Neuromodulatory effects of psychedelics:
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Paper associated with this video lecture:
Catlow, B. J., Song, S., Paredes, D. A., Kirstein, C. L., & Sanchez-Ramos, J. (2013). Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning. Experimental brain research. 228(4), 481–491. https://doi.org/10.1007/s00221-013-3579-0
de Sousa Fernandes, M. S., Ordônio, T. F., Santos, G. C. J., Santos, L. E. R., Calazans, C. T., Gomes, D. A., & Santos, T. M.. (2020). Effects of Physical Exercise on Neuroplasticity and Brain Function: A Systematic Review in Human and Animal Studies. Neural Plasticity, 2020, 1–21.
“Background. physical exercise (pe) has been associated with increase neuroplasticity, neurotrophic factors, and improvements in brain function. objective. to evaluate the effects of different pe protocols on neuroplasticity components and brain function in a human and animal model. methods. we conducted a systematic review process from november 2019 to january 2020 of the following databases: pubmed, sciencedirect, scielo, lilacs, and scopus. a keyword combination referring to pe and neuroplasticity was included as part of a more thorough search process. from an initial number of 20,782 original articles, after reading the titles and abstracts, twenty-one original articles were included. two investigators evaluated the abstract, the data of the study, the design, the sample size, the participant characteristics, and the pe protocol. results. pe increases neuroplasticity via neurotrophic factors (bdnf, gdnf, and ngf) and receptor (trkb and p75ntr) production providing improvements in neuroplasticity, and cognitive function (learning and memory) in human and animal models. conclusion. pe was effective for increasing the production of neurotrophic factors, cell growth, and proliferation, as well as for improving brain functionality.”
Kraus, C., Castrén, E., Kasper, S., & Lanzenberger, R.. (2017). Serotonin and neuroplasticity – Links between molecular, functional and structural pathophysiology in depression. Neuroscience & Biobehavioral Reviews, 77, 317–326.
“Serotonin modulates neuroplasticity, especially during early life, and dysfunctions in both systems likewise contribute to pathophysiology of depression. recent findings demonstrate that serotonin reuptake inhibitors trigger reactivation of juvenile-like neuroplasticity. how these findings translate to clinical antidepressant treatment in major depressive disorder remains unclear. with this review, we link preclinical with clinical work on serotonin and neuroplasticity to bring two pathophysiologic models in clinical depression closer together. dysfunctional developmental plasticity impacts on later-life cognitive and emotional functions, changes of synaptic serotonin levels and receptor levels are coupled with altered synaptic plasticity and neurogenesis. structural magnetic resonance imaging in patients reveals disease-state-specific reductions of gray matter, a marker of neuroplasticity, and reversibility upon selective serotonin reuptake inhibitor treatment. translational evidence from magnetic resonance imaging in animals support that reduced densities and sizes of neurons and reduced hippocampal volumes in depressive patients could be attributable to changes of serotonergic neuroplasticity. since ketamine, physical exercise or learning enhance neuroplasticity, combinatory paradigms with selective serotonin reuptake inhibitors could enhance clinical treatment of depression.”
Wu, H., Yan, H., Yang, Y., Xu, M., Shi, Y., Zeng, W., … Wang, N.. (2020). Occupational Neuroplasticity in the Human Brain: A Critical Review and Meta-Analysis of Neuroimaging Studies. Frontiers in Human Neuroscience, 14
“Many studies have revealed the structural or functional brain changes induced by occupational factors. however, it remains largely unknown how occupation-related connectivity shapes the brain. in this paper, we denote occupational neuroplasticity as the neuroplasticity that takes place to satisfy the occupational requirements by extensively professional training and to accommodate the long-term, professional work of daily life, and a critical review of occupational neuroplasticity related to the changes in brain structure and functional networks has been primarily presented. furthermore, meta-analysis revealed a neurophysiological mechanism of occupational neuroplasticity caused by professional experience. this meta-analysis of functional neuroimaging studies showed that experts displayed stronger activation in the left precentral gyrus [brodmann area (ba)6], left middle frontal gyrus (ba6), and right inferior frontal gyrus (ba9) than novices, while meta-analysis of structural studies suggested that experts had a greater gray matter volume in the bilateral superior temporal gyrus (ba22) and right putamen than novices. together, these findings not only expand the current understanding of the common neurophysiological basis of occupational neuroplasticity across different occupations and highlight some possible targets for neural modulation of occupational neuroplasticity but also provide a new perspective for occupational science research.”
