Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo

Neuron, Journal Year: 2021, Volume and Issue: 109(16), P. 2535 - 2544.e4

Published: July 5, 2021

Language: Английский

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Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors

Science, Journal Year: 2023, Volume and Issue: 379(6633), P. 700 - 706

Published: Feb. 16, 2023

Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and ability to promote cortical neuron growth has been hypothesized underlie rapid sustained therapeutic effects psychedelics. Activation 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) essential for psychedelic-induced plasticity, but it currently unclear why some 5-HT2AR agonists neuroplasticity, whereas others do not. We used molecular genetic tools demonstrate that intracellular 5-HT2ARs mediate plasticity-promoting properties psychedelics; these results explain serotonin does not engage similar plasticity mechanisms. This work emphasizes role location bias signaling, identifies as target, raises intriguing possibility might be endogenous ligand cortex.

Language: Английский

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The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects

ACS Pharmacology & Translational Science, Journal Year: 2020, Volume and Issue: 4(2), P. 563 - 567

Published: Dec. 10, 2020

Psychedelics represent one of the most promising classes experimental medicines for treatment neuropsychiatric disorders due to their ability promote neural plasticity and produce both rapid sustained therapeutic effects following a single administration. Conventional wisdom holds that peak mystical experiences induced by psychedelics are critical component mechanisms action, though evidence supporting claim is largely correlational. Here, I present data suggesting subjective may not be necessary long-lasting changes in mood behavior. Understanding role will have important implications basic neuroscience increasing patient access next generation developed as result psychedelic research.

Language: Английский

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Psychedelics promote plasticity by directly binding to BDNF receptor TrkB

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(6), P. 1032 - 1041

Published: June 1, 2023

Abstract Psychedelics produce fast and persistent antidepressant effects induce neuroplasticity resembling the of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine ketamine, act by binding to TrkB, receptor for BDNF. Here we show lysergic acid diethylamide (LSD) psilocin directly bind TrkB with affinities 1,000-fold higher than those other psychedelics antidepressants distinct but partially overlapping sites within transmembrane domain dimers. The on neurotrophic signaling, plasticity antidepressant-like behavior in mice depend promotion endogenous BDNF signaling are independent serotonin 2A (5-HT ) activation, whereas LSD-induced head twitching is dependent 5-HT binding. Our data confirm as a common primary target suggest high-affinity positive allosteric modulators lacking activity may retain potential without hallucinogenic effects.

Language: Английский

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Towards an understanding of psychedelic-induced neuroplasticity

Neuropsychopharmacology, Journal Year: 2022, Volume and Issue: 48(1), P. 104 - 112

Published: Sept. 19, 2022

Classic psychedelics, such as LSD, psilocybin, and the DMT-containing beverage ayahuasca, show some potential to treat depression, anxiety, addiction. Importantly, clinical improvements can last for months or years after treatment. It has been theorized that these long-term arise because psychedelics rapidly lastingly stimulate neuroplasticity. The focus of this review is on answering specific questions about effects Firstly, we evidence promote neuroplasticity examine cellular molecular mechanisms behind different aspects neuroplasticity, including dendritogenesis, synaptogenesis, neurogenesis, expression plasticity-related genes (e.g., brain-derived neurotrophic factor immediate early genes). We then where in brain particularly discussing prefrontal cortex hippocampus. also what doses are required produce effect hallucinogenic vs. "microdoses"), how long purported changes last. Finally, discuss likely consequences psychedelics' both patients healthy people, identify important research would further scientific understanding its applications.

Language: Английский

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Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics

Trends in Pharmacological Sciences, Journal Year: 2021, Volume and Issue: 42(11), P. 929 - 942

Published: Sept. 24, 2021

Language: Английский

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The neural basis of psychedelic action

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(11), P. 1407 - 1419

Published: Oct. 24, 2022

Language: Английский

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Psychedelics and Other Psychoplastogens for Treating Mental Illness

Frontiers in Psychiatry, Journal Year: 2021, Volume and Issue: 12

Published: Oct. 4, 2021

Psychedelics have inspired new hope for treating brain disorders, as they seem to be unlike any treatments currently available. Not only do produce sustained therapeutic effects following a single administration, also appear broad potential, demonstrating efficacy depression, post-traumatic stress disorder (PTSD), anxiety substance abuse disorder, and alcohol use among others. belong more general class of compounds known psychoplastogens, which robustly promote structural functional neural plasticity in key circuits relevant health. Here we discuss the importance treatment neuropsychiatric diseases, well evidence that psychedelics are most effective chemical modulators studied date. Furthermore, provide theoretical framework with potential explain why psychedelic long-lasting across wide range disorders. Despite their promise broadly efficacious neurotherapeutics, there several issues associated psychedelic-based medicines drastically limit clinical scalability. We these challenges how might overcome through development non-hallucinogenic psychoplastogens. The other psychoplastogenic marks paradigm shift neuropsychiatry toward approaches relying on selective modulation small molecule drugs. Psychoplastogen research brings us one step closer actually curing mental illness by rectifying underlying pathophysiology disorders like moving beyond simply disease symptoms. However, determining effectively deploy at scale will an important consideration field moves forward.

Language: Английский

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Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity

Biochemistry, Journal Year: 2022, Volume and Issue: 61(3), P. 127 - 136

Published: Jan. 21, 2022

In addition to producing profound subjective effects following acute administration, psychedelic compounds can induce beneficial behavioral changes relevant the treatment of neuropsychiatric disorders that last long after have been cleared from body. One hypothesis with potential explain remarkable enduring psychedelics is related their abilities promote structural and functional neuroplasticity in prefrontal cortex (PFC). A hallmark many stress-related diseases, including depression, post-traumatic stress disorder (PTSD), addiction, atrophy neurons PFC. Psychedelics appear be particularly effective catalysts for growth these key neurons, ultimately leading restoration synaptic connectivity this critical brain region. Furthermore, evidence suggests hallucinogenic are not directly linked ability neuroplasticity. If we develop improved alternatives treating must fully characterize molecular mechanisms give rise psychedelic-induced Here, I review our current understanding biochemical signaling pathways activated by neuroplasticity-promoting molecules, an emphasis on unanswered questions.

Language: Английский

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A non-hallucinogenic LSD analog with therapeutic potential for mood disorders

Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112203 - 112203

Published: March 1, 2023

Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism several GPCRs, including 5-HT2A, and does not induce head-twitch response (HTR) in mice, supporting its classification a 5-HT2A agonist. Unlike LSD, lacks 5-HT2B agonism, an effect linked to cardiac valvulopathy. Additionally, produces weak β-arrestin recruitment internalization vitro tolerance vivo after repeated administration. induces dendritogenesis spinogenesis cultured rat cortical neurons increases active coping behavior blocked by 5-HT2A-selective antagonist volinanserin (M100907). also reverses behavioral effects chronic stress. Overall, has improved pharmacological profile compared with LSD may have profound value for mood disorders other indications.

Language: Английский

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