Proceedings of the National Academy of Sciences of the United States of America
May 26, 2009
Kalina Christoff, Alan M Gordon, Jonathan Smallwood et al.
1,832 citations
Mind wandering, which occupies a large portion of waking life, involves parallel recruitment of both default and executive brain networks, two systems previously thought to work in opposition. Using fMRI with experience sampling during a task, activation in default network regions, particularly medial prefrontal cortex, was linked to subjective reports of mind wandering and to performance errors. Executive network recruitment also occurred, especially when participants lacked meta-awareness of their mind wandering. The findings suggest that mind wandering represents a unique mental state where these networks cooperate rather than oppose each other.
Proceedings of the National Academy of Sciences of the United States of America
September 3, 2002
Bryan L Roth, Karen Baner, Richard Westkaemper et al.
782 citations
Salvinorin A, the active compound in the hallucinogenic plant Salvia divinorum, potently and selectively activates kappa opioid receptors while having no effect on the serotonin 5-HT(2A) receptor targeted by classical hallucinogens like LSD. This makes it the first known naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A produces perceptual distortions, the findings suggest that kappa opioid receptors play a key role in modulating human perception and that kappa opioid-selective antagonists could be developed as novel treatments for disorders involving perceptual distortions, such as schizophrenia, dementia, and bipolar disorders.
Proceedings of the National Academy of Sciences of the United States of America
March 28, 2023
Christopher Timmermann, Leor Roseman, Sharad Haridas et al.
217 citations
Intravenous DMT, a potent psychedelic and serotonin 2A receptor agonist, profoundly alters brain function in healthy volunteers. In a placebo-controlled study with 20 participants, multimodal neuroimaging (EEG-fMRI) showed that DMT robustly increases global functional connectivity, disrupts and desegregates brain networks, and compresses the principal cortical gradient. These changes overlapped with brain regions rich in serotonin 2A receptors and associated with human-specific psychological functions. EEG and fMRI measures correlated, linking neurophysiological changes to network-level effects. The findings indicate DMT predominantly acts on the brain's transmodal association cortex, the evolutionarily recent area tied to advanced cognition and high 5-HT2A receptor density.
Proceedings of the National Academy of Sciences of the United States of America
June 4, 2019
Melanie J Miller, Juan Albarracin-Jordan, Christine Moore et al.
171 citations
Chemical analysis of a ritual bundle from a Bolivian rock shelter, dated to about 1,000 C.E., detected traces of bufotenine, dimethyltryptamine, harmine, and cocaine (with its breakdown product benzoylecgonine). These compounds come from at least three different psychoactive plants, including the two key ingredients of ayahuasca—harmine and dimethyltryptamine—found together in a single artifact for the first time in this region. The plants originated from distant and ecologically distinct areas of South America, indicating that hallucinogenic substances were traded or transported over long distances. This suggests that pre-Columbian peoples possessed sophisticated botanical knowledge and incorporated such plants into shamanic rituals.
Proceedings of the National Academy of Sciences of the United States of America
February 22, 2019
E. Lumsden, Timothy A. Troppoli, S. J. Myers et al.
159 citations
A single low dose of the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) produces rapid antidepressant-like effects in mice without blocking NMDA glutamate receptors (NMDARs), unlike ketamine itself. At a dose of 10 mg/kg, which triggers antidepressant-related behavioral and cellular responses, (2R,6R)-HNK reaches hippocampal concentrations of about 8 µM—far below the levels needed to inhibit NMDARs in vitro. The dose required to prevent NMDA-induced lethality was 228 mg/kg for (2R,6R)-HNK versus 6.4 mg/kg for ketamine, indicating weak NMDAR inhibition. These findings suggest that (2R,6R)-HNK's antidepressant effects occur through alternative molecular targets, potentially avoiding ketamine's adverse effects such as dissociation and abuse potential.
Proceedings of the National Academy of Sciences of the United States of America
January 15, 2020
Matthew E. Klein, Joshua Chandra, Salma A. Sheriff et al.
157 citations
Ketamine, a rapid antidepressant for treatment-resistant depression, requires functional opioid receptors to produce its effects, but it does not act as an opioid itself. In rodent models, blocking opioid receptors prevented ketamine's antidepressant-like behavioral and cellular effects, while activating opioid receptors alone caused hedonic responses and failed to alleviate anhedonia. Ketamine's cellular actions were mimicked by an NMDA receptor antagonist but not by a μ-opioid agonist. The findings suggest that ketamine's antidepressant action depends on both NMDA and opioid receptor signaling, with opioid receptors playing a permissive role rather than mediating the effects directly.
