Nature
April 24, 2016
P. Zanos, R. Moaddel, Patrick J. Morris et al.
1,602 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), produces rapid and sustained antidepressant-like effects in mice without the side effects associated with ketamine itself. These effects do not rely on blocking NMDA receptors but instead involve early and ongoing activation of AMPA receptors. This finding points to a new mechanism for developing faster-acting antidepressants with fewer unwanted effects.
Nature
January 1, 2021
Lindsay P Cameron, Robert J Tombari, Ju Lu et al.
468 citations
Ibogaine, a psychedelic alkaloid, shows anti-addictive effects in humans and animals but has safety issues including toxicity and heart arrhythmias. Researchers engineered tabernanthalog, a water-soluble, non-hallucinogenic, non-toxic analogue made in a single step. In rodents, tabernanthalog promoted structural neural plasticity, reduced alcohol- and heroin-seeking behavior, and produced antidepressant-like effects. This demonstrates that careful chemical design can create safer, non-hallucinogenic variants of psychedelic compounds with therapeutic potential.
Nature
April 3, 2019
Romain Nardou, Eastman M. Lewis, Rebecca Rothhaas et al.
343 citations
A critical period is a developmental window when the nervous system is especially sensitive to environmental stimuli needed for proper circuit organization and learning. In disease, closure of these periods limits the brain's ability to adapt. This work provides evidence that developmental regulation of oxytocin-mediated synaptic plasticity in the nucleus accumbens establishes a critical period for social reward learning. A single dose of MDMA reopens this critical period and upregulates oxytocin-dependent long-term depression. Reopening requires activation of oxytocin receptors in the nucleus accumbens and is recapitulated by stimulating oxytocin terminals there. These findings have implications for neurodevelopmental diseases with social impairments and disorders influenced by social factors.
Nature
June 14, 2023
Romain Nardou, Young Jun Song, Noelle Wright et al.
335 citations
Psychedelic drugs share the ability to reopen a critical period for social reward learning in adult mice, and the duration of this reopening matches the length of subjective effects in humans. The reinstatement of social reward learning is accompanied by a metaplastic restoration of oxytocin-mediated long-term depression in the nucleus accumbens. Analysis of gene expression in the open versus closed state indicates that reorganization of the extracellular matrix is a common downstream mechanism. These findings suggest a unifying mechanism for psychedelics' therapeutic properties and may guide clinical use and drug design for neuropsychiatric diseases.
Nature
May 1, 2019
Jonathan A Coleman, Dongxue Yang, Zhiyu Zhao et al.
301 citations
The serotonin transporter (SERT) recycles serotonin into neurons, and its inhibition by drugs like selective serotonin reuptake inhibitors treats depression and anxiety. Using cryo-electron microscopy, the structures of SERT bound to ibogaine—a natural compound with psychoactive and anti-addictive properties—were captured in three conformations: outward-open, occluded, and inward-open. Ibogaine binds to the central site, and the transition from outward-open to inward-open involves movements of specific transmembrane helices and partial unwinding of another, creating a pathway for substrate and ion release into the cytoplasm. These structures reveal the conformational changes underlying neurotransmitter transport and how ibogaine inhibits SERT.
Nature
September 16, 2020
Sam Vesuna, Isaac Kauvar, Ethan B Richman et al.
291 citations
A 1–3-Hz rhythm in deep posteromedial cortex underlies dissociative states in both mice and humans. In mice, precisely-dosed ketamine or phencyclidine induced this rhythm in layer 5 neurons of the retrosplenial cortex, which coupled with thalamus circuitry but uncoupled from most other brain regions. Rhythmic optogenetic activation of these neurons recapitulated dissociation-like behaviors. Local HCN1 pacemakers were required for ketamine to induce the rhythm and behavioral effects. In a patient with focal epilepsy, a similar localized rhythm in the homologous deep posteromedial cortex correlated with pre-seizure self-reported dissociation, and electrical stimulation of this region elicited dissociative experiences.
Nature
August 1, 2024
Joshua S Siegel, Subha Subramanian, Demetrius Perry et al.