de Vos, C. M. H., Mason, N. L., & Kuypers, K. P. C.. (2021). Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. Frontiers in Psychiatry, 12
“Clinical studies suggest the therapeutic potential of psychedelics, including ayahuasca, dmt, psilocybin, and lsd, in stress-related disorders. these substances induce cognitive, antidepressant, anxiolytic, and antiaddictive effects suggested to arise from biological changes similar to conventional antidepressants or the rapid-acting substance ketamine. the proposed route is by inducing brain neuroplasticity. this review attempts to summarize the evidence that psychedelics induce neuroplasticity by focusing on psychedelics’ cellular and molecular neuroplasticity effects after single and repeated administration. when behavioral parameters are encountered in the selected studies, the biological pathways will be linked to the behavioral effects. additionally, knowledge gaps in the underlying biology of clinical outcomes of psychedelics are highlighted. the literature searched yielded 344 results. title and abstract screening reduced the sample to 35; eight were included from other sources, and full-text screening resulted in the final selection of 16 preclinical and four clinical studies. studies ( n = 20) show that a single administration of a psychedelic produces rapid changes in plasticity mechanisms on a molecular, neuronal, synaptic, and dendritic level. the expression of plasticity-related genes and proteins, including brain-derived neurotrophic factor (bdnf), is changed after a single administration of psychedelics, resulting in changed neuroplasticity. the latter included more dendritic complexity, which outlasted the acute effects of the psychedelic. repeated administration of a psychedelic directly stimulated neurogenesis and increased bdnf mrna levels up to a month after treatment. findings from the current review demonstrate that psychedelics induce molecular and cellular adaptations related to neuroplasticity and suggest those run parallel to the clinical effects of psychedelics, potentially underlying them. future (pre)clinical research might focus on deciphering the specific cellular mechanism activated by different psychedelics and related to long-term clinical and biological effects to increase our understanding of the therapeutic potential of these compounds.”
Cramer, S. C., Sur, M., Dobkin, B. H., O’Brien, C., Sanger, T. D., Trojanowski, J. Q., … Vinogradov, S.. (2011). Harnessing neuroplasticity for clinical applications. Brain
“Mounting evidence suggests safety and efficacy of psychedelic compounds as potential novel therapeutics in psychiatry. ketamine has been approved by the food and drug administration in a new class of antidepressants, and 3,4-methylenedioxymethamphetamine (mdma) is undergoing phase iii clinical trials for post-traumatic stress disorder. psilocybin and lysergic acid diethylamide (lsd) are being investigated in several phase ii and phase i clinical trials. hence, the concept of psychedelics as therapeutics may be incorporated into modern society. here, we discuss the main known neurobiological therapeutic mechanisms of psychedelics, which are thought to be mediated by the effects of these compounds on the serotonergic (via 5-ht2a and 5-ht1a receptors) and glutamatergic [via n-methyl-d-aspartate (nmda) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (ampa) receptors] systems. we focus on 1) neuroplasticity mediated by the modulation of mammalian target of rapamycin-, brain-derived neurotrophic factor-, and early growth response-related pathways; 2) immunomodulation via effects on the hypothalamic-pituitaryadrenal axis, nuclear factor kb, and cytokines such as tumor necrosis factor-a and interleukin 1, 6, and 10 production and release; and 3) modulation of serotonergic, dopaminergic, glutamatergic, gabaergic, and norepinephrinergic receptors, transporters, and turnover systems. we discuss arising concerns and ways to assess potential neurobiological changes, dependence, and immunosuppression. although larger cohorts are required to corroborate preliminary findings, the results obtained so far are promising and represent a critical opportunity for improvement of pharmacotherapies in psychiatry, an area that has seen limited therapeutic advancement in the last 20 years. studies are underway that are trying to decouple the psychedelic effects from the therapeutic effects of these compounds.”
