INMT: the enzyme said to make DMT, and why knockout studies put it in doubt

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Every explanation of how the body might make DMT names the same enzyme: INMT. It appears in textbook diagrams, review articles and, often, in confident online claims that “your body has the enzyme to make DMT”. The enzyme is real, and its chemistry is well described. What has changed in the past few years is the evidence that it is the enzyme that matters.

This explainer covers what INMT is, how it was found, where it sits in the body, and the knockout experiments that unsettled the story. For the bigger question it feeds into, see does the brain make DMT?; for the molecule itself, our pillar guide, what is DMT.

What is the INMT enzyme?

INMT stands for indolethylamine N-methyltransferase. It is a transmethylation enzyme: it takes a methyl group (one carbon with three hydrogens) from the body’s common methyl donor, S-adenosyl-L-methionine (SAM), and attaches it to a nitrogen on a small acceptor molecule. In the textbook DMT pathway it does this twice, turning tryptamine into N-methyltryptamine (NMT) and then NMT into DMT (Glynos et al., 2023). Tryptamine itself comes from the amino acid tryptophan, through a different enzyme, AADC (Barker, 2018). Evidence: established as the textbook pathway.

1. Tryptophan, an amino acid from the diet, loses its carboxyl group to become tryptamine. Enzyme: AADC.
2. Tryptamine gains one methyl group from SAM to become N-methyltryptamine (NMT). Enzyme credited: INMT.
3. NMT gains a second methyl group to become DMT. Enzyme credited: INMT.

INMT is not a DMT specialist. It has a broad substrate range, working on several of the body’s own amines and other small molecules (Glynos et al., 2023). A 2025 review notes that it is also called a thioether S-methyltransferase because it methylates sulfur-containing compounds and related selenium and tellurium compounds, and that it belongs to the same family as nicotinamide N-methyltransferase (NNMT) and phenylethanolamine N-methyltransferase (PNMT) (Abouheif et al., 2025). The 2019 brain study likewise lists histamine, sulfur compounds and selenium metabolism among its DMT-independent jobs (Dean et al., 2019). Evidence: established.

How was INMT discovered?

In 1961, Julius Axelrod reported in Science an enzyme that N-methylates serotonin and tryptamine into bufotenine and DMT, which he called psychotomimetic metabolites. His abstract says the enzyme is highly localised in rabbit lung and also methylates other amines, including tyramine, phenylethylamine and dopamine (Axelrod, 1961). A 2023 paper describes the experiment: rabbit lung extracts incubated with tryptamine and a radio-labelled methyl donor produced labelled NMT and DMT, one of the first demonstrations that such compounds could be formed enzymatically from naturally occurring ones (Glynos et al., 2023). Evidence: established.

A note on the record: a 2018 review places Axelrod’s 1961 discovery in rat brain (Barker, 2018), but Axelrod’s own abstract describes the enzyme in rabbit lung, and we follow the original. Axelrod’s search was part of the “transmethylation hypothesis”, the idea that conditions such as schizophrenia might involve the body making its own hallucinogens. That premise remains unproven, but it led to INMT (Barker, 2022). Evidence: established as history.

The brain came into the story in 1972. Juan Saavedra and Axelrod reported that tryptamine occurs normally in rat brain, that labelled tryptamine placed in the fluid space of the rat brain was converted to NMT and DMT, and that an enzyme able to do this was present in rat and human brain (Saavedra and Axelrod, 1972). Evidence: established as a published finding; the enzyme activity was measured in tissue extracts, not attributed to one purified protein.

INMT research at a glance

Where in the body is INMT found?

Mostly outside the brain, as far as older methods could tell. Rabbit lung has historically shown the highest INMT expression and methylating activity (Glynos et al., 2023). When the human gene was cloned in 1999, its messenger RNA showed up in most of 35 tissues tested by Northern blot (Thompson et al., 1999); a 2025 review notes high levels in human lung and adrenal gland and significant levels in spinal cord (Abouheif et al., 2025). Relatively high INMT activity has also been reported in the placenta of several species, including humans (Barker, 2018). Evidence: established.

The brain was the gap. Northern blots found INMT messenger RNA at very low levels in rabbit brain and not at all in human brain, which led to speculation that DMT is made in the body and carried to the brain (Dean et al., 2019). Then, in 2019, a more sensitive method found INMT messages in rat and human cortex, pineal gland and choroid plexus. In rat brain, INMT messages sat in the same cells as AADC messages; in rat lung, heart, kidney and adrenal gland they rarely overlapped, which led the authors to suggest that INMT in the body may mostly do other jobs (Dean et al., 2019). Evidence: preliminary. One lab’s staining results; messenger RNA is not enzyme activity.

Does INMT work the same way in every species?

