The Liver and Mitragyna speciosa: What the Case Reports Show — and the Scale That Belongs with Them
Among the risk claims circulating about Mitragyna speciosa, one is comparatively well documented: substance-related liver injury. The cases exist, they are carefully described, and this article works through them. But it also answers the question that is almost always missing from the public discussion — the question of scale. How many documented cases stand against what level of use? How did the described courses end? And what instrument does medicine actually use to decide whether a causal connection holds?
What "substance-related liver injury" means in medicine
The technical term is DILI, short for "drug-induced liver injury" — damage to the liver that is traced back to an ingested substance; for botanical triggers the parallel term HILI ("herb-induced liver injury") is used alongside it. The liver converts foreign substances, and in doing so it can be damaged itself.
Medicine distinguishes two forms here. Predictable injury occurs above a certain amount in practically every organism — the textbook example is acetaminophen (paracetamol) in high overdose. Idiosyncratic injury affects individual people, follows no clean dose logic and sets in with a delay. Everything published on Mitragyna speciosa belongs in the second group — hence the small case numbers and the laborious attribution.
Three patterns — and how the blood values tell them apart
In liver injury certain blood values rise; two of them carry the classification. ALT (alanine aminotransferase) comes from inside the liver cell — a rise shows that liver cells are dying. Alkaline phosphatase (ALP) sits chiefly along the small bile ducts and indicates disturbed bile flow. From the ratio of the two values, each expressed relative to its upper limit of normal, the R value is formed.
| Pattern | What predominates in the tissue | R value |
|---|---|---|
| hepatocellular | loss of liver cells | 5 and above |
| mixed | both side by side | above 2 to below 5 |
| cholestatic | disturbed bile flow | 2 and below |
The distinction narrows down which triggers come into question, because many substances produce a pattern that is typical for them. In the literature on Mitragyna speciosa the pattern described in tissue is predominantly cholestatic; biochemically it turns out less uniform, with a mean R value of 3.4 across the collected cases.
The scale: how many cases, how many users
This question is rarely asked — although it can be answered.
On the side of prevalence, the US population survey NSDUH supplies a robust figure. An analysis of the 2021 to 2023 survey years covering 139,524 adults determined a weighted past-twelve-month prevalence of use of 0.68 percent (95 percent interval 0.60 to 0.77 percent), stable across the three years. Applied to the adult US population, that corresponds to an order of magnitude of more than one million people per year. NSDUH analysis 2021–2023 A survey published in 2025 with 11,545 participants even arrived at 9.1 percent — but through a non-probability sample, which is why the lower NSDUH figure is the more conservative and the more dependable one. Survey 2025
On the side of the cases, the most thorough review to date supplies the counter-figure. A systematic review by Schimmel and Dart, published in Drugs in 2020 (volume 80, issue 3, pages 263–283), gathered together everything that was available at that point: 26 case reports and conference contributions, plus seven from the US DILI network, 25 from databases of the US Food and Drug Administration and 27 from internet forums. Systematic review 2020
The same work explicitly names the methodological problem of the debate: the same few case reports are cited again and again without the broader context being supplied with them. A few dozen documented cases against use running into the millions are not an all-clear — idiosyncratic injury is by definition rare and still affects someone. But it is the scale without which any number looks arbitrary: without a denominator, "26 cases" says nothing at all.
What the NIH LiverTox entry brings together
LiverTox is a public collection maintained by the US National Institutes of Health on the state of the literature regarding liver injury. The entry on Mitragyna speciosa describes rare cases of acute, clinically apparent liver injury. Recorded there are an onset usually within one to eight weeks after regular intake begins, a predominantly cholestatic or mixed pattern, and courses in which serum bilirubin reaches very high values — values above 20 mg/dl are named. Rash, eosinophilia and autoantibodies are usually absent. LiverTox entry
The prospective cohort of the US DILI network
Case reports have a known weakness: what gets published is what stands out. A prospective cohort partly circumvents this, because it records cases continuously and according to fixed rules. The US Drug Induced Liver Injury Network (DILIN) maintains such a registry.
Its analysis names hard reference figures. Between 2004 and 2019, 2,193 suspected cases of substance-related liver injury were enrolled, 1,950 of which were assessed for causality. 369 cases — around 19 percent — were attributable to herbal and dietary supplements. Eleven cases were assigned to Mitragyna speciosa. That is about three percent of the herbal cases and around one percent of all cases. Eight of the eleven were reported between 2017 and 2019. The median age was 40 years, and the median latency — the interval between the start of intake and the onset of symptoms — was 14 days. Analysis of the DILI network
How the courses ended
This point is among the most clearly documented — and it is often left out of summaries.
In all eleven DILIN cases jaundice is documented, the majority were treated as inpatients, and all eleven courses ended in recovery. That agrees with the LiverTox entry: the cholestasis drags on for weeks, but afterwards it usually resolves on its own. The systematic review of 2020 names a mean latency of 20.6 days (range 2 to 49) and, as the most frequent complaints, upper abdominal symptoms, jaundice, itching and dark urine.
What this establishes is that the injuries described in the literature were predominantly temporary and resolved after discontinuation. That is a statement about the published courses, not about every conceivable case — liver injury with jaundice and inpatient treatment remains a serious finding, even when it heals.
