Scientific Reports
February 10, 2020
Frederick S. Barrett, Manoj K. Doss, Nathan D. Sepeda et al.
375 citations
A single 25 mg/70 kg dose of psilocybin temporarily reduced negative affect and amygdala response to negative facial expressions one week later in twelve healthy volunteers, while positive affect and prefrontal cortex responses to emotional conflict increased. One month later, negative affect and amygdala reactivity returned to baseline, but positive affect remained elevated and trait anxiety was lower. The number of resting-state functional connections across the brain increased from baseline to both one week and one month after dosing. These preliminary findings suggest psilocybin may enhance emotional and brain plasticity, with negative affect as a potential therapeutic target.
Translational Psychiatry
November 8, 2021
Manoj K. Doss, Michal Považan, Monica D Rosenberg et al.
343 citations
Psilocybin therapy increased cognitive flexibility for at least four weeks in 24 patients with major depressive disorder, though these improvements were not linked to antidepressant effects. One week after treatment, glutamate and N-acetylaspartate concentrations decreased in the anterior cingulate cortex (ACC), and functional connectivity dynamics increased between the ACC and posterior cingulate cortex. Surprisingly, larger increases in this neural flexibility were associated with smaller gains in cognitive flexibility. Baseline brain connectivity from the ACC predicted cognitive flexibility improvements, with greater baseline connectivity linked to better baseline flexibility but less improvement. The findings suggest that while some increase in neural dynamics may help shift from rigid states, larger persisting increases may be less beneficial.
Brain
October 22, 2021
Manoj K. Doss, Maxwell B. Madden, Andrew Gaddis et al.
196 citations
Classic psychedelic drugs like psilocybin and LSD may help treat psychiatric disorders by altering brain circuits. Two existing models—the cortico-striatal thalamo-cortical (CSTC) model and the relaxed beliefs under psychedelics (REBUS) model—highlight different subcortical structures in mediating these effects. This paper introduces a third circuit-level model, the cortico-claustro-cortical (CCC) model, focusing on the claustrum, a thin strip of grey matter that densely expresses serotonin 2A receptors. The CCC model proposes that the claustrum entrains canonical cortical network states, and psychedelic drugs disrupt 5-HT2A-mediated coupling between claustrum and cortex, attenuating these networks. Together, the three models may explain many phenomena of the psychedelic experience.
The International Journal of Neuropsychopharmacology
May 10, 2021
Natalie Gukasyan, David B. Yaden, Matthew W. Johnson et al.
56 citations
Psychedelic substances produce unusual changes in conscious experience, leading some to propose they offer unique insights into consciousness. However, psychedelics are unlikely to provide information relevant to the "hard problem of consciousness," which involves explaining how first-person experience emerges. Instead, they bear on multiple "easy problems of consciousness," involving relations between subjectivity, brain function, and behavior. This review discusses common meanings of "consciousness" regarding psychedelics and considers models of their effects on the brain linked to explanatory claims about consciousness. It calls for epistemic humility about psychedelic research's potential to explain the hard problem while noting ways psychedelics may advance study of specific aspects of consciousness.
Scientific Reports
October 2, 2020
Manoj K. Doss, Darrick G. May, Matthew W. Johnson et al.
52 citations
Salvinorin A, a κ-opioid receptor agonist and dissociative hallucinogen found in Salvia divinorum, alters human brain functional connectivity in ways similar to other hallucinogens. In a placebo-controlled, within-subject fMRI study, inhaled Salvinorin A tended to decrease functional connectivity within brain networks while increasing connectivity between networks, most notably attenuating the default mode network during peak effects. It reduced brainwide dynamic functional connectivity but increased brainwide entropic functional connectivity, though only the reduction survived statistical correction. Connectome-based classification models trained on dynamic connectivity accurately identified Salvinorin A scans, especially when using default mode network interactions. These findings suggest shared neural mechanisms across hallucinogen types.
Neuroscience and Biobehavioral Reviews
July 1, 2023
Manoj K. Doss, Harriet de Wit, David A Gallo
30 citations
Psychoactive drugs affect emotional episodic memory at three stages: encoding, consolidation, and retrieval. Drugs given before encoding can impair (e.g., alcohol, benzodiazepines, THC, ketamine), enhance (e.g., dextroamphetamine), or both impair and enhance (e.g., MDMA) emotional memories compared to neutral ones. Sedatives given after encoding can preferentially boost emotional memories during consolidation, but this selectivity may weaken or reverse over time. Retrieving memories under THC, dextroamphetamine, MDMA, or sedatives can distort memory, especially for positive emotional content. The review proposes neural mechanisms and discusses how these effects might influence drug use and abuse.
