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The neural basis of psychedelic action

NATURE NEUROSCIENCE (2022)

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Review Clinical Neurology

Models of psychedelic drug action: modulation of cortical-subcortical circuits

Manoj K. Doss et al.

Summary: Classic psychedelic drugs have potential in treating psychiatric disorders, and the involvement of the serotonin 2A receptor and the cerebral cortex is crucial in their action. Different models, including the CSTC model, REBUS model, and CCC model, have been proposed to explain the impact of 5-HT2A activation on neural systems during psychedelic drug effects.

BRAIN (2022)

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Article Biochemistry & Molecular Biology

Psychedelics

Benjamin Kelmendi et al.

CURRENT BIOLOGY (2022)

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Article Multidisciplinary Sciences

Synthon-based ligand discovery in virtual libraries of over 11 billion compounds

Arman A. Sadybekov et al.

Summary: Structure-based virtual ligand screening using V-SYNTHES method is effective in rapidly identifying high-scoring compounds from a large chemical space, with experimental results demonstrating successful hit rates and potencies. This approach shows promise for lead discovery and is easily scalable for use with diverse docking algorithms.

NATURE (2022)

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Article Multidisciplinary Sciences

Structure-based discovery of nonhallucinogenic psychedelic analogs

Dongmei Cao et al.

Summary: This study provides structural insights into the binding of drugs to 5-HT2AR and offers a foundation for the design of safe and effective nonhallucinogenic psychedelic analogs for the treatment of neuropsychiatric diseases.

SCIENCE (2022)

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Review Pharmacology & Pharmacy

Selective serotonin 5-HT2A receptor antagonists

Austen B. Casey et al.

Summary: This review discusses the importance of blockade and activation of the serotonin 5-HT2A G protein-coupled receptor (5-HT2AR) in the treatment of psychiatric disorders, and the limitations and strengths of currently available selective 5-HT2AR antagonists.

BIOCHEMICAL PHARMACOLOGY (2022)

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Article Clinical Neurology

Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals

Drummond E-Wen McCulloch et al.

Summary: This study evaluated the long-term effects of psilocybin on resting-state functional connectivity in healthy psychedelic-naive volunteers. The results showed that psilocybin decreased executive control network connectivity at 1 week, which predicted increased mindfulness at 3 months. This suggests that psilocybin may have lasting effects on brain connectivity and mindfulness.

JOURNAL OF PSYCHOPHARMACOLOGY (2022)

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Article Biochemistry & Molecular Biology

Increased global integration in the brain after psilocybin therapy for depression

Richard E. Daws et al.

Summary: Psilocybin therapy has the potential to treat depression by increasing brain network integration, according to two clinical trials. The antidepressant response to psilocybin was rapid and sustained, while escitalopram had milder effects on brain network organization.

NATURE MEDICINE (2022)

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Article Biotechnology & Applied Microbiology

The promises and perils of psychedelic pharmacology for psychiatry

Tristan D. McClure-Begley et al.

Summary: Psychedelic drugs have emerging therapeutic potential for neuropsychiatric diseases, but there are still many challenges and uncertainties. Further research is needed to understand the mechanisms of action and develop cleaner drugs to fully realize their therapeutic potential.

NATURE REVIEWS DRUG DISCOVERY (2022)

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Article Clinical Neurology

Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans

Dea Siggaard Stenbaek et al.

Summary: This study found associations between brain 5-HT2AR binding and the intensity and duration of psilocybin effects, as well as mystical experiences. The findings suggest a potential link between individual brain levels of 5-HT2AR and therapeutic outcomes in clinical studies.

JOURNAL OF PSYCHOPHARMACOLOGY (2021)

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Article Biochemistry & Molecular Biology

A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain

Nakul Ravi Raval et al.