Proceedings of the National Academy of Sciences of the United States of America
June 10, 2008
Sebastien Carnicella, Viktor Kharazia, Jerome Jeanblanc et al.
132 citations
Infusing GDNF directly into the ventral tegmental area (VTA) of rats rapidly and dose-dependently reduces their operant self-administration of alcohol, but not sucrose. This effect is specific to the VTA, as infusion into the neighboring substantia nigra does not alter alcohol responding. GDNF activates the MAPK signaling pathway in the VTA, and blocking this pathway prevents the reduction in alcohol self-administration. GDNF also blocks the reacquisition of alcohol self-administration after extinction, indicating it reduces relapse-like behavior. The findings suggest GDNF, via MAPK activation, acts as a fast-acting and selective agent to diminish alcohol consumption and seeking.
Proceedings of the National Academy of Sciences of the United States of America
April 4, 2017
Johannes J Fahrenfort, Jonathan Van Leeuwen, Christian N L Olivers et al.
102 citations
The visual system can integrate fragmented input into organized surfaces and objects, a process called perceptual integration. Whether this requires conscious access was tested using the attentional blink, which impairs conscious perception. Behaviorally, the attentional blink reduced accurate conscious decisions about integrated surface structure. Yet, multivariate EEG decoding showed the brain still represented integrated percepts even when conscious access was blocked. In contrast, masking impaired both conscious decisions and neural decoding of integration, while leaving feedforward signals intact. These findings indicate that perceptual integration can occur without access to consciousness, dissociating the two processes.
Proceedings of the National Academy of Sciences of the United States of America
November 27, 2023
J. Krystal, Alfred P. Kaye, S. Jefferson et al.
66 citations
Ketamine represents a new type of antidepressant that works quickly, helps people whose depression has not responded to other treatments, and reduces the chance of relapse. Its development came from a new understanding of depression's biology, and studying how ketamine works has deepened knowledge of depression and related conditions. Twenty-five years after the first findings on ketamine for depression were presented, this review examines what has been learned and suggests future ways to improve rapid-acting antidepressant therapy.
Proceedings of the National Academy of Sciences of the United States of America
July 16, 2021
J. Parvizi, R. Braga, A. Kucyi et al.
59 citations
Electrical stimulation of the posteromedial cortex (PMC) can induce a temporary sense of self-dissociation—a distorted awareness of one's body in space and feeling like an outside observer to one's own thoughts. A patient with seizures originating in the right dorsal posterior cingulate cortex (Brodmann area 31) reported this reproducible experience at seizure onset. Stimulating the seizure zone or a homotopical region in the left PMC at 50 Hz induced a subjectively similar state. The findings suggest a causal link between the PMC and the integration of self-referential information, offering clues about the pathophysiology of self-dissociation in neuropsychiatric conditions.
Proceedings of the National Academy of Sciences of the United States of America
May 17, 2016
Yuan-Wei Zhang, Benjamin E Turk, Gary Rudnick
53 citations
The serotonin transporter (SERT) clears serotonin from synapses, and mutations in human SERT are linked to psychiatric disorders and autism. Phosphorylation at a specific site, threonine 276 near the cytoplasmic end of transmembrane helix 5, regulates SERT activity. Agents that stabilize the outward-open conformation of SERT, such as sodium ions and cocaine, decrease phosphorylation, while agents that stabilize the inward-open conformation, such as serotonin and ibogaine, increase phosphorylation. The opposing effects of cocaine and ibogaine are reversible by an excess of the other inhibitor. These findings suggest that serotonin transport itself activates a regulatory mechanism, possibly involving unwinding of the helix to allow phosphorylation.
Proceedings of the National Academy of Sciences of the United States of America
December 8, 2020
David W Robinson, Kelly Brown, Moira Mcmenemy et al.
40 citations
At a California rock art site called Pinwheel Cave, fibrous quids found in the ceiling alongside a painting possibly depicting Datura flowers were analyzed. Chemical tests detected hallucinogenic alkaloids scopolamine and atropine in the quids, and microscopic analysis identified most as Datura wrightii. Three-dimensional analysis showed the quids were chewed, indicating consumption of the plant in the cave beneath the paintings. Archaeological evidence and dating show the site was used from the Late Prehistoric through Colonial periods for various activities. The findings suggest the rock painting represents the plant and codified communal rituals involving this powerful entheogen, providing the first unambiguous evidence of hallucinogen consumption at a rock art site and challenging prior assumptions about trance and rock art imagery.
