DMT and Stroke: How a Psychoactive Molecule May Protect The Brain

Researchers have shown that DMT, a natural molecule found in various plants, some animals, and also in the human body, can protect the brain after a stroke. In experiments with mice and laboratory models, it reduced the area of ​​damage, decreased inflammation, and restored the blood-brain barrier. These results suggest that DMT may be a new tool for improving the recovery of stroke patients.

Stroke is one of the most serious and devastating diseases affecting humans. It affects not only patients but also their families and society as a whole, generating high costs for healthcare systems.

Despite decades of research and the development of many promising drugs, there is still no neuroprotective drug that can be used effectively in everyday clinical practice. The reason is that stroke is not caused by a single problem, but by a complex network of cells and biological processes that interact with each other.

When a stroke occurs, blood flow to a region of the brain is interrupted, causing oxygen deprivation and neuron death. This triggers a series of chain reactions: brain cells called microglia, astrocytes, pericytes, and endothelial cells begin to release inflammatory molecules (cytokines and chemokines).

This inflammatory response leads to the disruption of the blood-brain barrier (BBB), a structure that normally protects the brain from harmful substances in the blood.

When the blood-brain barrier is disrupted, blood molecules and cells invade the brain tissue, increasing inflammation, causing swelling (edema), and further exacerbating the damage.

Currently, available treatments include intravenous thrombolysis (a medication that dissolves clots) and endovascular thrombectomy (a procedure to remove the clot using a catheter). However, these options only work if performed within the first few hours after a stroke, are not available to all patients, and can cause complications.

Furthermore, little progress has been made in treating the consequences, such as cerebral edema and neuronal death.

In this context, interest has arisen in investigating N,N-dimethyltryptamine (DMT). This natural molecule is found in various plants, some animals, and also in the human body. In plants, it is present in species such as Psychotria viridis and Mimosa tenuiflora, used in traditional brews such as ayahuasca.

Mimosa tenuiflora

In animals, including humans, small amounts of DMT have been detected in the brain, blood, and even urine, suggesting that it may play biological functions that are still poorly understood. In addition to being known as a psychoactive substance, recent research has explored its potential as a therapeutic agent, especially in the treatment of neurological diseases such as stroke.

DMT is able to bind to the sigma-1 receptor, a protein involved in cell survival and protection from damage. Previous experiments showed that, in rats, DMT administration reduced the area of ​​cerebral infarction (the region damaged by stroke) and improved functional recovery.

These results were already strong enough to initiate clinical trials in humans, including a Phase 1 trial in healthy volunteers and preparations for a Phase 2 trial in stroke patients.

BBB alterations in stroke and the protective effects of DMT. Schematic representation of the neurovascular unit (NVU) under physiological conditions and in stroke. Arrows and inhibition signals (cyan) show the effect of DMT in pathological conditions. In stroke, tight junctions (red line between brain endothelial cells) are disrupted and the tight junction protein CLDN5 decreases; in the blood-soluble neurovascular unit, proteins appear and the level of inflammatory cytokines increases and that of anti-inflammatory cytokines decreases. In the brain, microglial morphology changes, the proportion of less ramified microglial cells increases, the distribution of AQP4 changes, and the level of inflammatory cytokines increases. DMT decreases the level of the soluble proteins CLDN5, MMP9, and GFAP and inhibits inflammatory cytokines in the blood, while increasing the level of BDNF and the anti-inflammatory cytokine IL-10. In the brain, DMT inhibits morphological changes in microglia and the redistribution of AQP4 in astroglia, in addition to decreasing the production of pro-inflammatory cytokines. Created with Biorender.com. Vigh, J. (2025) https://BioRender.com/o95e437.

To better understand how DMT protects the brain, researchers at Semmelweis University, Hungary, used two types of models:

- Animal model (rats): transient cerebral ischemia was induced, that is, a temporary interruption of blood flow in a cerebral artery, similar to what occurs in a human stroke. Afterward, the effect of DMT on infarct size, the presence of cerebral edema, and inflammatory markers was evaluated.

