eLife
October 25, 2018
Katrin H. Preller, Joshua B. Burt, Jie Lisa Ji et al.
416 citations
Lysergic acid diethylamide (LSD) reduces associative brain connectivity while increasing sensory-somatomotor and thalamic connectivity. These neural effects, along with the subjective experience, are fully blocked by ketanserin, a selective 5-HT2A receptor antagonist. The spatial pattern of LSD's effects across the brain matches the distribution of 5-HT2A receptor gene expression in humans. These results strongly implicate the 5-HT2A receptor in LSD's neuropharmacology, informing the neurobiology of psychedelics and guiding development of psychedelic-based therapeutics.
EClinicalMedicine
February 1, 2023
Robin von Rotz, Eva M Schindowski, Johannes Jungwirth et al.
345 citations
A single, moderate dose of psilocybin (0.215 mg/kg body weight) significantly reduced depressive symptoms compared to placebo in adults with major depressive disorder. Over two weeks, depression severity scores dropped by 13.0 points on the MADRS and 13.2 points on the BDI in the psilocybin group, with improvements significantly larger than in the placebo group. 54% of participants receiving psilocybin met remission criteria. No serious adverse events occurred. The findings suggest psilocybin offers rapid antidepressant effects, though larger, longer-term trials are needed.
Biological Psychiatry
April 26, 2014
Rainer Kraehenmann, Katrin H. Preller, Milan Scheidegger et al.
325 citations
A double-blind, randomized, crossover study in 25 healthy volunteers found that a single dose of psilocybin (0.16 mg/kg) reduced amygdala reactivity to negative and neutral stimuli, measured with functional magnetic resonance imaging, compared with placebo. The reduction in right amygdala reactivity to negative stimuli was linked to an increase in positive mood, assessed with the Positive and Negative Affect Schedule and the State-Trait Anxiety Inventory. These findings suggest psilocybin may dampen neural responses to negative emotional cues and improve mood, which could be relevant for treating conditions like major depression where amygdala hyperactivity and negative mood states are common.
Biological Psychiatry
May 9, 2012
Michael Kometer, André Schmidt, Rosilla Bachmann et al.
300 citations
Psilocybin enhanced positive mood and reduced recognition of negative facial expressions in healthy volunteers. It also increased goal-directed behavior toward positive emotional cues while inhibiting negative sequential emotional effects and valence-dependently attenuated the P300 brain response. These emotional shifts occurred across multiple psychological domains and were blocked by the 5-HT2A antagonist ketanserin, indicating that activation of 5-HT2A receptors is central to mood regulation and emotional face recognition. The findings suggest a mechanism for psilocybin's potential antidepressant effects.
PLoS ONE
September 24, 2012
Milan Scheidegger, Martin Walter, Mick Lehmann et al.
282 citations
Ketamine, an NMDA receptor antagonist that modulates glutamate signaling, rapidly reduces functional connectivity between the default mode network (DMN) and the dorsal nexus, a dorsal medial prefrontal cortex region linked to depression. In a randomized, placebo-controlled, double-blind, crossover resting-state fMRI study in healthy subjects, ketamine decreased connectivity from the DMN's posterior cingulate cortex hub to the dorsal nexus, pregenual anterior cingulate, and medioprefrontal cortex. This subacute modulation at 24 hours overlaps with ketamine's peak antidepressant efficacy in treatment-resistant depression, suggesting that targeting glutamatergic system-driven network dysconnectivity may underlie successful depression treatment.
Biological Psychiatry
January 13, 2020
Katrin H. Preller, Patricia Duerler, Joshua B. Burt et al.
199 citations
Psilocybin reduces connectivity in associative brain regions while increasing connectivity in sensory regions, a pattern that emerges over time from administration to peak effects. Baseline connectivity predicts the extent of these changes. The shifts correlate with spatial gene expression patterns of the serotonin 2A and 1A receptors, pinpointing their critical role in the psychedelic state. These findings suggest that sensory integration and associative disintegration may underlie the psychedelic experience, and baseline connectivity could serve as a predictive marker for personalized psychedelic treatment.
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.
Psychopharmacology
July 31, 2015
Michael Kometer, Thomas Pokorny, Erich Seifritz et al.
165 citations
A moderate dose of psilocybin, a naturally occurring hallucinogen, decreased brain electrical activity at 1.5-20 Hz in a network involving the anterior and posterior cingulate cortices and parahippocampal regions. The intensity of spiritual experience and insightfulness correlated with the synchronization of delta oscillations (1.5-4 Hz) between the retrosplenial cortex, parahippocampus, and lateral orbitofrontal area. These findings directly link a specific spatiotemporal neuronal mechanism to spiritual experiences and enhanced insight into life, suggesting a pathway for modulating mental health and promoting well-being.
Frontiers in Pharmacology
November 8, 2017
Rainer Kraehenmann, Dan Pokorný, Helena Aicher et al.
115 citations
Lysergic acid diethylamide (LSD) increases primary process thinking—an early, implicit, associative, and automatic mode of thinking typical of dreaming—via activation of serotonin 2A (5-HT2A) receptors. In a placebo-controlled experiment with 25 healthy subjects, LSD (100 mcg orally) significantly raised the primary index, a measure of primary process thinking, compared with placebo. This increase correlated with feelings of disembodiment and a blissful state. Both the rise in primary process thinking and altered states of consciousness were fully blocked by the 5-HT2A receptor antagonist ketanserin, indicating that 5-HT2A receptor activation is necessary for these effects. Primary process thinking appears to organize inner experiences during both dreams and psychedelic states.
NeuroImage Clinical
August 22, 2015
Rainer Kraehenmann, André Schmidt, Karl Friston et al.