Lord, L.-D., Expert, P., Atasoy, S., Roseman, L., Rapuano, K., Lambiotte, R., … Cabral, J.. (2019). Dynamical exploration of the repertoire of brain networks at rest is modulated by psilocybin. NeuroImage, 199, 127–142.
“Growing evidence from the dynamical analysis of functional neuroimaging data suggests that brain function can be understood as the exploration of a repertoire of metastable connectivity patterns (‘functional brain networks’), which potentially underlie different mental processes. the present study characterizes how the brain’s dynamical exploration of resting-state networks is rapidly modulated by intravenous infusion of psilocybin, a tryptamine psychedelic found in ‘magic mushrooms’. we employed a data-driven approach to characterize recurrent functional connectivity patterns by focusing on the leading eigenvector of bold phase coherence at single-tr resolution. recurrent bold phase-locking patterns (pl states) were assessed and statistically compared pre- and post-infusion of psilocybin in terms of their probability of occurrence and transition profiles. results were validated using a placebo session. recurrent bold pl states revealed high spatial overlap with canonical resting-state networks. notably, a pl state forming a frontoparietal subsystem was strongly destabilized after psilocybin injection, with a concomitant increase in the probability of occurrence of another pl state characterized by global bold phase coherence. these findings provide evidence of network-specific neuromodulation by psilocybin and represent one of the first attempts at bridging molecular pharmacodynamics and whole-brain network dynamics.”
Kringelbach, M. L., Cruzat, J., Cabral, J., Knudsen, G. M., Carhart-Harris, R., Whybrow, P. C., … Deco, G.. (2020). Dynamic coupling of whole-brain neuronal and neurotransmitter systems. Proceedings of the National Academy of Sciences, 117(17), 9566–9576.
“Remarkable progress has come from whole-brain models linking anatomy and function. paradoxically, it is not clear how a neuronal dynamical system running in the fixed human anatomical connectome can give rise to the rich changes in the functional repertoire associated with human brain function, which is impossible to explain through long-term plasticity. neuromodulation evolved to allow for such flexibility by dynamically updating the effectivity of the fixed anatomical connectivity. here, we introduce a theoretical framework modeling the dynamical mutual coupling between the neuronal and neurotransmitter systems. we demonstrate that this framework is crucial to advance our understanding of whole-brain dynamics by bidirectional coupling of the two systems through combining multimodal neuroimaging data (diffusion magnetic resonance imaging [dmri], functional magnetic resonance imaging [fmri], and positron electron tomography [pet]) to explain the functional effects of specific serotoninergic receptor (5-ht 2a r) stimulation with psilocybin in healthy humans. this advance provides an understanding of why psilocybin is showing considerable promise as a therapeutic intervention for neuropsychiatric disorders including depression, anxiety, and addiction. overall, these insights demonstrate that the whole-brain mutual coupling between the neuronal and the neurotransmission systems is essential for understanding the remarkable flexibility of human brain function despite having to rely on fixed anatomical connectivity.”
Meinhardt, M. W., Pfarr, S., Fouquet, G., Rohleder, C., Meinhardt, M. L., Barroso-Flores, J., … Sommer, W. H.. (2021). Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism. Science Advances, 7(47)
“Alcohol-dependent patients commonly show impairments in executive functions that facilitate craving and can lead to relapse. however, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood, and new effective pharmacological treatments are desired. here, using a bidirectional neuromodulation approach, we demonstrate a causal link between reduced prefrontal mglur2 function and both impaired executive control and alcohol craving. a neuron-specific prefrontal mglur2 knockdown in rats generated a phenotype of reduced cognitive flexibility and excessive alcohol seeking. conversely, virally restoring prefrontal mglur2 levels in alcohol-dependent rats rescued these pathological behaviors. in the search for a pharmacological intervention with high translational potential, psilocybin was capable of restoring mglur2 expression and reducing relapse behavior. last, we propose a fdg-pet biomarker strategy to identify mglur2 treatment-responsive individuals. in conclusion, we identified a common molecular pathological mechanism for both executive dysfunction and alcohol craving and provided a personalized mglur2 mechanism-based intervention strategy for medication development for alcoholism.”