Psychological review
March 1, 2024
Manoj K. Doss, Jason Samaha, Frederick S. Barrett et al.
24 citations
Psychoactive drugs produce unique subjective states, but their effects on episodic memory often overlap. This reanalysis of 10 data sets (28 drug conditions) used signal detection models to separate three memory processes: recollection (retrieving specific details), familiarity (recognizing without details), and metamemory (introspecting about memory accuracy). Sedatives impaired both recollection and familiarity during encoding but enhanced recollection during consolidation. Dissociatives and cannabinoids impaired recollection during encoding, and cannabinoids increased false recollections during retrieval. Psychedelics impaired recollection during encoding but tended to enhance familiarity. Stimulants enhanced metamemory during encoding and retrieval but impaired metamemory during consolidation. These distinct patterns help explain drug-specific phenomena like sedative-induced blackouts and psychedelic presque vu, and suggest that memory quantity and stability influence metamemory.
Neurotherapeutics
January 25, 2024
Bryan R. Barksdale, Manoj K. Doss, Gregory A. Fonzo et al.
22 citations
Psychedelics show promise as treatments for severe psychiatric disorders, especially those resistant to standard therapies. Their effects arise from receptor binding and downstream changes in cells and genes, altering brain structure and function from individual neurons to large-scale circuits. This perspective reviews evidence on how psychedelics produce acute and lasting changes in consciousness, linking molecular, cellular, circuit, and psychological levels. A key controversy is that theoretical models from different levels of inquiry often conflict. Bridging these explanations through innovative methods and collaboration is essential to fully harness psychedelics' therapeutic potential.
ACS Chemical Neuroscience
August 24, 2022
Manoj K. Doss, Frederick S. Barrett, Philip R. Corlett
21 citations
A critique of a Nature Medicine paper claiming psilocybin therapy reduces brain network modularity in depressed patients, an effect not seen with the SSRI S-citalopram. The authors identify multiple problems: inconsistent reporting of the primary clinical outcome, statistical flaws including a one-tailed test and a nonsignificant interaction, regression to the mean, ambiguous interpretation of resting-state fMRI data, and a missing reference to a similar study that undermines the justification for a one-tailed test. These issues cast doubt on the uniqueness and impact of the original findings and the media hype they generated.
Drugs
November 1, 2024
Manoj K. Doss, Annamarie Demarco, Joseph E Dunsmoor et al.
14 citations
PTSD involves abnormalities in memory, and psychedelics may help treat it by affecting multiple memory systems. Most research has focused on fear conditioning and extinction, which are limited models. A review of 25 studies found that the acute effects of psychedelics can enhance extinction learning, which is impaired in PTSD, though they may also enhance fear conditioning. Post-acute effects may also boost extinction learning. PTSD and psychedelics both impair hippocampal-dependent episodic memory formation, but psychedelics may enhance cortical-dependent semantic learning, potentially helping integrate trauma memories and disrupt maladaptive beliefs. More research is needed on episodic memory consolidation, retrieval, and reconsolidation, and on post-acute effects across all memory phases.
June 10, 2021
Drummond E-Wen Mcculloch, Gitte M. Knudsen, Frederick S. Barrett et al.
14 citations
preprint
Research into psychedelic drugs like psilocybin, LSD, and DMT is growing, with clinical trials showing promise for psychiatric conditions. Resting-state fMRI is a common method to study brain mechanisms in these contexts. A review of 42 articles from 17 datasets found high heterogeneity in methods and analyses; two datasets underlie over half the publications, and terms like "entropy" are used inconsistently. The authors suggest that the field needs greater methodological consistency and replicability to identify stable neural markers of psychedelic effects, and encourage development of new models and quantification methods.
July 3, 2023
Hugh McGovern, Hilary Jane Grimmer, Manoj K. Doss et al.
12 citations
preprint
Psychedelics can reorient beliefs, but they may also lead to false insights and false beliefs. A review of laboratory research on false insights and false memories is connected to belief formation under psychedelics through the active inference framework. Psychedelics increase both the quantity and subjective intensity of insights and beliefs, including false ones. Future research should aim to minimize the risk of false and potentially harmful beliefs arising from psychedelics. Understanding this risk is crucial for safely leveraging the therapeutic potential of psychedelics.
Psychedelic Medicine
June 1, 2023
Praachi Tiwari, Andrea P Berghella, Ceyda Sayalı et al.