Summary: This study showed that a single dose of psilocybin can lead to increased SV2A density and decreased 5-HT2AR density in the pig brain, suggesting a potential role in the antidepressant effects of psilocybin.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

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Article Multidisciplinary Sciences

A non-hallucinogenic psychedelic analogue with therapeutic potential

Lindsay P. Cameron et al.

Summary: The study identifies key structural elements of the potential therapeutic pharmacophore of ibogaine and designs tabernanthalog, a safer, non-hallucinogenic analogue of ibogaine. Tabernanthalog is found to promote neural plasticity, reduce addiction-related behavior, and produce antidepressant effects in rodents. Through careful chemical design, it is possible to modify psychedelic compounds to produce safer, non-hallucinogenic variants with therapeutic potential.

NATURE (2021)

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Review Pharmacology & Pharmacy

The History of Psychedelics in Psychiatry

David E. Nichols et al.

Summary: Interest in the value of psychedelic drugs in psychiatry began in the early 20th century, with a focus on their potential effects on mental disorders. Over time, attention shifted to the role of psychedelics as adjuncts to psychotherapy, which has since become the main focus of research in this field.

PHARMACOPSYCHIATRY (2021)

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Review Neurosciences

A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics

Neil K. Savalia et al.

Summary: Studies have shown that serotonergic psychedelics like psilocybin and ketamine may relieve depression by promoting neural plasticity. Despite targeting distinct molecular receptors in the brain, the behavioral and neural effects of these compounds are similar, possibly by enhancing and suppressing membrane excitability at dendrites.

TRENDS IN NEUROSCIENCES (2021)

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Article Biochemistry & Molecular Biology

Structural insights into the human D1 and D2 dopamine receptor signaling complexes

Youwen Zhuang et al.

Summary: This study presents cryo-EM structures of D1R-G(s) and D2R-G(i) signaling complexes with dopamine agonists, revealing insights into dopamine signaling, ligand selectivity, receptor activation, and G protein-coupling selectivity, providing valuable information for drug design targeting the dopaminergic system.

CELL (2021)

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Article Cell Biology

Prolonged epigenomic and synaptic plasticity alterations following single exposure to a psychedelic in mice

Mario de la Fuente Revenga et al.

Summary: Clinical evidence shows that rapid and sustained antidepressant effects can be achieved with a single exposure to psychedelics. The study found that a single dose of the psychedelic DOI has fast-acting effects on the frontal cortex dendritic spine structure and accelerates fear extinction through the 5-HT2A receptor. Furthermore, DOI induces changes in chromatin organization, particularly at enhancer regions of genes involved in synaptic assembly, which overlap with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder.

CELL REPORTS (2021)

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Article Biochemistry & Molecular Biology

Psychedelic-inspired drug discovery using an engineered biosensor

Chunyang Dong et al.

Summary: The study introduces psychLight, a genetically encoded fluorescent sensor based on the structure of 5-HT2AR, which can detect behaviorally relevant serotonin release and predict the effects of different 5-HT2AR ligands. This new technology identified a non-hallucinogenic psychedelic analog with rapid-onset and long-lasting antidepressant-like effects.

CELL (2021)

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Article Psychiatry

Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder

Manoj K. Doss et al.

Summary: The study investigated the enduring effects of psilocybin therapy on cognitive and neural flexibility, finding that cognitive flexibility improved post-treatment and some neural dynamics changes were associated with changes in cognitive flexibility one week after treatment.

TRANSLATIONAL PSYCHIATRY (2021)

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Review Psychiatry

Psychedelics and Other Psychoplastogens for Treating Mental Illness

Maxemiliano V. Vargas et al.

Summary: Psychedelics offer new hope for treating brain disorders due to their sustained therapeutic effects and broad potential, but face challenges in clinical scalability. Research on psychoplastogens provides insight into neural plasticity and offers a new paradigm for addressing the underlying pathophysiology of mental illness. Effectively deploying psychoplastogenic medicines at scale will be a key consideration for future development in the field.

