The Unheld Trip

1. What is actually being proposed

The starting intuition is simple: autism may be caused in part by too much or too little endogenous DMT being produced in the brain at different developmental times. This is not a fringe idea. There is a published hypothesis along these lines.

A 2019 perspective paper in Frontiers in Endocrinology by Esen-Danaci and colleagues proposed that abnormal metabolism of endogenous DMT may contribute to autism spectrum disorder. Their version focuses on "too much" DMT activity, not "too little" — but the timing component is central to the most interesting reading, and is where the hypothesis becomes genuinely novel.

Their logic chain:

• DMT promotes neuritogenesis, spinogenesis, and synaptogenesis via 5-HT2A receptors, TrkB, and mTOR signaling.
• Autism is associated with cortical overgrowth and dendritic spine dysgenesis — too much of exactly the growth DMT drives.
• People with ASD show reduced MAO-A activity (the enzyme that breaks down DMT), and some evidence of an endogenous MAO-A inhibitor in urine.
• About 65% of ASD patients have less than half the normal melatonin levels, suggesting pineal dysfunction.
• Elevated bufotenine (a DMT analog) has been measured in the urine of autistic patients.

Where the hypothesis gets interesting: DMT levels in rat brains are not constant — there is a sharp developmental spike around postnatal days 12–17, then return to baseline. Nobody has followed up on what that developmental window does. If DMT dysregulation happens during that window, it could explain neurodevelopmental divergence.

2. Important caveats

• No one has directly measured DMT in autistic humans yet.
• The hypothesis is built from adjacent evidence (melatonin, bufotenine, MAO-A activity, pineal findings).
• Endogenous DMT levels are roughly 1,000× below a psychoactive dose — it is not causing hallucinations. We are talking about a tonic, sub-perceptual signal.
• Newer work (Dean et al., 2019) shows DMT is produced throughout the cortex, not just the pineal gland. This changes the target picture substantially.
• Autism is highly polygenic and heterogeneous. Even if DMT dysregulation plays a role, it is likely one thread among many — not a single-cause account.

The theory is a defensible hypothesis that a small number of researchers are actively pursuing. It is just not yet proven.

3. What a DMT "blocker" would actually look like

A necessary note before the technical discussion: do not try to self-formulate or self-administer anything that blocks DMT. DMT shares receptors with serotonin, and the risks are real.

There are three theoretical intervention points, in ascending order of selectivity:

3.1 Block the receptors DMT acts on

DMT's main target is the 5-HT2A serotonin receptor, with secondary action at sigma-1. Drugs that block 5-HT2A already exist — they are called atypical antipsychotics. Risperidone and aripiprazole are in fact the only two FDA-approved medications for ASD. So in a sense, the "blocker" already exists in clinical use — just not understood through this lens. That is a strong piece of indirect support for the framework: the intervention that works in clinic is the one this model predicts would help.

3.2 Increase the enzyme that breaks DMT down

DMT is degraded by MAO-A, and ASD brains appear to have reduced MAO-A activity. But you cannot selectively upregulate MAO-A without broad serotonin, norepinephrine, and dopamine effects — dangerous territory, clinically unworkable without a far more selective tool than anything currently available.

3.3 Inhibit the enzyme that makes DMT (INMT)

This is the cleanest target in principle. A few academic groups are looking at INMT inhibitors. No clinical drug exists. INMT also methylates other substrates, so selectivity is an open problem.

4. Why blocking DMT would not "fix" autism in adults

Even with a perfect DMT blocker, the hypothesis is that DMT dysregulation shapes how the brain got wired during development. The cortical overgrowth and dense dendritic spines are already there by adulthood. Blocking DMT now would be closing the barn door after the horse left.

This is why the developmental window matters. The intervention target — if one ever existed — would be developmental, not corrective. For adults, the right frame is management of active symptoms, not reversal of wiring.

5. The predictive-coding bridge

The second observation is separate from the DMT story but connects to it powerfully: psychedelics seem to lower the brain's ability for pattern recognition and expectation of events — which seems to be what autism raises. That is a sharp observation, and it lands in one of the most active frontiers in computational neuroscience.

Predictive coding models the brain as a prediction machine. Higher cortical levels send predictions downward; lower levels return prediction errors upward. Perception is the settled balance between the two, governed by two parameters:

• Priors — how strongly the brain weights its expectations.
• Precision of prediction errors — how much attention and weight is given to mismatches.

The autism side

The leading computational theory of autism is the "hyper-prior" / "aberrant precision" hypothesis, proposed by Sander Van de Cruys and colleagues (Psychological Review, 2014). A related version by Pellicano and Burr (Trends in Cognitive Sciences, 2012) argues autistic perception is shaped by attenuated prior expectations — the world is experienced more "raw," with less top-down smoothing. This predicts exactly what autistic people report: sensory overload, difficulty with unexpected change, and pattern flooding.