Grassi, G., Cecchelli, C., Vignozzi, L., & Pacini, S.. (2021). Investigational and Experimental Drugs to Treat Obsessive-Compulsive Disorder. Journal of Experimental Pharmacology, Volume 12, 695–706.
“Giacomo grassi, chiara cecchelli, luisa vignozzi, silvia pacini neuroscience department, brain center firenze, florence, italy correspondence: giacomo grassi brain center firenze, viale belfiore 36, florence 50144, italy email firstname.lastname@example.org treatment-resistance is a frequent condition for obsessive-compulsive disorder (ocd). over the past decades, a lot of effort has been made to address this issue, and several augmentation strategies of serotonergic drugs have been investigated. antidopaminergic drugs are considered the first choice as augmentation strategy for treatment-resistant ocd patients, but they seem to work only for a subset of patients, and none of them have been officially approved for ocd. recently, the role of glutamate and inflammation in ocd pathophysiology clearly emerged, and this has led to several investigations on glutamatergic and anti-inflammatory agents. results seem promising but still inconclusive. probiotic interventions (considered to modulate the immune systems and the brain activity) are gaining attention in several psychiatric fields but are still at their early stages in the ocd field. research on new treatment approaches for ocd is moving forward, and more than one hundred interventional trials are ongoing around the world. while the vast majority of these trials involve neuromodulation and psychotherapeutic approaches, only a small proportion (around 20%) involve the investigation of new pharmacological approaches (tolcapone, nabilone, psilocybin, troriluzole, nitrous oxide, rituximab, naproxen, and immunoglobulins). here, we provide a comprehensive review of investigational and experimental drugs to treat ocd. keywords: ocd, glutamate, immune system, inflammation, probiotics, pharmacotherapy”
Ho, J. T., Preller, K. H., & Lenggenhager, B.. (2020). Neuropharmacological modulation of the aberrant bodily self through psychedelics. Neuroscience & Biobehavioral Reviews, 108, 526–541.
“As a continual source of sensory input and fundamental component of self-referential processing, the body holds an integral modulatory role in cognition. in a healthy state, predictive coding of multisensory integration promotes the construction of a coherent self. however, several psychiatric disorders comprise aberrant perceptions of the bodily self that are purported to involve discrepancies in the integration and updating of multisensory systems. changes in functional connectivity of somatomotor and high-level association networks in these disorders could be successfully remediated through 5-ht2a receptor agonism via psychedelics. reported alterations of bodily self-awareness during psychedelic experiences allude to a potentially central role of the bodily self. in this article, we bridge the domains of (aberrant) bodily self-awareness and psychedelics by discussing the predictive coding mechanisms underlying the bodily self and psychedelics. furthermore, we propose that psychedelically-induced desynchronization of predictive coding might involve modulation of somatomotor, sensorimotor, and high-level association networks that could remediate aberrant perceptions of the bodily self.”
Teixeira-Machado, L., Arida, R. M., & de Jesus Mari, J.. (2019). Dance for neuroplasticity: A descriptive systematic review. Neuroscience and Biobehavioral Reviews
“We conducted a systematic review of randomized clinical trials to investigate whether dance practice promotes neuroplasticity. we also determined how dancing is able to alter (1) brain volumes and structures (2) brain function, (3) psychomotor adjustment and (4) levels of neurotrophic factors. this systematic review formulated a research question based on pico, according to the guidelines for systematic reviews and meta-analyzes (prisma), ‘what is the influence of dance practice on neuroplasticity in already mature brains?’ we screened 1071 studies and from these eight studies were included in the review. of the selected studies, all demonstrated positive structural and/or functional changes. structural changes included increased hippocampal volume, gray matter volume in the left precentral and parahippocampal gyrus, and white matter integrity. functional changes included alterations in cognitive function such as significant improvement in memory, attention, body balance, psychosocial parameters and altered peripheral neurotrophic factor. based on the evidence, dance practice integrates brain areas to improve neuroplasticity.”