FRONTIERS IN PSYCHIATRY (2021)

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Article Biochemistry & Molecular Biology

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study

Jennifer M. Mitchell et al.

Summary: The results demonstrate that MDMA-assisted therapy is safe and effective in treating severe post-traumatic stress disorder. Compared with placebo, MDMA significantly reduces CAPS-5 scores and improves functional impairment.

NATURE MEDICINE (2021)

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Article Medicine, General & Internal

Trial of Psilocybin versus Escitalopram for Depression

Robin Carhart-Harris et al.

Summary: The study compared the efficacy of psilocybin and escitalopram in treating patients with major depressive disorder. While there was no significant difference in antidepressant effects between the two drugs at week 6, secondary outcomes generally favored psilocybin over escitalopram, though these results were not adjusted for multiple comparisons. Larger and longer trials are needed to further compare psilocybin with established antidepressants.

NEW ENGLAND JOURNAL OF MEDICINE (2021)

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Article Multidisciplinary Sciences

Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice

Natalie Hesselgrave et al.

Summary: Psilocybin has shown promising rapid and persistent antidepressant effects in mice, possibly through enhancing excitatory synapses in the hippocampus, independent of 5-HT2A receptor activation. Further research is needed to explore the potential combination of psychedelic compounds and 5-HT2AR antagonists for clinical utility in human depression.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2021)

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Article Psychiatry

Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder A Randomized Clinical Trial

Alan K. Davis et al.

Summary: The study showed that psilocybin therapy with psychological support is effective in treating MDD, building on previous findings in patients with cancer and depression, as well as in a nonrandomized study in patients with treatment-resistant depression.

JAMA PSYCHIATRY (2021)

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Article Clinical Neurology

Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience

Martin K. Madsen et al.

Summary: The novel therapeutic psilocybin exerts its psychedelic effects by engaging cerebral serotonergic targets with its active metabolite psilocin. The serotonin 2A receptor plays a critical role in altering neural processes, leading to increased entropy, reduced network integrity, and decreased segregation between brain networks. Psilocin is shown to shape the time course and magnitude of changes in cerebral functional architecture and subjective experience, providing novel insight into the neurobiological mechanisms underlying the psychedelic experience and consciousness.

EUROPEAN NEUROPSYCHOPHARMACOLOGY (2021)

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Article Neurosciences

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

Ling-Xiao Shao et al.

Summary: The study showed that psilocybin can induce rapid and lasting synaptic rewiring in the cortex, increasing spine size and density. This structural change may have potential implications for long-term integration of experiences and lasting beneficial actions.

NEURON (2021)

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Review Pharmacology & Pharmacy

Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics

Lily R. Aleksandrova et al.

Summary: The emerging therapeutic efficacy of ketamine and classical psychedelics for depression has sparked considerable interest in the mechanisms underlying neuroplasticity. Preclinical and clinical evidence suggests that these drugs induce synaptic, structural, and functional changes, particularly in pyramidal neurons in the prefrontal cortex, resulting in adaptive rewiring of pathological neurocircuitry.

TRENDS IN PHARMACOLOGICAL SCIENCES (2021)

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Article Multidisciplinary Sciences

LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1

Ramona M. Rodriguiz et al.

Summary: Recent evidence suggests that psychedelic drugs can have beneficial effects on anxiety, depression, and substance abuse. However, their hallucinogenic side-effects often limit their clinical use. LSD's psychedelic actions appear to require the activation of 5-HT2AR and interaction with beta Arr2.

SCIENTIFIC REPORTS (2021)

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Article Cell Biology

LSD degrades hippocampal spatial representations and suppresses hippocampal-visual cortical interactions

Carli Domenico et al.

Summary: The study shows that LSD alters the activity of hippocampal and visual cortical neurons in rats, increasing firing rates in specific behavioral states while reducing interaction with external sensory input. Additionally, LSD influences neural activity in rats during rest, leading to degraded internal representations.

