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Journal articleAgnorelli C, Spriggs M, Godfrey K, et al., 2025,
Neuroplasticity and Psychedelics: A comprehensive examination of classic and non-classic compounds in pre and clinical models.
, Neurosci Biobehav RevNeuroplasticity, the ability of the nervous system to adapt throughout an organism's lifespan, offers potential as both a biomarker and treatment target for neuropsychiatric conditions. Psychedelics, a burgeoning category of drugs, are increasingly prominent in psychiatric research, prompting inquiries into their mechanisms of action. Distinguishing themselves from traditional medications, psychedelics demonstrate rapid and enduring therapeutic effects after a single or few administrations, believed to stem from their neuroplasticity-enhancing properties. This review examines how classic psychedelics (e.g., LSD, psilocybin, N,N-DMT) and non-classic psychedelics (e.g., ketamine, MDMA) influence neuroplasticity. Drawing from preclinical and clinical studies, we explore the molecular, structural, and functional changes triggered by these agents. Animal studies suggest psychedelics induce heightened sensitivity of the nervous system to environmental stimuli (meta-plasticity), re-opening developmental windows for long-term structural changes (hyper-plasticity), with implications for mood and behavior. Translating these findings to humans faces challenges due to limitations in current imaging techniques. Nonetheless, promising new directions for human research are emerging, including the employment of novel positron-emission tomography (PET) radioligands, non-invasive brain stimulation methods, and multimodal approaches. By elucidating the interplay between psychedelics and neuroplasticity, this review informs the development of targeted interventions for neuropsychiatric disorders and advances understanding of psychedelics' therapeutic potential. "And one finds oneself, to put it all in perspective, in a situation where fifty different onomatopoeias, simultaneous, contradictory, and each constantly changing, would be the most faithful expression of it." Henri Michaux, Misérable Miracle, 1956.
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Journal articleColeman CR, Shinozuka K, Tromm R, et al., 2025,
The Role of the Dorsolateral Prefrontal Cortex in Ego Dissolution and Emotional Arousal During the Psychedelic State
, Human Brain Mapping, Vol: 46, ISSN: 1065-9471Lysergic acid diethylamide (LSD) is a classic serotonergic psychedelic that induces a profoundly altered conscious state. In conjunction with psychological support, it is currently being explored as a treatment for generalized anxiety disorder and depression. The dorsolateral prefrontal cortex (DLPFC) is a brain region that is known to be involved in mood regulation and disorders; hypofunction in the left DLPFC is associated with depression. This study investigated the role of the DLPFC in the psycho-emotional effects of LSD with functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) data of healthy human participants during the acute LSD experience. In the fMRI data, we measured the correlation between changes in resting-state functional connectivity (RSFC) of the DLPFC and post-scan subjective ratings of positive mood, emotional arousal, and ego dissolution. We found significant, positive correlations between ego dissolution and functional connectivity between the left & right DLPFC, thalamus, and a higher-order visual area, the fusiform face area (FFA). Additionally, emotional arousal was significantly associated with increased connectivity between the right DLPFC, intraparietal sulcus (IPS), and the salience network (SN). A confirmational “reverse” analysis, in which the outputs of the original RSFC analysis were used as input seeds, substantiated the role of the right DLPFC and the aforementioned regions in both ego dissolution and emotional arousal. Subsequently, we measured the effects of LSD on directed functional connectivity in MEG data that was source-localized to the input and output regions of both the original and reverse analyses. The Granger causality (GC) analysis revealed that LSD increased information flow between two nodes of the ‘ego dissolution network’, the thalamus and the DLPFC, in the theta band, substantiating the hypothesis that disruptions in thalamic gating underlie the experience of eg
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Journal articleRoseman L, 2025,
A reflection on paradigmatic tensions within the FDA advisory committee for MDMA-assisted therapy.
