PloS one
January 1, 2014
Attila Szabo, Attila Kovács, Ede Frecska et al.
191 citations
The sigma-1 receptor, a protein found in the central nervous system and immune cells, can be activated by the psychedelic compounds N,N-dimethyltryptamine (NN-DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) to dampen inflammatory responses in human immune cells. When human dendritic cells were exposed to inflammatory triggers along with these compounds, production of pro-inflammatory cytokines IL-1β, IL-6, TNFα, and chemokine IL-8 decreased, while the anti-inflammatory cytokine IL-10 increased. The compounds also reduced the cells' ability to activate inflammatory T-cells. This suggests dimethyltryptamines may act as endogenous regulators of inflammation and immune balance, pointing toward potential treatments for autoimmune and chronic inflammatory conditions.
Frontiers in Immunology
July 14, 2015
Attila Szabo
153 citations
Classical psychedelics, including DMT, 5-MeO-DMT, LSD, and others, modulate immune responses by altering signaling pathways involved in inflammation, cellular proliferation, and survival. These substances activate NF-κB and mitogen-activated protein kinases, and their effects are mediated through serotonin and sigma-1 receptors, which also play roles in immunological processes. The review discusses the immunomodulatory potential of these compounds from a molecular immunology and pharmacology perspective, focusing on the interaction between serotonin and sigma-1 receptors and their cross-talk with pattern-recognition receptor signaling. It suggests novel approaches for treating chronic inflammatory diseases such as atherosclerosis, rheumatoid arthritis, multiple sclerosis, schizophrenia, depression, and Alzheimer's disease, aiming to reframe psychedelics as potential therapeutic agents rather than solely as drugs of abuse.
Psychopharmacology
December 10, 2019
Malin V. Uthaug, Rafael Lancelotta, Attila Szabo et al.
116 citations
Inhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine significantly increased cortisol levels and decreased IL-6 concentrations in saliva immediately after the session. These biomarker changes were not correlated with ratings of mental health or the psychedelic experience. Ratings of non-judgment increased and depression decreased from baseline to immediately post-session and at 7-day follow-up. Anxiety and stress ratings decreased from baseline to 7-day follow-up. Participant ratings of the psychedelic experience correlated negatively with affect ratings and positively with non-judgment ratings. The findings suggest that 5-methoxy-N,N-dimethyltryptamine produces changes in inflammatory markers and improves affect and non-judgment.
Journal of Neurochemistry
February 12, 2022
Johannes T. Reckweg, Malin V. Uthaug, Attila Szabo et al.
108 citations
5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a naturally occurring tryptamine that acts primarily as an agonist at 5-HT1A and 5-HT2A receptors, with highest affinity for the 5-HT1A subtype. Its subjective effects include distortions in auditory and time perception, amplification of emotional states, and feelings of ego dissolution that are usually short-lasting depending on route of administration. Individual dose escalation reliably induces a peak experience thought to be a core predictor of therapeutic efficacy. Observational studies and surveys suggest single exposure can cause rapid and sustained reductions in symptoms of depression, anxiety, and stress.
J Neural Transm (Vienna)
April 26, 2013
Ede Frecska, Attila Szabo, Michael J. Winkelman et al.
107 citations
DMT, a naturally occurring hallucinogen found in plants and animal tissues, may have biological functions beyond its psychedelic effects. Its role as an endogenous ligand of the sigma-1 receptor suggests involvement in cellular protective mechanisms, including effects on cellular bioenergetics, immunoregulation, and gene expression related to its synthesizing enzyme in carcinogenesis. The evidence indicates DMT is not merely a drug of abuse but an agent of adaptive mechanisms with potential for future medical therapies.
Experimental Neurology
February 14, 2020
Sándor Nardai, Marcell László, Attila Szabo et al.
91 citations
A single intraperitoneal dose of DMT (1 mg/kg) followed by a 24-hour infusion (2 mg/kg/h) reduced ischemic brain lesion volume and improved functional recovery in male Wistar rats after 60 minutes of transient middle cerebral artery occlusion. The neuroprotective effect was blocked by a Sigma-1 receptor antagonist, indicating a Sigma-1 receptor-dependent mechanism. DMT treatment lowered expression of the pro-apoptotic protein APAF1, increased brain-derived neurotrophic factor (BDNF), and shifted the inflammatory cytokine profile toward an anti-inflammatory state (decreased TNF-α, IL-1β, IL-6; increased IL-10). The findings suggest DMT protects against ischemic injury through combined anti-apoptotic, pro-neurotrophic, and anti-inflammatory actions.
Brain Behavior and Immunity
September 7, 2023
Natasha L. Mason, Attila Szabo, Kim P. C. Kuypers et al.
83 citations
A single dose of psilocybin (0.17 mg/kg) in 60 healthy participants immediately reduced the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), while interleukin-1β, interleukin-6 (IL-6), and C-reactive protein (CRP) were unchanged. Seven days later, TNF-α returned to baseline, but IL-6 and CRP were persistently reduced. Greater reductions in IL-6 and CRP at seven days correlated with more positive mood and social effects. Acute TNF-α reductions linked to lower hippocampal glutamate. Psilocybin did not significantly alter the stress response to a psychosocial stressor. The findings suggest psilocybin has persisting anti-inflammatory effects that may relate to its therapeutic benefits.