CELL REPORTS (2021)

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Article Biology

Transcriptomics-informed large-scale cortical model captures topography of pharmacological neuroimaging effects of LSD

Joshua B. Burt et al.

Summary: Psychoactive drugs like LSD can temporarily disrupt brain physiology while preserving brain structure. Research has shown that the neural and experiential effects of LSD are due to its agonism of the serotonin-2A receptor. By integrating brainwide transcriptomics with circuit modeling, this study simulated the effects of LSD on human cortical dynamics and found that serotonin-2A-mediated modulation of pyramidal-neuronal gain is a key mechanism through which LSD alters cortical functional topography. This work establishes a framework for linking molecular-level manipulations to systems-level functional alterations.

ELIFE (2021)

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Article Chemistry, Medicinal

Investigation of the Structure-Activity Relationships of Psilocybin Analogues

Adam K. Klein et al.

Summary: This study investigated the pharmacological properties of tryptamine derivatives containing N,N-dialkyl substituents and a 4-hydroxy or 4-acetoxy group, revealing their similar potencies at 5-HT2A and 5-HT2B receptors. The compounds acted as full or partial agonists at 5-HT2 subtypes and induced LSD-like head twitches in mice. O-acetylation reduced the in vitro potency of the compounds but had little effect on their in vivo head twitch response potency, suggesting a prodrug mechanism.

ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE (2021)

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Article Chemistry, Medicinal

Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth

Calvin Ly et al.

Summary: Cortical neuron atrophy is a hallmark of depression, and psychoplastogens like ketamine and LSD have been shown to promote sustained growth of cortical neurons after short periods of stimulation. These psychoplastogens induce cortical neuron growth through distinct phases, with early TrkB activation and later sustained mTOR and AMPA receptor activation being crucial. It is suggested that rapidly excreted psychoplastogens may have unique advantages as neurotherapeutics compared to compounds like ketamine and LSD.

ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE (2021)

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Article Chemistry, Medicinal

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

David E. Olson

Summary: Psychedelics have shown promise for treating neuropsychiatric disorders due to their ability to promote neural plasticity and produce rapid and sustained therapeutic effects, but evidence suggests that the subjective effects induced by these drugs may not be necessary for long-lasting changes in mood and behavior. Understanding the role of subjective effects in the therapeutic mechanisms of psychedelics will have important implications for basic neuroscience and patient access to future medicines developed from psychedelic research.

ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE (2021)

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Article Chemistry, Medicinal

The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects

David B. Yaden et al.

Summary: The subjective effects of psychedelics are crucial for their lasting benefits, accounting for the majority of their therapeutic outcomes.

ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE (2021)

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Article Biochemistry & Molecular Biology

Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression

Meghan Hibicke et al.

ACS CHEMICAL NEUROSCIENCE (2020)

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Article Neurosciences

Psilocybin Induces Time-Dependent Changes in Global Functional Connectivity

Katrin H. Preller et al.

BIOLOGICAL PSYCHIATRY (2020)

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Article Chemistry, Medicinal

Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogues through Structure-Activity Relationship Studies

Lee E. Dunlap et al.

JOURNAL OF MEDICINAL CHEMISTRY (2020)

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Article Multidisciplinary Sciences

Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

Farhan Ali et al.

NATURE COMMUNICATIONS (2020)

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Article Multidisciplinary Sciences

Emotions and brain function are altered up to one month after a single high dose of psilocybin

Frederick S. Barrett et al.

SCIENTIFIC REPORTS (2020)

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Article Multidisciplinary Sciences

Dynamic coupling of whole-brain neuronal and neurotransmitter systems

Morten L. Kringelbach et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2020)

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Article Neurosciences

Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention

Frederick S. Barrett et al.

NEUROIMAGE (2020)

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Article Neurosciences

Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species

Adam L. Halberstadt et al.

