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.
Brain Research 2025 DOI: 10.1016/j.brainres.2024.149226 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Literature review Peer reviewed |
|---|---|
| Topics | Anxiety Depression Serotonin |
| Keywords | Anterior cingulate cortex Brain networks Neurotransmission Psychedelics |
| Citations | 59 |
| Key findings | 5HT2A receptor activation in the ACC reduces anxious preoccupation and anhedonia while promoting cognitive flexibility through altered glutamate and GABA neurotransmission, changes in brain network connectivity, and downstream effects on amygdala reactivity and mesolimbic dopamine. |
Abstract
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.
Comparable studies
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Citations in the library
Cited by 29
- Novel 3-Pyrrolidineindole Derivatives as Serotonergic Psychedelic Agents for Treating Psychosis and Mental Illnesses Such as Depression and Post-Traumatic Stress Disorder. ACS Medicinal Chemistry Letters January 9, 2025
- Psychoanalytically informed MDMA-assisted therapy for pathological narcissism: a novel theoretical approach. Frontiers in Psychiatry 2025
- Novel Indole Derivatives as Serotonergic Psychedelic Agents for Treating Psychosis, Mental Illness, and CNS Disorders. ACS Medicinal Chemistry Letters June 12, 2025
- Novel Indoline Derivatives as Serotonergic Psychedelic Agents for Treating Psychosis, Mental Illness and CNS Disorders. ACS Medicinal Chemistry Letters January 23, 2025
- Novel 6,5-Bicyclic Compounds as 5-HT2A Receptor Agonists for Treating Depression, Anxiety, Substance Abuse, and Headaches ACS Medicinal Chemistry Letters July 3, 2026
and 24 more in the library
Cites 28
- The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs Frontiers in Human Neuroscience 2014
- The salience network is responsible for switching between the default mode network and the central executive network: Replication from DCM Neuroimage May 24, 2014
- Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial Psychological Medicine June 15, 2018
- Emotions and brain function are altered up to one month after a single high dose of psilocybin. Scientific Reports February 10, 2020
- Activation of Serotonin 2A Receptors Underlies the Psilocybin-Induced Effects on Oscillations, N170 Visual-Evoked Potentials, and Visual Hallucinations Journal of Neuroscience June 19, 2013
and 23 more in the library