Antidepressant and anxiolytic effects of activating 5HT2A receptors in the anterior cingulate cortex and the theoretical mechanisms underlying them – A scoping review of available literature
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Psychedelic drugs that activate the 5HT2A receptor have long been the target of extensive clinical research, particularly in models of psychiatric illness. The aim of this literature review was to investigate the therapeutic effects of 5HT2A receptor activation in the anterior cingulate cortex (ACC) and the respective mechanisms that underlie them. Based on the available research, I suggest that 5HT2A receptors in the ACC exert profound changes in excitatory neurotransmission and brain network connectivity in a way that reduces anxious preoccupation and obsessional thoughts, as well as promoting cognitive flexibility and long-lasting mood improvements in anhedonia. This is possibly due to a complex interplay with glutamate and gamma-butyric acid neurotransmission, particularly 5HT2A activation enhances α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor signalling, thus altering the ratio of AMPA to N-methyl-D-Aspartate (NMDA) activity in the ACC, which can dismantle previously established neuronal connections and aid the formation of new ones, an effect that may be beneficial for fear extinction and reversal learning. Psychedelics potentially change intra- and internetwork connectivity, strengthening connectivity from the dorsal ACC / Salience Network to the Default Mode Network (DMN) and Central Executive Network (CEN), which correlates with improvements in attentional shifting and anti-anhedonic effects. Additionally, they may decrease inhibitory influence of the DMN over the CEN which may reduce overevaluation of internal states and ameliorate cognitive deficits. Activation of ACC 5HT2A receptors also has important downstream effects on subcortical areas, including reducing amygdala reactivity to threatening stimuli and enhancing mesolimbic dopamine, respectively improving anxiety and the experience of natural rewards.
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By enhancing ACC function and promoting cognitive flexibility, emotion regulation, and fear extinction via 5-HT2A receptor activation, MDMA may help reduce defensive rigidity and social threat hypersensitivity.
“By enhancing ACC function and promoting cognitive flexibility, emotion regulation, and fear extinction via 5-HT2A receptor activation (97), MDMA may help reduce defensive rigidity and social threat hypersensitivity - core features of PN that contribute to its paradoxical combination of emotional detachment and heightened sensitivity to threats against self-image or social status (98).”
From Psychoanalytically informed MDMA-assisted therapy for pathological narcissism: a novel theoretical approach (2025) · cites this paper as [97]
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Albert, A. E., & Back, A. L. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1529427 · Cited by 6 · see citing works
- Authors
- Miranda, L.
- Affiliations
- University of Westminster (GB)
- Corresponding author
- Miranda, Leonor
- ORCID
- Miranda, Leonor
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2025-01
- Volume
- 1846
- Pages
- 149226
- ISSN
- 0006-8993 (ISSN-L)
- OpenAlex
- W4402327722
- Cited by
- 66
- References
- 134
- Citations by year
- 2026: 16 · 2025: 47 · 2024: 3
- FWCI
- 5.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain Research (publishedVersion, cc-by-nc-nd)
- SSRN Electronic Journal (acceptedVersion)
- PubMed (publishedVersion)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- 5-HT2A receptor, anterior cingulate cortex, psychedelics, antidepressant effects, anxiolytic effects, AMPA/NMDA ratio, glutamatergic neurotransmission, brain network connectivity, salience network, default mode network, frontoparietal network, fear extinction, reversal learning, anhedonia, mesolimbic dopamine system, amygdala reactivity, cognitive flexibility
- MeSH terms
- Animals, Antidepressive Agents, Anxiety, Gyrus Cinguli, Humans, Anti-Anxiety Agents, Receptor, Serotonin, 5-HT2A, Serotonin 5-HT2 Receptor Agonists
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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