Neural Regeneration Research
January 1, 2016
Attila Szabo, Ede Frecska
42 citations
Inflammation in the brain, driven by microglia and pattern recognition receptors like Toll-like receptors, is linked to neuropsychiatric illnesses such as schizophrenia, depression, and Alzheimer's disease. The orphan receptor sigma-1 (Sig-1R) and serotonin receptors (5-HTRs), both G protein-coupled receptors, modulate immune responses by controlling NF-κB and MAPK pathways, influencing cytokine release. The endogenous tryptamine N,N-dimethyltryptamine (DMT) acts on both Sig-1R and 5-HTRs, suppressing inflammation by blocking cytokine release from dendritic cells and inhibiting Th1 and Th17 T cell activation. DMT's regulation of NF-κB and MAPKs via G proteins suggests potential as a therapeutic for chronic inflammatory and autoimmune diseases, though its hallucinogenic properties remain a challenge. Selective Sig-1R agonists promote neuroprotection and regeneration.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
November 1, 2023
Michael James Winkelman, Attila Szabo, Ede Frecska
26 citations
Serotonergic psychedelics show potential for treating Alzheimer's disease by promoting neuroplasticity and counteracting brain atrophy. Classic psychedelics modulate glutamatergic neurotransmission, stimulate synaptic and network remodeling, and up-regulate neurotrophic factors that support neuronal survival. Muscimol reduces Aβ-induced neurotoxicity, and Sigma-1 receptor agonists protect against Aβ toxicity. Psychedelics activate mTOR pathways in brain regions that atrophy in Alzheimer's, induce structural and functional neural plasticity, increase neurogenesis, and rewire pathological neurocircuitry. These effects enhance brain functional connectivity and address multiple degenerative mechanisms, warranting immediate investigation of psychedelics as treatments for Alzheimer's patients.
Comprehensive psychoneuroendocrinology
February 1, 2023
Daniel Rødbro Burmester, Martin Korsbak Madsen, Attila Szabo et al.
24 citations
A single dose of psilocybin did not significantly change peripheral biomarkers of inflammation—high-sensitivity C-reactive protein (hsCRP), tumor-necrosis-factor (TNF), and soluble urokinase plasminogen activator receptor (suPAR)—in 16 healthy individuals one day after administration. All effect sizes were small (Cohen's d ≤ 0.31) and p-values were ≥ 0.23. These findings do not support that a single dose of psilocybin reduces inflammation in healthy people, though future studies should examine additional markers and clinical populations where effects may be more detectable.
Frontiers in Neuroscience
September 14, 2016
Attila Szabo, A. Kovács, Jordi Riba et al.
18 citations
N,N-dimethyltryptamine (DMT), an endogenous hallucinogen found in the human brain, activates the sigma-1 receptor (Sig-1R), an intracellular chaperone that helps manage cellular stress. This study tested whether DMT protects brain cells from hypoxia by activating Sig-1R. In cultured human cortical neurons, macrophages, and dendritic cells exposed to severe hypoxia (0.5% O2), DMT robustly increased cell survival through Sig-1R activation. This effect was linked to decreased expression and function of hypoxia-inducible factor 1 alpha (HIF-1α), suggesting DMT alleviates hypoxic stress independently of HIF-1. The results indicate DMT may be endogenously produced during stress to protect the brain from hypoxic or ischemic damage.
Science advances
August 15, 2025
Marcell J László, Judit P Vigh, Anna E Kocsis et al.
9 citations
In a rat stroke model, DMT reduces brain damage by decreasing swelling, restoring the blood-brain barrier, and shifting the body toward an anti-inflammatory state. DMT also suppresses inflammatory signals from brain and immune cells via the sigma-1 receptor. These effects suggest DMT could complement existing stroke therapies.
medRxiv
November 1, 2022
Natasha L. Mason, Attila Szabo, Kim P. C. Kuypers et al.
6 citations
preprint
Psilocybin immediately reduced concentrations of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), while other inflammatory markers (interleukin-1α, IL-1β, IL-6, and C-reactive protein) remained unchanged. Seven days later, TNF-α returned to baseline, but IL-6 and CRP were persistently reduced in the psilocybin group. Changes in immune profile were linked to acute neurometabolic activity: reductions in TNF-α were associated with lower hippocampal glutamate concentrations. Greater reductions in IL-6 and CRP at seven days correlated with persisting positive mood and social effects. Psilocybin also blunted the cortisol response to a psychosocial stressor compared to placebo.