, J Psychopharmacol, Vol: 39, Pages: 313-315The recent rejection of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy by the U.S. Food and Drug Administration (FDA) is a dramatic moment in the re-emergence of psychedelic research. In this perspective, I argue that it represents a case study for paradigmatic tensions within psychopharmacology. The regulatory system is still influenced by a paradigm that sees the therapeutic effects of drugs as primarily biological, and context is noise to control for. An emergent paradigm considers the therapeutic effects of drugs as interactive with context. Psychedelics are the anomaly that questions the dominant paradigm, mainly due to the determination of psychedelic researchers that the medicines are drugs with psychotherapy. While some of the critique offered by the FDA towards MAPS/Lykos's studies is crucial, much of it is related to the experiential and psychotherapeutic elements - which the FDA claims not to regulate. This leads to some paradoxes within the regulatory procedure, which hint at a need for a shift in how psychedelic-assisted therapy is regulated and researched. Both regulators and researchers will need to find ways to accommodate each other in service of a successful integration of a new paradigm in which drugs and psychotherapy interact.
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Journal articleTimmermann Slater CB, Sanders J, Reydellet D, et al., 2025,
Exploring 5-MeO-DMT as a pharmacological model for deconstructed consciousness
, Neuroscience of Consciousness, ISSN: 2057-2107 -
Journal articlePiccinini JI, Sanz Perl Y, Pallavicini C, et al., 2025,
Transient destabilization of whole brain dynamics induced by N,N-Dimethyltryptamine (DMT).
, Commun Biol, Vol: 8The transition towards the brain state induced by psychedelic drugs is frequently neglected in favor of a static description of their acute effects. We use a time-dependent whole-brain model to reproduce large-scale brain dynamics measured with fMRI from 15 volunteers under 20 mg intravenous N,N-Dimethyltryptamine (DMT), a short-acting psychedelic. To capture its transient effects, we parametrize the proximity to a global bifurcation using a pharmacokinetic equation. Simulated perturbations reveal a transient of heightened reactivity concentrated in fronto-parietal regions and visual cortices, correlated with serotonin 5HT2a receptor density, the primary target of psychedelics. These advances suggest a mechanism to explain key features of the psychedelic state and also predicts that the temporal evolution of these features aligns with pharmacokinetics. Our results contribute to understanding how psychedelics introduce a transient where minimal perturbations can achieve a maximal effect, shedding light on how short psychedelic episodes may extend an overarching influence over time.
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Journal articleCarrithers BM, Roberts DE, Weiss BM, et al., 2025,
Exploring serotonergic psychedelics as a treatment for personality disorders.
, Neuropharmacology, Vol: 272Both psychotherapeutic interventions and pharmacological agents have demonstrated limited efficacy in the treatment of personality disorders (PDs). Emerging evidence suggests that psychedelic therapy, already showing promise in treating various psychiatric conditions commonly comorbid with PDs, may exert therapeutic effects by promoting adaptive changes in personality. Thus, psychedelic therapy could hold potential for addressing core features of PDs through shared mechanisms of personality modulation. Although historical literature and observational studies suggest the potential clinical utility of psychedelics in treating PDs, rigorous research is lacking, and individuals with PDs are often excluded from modern psychedelic therapy trials. In the present review, we first discuss research on the effects of psychedelics in individuals with a PD through the conventional lens of the Diagnostic and Statistical Manual of Mental Disorders (5th ed., text rev.; DSM-5-TR) categorical model. Next, using the dimensional DSM Alternative Model of Personality Disorders (DSM-AMPD) as a framework, we examine how psychedelics may affect self-functioning, interpersonal functioning, and pathological personality traits. We conclude by discussing the clinical relevance of psychedelic therapy as a treatment for personality pathology, including safety considerations, gaps and limitations, and recommendations for approaching psychedelic therapy within these more complex clinical populations.
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Journal articleCardone P, Núñez P, Alnagger NLN, et al., 2025,
Psilocybin for disorders of consciousness: A case-report study.