Proceedings of the National Academy of Sciences of the United States of America
October 15, 2024
Yihan Sophy Xiong, Jacob A Donoghue, Mikael Lundqvist et al.
32 citations
Predictive coding in the cortex relies on predictions fed back from deep layers via alpha/beta oscillations (8–30 Hz) that inhibit gamma (40–100 Hz) and spiking carrying sensory input forward. Intracranial recordings in macaques during passive auditory oddball tasks showed that in the awake state alpha/beta oscillations inhibited processing of predictable sounds. Propofol-induced loss of consciousness eliminated this alpha/beta modulation in sensory cortex and reduced alpha/beta coherence between sensory and frontal areas. Consequently, oddball stimuli evoked enhanced gamma power, late spiking, and superficial layer sinks in auditory cortex, indicating a disinhibited state. However, differential spiking to oddballs in higher-order cortex was lost, likely due to disrupted spike-field coupling. These findings constrain theories of consciousness.
Proceedings of the National Academy of Sciences of the United States of America
May 28, 2024
Elie Adam, Marek Kowalski, Oluwaseun Akeju et al.
30 citations
Ketamine, an NMDA-receptor antagonist, produces sedation and dissociation at low doses and unconsciousness at high doses, while generating gamma oscillations (>25 Hz) in the EEG that are interrupted by slow-delta oscillations (0.1–4 Hz) at high doses. Using a biophysical model of cortical circuits, the authors show how NMDA-receptor antagonism leads to disinhibition in neuronal circuits, and how disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition produces gamma oscillations at both doses and slow-delta oscillations at high doses. This work reveals general mechanisms for generating oscillatory brain dynamics and provides insights into ketamine's actions as an anesthetic and therapy for treatment-resistant depression.
Proceedings of the National Academy of Sciences of the United States of America
November 1, 2022
Péter Simor, Tamás Bogdány, Philippe Peigneux
23 citations
Lucid dreaming occurs when a person realizes they are dreaming while still asleep, often involving vivid images and unusual bodily sensations like flying. A new multicomponent framework proposes that lucid dreaming arises from prediction error signals during sleep, which are resolved by creating a superordinate self-model that integrates ambiguous sensory inputs from both the body and higher brain regions. Multisensory integration maintains lucidity and contributes to kinesthetic experiences, while attentional control balances top-down mental models and bottom-up sensory precision. This framework links neural correlates of lucid dreaming to sleep and arousal regulation, generating testable predictions about individual differences and neurocognitive mechanisms that induce lucid dreams.
Proceedings of the National Academy of Sciences of the United States of America
March 18, 2025
Yusuke Moriguchi, Ryoichi Watanabe, Chifumi Sakata et al.
13 citations
Color qualia—the subjective experience of color, such as the quality of redness—are similar across age and culture. Using a task that obtained pairwise similarity judgments via intuitive visual interfaces, researchers tested children aged 3 to 12 in Japan and 6 to 8 in China, comparing them with Japanese adults. About half of 3-year-olds completed the touch-panel task reliably. Despite developmental and cultural differences in color-term usage, color qualia structures were quite similar across all groups. This suggests that these structures emerge early in life. Subtle age-related differences in evaluations of some color pairs imply minor changes in color experience with development.
Proceedings of the National Academy of Sciences of the United States of America
March 19, 2024
Hyuk-June Moon, Louis Albert, Emanuela De Falco et al.
9 citations
Grid cells in the entorhinal cortex, which encode location in space using environmental and bodily cues, also respond to illusory shifts in self-location caused by multisensory bodily stimulation, even without actual movement or visual navigation. In this fMRI study, participants experienced controlled illusory forward drifts in self-location through visuo-tactile stimulation while their visual viewpoint remained fixed. The entorhinal cortex showed grid cell-like representations that correlated with the magnitude of the perceived self-location and had the same grid orientation as during conventional virtual navigation. This indicates that the same neural representation is recruited for navigation based on environmental cues and for self-location changes driven by bodily signals.
