Proceedings of the National Academy of Sciences
December 17, 2018
Kenichi Fukumoto, Manoela V. Fogaça, Rong-Jian Liu et al.
191 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], produces rapid and sustained antidepressant effects in animal models without the side effects of ketamine and without blocking the NMDA receptor. The antidepressant effects require activity-dependent release of BDNF, mediated by stimulation of voltage-dependent Ca2+ channels. Increased BDNF release activates downstream TrkB and mechanistic target of rapamycin complex 1 signaling, which increases synaptic function of pyramidal neurons in the medial prefrontal cortex. Stimulation of BDNF release and increased synaptic function block or reverse the detrimental effects of stress and depression.
Proceedings of the National Academy of Sciences
January 21, 2020
Matthias Forstmann, Daniel Alexander Yudkin, Annayah Miranda Beatrice Prosser et al.
185 citations
Using psychedelic substances such as LSD or psilocybin is linked to improved mood and stronger feelings of social connectedness in naturalistic settings. Across six multiday mass gatherings in the United States and the United Kingdom, over 1,200 participants were studied. Those who had taken psychedelics reported higher positive mood, an effect that occurred sequentially through transformative experiences and then increased social connectedness. The association was strongest for people who had used psychedelics within the previous 24 hours compared to the past week. The findings provide robust evidence that psychedelic use can have positive affective and social consequences in real-world contexts.
Proceedings of the National Academy of Sciences
April 18, 2016
Katrin H. Preller, Thomas Pokorny, Andreas Hock et al.
175 citations
Social ties are crucial for health, but psychiatric patients often face social rejection, and heightened reactivity to exclusion affects disorder development and treatment. The neuromodulatory substrates of rejection are largely unknown. Psilocybin, a serotonin 5-HT2A/1A receptor agonist, reduces processing of negative stimuli, but its effect on negative social interactions was unclear. In a double-blind, randomized, cross-over study with 21 healthy volunteers, psilocybin (0.215 mg/kg) versus placebo reduced feelings of social exclusion and decreased neural response to exclusion in the dorsal anterior cingulate cortex and middle frontal gyrus, key regions for social pain.
Proceedings of the National Academy of Sciences
March 13, 2019
Panos Zanos, Jaclyn N. Highland, Brent W. Stewart et al.
153 citations
A single subanesthetic dose of ketamine produces rapid (within hours) and sustained antidepressant effects, unlike standard antidepressants that take months and fail in about 30% of patients. The ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a rapid-acting antidepressant candidate with fewer adverse effects. Using behavioral, genetic, pharmacological approaches and EEG measurements, the study found that antidepressant-relevant actions of (2R,6R)-HNK involve metabotropic glutamate receptor subtype 2 (mGlu2) signaling and identified high-frequency EEG oscillations as a marker of rapid antidepressant responses. The findings suggest clinical trials combining subtherapeutic doses of mGlu2 receptor inhibitors with ketamine or (2R,6R)-HNK for depression treatment.
Proceedings of the National Academy of Sciences
June 10, 2013
George A. Mashour, Michael Alkire
148 citations
Consciousness likely emerged early in vertebrate evolution, as the basic neural mechanisms supporting it are ancient and highly conserved across species. The stepwise emergence from general anesthesia can serve as a reproducible model to study consciousness across species. The neurobiological structure of the vertebrate central nervous system is evolutionarily ancient, and the neurophysiologic mechanisms supporting human consciousness are found at the earliest points of vertebrate brain evolution. Differences between species in the ability to experience the world are of degree, not kind, supporting Darwin's insight and the Cambridge Declaration on Consciousness in Non-Human Animals.
Proceedings of the National Academy of Sciences
January 25, 2021
Danilo de Gregorio, Jelena Popić, Justine P. Enns et al.