, Clin Neurophysiol, Vol: 173, Pages: 181-189OBJECTIVE: With very few treatments available, post-comatose disorders of consciousness (DoC) pose one of the hardest challenges in modern neurology. Following promising clinical trial results in psychiatry, and a deepening understanding of their brain mechanisms, psychedelics have been suggested as a novel therapeutic drug for DoC patients, given that they increase the entropy or complexity of spontaneous activity in healthy participants. However, no attempts have been so far performed in patients with DoC. METHODS: In this case report, we describe the first-ever administration of psilocybin, a classic psychedelic (i.e., agonist at the 5-HT2A receptor), to a patient in a minimally conscious state plus. We report the behavioural effects and changes in neurophysiology measured with EEG. RESULTS: We report no increase in overt behavioural repertoire with validated scales, yet new spontaneous behaviour not previously seen, and increased brain complexity, as measured by the Lempel-Ziv complexity index, with changes in the underlying periodic rhythms. CONCLUSIONS: This study contributes to future investigations exploring the use of psychedelics in DoC, enriching the discussion surrounding the role of psychedelics in medicine, and the link between brain complexity and consciousness. SIGNIFICANCE: This is the first-ever report of a classic psychedelic used as a treatment for post-comatose DoC.
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Journal articleGoodwin GM, Aaronson ST, Alvarez O, et al., 2025,
The role of the psychedelic experience in psilocybin treatment for treatment-resistant depression.
, J Affect Disord, Vol: 372, Pages: 523-532OBJECTIVE: To determine the relationships between psilocybin dose, psychedelic experiences, and therapeutic outcome in treatment-resistant depression. METHODS: For treatment-resistant depression, 233 participants received a single dose of 25, 10, or 1 mg of COMP360 psilocybin (a proprietary, pharmaceutical-grade synthesized psilocybin formulation, developed by the sponsor, Compass Pathfinder Ltd.) with psychological support. The resulting psychedelic experience (Five-Dimensional Altered States of Consciousness questionnaire [5D-ASC] and Emotional Breakthrough Inventory [EBI]) were measured. These proximal variables and outcome 3 weeks post-administration (change in Montgomery-Åsberg Depression Rating Scale [MADRS]) were explored using correlation analysis. RESULTS: The mean intensity of psychedelic effects was dose-related, but distributions of scores for different doses overlapped considerably. Depression response correlated with select aspects of the psychedelic experience overall and for individual doses. At the 25 mg dose, 5D-ASC dimensions Oceanic Boundlessness (Pearson correlation coefficient r = -0.508) and Visual Restructuralization (r = -0.516), and EBI (r = -0·637) were the variables with the strongest correlation to the Week 3 change from Baseline in MADRS score. LIMITATIONS: The existence of correlation does not establish causation and exploratory findings require further replication, preferably in larger independent samples. CONCLUSIONS: The intensity of psychedelic experience overlaps widely across doses and mitigates the risk of unblinding to dose. Correlations between psychedelic experience and outcome suggest specificity in psilocybin's mechanism of action. Quality and intensity of psychedelic experience may be a measure of pharmacodynamic effect and reveal an effective dose response phenomenon for single oral doses.
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Journal articleEvans J, Aixalà M, Anderson BT, et al., 2025,
On Minimizing Risk and Harm in the Use of Psychedelics
, Psychiatric Research and Clinical Practice, Vol: 7, Pages: 4-8Objective: This article outlines recommendations from 30 psychedelic researchers on how to create a better psychedelic safety net. Methods: A survey of 30 psychedelic researchers asked them to identify key critical research gaps around psychedelic harm and safety. Results: The critical research gaps identified by the authors included defining the main types of psychedelic harm, the predictors of those harms, and the most effective way to treat those harms. They also call for better support for those experiencing post-psychedelic difficulties, including better online information, peer support groups, affordable therapy, and psychiatric consultation and medication. Finally, the authors call for better funding to create a psychedelic safety net, and suggest psychedelic philanthropists, investors and companies could commit 1% of their investment in psychedelics into supporting safety measures such as research and support services. Conclusions: The authors identify several practical steps to create a better psychedelic safety net and call for more funding to psychedelic safety measures such as research and support services. Relevance to clinical practice: The authors outline important gaps in our knowledge around the safety and risk profile of psychedelic medicines and identify practical steps forward for researchers and clinical practitioners to make this promising field safer.
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Journal articleYaden DB, Graziosi M, Owen AM, et al., 2025,
A Field-Wide Review and Analysis of Study Materials Used in Psilocybin Trials: Assessment of Two Decades of Research
, Psychedelic Medicine, Vol: 3, Pages: 1-18, ISSN: 2831-4425
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