Preclinical Comparison of DMT and 5-MeO-DMT Reveals Behavioral Dissociation, Distinct TrkB Activation and Differential Plasticity Profiles
Orr Shahar, Alexander Botvinnik, Masha Chaykin, Amit Shwartz, Elad Lerer, Peretz Golding, May Ben Ari, Ori Shalev, Tzuri Lifschytz, Bernard Lerer
bioRxiv (Cold Spring Harbor Laboratory) August 12, 2026 preprint DOI: 10.64898/2026.08.06.743248 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study |
|---|---|
| Population | Mice |
| Interventions | DMT 5-MeO-DMT |
| Duration | 12 days post-dose |
| Measures | head-twitch response (HTR), marble burying, TrkB phosphorylation, PSD-95, synaptophysin, SV2A, BDNF |
| Topics | 5-MeO-DMT DMT |
| Key points | DMT and 5-MeO-DMT produce distinct acute profiles (bell-shaped vs. monotonic HTR), and their hallucinogenic-like activity can be pharmacologically dissociated from therapeutic-like behavioral and plasticity outcomes, as receptor manipulations attenuate HTR without blocking marble-burying reduction. |
Abstract
Abstract N, N-dimethyltryptamine (DMT) and 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) are structurally related tryptamine psychedelics with emerging therapeutic potential, yet their comparative acute pharmacology and longer-term neuroplastic effects remain incompletely defined. Here we show that DMT produces a bell-shaped dose–response curve in the mouse head-twitch response (HTR) assay, whereas 5-MeO-DMT elicits a monotonic increase. Selective antagonism at 5-HT2A or 5-HT1D receptors, or agonism at 5-HT1A, robustly attenuates HTR for both compounds without abolishing their ability to reduce marble burying, a screening assay for OCD-like behavior. Acutely, both agents elevate TrkB phosphorylation in a region-specific manner, with broader engagement by DMT across default-mode-network and hippocampal territories. Twelve days after a single dose, both compounds increase synaptic proteins (PSD-95, synaptophysin; SV2A for DMT), while DMT uniquely lowers hippocampal BDNF and reprograms frontal-cortex glutathione and energy metabolism. These findings demonstrate that acute hallucinogenic-like activity and selected therapeutic-like behavioral and plasticity outcomes can be pharmacologically dissociated, informing the rational design of more tolerable, scalable psychedelic-based treatments.
Comparable studies
Other preclinical and animal studies on 5-MeO-DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| 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 | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| Hallucinogen-like actions of 5-methoxy-N,N-diisopropyltryptamine in mice and rats. Mice and rats | 2006 | Preclinical study | |
| Agonist Properties of N,N-Dimethyltryptamine at Serotonin 5-HT2A and 5-HT2C Receptors Rats and transfected fibroblasts | 1998 | Experimental study | |
| Subtypes of the 5-HT receptor mediating the behavioural responses to 5-methoxy-N,N-dimethyltryptamine in the rat Intact rats and rats depleted of monoamines with reserpine | 1985 | Experimental study |
Citations in the library
Cites 46
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial Psychological Medicine June 15, 2018
- Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report Brazilian Journal of Psychiatry March 1, 2015
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
- Dose-Response Study of N,N-Dimethyltryptamine in Humans Archives of General Psychiatry February 1, 1994
and 41 more in the library