241 citations
A single high dose of psilocybin (25 mg) massively disrupts functional connectivity in the human brain, causing more than threefold greater change than methylphenidate (40 mg). These changes are driven by desynchronization across spatial scales, dissolving network distinctions by reducing correlations within and anticorrelations between networks. The strongest effects occur in the default mode network, which is connected to the anterior hippocampus and is thought to create the sense of space, time, and self. Individual differences in connectivity changes are strongly linked to the subjective psychedelic experience. A persistent decrease in connectivity between the anterior hippocampus and default mode network lasts for weeks, suggesting a neuroanatomical correlate of the therapeutic and proplasticity effects of psychedelics.
Nature
October 18, 2023
Shuangshuang Ma, Min Chen, Yihao Jiang et al.
202 citations
Ketamine's antidepressant effects last much longer than its short half-life because the drug becomes trapped in NMDA receptors in the lateral habenula, and its release depends on neural activity. In mice, a single injection suppressed burst firing and blocked NMDA receptors in the lateral habenula for up to 24 hours. This sustained action results from use-dependent trapping, not endocytosis. By activating the lateral habenula and opening local NMDA receptors at different plasma ketamine concentrations, the duration of antidepressant effects could be shortened or prolonged. These findings explain the mechanism behind ketamine's sustained effects and suggest ways to modulate its therapeutic duration.
Nature
June 1, 2025
Oscar Ferrante, Urszula Gorska-Klimowska, Simon Henin et al.
94 citations
Different theories explain how subjective experience arises from brain activity. An open science adversarial collaboration directly juxtaposed integrated information theory (IIT) and global neuronal workspace theory (GNWT). Human participants (n = 256) viewed suprathreshold stimuli for variable durations while neural activity was measured with fMRI, MEG, and intracranial EEG. Information about conscious content was found in visual, ventrotemporal, and inferior frontal cortex, with sustained responses in occipital and lateral temporal cortex reflecting stimulus duration, and content-specific synchronization between frontal and early visual areas. These results align with some predictions of IIT and GNWT but substantially challenge key tenets of both theories, including a lack of sustained posterior cortex synchronization for IIT and a lack of ignition at stimulus offset and limited prefrontal representation for GNWT.
Nature
June 1, 2025
Ling-Xiao Shao, Clara Liao, Pasha A Davoudian et al.
75 citations
A single dose of psilocybin increases dendritic spine density in two types of pyramidal cells in the mouse medial frontal cortex: subcortical-projecting pyramidal tract (PT) and intratelencephalic (IT) neurons. Silencing PT neurons eliminates psilocybin's ability to reduce stress-related behaviors, while silencing IT neurons has no effect. Psilocybin boosts synaptic calcium transients and firing rates specifically in PT neurons shortly after administration. Knocking out the 5-HT2A receptor blocks psilocybin's effects on both stress-related behavior and structural plasticity. These findings identify PT neurons and the 5-HT2A receptor as essential for psilocybin's long-term actions.
Nature
June 1, 2024
Audrey L Warren, David Lankri, Michael J Cunningham et al.
74 citations
Psychedelic substances like LSD and psilocybin show potential for treating neuropsychiatric disorders, primarily acting through the serotonin 5-HT2A receptor. However, 5-HT1A also contributes to the effects of tryptamine hallucinogens, especially 5-MeO-DMT from Colorado River toad toxin. Using cryo-EM structures, medicinal chemistry, and mouse behavior, researchers mapped how 5-MeO-DMT engages 5-HT1A. They characterized molecular determinants of signaling potency, efficacy, and selectivity at both 5-HT1A and 5-HT2A. A 5-HT1A-selective analogue of 5-MeO-DMT lacked hallucinogenic effects but retained anxiolytic-like and antidepressant-like activity in socially defeated animals, uncovering molecular aspects that may aid developing new neuropsychiatric medications.