International review of neurobiology
January 1, 2025
Ede Frecska, Attila Kovács, Attila Szabo
2 citations
DMT, an endogenous agonist of the sigma-1 receptor (Sig-1R) in addition to its serotonin receptor actions, shows therapeutic potential for neuroprotection against ischemia-reperfusion injury (IRI) and neurodegenerative disorders. Sigma-1 receptors are highly expressed in the brain and spinal cord and are implicated in central nervous system disorders. Previous theoretical and experimental work suggests targeting sigma and serotonin receptors via DMT may treat conditions like stroke, global brain ischemia, Alzheimer's disease, and amyotrophic lateral sclerosis. The paper reviews Sig-1R's role in cellular bioenergetics related to IRI and summarizes preclinical DMT studies that mitigated IRI and related neuropathologies. DMT's effect may involve universal cellular protective mechanisms, positioning it as a model molecule for developing treatments for neurodegenerative disorders.
Journal of Psychedelic Studies
September 8, 2025
Malin Vedøy Uthaug, Giancarlo Allocca, Martha Havenith et al.
1 citation
The paper introduces the concept of 'bodyset'—the state of the body, including both body and brain—as a vital element in preparing for psychedelic experiences, expanding the traditional 'set and setting' framework. Through a literature review, it argues that the body likely matters for wellbeing, peak performance, and peak experiences. Comprehensive multidisciplinary research, especially on biomarkers, is needed to clarify the role of bodyset in psychedelic experiences and therapy outcomes. The authors suggest that considering physical state alongside psychological and environmental factors may enhance understanding of psychedelic effects and inform other treatments like breathwork.
Journal of Psychedelic Studies
June 26, 2026
Malin V. Uthaug, Jack G. Allocca, Martha Havenith et al.
A new construct called Pivotal Physical States (PiPS) is proposed as the bodily counterpart to Pivotal Mental States (PiMS). PiMS theory holds that psychedelics and stressors like fasting and hypoxia can trigger transformative mental states via serotonin receptor activation, enhancing cognitive flexibility and learning. The paper argues that these same stressors also induce profound bodily changes through the peripheral serotonin system and other somatic mechanisms, creating 'pivotal states' spanning the mind–body continuum. This dual action may enable psychological and physiological recalibration in positive or negative directions depending on moderators. The authors call for empirical validation of PiPS to guide integrated research and therapeutic applications.
bioRxiv (Cold Spring Harbor Laboratory)
April 12, 2026
Ibrahim A. Akkouh, Jordi Requena Osete, N. W. Steen et al.
Activating GABA-A receptors with muscimol, a non-classic psychedelic, suppresses inflammatory signaling and promotes neuroplasticity in human cortical spheroids and astrocytes derived from patients with schizophrenia. Inflammatory stimulation triggered interferon-responsive gene programs, with astrocytes acting as key mediators. Muscimol reduced proinflammatory cytokine secretion, attenuated interferon signaling, and upregulated neuroplasticity-related genes such as NTRK2 and ELK1. It also restored impaired glutamate uptake in schizophrenia-derived astrocytes. These effects depended on GABA-A receptor activation. Proteomic analyses of spheroids and human brain tissue confirmed baseline dysregulation of GABAergic and neurotrophin signaling in schizophrenia, supporting the therapeutic potential of targeting astrocyte GABAergic signaling to restore neural homeostasis.
Journal of behavioral addictions
February 3, 2026
Atanas Tannous, Zsolt Demetrovics, Bhavya Chhabra et al.
Mindfulness-based interventions (MBIs) consistently reduce gambling frequency and cravings while improving psychological outcomes. When combined with cognitive behavioral therapy, MBIs produce significant declines in problem gambling behavior. Psychological distress and cravings also decrease notably across different intervention types. However, it remains unclear how much of these effects come from mindfulness-specific mechanisms. The evidence comes from 12 studies, including five randomized controlled trials, but small sample sizes and methodological limitations mean more robust research is needed.
July 3, 2025
Natasha L. Mason, Pablo-Alexandre Mallaroni, Attila Szabo et al.
preprint
The long-term antidepressant effects of classic psychedelics may arise from changes in behavioral processes (decreased rumination, enhanced cognitive flexibility), central processes (downregulation of the hippocampal-prefrontal cortex axis, normalization of glutamate concentrations, increased neuroplasticity), and peripheral processes (downregulation of inflammatory markers). These interconnected changes collectively trigger a sustained therapeutic response, with the glutamatergic system serving as the main interface orchestrating them. The proposed Syner-G model emphasizes glutamatergic-dependent signaling as the primary unifying and synergizing interface between these processes. Future research avenues are suggested to advance understanding of psychedelic mechanisms and neuropsychiatric disease.
The International journal of clinical and experimental hypnosis
January 1, 2022
Eniko Kasos, Krisztian Kasos, Emese Józsa et al.
A nonrandomized comparison examined whether exercise produces states of consciousness similar to active-alert hypnosis (AAH). Runners, spinning-class participants, AAH subjects, and a control class completed the Phenomenology of Consciousness Inventory. Runners and spinners scored higher than controls on altered experience and altered state of awareness, similar to AAH participants. Runners scored highest on rationality, while the AAH group scored lowest on self-awareness. On volitional control, spinners and controls scored higher than runners and the AAH group. The findings suggest exercise may induce hypnotic-like states that could increase responsiveness to a coach's suggestions.