9 citations
Classic psychedelics may treat mood and substance use disorders by reversing learned helplessness, a well-studied phenomenon across mammals. The neural circuits underlying resilience to learned helplessness, including the dorsal raphe nucleus, overlap with those activated by psychedelics. Preclinical data show psychedelics improve performance in rodent behavioral despair tasks, supporting this hypothesis. The learned helplessness paradigm offers a robust model for investigating psychedelic mechanisms across behavioral, neurobiological, and clinical levels, potentially explaining transdiagnostic therapeutic effects.
Nature Medicine
April 1, 2026
Manesh Girn, Manoj K. Doss, Leor Roseman et al.
8 citations
Psychedelic drugs are being studied again for their therapeutic potential, but how they change brain function is not well understood. By combining 11 brain-scanning datasets from five different psychedelics (psilocybin, LSD, mescaline, DMT, and ayahuasca) across three continents, researchers found a common pattern: increased communication between brain networks that handle high-level thinking (default, frontoparietal, and limbic) and those that handle sensory input (visual and somatomotor). Key deep-brain regions (thalamus, caudate, putamen) and the cerebellum also changed how they connect with sensorimotor networks. Contrary to some earlier studies, reductions in within-network connectivity were weak to moderate and varied by drug. These findings help resolve previous inconsistencies and provide a comprehensive map of how psychedelics alter large-scale brain organization.
Biological psychiatry. Cognitive neuroscience and neuroimaging
October 1, 2024
Manoj K. Doss, Pablo Mallaroni, Natasha L. Mason et al.
7 citations
Two psychedelics, psilocybin and 2C-B, impair the encoding of detailed recollections and distort feelings of familiarity for emotional memories. In a double-blind, placebo-controlled study with 20 participants, both drugs reduced estimates of recollection and familiarity the next day, but increased false alarms based on familiarity, especially for negative and positive images. The drugs also tended to impair metamemory for negative and neutral memories while enhancing it for positive ones, though these effects were less reliable. The similar pattern across both substances suggests a shared neurocognitive mechanism among psychedelics that may underlie other phenomena.
bioRxiv (Cold Spring Harbor Laboratory)
May 24, 2022
Manoj K. Doss, Jason Samaha, Frederick S. Barrett et al.
6 citations
preprint
Different classes of psychoactive drugs—sedatives, dissociatives, psychedelics, stimulants, and cannabinoids—each produce unique patterns of effects on the conscious processes underlying episodic memory, depending on whether they act during encoding, consolidation, or retrieval. Reanalyzing confidence data from 10 published datasets (28 drug conditions) with signal detection models, the authors found that all drugs except stimulants impaired recollection when given at encoding; sedatives, dissociatives, and cannabinoids also impaired familiarity at encoding. Psychedelics at encoding enhanced familiarity and did not affect metamemory, while dissociatives and cannabinoids tended to enhance metamemory. Stimulants enhanced metamemory at encoding and retrieval but impaired it at consolidation. These distinct profiles may help explain drug-specific subjective phenomena such as sedative-induced blackouts or psychedelic déjà vu.
Journal of psychopharmacology (Oxford, England)
April 1, 2025
Manoj K. Doss, Lilian Kloft, Natasha L. Mason et al.
5 citations
In experienced users, ayahuasca acutely enhances recollection-based memory—the ability to recall specific details—without increasing false memories or affecting familiarity-based memory, a feeling of knowing. In an observational study of 24 Santo Daime members who had consumed ayahuasca over 500 times on average, participants completed a false memory task before and after taking a self-selected church dose. After ayahuasca, hit rates, memory accuracy, and recollection improved, while familiarity and false memory remained unchanged. The authors suggest that β-carboline activity in the brew may account for this recollection enhancement, which contrasts with past psychedelic research showing impaired recollection. Practice effects could not be ruled out, but multiple measures of false memory and metamemory did not improve across sessions.
May 26, 2024
Hugh McGovern, Nick Wellman, Brendan Hutchinson et al.
2 citations
preprint
Psychedelics such as psilocybin show promise for treating anxiety, but how they work is unclear. This review proposes a model where anxiety disorders involve the hippocampus biasing the amygdala and salience network toward anxiety-related information, creating a self-perpetuating cycle. Psychedelics temporarily free cortical networks from this hippocampal constraint, and increased plasticity afterward allows the hippocampus to integrate new information into a less biased contextual frame, reducing anxious thoughts. The model highlights that psychedelics can acutely increase anxiety, and future research should determine optimal treatment approaches informed by cognitive neuroscience.
bioRxiv (Cold Spring Harbor Laboratory)
September 23, 2019
Kirsten C. S. Adam, Manoj K. Doss, Elisa Pabon et al.
