Inhaled N,N-Dimethyltryptamine Diminishes Connectivity between the Ventral Tegmental Area and the Nucleus Accumbens : relevance to pathologies of mesolimbic and mesocortical pathways
Gisela Lima, Carla Soares, Marta Teixeira, Marta Lapo Pais, Célia Cabral, Patrícia Rijo, Miguel Castelo-Branco
Research Square September 17, 2025 preprint DOI: 10.21203/rs.3.rs-7141119/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Within-subject pharmacoimaging study |
|---|---|
| Sample size | 11 |
| Population | Healthy participants with prior experience in psychedelics |
| Interventions | inhaled N N-dimethyltryptamine (DMT) |
| Topics | 5-MeO-DMT DMT |
| Keywords | Ventral tegmental area Nucleus accumbens Dopamine Anterior cingulate cortex Thalamus Reward system Mesolimbic pathway Cortex anatomy Ventrolateral prefrontal cortex Brain mapping Midbrain Functional connectivity |
| Key points | Inhaled DMT decreased connectivity between the right nucleus accumbens and left ventral tegmental area, and increased connectivity between the right nucleus accumbens and anterior cingulate cortex and between the medial prefrontal cortex and anterior cingulate cortex. |
Abstract
Abstract Reward processing is a broad psychological construct that can be parsed into distinct components known as “reinforcement learning” (learning), “reward responsiveness” (liking), and “motivation to obtain a reward” (wanting). Dysfunctions in reward processing in mesolimbic and mesocortical pathways, are a core feature of many pathologies. Psychedelics have been proposed as a treatment option for multiple disorders affecting the reward system, but mechanistic studies are lacking.In the present study, we evaluated the effects of inhaled N,N-dimethyltryptamine (DMT) with a particular focus on the connectivity of the mesocorticolimbic circuitry. Our within-subject pharmacoimaging design included 11 healthy participants with prior experience in psychedelics. In the active condition, DMT was self-administered immediately before MRI acquisition, while in the control condition there was no administration.We found decreased connectivity between the right nucleus accumbens (NAc) and the left ventral tegmental area (VTA), increased connectivity between the right NAc and anterior cingulate cortex (ACC) and increased connectivity between the medial prefrontal cortex (mPFC) and the ACC. These results correlated with changes in volition and perception, as measured with the hallucination rating scale.In sum, we found reduced connectivity in the midbrain-NAc pathway, which connectivity is often increased in addiction, and increased connectivity between reward/affective regions and the ACC. These findings suggest a potential therapeutic potential of psychedelics in disorders affecting reward processing.
Comparable studies
Other experimental studies on 5-MeO-DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Human cerebral organoids | 2017 | Experimental study | |
| Bufo alvarius: a potent hallucinogen of animal origin. Bufo alvarius toad venom | 1994 | Experimental study | |
| Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment Volunteers | 2019 | Within-subjects experimental study | n = 11 |
| Unmasking of a neonatal somatovesical reflex in adult cats by the serotonin autoreceptor agonist 5-methoxy-N,N-dimethyltryptamine. Adult cats | 1990 | Experimental study | n = 10 |
| Studies on the Mechanism of Action of Monoamine Oxidase: Metabolism of N,N-Dimethyltryptamine and N,N-Dimethyltryptamine-N-Oxide | 1962 | Experimental study |
Citations in the library
Cites 31
- 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 Journal of Clinical Psychopharmacology December 11, 2015
- Dose-Response Study of N,N-Dimethyltryptamine in Humans Archives of General Psychiatry February 1, 1994
- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
- Human Psychopharmacology of Hoasca, A Plant Hallucinogen Used in Ritual Context in Brazil The Journal of Nervous and Mental Disease February 1, 1996
and 26 more in the library