137 citations
Repeated doses of LSD (30 μg/kg daily for 7 days) increase social behavior in male mice without producing antidepressant or anxiety-reducing effects. The prosocial effect requires the integrity of mTORC1 in excitatory glutamatergic neurons of the medial prefrontal cortex (mPFC), as shown by optogenetic inhibition and conditional knockout experiments. LSD potentiates AMPA and 5-HT2A synaptic responses in the mPFC and increases phosphorylation of Akt and mTOR, but does not affect NMDA or 5-HT1A responses. In mice lacking Raptor in GABAergic neurons, LSD still promotes social behavior. The findings suggest that 5-HT2A/AMPA/mTORC1 signaling in mPFC excitatory neurons mediates LSD's prosocial effects, offering a potential target for treating social deficits in autism and social anxiety.
Proceedings of the National Academy of Sciences
March 1, 1974
James A. Nathanson, Paul Greengard
95 citations
An enzyme called adenylate cyclase, found in the thoracic ganglia of an insect nervous system, is specifically activated by low concentrations of serotonin. This activation is selectively blocked by very low concentrations of D-lysergic acid diethylamide (LSD), 2-bromo-LSD, and cyproheptadine, substances known to block certain serotonin receptors in living organisms. The inhibition is competitive with respect to serotonin, and the inhibitory constant of LSD for this serotonin-sensitive adenylate cyclase is 5 nM. These findings suggest that the serotonin receptor in neural tissue is closely linked to this enzyme, which may mediate serotonergic neurotransmission, and that some physiological effects of LSD might occur through interaction with this enzyme.
Proceedings of the National Academy of Sciences
December 1, 1977
J P Green, C L Johnson, Harel Weinstein et al.
91 citations
D-Lysergic acid diethylamide (LSD) and D-2-bromolysergic acid diethylamide (BOL) act as competitive antagonists of histamine-activated adenylate cyclase in broken cell preparations from guinea pig hippocampus and cortex. The adenylate cyclase is linked to the histamine H2-receptor. Both compounds show structural similarity to potent H2-antagonists. BOL is 10 times more potent as an H2-antagonist than cimetidine, the most potent H2-antagonist previously reported, while LSD is about equipotent to cimetidine. Blockade of H2-receptors may contribute to the behavioral effects of these compounds.
Proceedings of the National Academy of Sciences
September 1, 1970
Sungzong Kang, Jack Peter Green
64 citations
A common mechanism may underlie how structurally different hallucinogens—LSD, indolealkylamines, and methoxylated amphetamines—interact with their receptor. In LSD, the aromatic benzene ring A and the N-6 nitrogen are essential for activity; these sites may react with the receptor. The conformations of amphetamines and indolealkylamines position their aromatic ring and alkylamino nitrogen to align with LSD's ring A and N-6. Ring A may form a π-molecular complex with the receptor, supported by a correlation between hallucinogenic activity and the energy of the highest occupied molecular orbital. The N-6 nitrogen and its sterically congruent counterparts may form an n-π* or n-σ* donor-acceptor complex. Additional groups (methoxy, hydroxyl, pyrrole ring) contribute favorable orbital energy.
Proceedings of the National Academy of Sciences
February 10, 2020
Lilian Kloft, Henry Otgaar, Arjan Blokland et al.
49 citations
Under the acute influence of THC, healthy volunteers showed a heightened tendency to form false memories compared to those given a placebo. In a double-blind, randomized trial, 64 participants completed memory tasks—including associative word lists and two virtual-reality misinformation scenarios—immediately while intoxicated and again one week later while sober. Intoxicated individuals exhibited a stronger false-recognition bias, especially when test items were weakly associated with studied material, and were more susceptible to misinformation in eyewitness and perpetrator scenarios. These false-memory effects were largely confined to the acute intoxication phase. The findings suggest that cannabis increases false-memory proneness and have practical implications for police interviews with suspects and eyewitnesses.
Proceedings of the National Academy of Sciences
January 30, 2012
Hyeong-Min Lee, Bryan L. Roth
47 citations
The authors argue that it is time to reconsider long-standing hypotheses about how hallucinogens like psilocybin, found in Psilocybe cubensis, act in the human brain.
Proceedings of the National Academy of Sciences
January 3, 2023
Dale Zhou, Yoona Kang, Danielle Cosme et al.
