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Safron A, Juliani A, Reggente N, Klimaj V, Johnson M. On the varieties of conscious experiences: Altered Beliefs Under Psychedelics (ALBUS). Neurosci Conscious 2025; 2025:niae038. [PMID: 39949786 PMCID: PMC11823823 DOI: 10.1093/nc/niae038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 09/09/2024] [Accepted: 02/06/2025] [Indexed: 02/16/2025] Open
Abstract
How is it that psychedelics so profoundly impact brain and mind? According to the model of "Relaxed Beliefs Under Psychedelics" (REBUS), 5-HT2a agonism is thought to help relax prior expectations, thus making room for new perspectives and patterns. Here, we introduce an alternative (but largely compatible) perspective, proposing that REBUS effects may primarily correspond to a particular (but potentially pivotal) regime of very high levels of 5-HT2a receptor agonism. Depending on both a variety of contextual factors and the specific neural systems being considered, we suggest opposite effects may also occur in which synchronous neural activity becomes more powerful, with accompanying "Strengthened Beliefs Under Psychedelics" (SEBUS) effects. Such SEBUS effects are consistent with the enhanced meaning-making observed in psychedelic therapy (e.g. psychological insight and the noetic quality of mystical experiences), with the imposition of prior expectations on perception (e.g. hallucinations and pareidolia), and with the delusional thinking that sometimes occurs during psychedelic experiences (e.g. apophenia, paranoia, engendering of inaccurate interpretations of events, and potentially false memories). With "Altered Beliefs Under Psychedelics" (ALBUS), we propose that the manifestation of SEBUS vs. REBUS effects may vary across the dose-response curve of 5-HT2a signaling. While we explore a diverse range of sometimes complex models, our basic idea is fundamentally simple: psychedelic experiences can be understood as kinds of waking dream states of varying degrees of lucidity, with similar underlying mechanisms. We further demonstrate the utility of ALBUS by providing neurophenomenological models of psychedelics focusing on mechanisms of conscious perceptual synthesis, dreaming, and episodic memory and mental simulation.
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Affiliation(s)
- Adam Safron
- Allen Discovery Center, Tufts University, 200 Boston Avenue, Medford, MA 02155, United States
- Institute for Advanced Consciousness Studies, 2811 Wilshire Blvd #510, Santa Monica, CA 90403, United States
- Center for Psychedelic & Consciousness Research, Department of Psychiatry & Behavioral Sciences, Johns Hopkins University School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD 21224, United States
| | - Arthur Juliani
- Institute for Advanced Consciousness Studies, 2811 Wilshire Blvd #510, Santa Monica, CA 90403, United States
- Microsoft Research, Microsoft, 300 Lafayette St, New York, NY 10012, United States
| | - Nicco Reggente
- Institute for Advanced Consciousness Studies, 2811 Wilshire Blvd #510, Santa Monica, CA 90403, United States
| | - Victoria Klimaj
- Cognitive Science Program, Indiana University, 1001 E. 10th St, Bloomington, IN 47405, United States
- Department of Informatics, Indiana University, 700 N Woodlawn Ave, Bloomington, IN 47408, United States
| | - Matthew Johnson
- The Center of Excellence for Psilocybin Research and Treatment, Sheppard Pratt, 6501 N. Charles Street, Baltimore, MD 21204, United States
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Artin H, Zisook S, Ramanathan D. How do serotonergic psychedelics treat depression: The potential role of neuroplasticity. World J Psychiatry 2021; 11:201-214. [PMID: 34168967 PMCID: PMC8209538 DOI: 10.5498/wjp.v11.i6.201] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/07/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
Depression is a common mental disorder and one of the leading causes of disability around the world. Monoaminergic antidepressants often take weeks to months to work and are not effective for all patients. This has led to a search for a better understanding of the pathogenesis of depression as well as to the development of novel antidepressants. One such novel antidepressant is ketamine, which has demonstrated both clinically promising results and contributed to new explanatory models of depression, including the potential role of neuroplasticity in depression. Early clinical trials are now showing promising results of serotonergic psychedelics for depression; however, their mechanism of action remains poorly understood. This paper seeks to review the effect of depression, classic antidepressants, ketamine, and serotonergic psychedelics on markers of neuroplasticity at a cellular, molecular, electrophysiological, functional, structural, and psychological level to explore the potential role that neuroplasticity plays in the treatment response of serotonergic psychedelics.
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Affiliation(s)
- Hewa Artin
- Department of Psychiatry, UC San Diego, La Jolla, CA 92093, United States
| | - Sidney Zisook
- Department of Psychiatry, UC San Diego, San Diego, CA 92093, United States
| | - Dhakshin Ramanathan
- Department of Psychiatry, VA San Diego Healthcare System, San Diego, CA 92161, United States
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5-HT 2A receptor loss does not alter acute fluoxetine-induced anxiety and exhibit sex-dependent regulation of cortical immediate early gene expression. Neuronal Signal 2019; 3:NS20180205. [PMID: 32714597 PMCID: PMC7363295 DOI: 10.1042/ns20180205] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 01/07/2019] [Accepted: 01/16/2019] [Indexed: 01/14/2023] Open
Abstract
Background: Acute treatment with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (Flx), induces anxiety-like behavioral effects. The serotonin2A receptor (5-HT2A) is implicated in the modulation of anxiety-like behavior, however its contribution to the anxiogenic effects of acute Flx remains unclear. Here, we examined the role of the 5-HT2A receptor in the effects of acute Flx on anxiety-like behavior, serum corticosterone levels, neural activation and immediate early gene (IEG) expression in stress-responsive brain regions, using 5-HT2A receptor knockout (5-HT2A−/−) mice of both sexes. Methods: 5-HT2A−/− and wild-type (WT) male and female mice received a single administration of Flx or vehicle, and were examined for anxiety-like behavior, serum corticosterone levels, FBJ murine osteosarcoma viral oncogene homolog peptide (c-Fos) positive cell numbers in stress-responsive brain regions of the hypothalamus and prefrontal cortex (PFC), and PFC IEG expression. Results: The increased anxiety-like behavior and enhanced corticosterone levels evoked by acute Flx were unaltered in 5-HT2A−/− mice of both sexes. 5-HT2A−/− female mice exhibited a diminished neural activation in the hypothalamus in response to acute Flx. Further, 5-HT2A−/− male, but not female, mice displayed altered baseline expression of several IEGs (brain-derived neurotrophic factor (Bdnf), Egr2, Egr4, FBJ osteosarcoma gene (Fos), FBJ murine osteosarcoma viral oncogene homolog B (Fosb), Fos-like antigen 2 (Fosl2), Homer scaffolding protein (Homer) 1-3 (Homer1-3), Jun proto-oncogene (Jun)) in the PFC. Conclusion: Our results indicate that the increased anxiety and serum corticosterone levels evoked by acute Flx are not influenced by 5-HT2A receptor deficiency. However, the loss of function of the 5-HT2A receptor alters the degree of neural activation of the paraventricular nucleus (PVN) of the hypothalamus in response to acute Flx, and baseline expression of several IEGs in the PFC in a sexually dimorphic manner.
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