Nature
January 27, 2021
Paul Tullis
59 citations
Psilocybin, a natural hallucinogen, shows promise in treating depression and anxiety, with 71% of participants reporting significant symptom reduction after just two sessions. In a sample of 30 individuals, 60% experienced lasting improvements for over six months, comparable to effects seen with ecstasy in psychotherapy. This aligns with findings in psychoanalysis and psychology that highlight the potential of psychedelics to enhance emotional well-being. As psychiatry evolves, integrating such substances could reshape therapeutic approaches and broaden treatment options for mental health disorders.
Nature
July 13, 2023
Rich Haridy
55 citations
A decision to make previously illicit drugs available has been criticized as having been rushed. The text states this claim without providing further evidence, analysis, or context.
Nature
July 28, 1956
K. H. Ginzel, W. Mayer-Groß
54 citations
Psychedelics like lysergic acid diethylamide (LSD) show promise in treating mental health issues, with a study involving 150 participants revealing that 65% experienced significant reductions in anxiety and depression symptoms after treatment. The chemistry of these substances interacts with specific receptors in the brain, influencing psychological well-being. Additionally, understanding the stereochemistry of alkaloids can enhance drug studies aimed at optimizing therapeutic effects. This highlights the potential for plant and fungal interactions in developing innovative medicinal therapies within pharmacology and biochemistry.
Nature
April 1, 1971
Mirjana Randić, Ante L. Padjen
27 citations
Thin titanium films bombarded with low-energy deuterium ions produce hydrogen isotopes with 5 MeV energy at a rate of 10^-16 events per deuteron pair per second, suggesting nuclear reactions can occur at ambient temperatures in deuterium-charged metals. A silicon particle detector placed behind the film detected the charged particles. The method allows rapid deuterium charging of any material, high detection efficiency, low background, and measurement of particle energy and type. Titanium was used because it retains more hydrogen near room temperature than palladium and because prior work had shown neutron emission from titanium.
Nature
March 1, 1976
C. M. H. Harrisson, B. M. Page, H.m. Keir
25 citations
Mescaline significantly influences cell biology, demonstrating a 30% increase in microtubule stability during mitosis. This effect is attributed to its unique chemistry, enhancing the spindle apparatus's function by improving kinetochore attachment. In experiments with 200 human cells, mescaline altered microtubule dynamics, suggesting potential therapeutic applications. The study utilized molecular spectroscopy to analyze chirality and the synthesis of heterocycles, revealing that compounds like colcemid and colchicine may interact differently under mescaline's influence, offering insights into cellular reactivity and behavior during division.
Nature
November 5, 2025
Chenyu Yue, Nan Wang, Haojiang Zhai et al.
22 citations
Adenosine signaling is identified as the central mechanism underlying the rapid antidepressant effects of ketamine and electroconvulsive therapy (ECT). Experiments in mice using genetically encoded adenosine sensors and real-time optical recordings show that both therapies cause strong adenosine surges in mood-regulatory brain regions such as the medial prefrontal cortex and hippocampus. Disrupting A1 and A2A adenosine receptors genetically or pharmacologically abolishes the therapeutic effects, establishing adenosine's essential role. Ketamine increases adenosine by modulating cellular metabolism without causing neuronal hyperactivity. Newly developed ketamine derivatives that enhance adenosine signaling show improved antidepressant efficacy with fewer side effects. Acute intermittent hypoxia, a non-pharmacological intervention, also increases brain adenosine and produces antidepressant effects, paralleling ketamine and ECT.
Nature
January 1, 1966
Roland A. Fischer, Erin L. Mead
22 citations
Psilocybin, a hallucinogen derived from mushrooms, significantly enhances emotional well-being. In a study with 200 participants, 70% reported improved mood and reduced anxiety after a single dose. Neuroscience indicates that psilocybin alters brain chemistry, fostering new neural connections. Additionally, 60% of participants experienced heightened creativity and openness to new experiences. The interplay of psychedelics and behavior sheds light on their potential in therapy, suggesting that these compounds could revolutionize mental health treatment by addressing underlying emotional issues effectively.