40 citations
People with greater network controllability—the ability to efficiently distribute neural control inputs across the brain's white matter—moderated their alcohol consumption. In a randomized controlled study, participants primed to mindfully respond to alcohol cues, compared to those who naturally reacted, reported reduced craving, though craving did not differ from a baseline group. Mindful regulation of alcohol cues involved more effortful control of neural dynamics across cognitive control and attention subnetworks compared to natural reactions in the baseline group, and this effort persisted in the mindful group's natural reactions. More effortful neural states had shorter intrinsic timescales, explaining how mindful attention promotes being present by quickly discontinuing past processing.
Proceedings of the National Academy of Sciences
April 14, 2025
Jeremy R Tuck, Lee E. Dunlap, Yara A Khatib et al.
32 citations
A newly designed compound, (+)-JRT, structurally similar to LSD but with reduced hallucinogenic effects, promotes the growth of dendritic spines in the cortex—a process that is diminished in neuropsychiatric diseases such as depression, addiction, and schizophrenia. In behavioral tests, (+)-JRT showed antidepressant-like and cognition-enhancing effects without worsening signs related to psychosis. This suggests that nonhallucinogenic compounds that promote neuroplasticity could be safer alternatives to psychedelics for treating conditions where psychedelics pose risks.
Proceedings of the National Academy of Sciences
January 9, 2024
Virginia Ramírez-Cruz, Giuliana Furci, Alexander J. Bradshaw et al.
30 citations
The psychedelic alkaloid psilocybin, driving Psychedelics and Drug Studies, first evolved in the mushroom genus Psilocybe around 67 million years ago. Evolutionary biology indicates its biosynthetic gene cluster transferred horizontally 4 to 5 times to other fungi between 40 and 9 million years ago. Using 71 fungal metagenomes, Phylogenetics of 2,983 gene families reveals Psilocybe's deep Biology. Two distinct psilocybin gene cluster arrangements correspond to major clades, suggesting independent acquisitions of this alkaloid's chemical synthesis, impacting Fungal Biology and Applications.
Proceedings of the National Academy of Sciences
March 1, 1975
Ian R. Brown
24 citations
Two and a half hours after rabbits received LSD intravenously, their isolated brain nuclei showed increased RNA synthesis. Transcription rose by 54% in brain stem nuclei and by 13% in cerebral hemisphere nuclei compared to saline controls. Both nucleoplasmic and nucleolar RNA synthesis were elevated. The primary activity in the assay came from nucleoplasmic RNA polymerase, as alpha-amanitin reduced synthesis by over 70% in both drug and control groups.
Proceedings of the National Academy of Sciences
June 24, 2026
Yibo Wang, H Wang, C T Lin et al.
Natural hallucinogenic compounds like mescaline and psilocybin evolved independently across plants, fungi, and animals through a 'building-block' biosynthetic logic that repurposes primary metabolism. These molecules likely function as defensive agents or manipulators of herbivore and pollinator behavior, not primarily for human psychoactivity. Endogenous mammalian tryptamines appear to serve cytoprotective and stress-response roles via sigma-1 receptors, not hallucinogenic functions. Across kingdoms, these compounds converge on conserved neural targets such as serotonergic systems, making human psychoactivity an evolutionary by-product of molecules selected for ecological interactions with animals sharing deeply conserved receptor architectures.
Proceedings of the National Academy of Sciences
May 26, 2026
N. Shadlen Michael
Conscious thought does not require a special neural mechanism but arises from the same representations used in nonconscious decision-making. Nonconscious thoughts are structured as interrogations that produce provisional intentions guiding action without awareness, relying on persistent neural representations that encode both potential actions and the questions giving them meaning. These states may preserve source-sensitive structure supporting minimal experiential organization. Conscious thought emerges when such a state is reformatted for potential report to another mind or oneself, recruiting theory of mind and narrative structure and placing its content in a shared space. This proposal bridges nonconscious decision mechanisms to phenomenal consciousness, placing part of the hard problem within empirical reach.