2 citations
preprint
THC, the main psychoactive component in cannabis, impairs visual working memory—the ability to temporarily hold visual information in mind. Two double-blind, randomized crossover experiments with 23 healthy adults each found that oral THC (7.5 or 15 mg) reduced working memory performance, increased self-reported mind wandering, and decreased metacognitive accuracy about ongoing task performance. The authors also showed that short task durations and small sample sizes reduce the likelihood of detecting such drug effects.
Neuroscience and Biobehavioral Reviews
July 1, 2026
Bruno Moses, Manoj K. Doss, Enzo Tagliazucchi
1 citation
The entropic brain hypothesis suggests that brain entropy—the uncertainty in brain state distributions—increases during psychedelic states and other states of expanded consciousness, while decreasing in states of diminished consciousness. Many neuroimaging studies have reported heightened entropy under psychedelics, leading some to consider entropy a reliable biomarker of the psychedelic state. This paper argues that view is oversimplified. It reviews evidence for entropy metrics, then identifies four challenges: entropy changes are not specific to psychedelics; current methods do not capture multidimensional conscious states; multiple entropy metrics exist with different interpretations and limited consistency; and there is little evidence linking brain entropy directly to phenomenal richness. The authors conclude the concept warrants further investigation and offer suggestions for future research.
Neuroscience & Biobehavioral Reviews
May 30, 2026
Raquel Kosted, Manoj K. Doss, Jennifer J. Donegan et al.
1 citation
Psychedelics may enhance cognitive flexibility, but findings are mixed, with some studies showing impairment. This review proposes that acute effects of psychedelics boost learning from reward receipt, which can lead to perseveration, while post-acute effects enhance learning from reward omission, counteracting that perseveration. Different serotonin receptor subtypes (5-HT2C, 5-HT2A, 5-HT1A) may support these distinct learning processes. This hypothesis explains when psychedelics improve flexible decision-making and why insights reached under their influence can be held strongly, and it suggests strategies to reduce maladaptive belief formation.
Journal of Eating Disorders
December 4, 2025
Samuli Kangaslampi, Max Wolff, Manoj K. Doss et al.
1 citation
Psychedelics like psilocybin can trigger vivid memory-like experiences, but a recent case report claiming that two patients recovered dissociated traumatic memories during psilocybin treatment for anorexia nervosa may not have adequately considered alternative explanations. The cases do not necessarily show that psilocybin induces recovery of dissociated traumatic memories or could treat dissociative amnesia. The authors also caution against explicitly preparing patients for the emergence of forgotten material, as such suggestions warrant scrutiny.
April 28, 2022
Manoj K. Doss, Frederick S. Barrett, Philip R. Corlett
1 citation
preprint
A critical commentary identifies problems in a previously published study on psilocybin therapy. The authors argue that the original paper drew unsupported causal conclusions from correlational data, failed to account for placebo effects and participant expectations, and used statistical methods that inflated the apparent strength of the findings. The commentary suggests the original study's claims about psilocybin's therapeutic mechanisms are not justified by the evidence presented.
Neuroscience and Biobehavioral Reviews
July 1, 2022
Drummond E-Wen Mcculloch, Gitte Moos Knudsen, Frederick Streeter Barrett et al.
A large group of psychedelic imaging researchers reviewed 42 articles from 17 unique studies that used resting-state functional magnetic resonance imaging (rs-fMRI) to examine psychedelic effects. They found that nearly all studies varied in data processing and analysis methods, two datasets underpin over half of the published literature, and key outcome terms are used ambiguously. The authors recommend guidelines to improve consistency and replicability in future research, arguing that the field must balance novel methods with standardized approaches to reliably understand the neural mechanisms of psychedelics.
Frontiers in Psychology
January 24, 2023
Maria Beckman, Stig Poulsen, Manoj K. Doss et al.
This editorial introduces a Research Topic on the role of set and setting in psychedelic-assisted psychotherapy. It argues that the effects of psychedelic substances are profoundly shaped by the psychological state of the individual (set) and the physical, social, and cultural environment (setting), rather than being purely pharmacological. The editorial emphasizes that understanding and optimizing these contextual factors is crucial for both safe clinical practice and the design of future research. It calls for more systematic investigation into how set and setting influence therapeutic outcomes, and highlights the need to integrate these insights into training and clinical protocols to maximize the potential benefits and minimize risks of psychedelic-assisted therapy.