NEUROPHARMACOLOGY (2020)

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Article Biotechnology & Applied Microbiology

Metabolic engineering of Saccharomyces cerevisiae for the de novo production of psilocybin and related tryptamine derivatives

N. Milne et al.

METABOLIC ENGINEERING (2020)

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Article Biochemistry & Molecular Biology

Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor

Kuglae Kim et al.

CELL (2020)

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Review Neurosciences

Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders

Franz X. Vollenweider et al.

NATURE REVIEWS NEUROSCIENCE (2020)

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DMT alters cortical travelling waves

Andrea Alamia et al.

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Suhrid Banskota et al.

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Ketamine: A Paradigm Shift for Depression Research and Treatment

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NEURON (2019)

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Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels

Martin K. Madsen et al.

NEUROPSYCHOPHARMACOLOGY (2019)

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Article Multidisciplinary Sciences

Effective connectivity changes in LSD-induced altered states of consciousness in humans

Katrin H. Preller et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2019)

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A Hallucinogenic Serotonin-2A Receptor Agonist Reduces Visual Response Gain and Alters Temporal Dynamics in Mouse V1

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CELL REPORTS (2019)

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Review Pharmacology & Pharmacy

REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics

R. L. Carhart-Harris et al.

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Kee Wui Huang et al.

ELIFE (2019)

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Neural correlates of the DMT experience assessed with multivariate EEG

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Comparison of the behavioral responses induced by phenylalkylamine hallucinogens and their tetrahydrobenzodifuran (FLY) and benzodifuran (DragonFLY) analogs

Adam L. Halberstadt et al.

NEUROPHARMACOLOGY (2019)

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In vivo production of psilocybin in E. coli

Alexandra M. Adams et al.

METABOLIC ENGINEERING (2019)

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Psychedelics Promote Structural and Functional Neural Plasticity

Calvin Ly et al.

CELL REPORTS (2018)

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Altered network hub connectivity after acute LSD administration

Felix Mueller et al.

NEUROIMAGE-CLINICAL (2018)

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Whole-Brain Multimodal Neuroimaging Model Using Serotonin Receptor Maps Explains Non-linear Functional Effects of LSD

Gustavo Deco et al.

CURRENT BIOLOGY (2018)

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Article Biology

Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor

Katrin H. Preller et al.

ELIFE (2018)

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Vincent Beliveau et al.

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Long-term follow-up of psilocybin-facilitated smoking cessation

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Two dose investigation of the 5-HT-agonist psilocybin on relative and global cerebral blood flow

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A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

Jose M. Palacios et al.

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Pavlovian conditioning-induced hallucinations result from overweighting of perceptual priors

A. R. Powers et al.

SCIENCE (2017)

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Article Multidisciplinary Sciences

Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin

Michael M. Schartner et al.

SCIENTIFIC REPORTS (2017)

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Article Psychiatry

Increased thalamic resting-state connectivity as a core driver of LSD-induced hallucinations

F. Mueller et al.

ACTA PSYCHIATRICA SCANDINAVICA (2017)

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Article Biochemistry & Molecular Biology

The Fabric of Meaning and Subjective Effects in LSD-Induced States Depend on Serotonin 2A Receptor Activation

Katrin H. Preller et al.

CURRENT BIOLOGY (2017)

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Article Biochemistry & Molecular Biology

Crystal Structure of an LSD-Bound Human Serotonin Receptor

Daniel Wacker et al.

CELL (2017)

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Article Biochemical Research Methods

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Article Clinical Neurology

Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience

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LSD Alters Eyes-Closed Functional Connectivity within the Early Visual Cortex in a Retinotopic Fashion

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Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial

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Article Clinical Neurology

Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial

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Psychedelics Recruit Multiple Cellular Types and Produce Complex Transcriptional Responses Within the Brain

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Longitudinal Effects of Ketamine on Dendritic Architecture In Vivo in the Mouse Medial Frontal Cortex

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Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin

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Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer

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