Proceedings of the National Academy of Sciences
October 11, 2007
1,585 citations
Five days of brief, daily meditation using the integrative body-mind training method improved attention and reduced stress more than relaxation training alone. In a randomized experiment with 40 undergraduate Chinese students, those who practiced 20 minutes of integrative meditation for five days showed greater improvement on the Attention Network Test, lower anxiety, depression, anger, and fatigue, higher vigor, reduced cortisol, and increased immunoreactivity compared to a relaxation control group. The findings suggest that even short-term meditation can produce measurable cognitive and physiological benefits, offering a practical way to study meditation using controlled experimental designs.
Proceedings of the National Academy of Sciences
November 23, 2011
Judson A. Brewer, Patrick D. Worhunsky, Jeremy R. Gray et al.
1,410 citations
Experienced meditators show reduced activity in brain regions linked to self-referential thought and mind-wandering, particularly the medial prefrontal and posterior cingulate cortices, across different meditation types. They also exhibit stronger connections between areas involved in self-monitoring and cognitive control, such as the posterior cingulate, dorsal anterior cingulate, and dorsolateral prefrontal cortices, both at rest and during meditation. These neural patterns align with decreased mind-wandering, offering insight into how meditation may support present-moment awareness and well-being.
Proceedings of the National Academy of Sciences
January 23, 2012
Alessandro Colasanti, Robin J. Tyacke, Robert Leech et al.
1,191 citations
Psychedelic drugs like psilocybin, found in magic mushrooms, produce profound changes in consciousness by decreasing activity and connectivity in key brain hub regions. Using functional MRI, researchers observed that psilocybin reduced cerebral blood flow and BOLD signal, especially in the thalamus, anterior cingulate cortex (ACC), and posterior cingulate cortex (PCC). Decreased activity in the ACC and medial prefrontal cortex (mPFC) predicted the intensity of subjective psychedelic effects. Psilocybin also reduced positive coupling between the mPFC and PCC. These findings suggest that psychedelics work by dampening the brain's connector hubs, leading to a state of unconstrained cognition.
Proceedings of the National Academy of Sciences
June 19, 2009
706 citations
A natural reduction of consciousness during sleep alters the correlation between components of the default-mode network (DMN), particularly reducing the involvement of frontal cortex. This suggests the DMN may play an important role in sustaining conscious awareness. The finding contrasts with a recent study in anesthetized primates that proposed DMN activity reflects general network dynamics rather than conscious mentation.
Proceedings of the National Academy of Sciences
February 21, 2012
627 citations
A brain network called the default mode network (DMN), previously studied mainly in humans and primates, also exists in rats. The DMN in rats is broadly similar to that in nonhuman primates and humans, suggesting it is a fundamental feature of mammalian brains. The network appears to integrate sensory and emotional information to guide behavior in anticipation of changing environmental conditions, despite the distinct evolutionary paths of rodents and primates. The findings help clarify the DMN's core functions, which remain poorly understood in humans.
Proceedings of the National Academy of Sciences
March 1, 1992
Gary Rudnick, S C Wall
533 citations
MDMA (ecstasy) acts on serotonin transporters in both the plasma membrane and secretory vesicles. In plasma membrane vesicles from human platelets, MDMA inhibits serotonin transport and imipramine binding by directly interacting with the sodium-dependent serotonin transporter, and it stimulates serotonin efflux in a stereo-specific, sodium-dependent, and imipramine-sensitive manner via transporter-mediated exchange. In vesicles from bovine adrenal chromaffin granules containing the vesicular biogenic amine transporter, MDMA inhibits ATP-dependent serotonin accumulation and stimulates efflux by dissipating the transmembrane pH difference and directly interacting with the vesicular transporter.
Proceedings of the National Academy of Sciences
April 13, 2021
Natalie Hesselgrave, Timothy A. Troppoli, Andreas B. Wulff et al.
380 citations
Psilocybin, a psychedelic compound, has fast-acting antidepressant-like effects in mice. Using tests of hedonic behavior and a drug that blocks hallucinogenic 5-HT2A receptors, the results suggest that altered perception may not be required for its therapeutic benefits. Psilocybin also strengthens connections between brain cells in regions involved in reward and emotion processing. These findings indicate it may be possible to retain psilocybin's antidepressant actions while minimizing alterations in consciousness.
Proceedings of the National Academy of Sciences
April 13, 2020
Morten L. Kringelbach, Josephine Cruzat, Joana Cabral et al.
326 citations
By combining multimodal neuroimaging data, a framework was developed that demonstrates the fundamental principles of bidirectional coupling between neuronal and neurotransmitter dynamical systems. The work causally explains the functional effects of stimulating specific serotoninergic receptors (5-HT2AR) with psilocybin in healthy humans. This could lead to a better understanding of why psilocybin shows promise as a therapeutic intervention for neuropsychiatric disorders such as depression, anxiety, and addiction.
Proceedings of the National Academy of Sciences
August 27, 2018
291 citations
The default mode network (DMN), a set of brain regions traditionally linked to off-task or mind-wandering states, actually contributes to detailed, task-relevant cognition during active tasks. Using fMRI, participants performed working-memory tasks while reporting their thoughts. Patterns of neural activity showed that distinctions between on- and off-task thought involved regions near sensory and motor cortex, not the DMN. However, the level of detail in ongoing thought corresponded to activity patterns within the DMN during memory maintenance. These findings indicate the DMN supports detailed cognition under active task conditions, challenging the view that it is solely task-negative.
Proceedings of the National Academy of Sciences
December 15, 2014
261 citations
Resting-state functional connectivity MRI (rs-fcMRI) can be reliably performed in mice, producing high-resolution whole-brain images. The functional connections strongly align with the brain's structural wiring, as mapped by anterograde tracer studies. Large-scale network properties previously seen only in primates also exist in rodents, though with some differences. A potential default mode network (DMN)—a system important for social cognition and disrupted in many disorders—was identified in the mouse brain both structurally and functionally. These findings validate mouse rs-fcMRI as a translational bridge, allowing stronger links between cellular and molecular manipulations in mice and human brain conditions.
Proceedings of the National Academy of Sciences
December 24, 2012
246 citations
Spontaneous eyeblinks occur more often than needed to keep the eyes moist. While people watch videos, blinks tend to happen at natural breakpoints in attention. Brain scans show that immediately after a blink, activity briefly drops in the dorsal attention network and rises in the default-mode network, which is linked to internal thought. Physical blackouts of the video do not cause the same brain-network changes. This suggests that eyeblinks actively help disengage attention by momentarily shifting brain activity from external focus to internal processing.
Proceedings of the National Academy of Sciences
June 8, 2015
219 citations
The default mode network (DMN) and semantic network (SN) are thought to overlap in brain regions like the anterior temporal lobe (ATL) and angular gyrus (AG), but their relationship is rarely tested directly. Using fMRI data from 69 participants performing semantic and nonsemantic tasks, the authors found that both networks split into subparts depending on task demands, stimulus type, and difficulty. The left ATL was active for semantic tasks and deactivated for nonsemantic ones, while the left AG was deactivated for all tasks, with deactivation linked to difficulty. Thus, ATL and AG do not share a common role in semantic processing; instead, both are inactive during nonsemantic tasks. These findings challenge the idea that both regions are semantic hubs and have implications for understanding DMN variability and resting-state fMRI.
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
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
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
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.