What tissue samples showed
Blood values show that something is wrong with the liver. A tissue sample shows what. The first case presentation with a detailed description of liver tissue described acute cholestatic injury with bile stasis inside the liver cell and in the bile canaliculus, mild inflammation of the portal tracts and damage to the bile ducts (Riverso and colleagues, Gastroenterology Research 2018, volume 11, pages 79–82). Case report with histology
A later presentation additionally found cell loss around the central veins — a finding that had not been described before (Allison and colleagues, ACG Case Reports Journal 2022, article number e00715). The same work records that at the time only five case reports with histological images were available. Case report with histology
Histology sharpens the causality question, because it can rule out competing explanations: a gallstone, viral hepatitis or an autoimmune disease leave different traces in the tissue. If several independent specimens show the same picture, the argument reaches beyond the individual case.
The case that mimicked primary biliary cholangitis
Primary biliary cholangitis (PBC) is a chronic autoimmune disease in which the immune system attacks the small bile ducts. It is treated permanently — so a mix-up has consequences, in both directions.
Two published cases describe exactly that. In a report in the World Journal of Hepatology (2020, volume 12, issue 10, pages 863–869) the tissue showed centrilobular bile stasis, moderate inflammation of the portal tracts and lymphocytic damage to the bile ducts — histologically a PBC-like picture; the antibody test against mitochondria, a standard finding in PBC, came back negative. Case report A second report (Gastroenterology Research 2019, volume 12, pages 211–215) describes granulomatous inflammation with marked bile duct damage, again with a negative antimitochondrial antibody. Case report A picture that looks like a chronic autoimmune disease can therefore be a temporary substance-related injury — and the other way around.
RUCAM: how a connection is assessed rather than asserted
A single case proves nothing. Medicine therefore has a scoring system that discloses the strength of an attribution instead of asserting it: the Roussel Uclaf Causality Assessment Method, RUCAM for short, introduced in 1993.
RUCAM awards points for verifiable features: the temporal relationship between intake and onset of symptoms, the course after discontinuation, substances taken at the same time, the exclusion of other causes, prior description in the literature, and the behavior on renewed exposure. The total falls into one of five tiers.
| Total score | Assessment of the attribution |
|---|---|
| 0 and below | excluded |
| 1 to 2 | unlikely |
| 3 to 5 | possible |
| 6 to 8 | probable |
| above 8 | highly probable |
The case from the ACG Case Reports Journal named above reached 6 points and thus the tier "probable". RUCAM overview
The review of 2020 applied this procedure systematically to all traceable cases for the first time and arrives at a conclusion that names both sides at once: according to the totality of the findings, liver injury is probable — on the basis of human data of low quality. Which subgroup of users is more susceptible remains unclear. Both halves of that sentence belong together.
The documented case of recurrence
One constellation is rated particularly highly in the scoring system: renewed injury after renewed exposure, in technical language a positive rechallenge. A single temporal coincidence can be chance — that the same laboratory picture arises a second time after renewed intake, considerably less so.
Such a course has been published. After complete recovery, a liver finding with the same biochemical pattern occurred again around nine months later, this time with a shorter latency; the values subsequently normalized again (Osborne and colleagues, 2019). Case report A deliberate rechallenge is not carried out for ethical reasons — only what has happened anyway gets documented. That is why this kind of evidence remains rare, and that is why it carries weight.
Why attribution is so difficult: the example of the fatality statistics
How much co-ingested substances complicate an attribution is shown particularly clearly by an analysis outside the liver topic. The US Centers for Disease Control and Prevention examined 27,338 unintentional overdose deaths from 27 states (July 2016 to December 2017). In 152 decedents — 0.56 percent — Mitragyna speciosa was toxicologically detectable, and in almost all of them several substances were found at the same time: fentanyl in 65.1 percent, heroin in 32.9 percent, benzodiazepines in 22.4 percent, prescription opioids in 19.7 percent, cocaine in 18.4 percent. In seven cases the plant was the only substance detected — with the authors noting that further substances cannot be ruled out even there. CDC analysis 2019
The same problem applies to the liver cases: where several substances are involved, every individual attribution becomes weaker. That is precisely why RUCAM exists.
Where the data end
The limits of this literature are considerable, and they are named in the works themselves.
- Self-report of product identity. What was ingested rests almost throughout on the statement of the affected person.
- No analysis of the ingested sample. Whether an alkaloid of the plant, a contaminant or an added foreign substance triggered the injury remains open.
- Mixed exposure. Medicines, alcohol or dietary supplements were frequently taken at the same time.
- Reporting bias. Severe courses are more likely to be published than mild ones. An exact frequency cannot be read off from this.
What is established and what is being worked on
Established: there is a manageable number of carefully documented cases with a predominantly cholestatic tissue picture, a mean latency of around three weeks and — in the prospectively recorded cohort — uniformly recovering courses. In individual cases the attribution has been rated "probable" by RUCAM, and it is supported once by a documented recurrence after renewed exposure.
Open and being worked on: the exact frequency, because no case collection supplies the denominator along with it; the mechanism, that is, whether an alkaloid, a metabolite or an immunological reaction stands at the beginning; and individual susceptibility — which characteristics distinguish the few affected people from the majority. The review of 2020 explicitly names this last point as unresolved.
One classification at the end that requires no study: a yellowing of the skin or the eyes, conspicuously dark urine or persistent complaints in the right upper abdomen are reasons to seek medical advice — regardless of what preceded them.
Further reading
- The Risks and Safety of Kratom
- Heavy Metals & Pesticides in Kratom: Why Quality Testing Matters
- Pharmacology light: How the body processes plant compounds
- Kratom Research 2025/2026: Where Do We Stand?
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/