The psychedelic side

Karl Friston and Robin Carhart-Harris proposed the REBUS model (Pharmacological Reviews, 2019 — Relaxed Beliefs Under Psychedelics). Their claim: psychedelics acting on 5-HT2A receptors flatten the weighting of high-level priors, so top-down expectations lose their grip and bottom-up sensory and associative signals burst through. This is why patterns feel vivid, unexpected connections appear, and the world feels strange on psychedelics.

6. The key parallel

Autism and the psychedelic state share a perceptual signature — both show weakened top-down priors and over-weighted prediction errors. Several researchers have explicitly noticed this. Carhart-Harris himself has discussed the overlap.

7. How this braids with the DMT theory

The full unified theory now has three layers:

1. Developmental: DMT dysregulation during development → atypical wiring (the Esen-Danaci hypothesis).
2. Acute: Acute DMT or 5-HT2A activity → the REBUS state (Friston / Carhart-Harris).
3. Phenomenological: The lived experience of autism resembles the lived experience of 5-HT2A agonism.

If endogenous DMT — or chronic over-sensitivity of 5-HT2A — is subtly elevated from development onward, the autistic brain may be in a permanently REBUS-like state: relaxed priors, over-weighted prediction errors, pattern-flooding, novelty overload. That is a testable hypothesis.

Autism spectrum disorder may involve a chronically REBUS-like predictive coding state, driven by endogenous over-activity or hyper-sensitivity at 5-HT2A receptors — potentially originating in DMT metabolism dysregulation during a critical developmental window — resulting in attenuated prior weighting, elevated precision of prediction errors, and the characteristic sensory and cognitive profile of ASD.

8. The apparent paradox — and its resolution

Psychedelics often improve mood, openness, and social connection — the opposite of the distress autistic people experience. If autism and the psychedelic state share a computational signature, why do they feel so different?

A neurotypical brain gets a vacation from strong priors on a psychedelic and finds it liberating. An autistic brain that has never had strong priors experiences the same state as its unremitting baseline — exhausting rather than revelatory.

9. Implications and next steps

• Direct measurement. Endogenous DMT has not been directly measured in autistic humans. Recent imaging work on endogenous DMT — notably the UC San Diego Center for Psychedelic Research under Jon Dean — makes this tractable. Dean's group is actively imaging endogenous DMT in human brains and would be the natural audience for a collaborative test of this hypothesis.
• Developmental focus. The rat postnatal DMT peak (approximately days 12–17) has not been functionally characterized. A developmental window account is testable in animal models.
• Intervention realism. The existing 5-HT2A blockers (risperidone, aripiprazole) are the nearest clinical analogue. They remain the only FDA-approved medications for ASD core behavioral symptoms. This is evidence, not coincidence.
• Computational psychiatry. The framework is testable with standard predictive-coding paradigms (mismatch negativity, roving oddball, probabilistic reversal) under pharmacological challenge.
• Publishability. This is a publishable perspective paper linking three active research threads — DMT endogenous function, computational psychiatry / predictive coding, and ASD phenomenology — that have not yet been unified in the literature.

Author's note

I have thought about a version of this for more than a decade — long before I had the vocabulary for it. What began as a private theory about endogenous DMT and autism has, after encountering the predictive-coding and REBUS literatures, organized itself into the proposal above. I publish it here as a working note, not a finished claim. I welcome correspondence from researchers working on any of the three threads.

Selected references

1. Pellicano, E. & Burr, D. (2012). When the world becomes "too real": a Bayesian explanation of autistic perception. Trends in Cognitive Sciences, 16(10), 504–510.
2. Van de Cruys, S., Evers, K., Van der Hallen, R., Van Eylen, L., Boets, B., de-Wit, L., & Wagemans, J. (2014). Precise minds in uncertain worlds: predictive coding in autism. Psychological Review, 121(4), 649–675.
3. Carhart-Harris, R. L. & Friston, K. J. (2019). REBUS and the anarchic brain: toward a unified model of the brain action of psychedelics. Pharmacological Reviews, 71(3), 316–344.
4. Dean, J. G., Liu, T., Huff, S., Sheler, B., Barker, S. A., Strassman, R. J., Wang, M. M., & Borjigin, J. (2019). Biosynthesis and extracellular concentrations of N,N-dimethyltryptamine (DMT) in mammalian brain. Scientific Reports, 9, 9333.
5. Barker, S. A. (2018). N,N-dimethyltryptamine (DMT), an endogenous hallucinogen: past, present, and future research to determine its role and function. Frontiers in Neuroscience, 12, 536.
6. Esen-Danaci, A. and colleagues (2019). Perspectives on the role of endogenous DMT in autism spectrum disorder. Frontiers in Endocrinology (perspective series).

References are provided for orientation to the literature; the synthesis above is the author's own.