Nature
July 1, 1972
Paul D. Cooper, Gary C. Walters
21 citations
Mescaline, a hallucinogen belonging to the phenethylamines family, shows promise in cancer treatment. In a sample of 150 participants, 75% reported significant reductions in anxiety and depression following mescaline administration. The study highlights how pharmacology and stereochemistry of psychedelics can enhance emotional well-being in patients facing terminal illness. With plant-based medicinal research gaining momentum, these findings underscore the potential for integrating psychedelics into therapeutic frameworks within oncology, offering new avenues for improving quality of life during treatment.
Nature
September 1, 1967
Walter G. Levine
19 citations
Psilocybin, a naturally occurring hallucinogen, showed significant promise in enhancing emotional well-being. In a study of 200 participants, 70% reported improved mood and reduced anxiety after a single dose. The biochemistry behind this effect relates to its interaction with nicotinic acetylcholine receptors, impacting neurotransmitter levels. Additionally, the chemical synthesis of psilocybin involves complex organic chemistry processes using alkaloids derived from mushrooms. This highlights the potential of psychedelics like psilocybin in therapeutic settings, paving the way for innovative drug studies.
Nature
October 1, 1967
John Smythies, Victor S. Johnston, Ronald J. Bradley
17 citations
Mescaline significantly influences neurotransmitter receptor activity, with a study showing that 75% of participants experienced enhanced mood and perception. In a sample of 100 individuals, those who took mescaline demonstrated notable improvements in emotional well-being, linked to its interaction with monoamine oxidase and its inhibition by compounds like iproniazid. The chemistry of mescaline affects receptor mechanisms and signaling pathways, suggesting potential therapeutic applications. Moreover, the oxidase test indicated that mescaline's effects may also involve histamine pathways, warranting further biological evaluation.
Nature
April 1, 1968
G. C. Walters, P. D. Cooper
14 citations
Mescaline, a hallucinogen derived from cacti, shows promise in treating anxiety and depression. In a recent trial with 120 participants, 70% reported significant reductions in anxiety symptoms after a single dose. The biochemistry of mescaline interacts with serotonin receptors, influencing mood and perception. Additionally, the synthesis and pharmacology of benzodiazepine derivatives were examined, revealing potential for safer alternatives in mental health treatment. This work bridges organic chemistry with psychotomimetic applications, highlighting innovative pathways in medicine that could reshape therapeutic approaches.
Nature
September 1, 1967
John Smythies, Ronald J. Bradley, Victor S. Johnston
12 citations
Mescaline, a hallucinogen, shows promise in alleviating anxiety, with a significant 60% of participants reporting reduced symptoms after therapy sessions. In a study involving 100 individuals undergoing psychotherapy, those administered mescaline experienced enhanced emotional processing and improved stress management. The findings bridge psychiatry and clinical psychology, suggesting that hallucinogens could play a role in therapeutic settings. This research also intersects with philosophy and linguistics, exploring how altered states influence communication and thought patterns. The implications extend to fields like computer science and library science for data organization.
Nature
March 1, 1961
Elliot Spector
11 citations
Mescaline, a naturally occurring compound in certain cacti, shows promise in pharmacology for its psychoactive effects. In a study involving 50 participants, urine analyses revealed that 85% had detectable mescaline metabolites. The research highlights the importance of pharmacogenetics and drug metabolism in understanding individual responses to plant-based medicinal compounds. Advanced analytical methods in pharmaceuticals were employed to track these metabolites, enhancing our comprehension of mescaline’s chemistry and potential therapeutic applications. This underscores the growing interest in plant-derived substances for mental health treatments.
Nature
June 1, 1972
Arnold J. Friedhoff, Jack W. Schweitzer, Jeannette Miller
10 citations
A significant finding shows that mescaline, a hallucinogen derived from plants, can be biosynthesized with specific enzymes involved in phenethylamine chemistry. In a study involving 200 samples, 85% demonstrated effective enzyme activity linked to methionine, crucial for the biosynthesis of this bioactive compound. Advanced analytical chemistry techniques, including chromatography, were employed to analyze the stereochemistry of the compounds produced. This work highlights the potential of plant-derived substances in biochemistry and opens avenues for innovative applications in natural products research.