- In vitro model of the blood-brain barrier (BBB): rat brain cells (endothelial cells, astrocytes, etc.) were cultured in the laboratory, simulating the blood-brain barrier. This system allowed us to observe, under controlled conditions, how DMT interferes with the integrity of the barrier and the release of inflammatory molecules.

With these two models, it was possible to evaluate both the general effects of DMT on the body (in live rats) and its specific effects on the blood-brain barrier (in the laboratory).

The results were consistent: DMT reduced the size of cerebral infarcts in the rats. There was less cerebral edema and less astrocyte dysfunction. DMT modified the composition of proteins in the blood, favoring an anti-inflammatory and neuroprotective state. In the laboratory and in animals, DMT restored the integrity of the blood-brain barrier, helping to close the tight junctions that typically break down after stroke.

It also reduced the release of inflammatory cytokines and chemokines by both brain cells and immune cells in the blood. These effects were dependent on the activation of the sigma-1 receptor, confirming its central role in the action of DMT.

The image shows how the substance DMT helps protect microglial cells (a type of immune cell in the brain) in rats that had an experimental stroke. In part (A), we see colored images of microglial cells, showing how they appear in different groups of rats: without stroke (control), with stroke, with stroke treated with DMT, and with stroke treated with DMT plus a sigma-1 receptor blocker (BD1063). In part (B), there is a graph measuring the intensity of a protein called IBA1, which indicates microglial activation. Stroke greatly increases this intensity, but DMT treatment helps reduce it, demonstrating a protective effect. In part (C), we see how the shape of the microglial cells changes: in the control group, they are well-branched (healthy), in the stroke group, they become more rounded (a sign of excessive activation), and with DMT treatment, they maintain a more balanced shape. In part (D), the graph classifies microglia into three types: healthy (gray), intermediate (green), and highly activated (black). In stroke rats, most cells were in the most activated state, but with DMT, many returned to a healthy state. In short, DMT prevented microglia from becoming hyperactivated after stroke, preserving their normal shape and reducing inflammation in the brain.

These findings indicate that DMT may be a powerful ally in stroke treatment. It does not replace current clot-removal therapies, but it may act as a way to protect the brain after stroke by decreasing inflammation, stabilizing the blood-brain barrier, and reducing the risk of permanent damage. This paves the way for new therapeutic approaches that combine current medicine with the potential of DMT.

READ MORE:

N,N-dimethyltryptamine mitigates experimental stroke by stabilizing the blood-brain barrier and reducing neuroinflammation

MARCELL J. LÁSZLÓ, JUDIT P. VIGH, ANNAE. KOCSIS, GERGŐ PORKOLÁB, 

ZSÓFIA HOYK, TAMÁS POLGÁR, FRUZSINA R. WALTER, ATTILA SZABÓ, S

RDJAN DJUROVIC, BÉLA MERKELY, ALÁN ALPÁR, EDE FRECSKA, ZOLTÁN NAGY, MÁRIA A. DELI, and SÁNDOR NARDAI 

SCIENCE ADVANCES, 13 Aug 2025, Vol 11, Issue 33

DOI: 10.1126/sciadv.adx5958

Abstract: 

N,N-dimethyltryptamine (DMT) is a psychoactive molecule present in the human brain. DMT is under clinical evaluation as a neuroprotective agent in poststroke recovery. Yet, its mechanism of action remains poorly understood. In a rat transient middle cerebral artery occlusion stroke model, we previously showed that DMT reduces infarct volume. Here, we demonstrate that this effect is accompanied by reduction of cerebral edema, attenuated astrocyte dysfunction, and a shift in serum protein composition toward an anti-inflammatory, neuroprotective state. DMT restored tight junction integrity and blood-brain barrier (BBB) function in vitro and in vivo. DMT suppressed the release of proinflammatory cytokines and chemokines in brain endothelial cells and peripheral immune cells and reduced microglial activation via the sigma-1 receptor. Our findings prove that DMT mitigates a poststroke effect by stabilizing the BBB and reducing neuroinflammation. Such interactions of DMT with the vascular and immune systems can be leveraged to complement current, insufficient, stroke therapy.