depending on the route of administration, suggest that the relationship does not extend arbitrarily far.

Why the studies compare poorly with one another

Four reasons turn up repeatedly in the papers themselves as limitations, and three of them are now being worked on.

Non-standardized starting material. The alkaloid content of plant material varies with origin, time of harvest and processing. The more recent controlled studies address this by determining and reporting the alkaloid content of the material used analytically in advance.
Self-report on product identity. In observational studies, the statement of what the participants took rests on their own account. That is a self-report, not a measurement; in controlled studies this problem does not arise.
Combined use. If further substances are used, blood levels and observed events cannot be assigned cleanly.
Analytics. Limits of detection, sample preparation and duration of observation differ between laboratories. What is not measurable appears as zero, and that shortens the calculated half-life.

Interactions: what has been measured in humans

Because CYP3A4 is involved in the breakdown, the question of drug interactions suggests itself. Here too there have been human data rather than mere extrapolations since 2023. A paper in Clinical Pharmacology & Therapeutics gave twelve healthy adults a low dose of an analytically characterized infusion together with two probe substances: midazolam as a probe for CYP3A and dextromethorphan as a probe for CYP2D6.

The result was two-sided. For dextromethorphan no effect appeared; the parameters were practically unchanged at 0.99 and 0.96 of the baseline value. For midazolam, by contrast, total exposure and peak concentration rose by factors of 1.39 and 1.50 respectively. Because the half-life of midazolam did not change, the authors attribute the effect chiefly to an inhibition of CYP3A in the intestinal wall, and they record that interactions are to be expected with the concurrent intake of drugs that are heavily metabolized via CYP3A (Tanna et al. 2023). A general suspicion has thereby turned into a quantified effect at one enzyme and no effect at the other.

What this means for reading studies

Four questions make any statement about mitragynine testable.

In which system was the measurement made? Cell line, liver preparation, rodent or human: the four levels do not translate into one another.

Which substance was actually being observed? Because part of the mitragynine becomes a more potent metabolite, it is not immediately clear in whole-animal experiments which of the two caused the measured deflection.

For how long was the observation made? Short observation windows produce systematically shorter half-lives.

How large was the scatter? With mitragynine the values vary so strongly between individual subjects in several papers that a mean value on its own says little.

The summary runs as follows: the route of the substance through the body is described in its broad outlines, with low uptake through the digestive tract, extensive conversion in the liver via CYP3A, a small share of a more potent metabolite whose formation has an upper limit, and a slowly declining remainder that explains longer half-lives than were previously assumed. What is missing are robust individual figures across different dose ranges. That this gap can be named today is itself a step forward: five years ago it could not even have been described precisely.

Legal notice

This article is for informational purposes only and does not constitute legal advice. Its content is not intended to encourage consumption. Laws may change; the applicable regulations and information from official bodies are authoritative. Image source: https://www.kratoein.com/

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