No, and this turned out to matter a great deal. Human INMT made in cells in the lab methylates tryptamine, but with a much weaker apparent affinity than rabbit INMT, roughly ten times weaker by the reported constants (Glynos et al., 2023). Human INMT is 88% identical in sequence to rabbit INMT (Thompson et al., 1999). Rat INMT is the outlier: it shares only about 57% of its sequence with the rabbit or human enzyme, and in 2023 tests, rat INMT showed no ability to methylate tryptamine or NMT at all, while rabbit and human INMT both produced NMT and DMT (Glynos et al., 2023). Evidence: preliminary. Test-tube results with engineered proteins.

That creates an odd situation. The rat is the main animal in which DMT has been measured in the living brain, yet rat INMT, by these tests, cannot make it. So in rats at least, something else must be making the DMT that has been detected (Glynos et al., 2023). Evidence: preliminary.

What did the 2023 knockout rats show?

A knockout animal has a gene deliberately disabled, so researchers can see what changes without it. In 2023, the University of Michigan group that had measured DMT in rat brains used CRISPR gene editing to delete two letters of the rat INMT gene, which scrambled it and left the rats with no INMT protein. The rats showed no obvious behavioural or physiological abnormalities and could reproduce (Glynos et al., 2023). Then they tested tissue from six knockout and six normal littermates:

• Brain and lung tissue from knockout rats methylated tryptamine just as much as tissue from normal rats.
• In both groups, the products were neither NMT nor DMT, by two independent methods, thin-layer chromatography and mass spectrometry. Rabbit lung, used as a positive control, did make NMT and DMT.
• Rat INMT on its own did not methylate tryptamine; rabbit and human INMT did.

The authors concluded that INMT is not necessary for tryptamine methylation in rat brain and lung, and that an alternative enzymatic pathway for DMT likely exists in rats (Glynos et al., 2023). They were also open about a limit: the tests used tissue extracts under particular lab conditions, and different conditions might reveal DMT production that these assays missed. Note what the study did not do: it did not measure DMT in the living knockout rats. Evidence: preliminary.

What did the 2025 knockout mice show?

In 2025, a separate team developed mass-spectrometry methods sensitive enough to measure endogenous psychedelics in mice, and created mice lacking INMT. The knockout mice had no major abnormalities in reproduction or growth, but their behaviour differed across several distinct domains. Crucially, deleting INMT “did not result in an obvious decrease in endogenous psychedelic levels”, which the authors read as a sign that psychedelics might be made by alternative pathways in rodents (Hatzipantelis et al., 2025). Evidence: preliminary. We read the abstract only, so we do not list which compounds were measured.

If not INMT, what else might make DMT?

Nobody knows yet. The candidates are mostly educated guesses (Glynos et al., 2023):

• An unidentified N-methyltransferase. The 2023 authors think it likely that a distinct mammalian enzyme can methylate tryptamine to NMT and DMT under the right conditions.
• Enzymes already glimpsed decades ago. Older work on rabbit lung found two INMT-like tryptamine-methylating proteins with different properties, and work on rabbit liver separated two methyltransferases, “A” and “B”, with tryptamine-methylating activity.
• Different products altogether. The unknown products made by rat tissue in 2023 might be β-carbolines, a class of compounds tryptamine can form, according to the authors’ hypothesis. That would explain tryptamine use without explaining DMT.

INMT’s family members are natural suspects, since the human INMT gene is structurally similar to the genes for NNMT and PNMT (Thompson et al., 1999), but no source we read has shown that either makes DMT. One more piece of chemistry may matter for how any pathway is regulated: DMT itself inhibited rabbit lung INMT in lab tests, pointing to a regulatory site on the enzyme (Chu et al., 2014). Evidence: unresolved.

Is INMT linked to health or disease?

Researchers have looked. A 2025 review summarises reports linking changes in INMT levels to several cancers, including lower expression in some lung and liver cancers and higher expression in one form of prostate cancer, along with older ideas about psychiatric conditions, and concludes that INMT’s exact role in cancer and other disorders remains unclear (Abouheif et al., 2025). These are associations, mostly from tissue and database studies, not evidence that INMT or DMT causes or treats anything. Evidence: preliminary.

What is still unknown about INMT?

• Which enzyme makes DMT in rats and mice, given that INMT appears unnecessary there (unresolved).
• Whether human INMT makes meaningful DMT in living human tissue, as it does in the test tube (unresolved).
• What INMT’s main everyday job is: DMT, sulfur and selenium compounds, or something else (unresolved).
• Whether the INMT messages found in human brain tissue reflect active enzyme (unresolved).
• How results in rats, whose INMT is unusual, translate to humans (unresolved).

The fair summary: INMT is a real enzyme that can make DMT in the test tube when it comes from rabbits or humans, but the best recent experiments in living rodents suggest it is not what makes their DMT. The enzyme behind endogenous DMT is, for now, an open question. For how this fits the rat brain measurements, read the DMT rat brain study explained; for the pineal angle, is DMT in the pineal gland?.

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