Proceedings of the National Academy of Sciences of the United States of America
January 1, 1974
8 citations
Lymphoid cells from hyperimmune rabbits producing antibodies to a hapten, when incubated with d-lysergic acid diethylamide (LSD), synthesized protein at a normal rate. However, the low-molecular-weight protein secreted by these cells had isoelectric points (pI) of 4.9 and 5.2, whereas immune cells not exposed to LSD secreted only 7S IgG molecules with an average pI of about 7.0. This suggests LSD alters the type of protein secreted by these immune cells.
Proceedings of the National Academy of Sciences of the United States of America
February 11, 2025
Christina Maher, Lea Tortolero, Soyeon Jun et al.
7 citations
Loving-kindness meditation, which involves directing thoughts of goodwill toward oneself and others, alters neural activity in the amygdala and hippocampus. In first-time meditators with implanted brain-recording devices, the practice increased gamma-band (30 to 55 Hz) power and changed the duration of beta (13 to 30 Hz) and gamma oscillatory bursts in both regions. These changes were specific to periodic features of neural activity, not aperiodic ones. The findings suggest that even novice meditation can modulate limbic brain activity linked to emotional regulation and mood disorders.
Proceedings of the National Academy of Sciences of the United States of America
December 30, 2025
Esteban Munoz-Musat, Arthur Le Coz, Andrew W Corcoran et al.
5 citations
Mind blanking—a state of apparent mental emptiness—produces distinct brain signatures that separate it from mind wandering and focused attention. In 62 participants performing a sustained attention task, mind blanking was associated with behavioral lapses, reduced fast brain oscillations and complexity over posterior electrodes, and decreased long-range connectivity compared to both mind wandering and on-task states. Event-related potentials showed disrupted visual processing beginning 200 milliseconds after a stimulus, suggesting a breakdown in conscious access to sensory information. Brain activity patterns predicted mental states on individual trials, revealing dynamics that subjective reports alone miss. These findings indicate that being awake does not guarantee consciousness of something; mind blanking reflects genuine gaps in the stream of thought, arising from disruptions in generating or accessing thought content.
Proceedings of the National Academy of Sciences of the United States of America
June 16, 2026
Adam R Pines, Xue Zhang, John Kochalka et al.
Psychedelic drugs consistently reduce the strength and bottom-up direction of signal flow within the brain's default mode network, according to analyses of four independent datasets spanning humans and mice and three different psychedelic compounds (MDMA, psilocybin, and LSD). This attenuation of cortical propagations is not explained by data quality or previously known effects of psychedelics and is uniquely tied to self-reported outcomes. The findings clarify how psychedelics alter macroscale hierarchical processing in the brain.
Proceedings of the National Academy of Sciences of the United States of America
May 5, 2026
Roberto Malinow
Ketamine reduces depression and suicidality in treatment-resistant individuals, but its mechanism remains unknown. A new hypothesis proposes that synaptic and circuit plasticity underlies ketamine's effects, potentially leading to improved treatments for depression and other conditions.
Proceedings of the National Academy of Sciences of the United States of America
May 13, 2025
Sijia Gao, Yelena Bibineyshvili, Seyed A Safavynia et al.
A repeated, temporally discrete dynamical pattern called an 'Arousal Unit' (AU) appears during recovery of consciousness from anesthesia and brain injury coma in rodents. The pattern was prospectively validated in neonatal humans recovering from static hypoxic injuries and in senior patients emerging from anesthesia, indicating generalizability. AUs lawfully link changes in spectral power and breathing frequency and reliably associate with motor changes. Distinctive cortical patterns within AUs can be transformed into arousal indices that determine arousal levels. The reliability of these events is demonstrated across intact and brain-injured states and translates to the human brain. Extracting these stereotyped dynamics could aid anesthesia monitoring, tracking coma recovery, and identifying cognitive motor dissociation.
Proceedings of the National Academy of Sciences of the United States of America
December 30, 2025
Catherine Hume, Carrie Cuttler, Samantha L Baglot et al.
Cannabis vapor inhalation acutely increases food intake in both humans and rats, an effect driven by central cannabinoid 1 receptors. In humans, energy intake rose within the first 30 minutes of snack access, regardless of dose or gender, without altering the proportion of macronutrients consumed. In rats, cannabis vapor reduced the time to start eating and increased the number of feeding bouts, overriding homeostatic appetite regulation by boosting motivation to eat and reducing food reward devaluation. These feeding effects were not accompanied by changes in circulating appetite-associated hormones, and they depended on central, not peripheral, CB1 receptors.