Direct anti-inflammatory actions of N,N -dimethyltryptamine on microglia are revealed by proteomic profiling and receptor pharmacology
István Pesti, Ágnes Bessenyei, Rita Frank, Zsuzsanna Darula, Szabolcs Dvorácskó, Zoltán G. Páhi, Tibor Pankotai, Éva Hunyadi‐Gulyás, Krisztián Vinga, Sara Peto, Kata Klein, Ferenc Bari, Ákos Menyhárt, Nicholas V. Cozzi, Eszter Farkas
bioRxiv (Cold Spring Harbor Laboratory) August 11, 2026 preprint DOI: 10.64898/2026.08.05.742931 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Laboratory study |
|---|---|
| Population | Primary rat microglial cultures and acute mouse brain slices |
| Intervention | DMT |
| Topics | 5-MeO-DMT DMT |
| Key points | DMT directly suppresses LPS-induced microglial activation, promotes a homeostatic morphology, and reduces phagocytic activity in rat microglia. In mouse brain slices, DMT attenuates microglial activation, reduces spreading depolarizations and ischemic neuronal injury, with tissue-level neuroprotection depending on serotonergic signaling. |
Abstract
ABSTRACT N,N -dimethyltryptamine (DMT) is an endogenous psychedelic tryptamine that has recently emerged as a promising therapeutic candidate for acute ischemic stroke. Although DMT consistently reduces infarct size, attenuates neuroinflammation, and improves functional outcome in experimental stroke, the cellular and receptor mechanisms underlying these effects remain poorly understood. Primary rat microglial cultures were used to examine the direct anti-inflammatory effects of DMT following lipopolysaccharide (LPS)-induced activation. Microglial morphology, phagocytosis, and proteomic alterations were analyzed. Radioligand binding assays determined the affinity of DMT for microglial sigma-1 receptors (Sig-1Rs). Pharmacological inhibition of Sig-1Rs and serotonin (5-HT) receptors was performed to define receptor-specific mechanisms. Translational relevance was evaluated in acute mouse brain slices subjected to mild oxygen-glucose deprivation (mOGD) and anoxic episodes, where microglial activation, spreading depolarizations (SDs), and neuronal injury were assessed. DMT directly suppressed LPS-induced microglial activation, promoted a homeostatic morphology, and reduced phagocytic activity. Proteomic profiling demonstrated that DMT selectively reprogrammed inflammatory pathways by suppressing proteins involved in cytokine and chemokine signaling and oxidative stress while largely preserving arachidonic acid–prostaglandin synthesis. DMT bound microglial Sig-1Rs with micromolar affinity comparable to that reported in whole-brain preparations. Pharmacological inhibition revealed that DMT-induced morphological reprogramming required both Sig-1R and serotonergic signaling, whereas suppression of phagocytosis was largely independent of either receptor pathway. In acute brain slices, DMT attenuated microglial activation, reduced SD propagation and ischemic neuronal injury, and tissue-level neuroprotection depended on serotonergic signaling. DMT directly targets microglia and selectively remodels inflammatory states rather than broadly suppressing microglial activation. The receptor mechanisms underlying its actions are context dependent, with Sig-1R and serotonergic signaling contributing differentially according to the cellular response and experimental model. These findings provide mechanistic insight into the neuroprotective actions of DMT and support its ongoing clinical translation as a potential therapy for ischemic stroke.
Comparable studies
Other preclinical and animal studies on DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Mice and cell lines | 2009 | Experimental study | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. Human primary monocyte-derived dendritic cells | 2014 | In vitro study | |
| Inhibitory effect of chlorpromazine on the syndrome of hyperactivity produced by l‐tryptophan or 5‐methoxy‐N,N‐dimethyltryptamine in rats treated with a monoamine oxidase inhibitor Rats | 1971 | Experimental study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study |
Citations in the library
Cites 11
- The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Science February 13, 2009
- N,N-dimethyltryptamine reduces infarct size and improves functional recovery following transient focal brain ischemia in rats Experimental Neurology February 14, 2020
- N,N-Dimethyltryptamine attenuates spreading depolarization and restrains neurodegeneration by sigma-1 receptor activation in the ischemic rat brain. Neuropharmacology July 1, 2021
- Exploring DMT: Endogenous role and therapeutic potential. Neuropharmacology May 1, 2025
- Neurobiological research on N,N-dimethyltryptamine (DMT) and its potentiation by monoamine oxidase (MAO) inhibition: from ayahuasca to synthetic combinations of DMT and MAO inhibitors. Cellular and Molecular Life Sciences September 10, 2024
and 6 more in the library