Uncovering psychedelics: from neural circuits to therapeutic applications
Open accessAbstract
Psychedelics, historically celebrated for their cultural and spiritual significance, have emerged as potential breakthrough therapeutic agents due to their profound effects on consciousness, emotional processing, mood, and neural plasticity. This review explores the mechanisms underlying psychedelics' effects, focusing on their ability to modulate brain connectivity and neural circuit activity, including the default mode network (DMN), cortico-striatal thalamo-cortical (CSTC) loops, and the relaxed beliefs under psychedelics (REBUS) model. Advanced neuroimaging techniques reveal psychedelics' capacity to enhance functional connectivity between sensory cerebral areas while reducing the connections between associative brain areas, decreasing the rigidity and rendering the brain more plastic and susceptible to external changings, offering insights into their therapeutic outcome. The most relevant clinical trials of 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, and lysergic acid diethylamide (LSD) demonstrate significant efficacy in treating treatment-resistant psychiatric conditions such as post-traumatic stress disorder (PTSD), depression, and anxiety, with favorable safety profiles. Despite these advancements, critical gaps remain in linking psychedelics' molecular actions to their clinical efficacy. This review highlights the need for further research to integrate mechanistic insights and optimize psychedelics as tools for both therapy and understanding human cognition.
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MDMA increases cortical-limbic communication, integrating previously segregated brain networks while reducing rigid connectivity in associative areas.
“Neuroimaging studies demonstrate that MDMA increases cortical-limbic communication, integrating previously segregated brain networks while reducing rigid connectivity in associative areas - a pattern linked to greater cognitive flexibility and emotional openness (91).”
From Psychoanalytically informed MDMA-assisted therapy for pathological narcissism: a novel theoretical approach (2025) · cites this paper as [91]
Section 3 describes neuroimaging findings of greater integration between previously separate networks and reduced connectivity within associative networks, particularly in discussions of LSD and psilocybin. It does not establish that MDMA produces this pattern or specifically increases cortical–limbic communication. Section 2 discusses MDMA’s molecular, prosocial, and plasticity effects instead. (LLM, conf=0.85)
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- Authors
- Melani, A., Bonaso, M., Biso, L., Zucchini, B., Conversano, C., & Scarselli, M.
- Affiliations
- University of Pisa (IT)
- Corresponding author
- Scarselli, Marco
- Venue
- Pharmaceuticals
- Publisher
- MDPI AG
- Published
- 2025-01-19
- Volume
- 18
- Issue
- 1
- Pages
- 130
- ISSN
- 1424-8247 (ISSN-L)
- PMC
- PMC11769142
- OpenAlex
- W4406629036
- Cited by
- 17
- References
- 75
- Citations by year
- 2026: 8 · 2025: 9
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Pharmaceuticals (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Università degli Studi di Padova
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cognitive Neuroscience › Pain Management and Placebo Effect
- Keywords
- psychedelics, neural circuits, brain connectivity, default mode network, neuroplasticity, MDMA, psilocybin, LSD, treatment-resistant depression, post-traumatic stress disorder, anxiety, consciousness, functional connectivity
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