Mouse Study Distinguishes DMT and 5-MeO-DMT Mechanisms

Psiconáutica Editorial Team · September 9, 2026

A team from the Hadassah BrainLabs Center for Psychedelic Research at the Hebrew University of Jerusalem has published a study in mice comparing, molecule by molecule, how DMT and 5-MeO-DMT leave their mark on the brain. The paper, authored by Orr Shahar, Bernard Lerer, and colleagues, was posted as a preprint on bioRxiv on August 6 and has not yet undergone peer review.

Two similar molecules, different dose-response

The researchers first measured the head-twitch response, a reflex movement used in rodents as a proxy for the intensity of the psychedelic effect. With DMT, this response follows a bell-shaped curve: it appears at low doses (between 1.25 and 5 mg/kg) and tapers off at higher doses. With 5-MeO-DMT, the opposite occurs—a progressive increase that only becomes visible starting at 5 mg/kg and continues to grow with higher doses. Both substances rely on the same serotonin receptors to produce this response, but with different weightings: for example, blocking the 5-HT1B receptor reduced the twitch with DMT but had no effect with 5-MeO-DMT.

Separating the “trip” from potential benefit

The most striking experiment used the marble-burying test, a standard assay for approximating obsessive-compulsive behaviors in rodents. DMT reduced this behavior even when the researchers pharmacologically blocked the head-twitch; in other words, the behavioral effect persisted even when the “trip” indicator was turned off. With 5-MeO-DMT, the opposite happened: on its own, it did not change behavior, but when combined with certain receptor blockers, it did. At the molecular level, DMT activated a protein linked to neuronal plasticity (TrkB) in more brain regions, including the hippocampus, while 5-MeO-DMT did so in a more limited way, primarily in the frontal cortex. Twelve days later, DMT had reduced BDNF levels despite increasing several synaptic proteins, and it left a more marked metabolic footprint, with less oxidized glutathione. 5-MeO-DMT showed more discrete changes in almost all these measures.

What it implies

This is a non-peer-reviewed preprint conducted in male mice of a single strain, using behavioral tests that are imperfect approximations of human symptoms, a limitation the authors themselves acknowledge. None of this tells us how these substances behave in people, nor does it change what we already know about their use: DMT continues to act within minutes, while 5-MeO-DMT has a different potency and duration—something anyone informing themselves before consuming DMT or ayahuasca should keep in mind. What it does provide is a mechanistic clue: that the intense subjective effect and the potential benefit regarding brain plasticity might not depend on one another, a topic already being discussed in the field of psychedelic research. The most serious finding for harm reduction is another: mixing 5-MeO-DMT with a specific 5-HT1B receptor agonist killed several mice in the experiment, a reminder that combining substances that act on the same receptors is not a field for improvisation, neither in the lab nor outside of it. The hypothesis aligns with another recent study in rodents that already pointed in this direction.

Source

• Shahar O, Botvinnik A, Chaykin M, et al. Preclinical Comparison of DMT and 5-MeO-DMT Reveals Behavioral Dissociation, Distinct TrkB Activation and Differential Plasticity Profiles. bioRxiv (preprint), August 6, 2026.

Educational content written from a harm reduction perspective and with respect for individual freedom. It is not a substitute for advice from a healthcare professional and is not intended to encourage or condemn any drug use.