107 citations
Psilocybin reduces the brain's threat response by weakening top-down signals from the amygdala to the primary visual cortex. Using dynamic causal modeling of fMRI data, researchers found that psilocybin decreased the threat-induced modulation of this specific connection within the visual-limbic-prefrontal network. This neural mechanism may help explain how psilocybin shifts emotional processing away from negative toward positive stimuli, which could be relevant for treating mood and anxiety disorders.
Psychological Medicine
September 10, 2019
Thomas Pokorny, Patricia Duerler, Erich Seifritz et al.
102 citations
Lysergic acid diethylamide (LSD) acutely impairs executive functions, cognitive flexibility, and spatial working memory in healthy adults, but does not affect decision-making quality or risk-taking. These deficits are prevented by pretreatment with the serotonin 2A receptor antagonist ketanserin, indicating that LSD's cognitive effects are mediated through the 5-HT2A receptor. The findings suggest that 5-HT2A antagonists may have therapeutic potential for cognitive impairments in psychiatric and neurodegenerative disorders.
European Neuropsychopharmacology
April 25, 2018
O. Grimm, Rainer Kraehenmann, Katrin H. Preller et al.
94 citations
Psilocybin, a psychedelic 5-HT2A receptor agonist, modulates emotion processing networks in the brain. In a double-blind crossover study with 18 healthy volunteers, psilocybin increased reaction time to emotional faces and decreased connectivity between the amygdala and the striatum during angry face discrimination, and between the amygdala and the frontal pole during happy face discrimination. No effect was seen during fearful face discrimination. These findings suggest psilocybin alters connectivity in key emotion-processing hubs, which may underlie its antidepressant effects, though further research is needed to link connectivity changes to therapeutic outcomes.
Psychopharmacology
July 26, 2012
André Schmidt, Michael Kometer, Rosilla Bachmann et al.
94 citations
The glutamate NMDA receptor and the serotonin 5-HT receptor system contribute differently to how the brain encodes emotional facial expressions. In healthy volunteers, both S-ketamine (an NMDA receptor antagonist) and psilocybin (a 5-HT receptor agonist) impaired the encoding of fearful faces, as shown by a reduced N170 brain response over parieto-occipital regions. However, only S-ketamine also impaired the encoding of happy faces; psilocybin had no effect on happy-face processing. These findings suggest that early visual evoked responses can detect pharmacologically induced changes in emotional processing biases, offering a framework for studying dysfunctional emotional biases in psychiatric disorders.
Human Brain Mapping
February 25, 2016
Milan Scheidegger, A Henning, Martin Walter et al.
78 citations
Ketamine, an NMDA receptor antagonist, reduced neural reactivity in the bilateral amygdalo-hippocampal complex during emotional stimulation in 23 healthy subjects. Reduced amygdala reactivity to negative pictures correlated with resting-state connectivity to the pregenual anterior cingulate cortex. The intensity of psychedelic alterations of consciousness during ketamine infusion predicted the reduction in neural responsivity to negative but not to positive or neutral stimuli. These findings suggest that modulation of glutamate-responsive circuits, associated with a shift in emotional bias and reduced amygdalo-hippocampal reactivity, may represent an early mechanism to restore disrupted neurobehavioral homeostasis in major depressive disorder.
Journal of Neuroscience
March 19, 2018
Katrin H. Preller, Leonhard Schilbach, Thomas Pokorny et al.
75 citations
Lysergic acid diethylamide (LSD) reduces activity in brain areas important for self-processing and social cognition, and decreases the efficiency of establishing joint attention. These effects are attributable to stimulation of the serotonin 2A receptor (5-HT2AR), as they are blocked by the antagonist ketanserin. The findings point toward the 5-HT2AR system as a potential target for treating social impairments in psychiatric disorders.
Frontiers in Psychiatry
August 18, 2017
Zurina Hassan, Oliver G. Bosch, Darshan Singh et al.
62 citations
Human culture involves learning to consume natural or synthetic psychoactive compounds that alter mental states and behavior. After a novel psychoactive substance (NPS) emerges and is experimentally used, its benefits and harms can be estimated, leading to legal classifications ranging from medical use to complete bans. However, banned drugs often continue to be used, allowing better understanding of their properties, and views on a drug can shift from harmful to medically useful. This review summarizes recent neuropharmacological progress on several NPS, including mitragynine, synthetic cannabinoids, dimethyltryptamine, novel serotonergic hallucinogens, cathinones, ketamine, novel dissociatives, gamma-hydroxybutyrate, gamma-butyrolactone, and 1,4-butanediol, highlighting both emerging harm potentials and potential medical applications.
Cerebral Cortex
July 16, 2013
Fosco Bernasconi, André Schmidt, Thomas Pokorny et al.
62 citations
Psilocybin, a serotonin receptor agonist, alters how the brain processes emotional faces. Electrical brain recordings showed that psilocybin reduced brain activity in limbic areas—including the amygdala and parahippocampal gyrus—and the right temporal cortex when viewing neutral and fearful faces between 168-189 milliseconds after seeing the face. For happy faces, reduced activity occurred in limbic and right temporo-occipital areas between 211-242 milliseconds. These findings suggest psilocybin selectively and temporarily disrupts the brain's emotional face processing, likely by affecting top-down control mechanisms.
Social Cognitive and Affective Neuroscience
April 13, 2016
Mick Lehmann, Erich Seifritz, A Henning et al.
58 citations
Distraction and rumination are distinct ways people respond to negative thoughts and feelings. Rumination involves elevated self-focus, linked to increased resting state functional connectivity and decreased reactivity within the default mode network. The NMDA receptor antagonist ketamine reduces functional connectivity in this network, but its effects on brain responses during stimulus perception were unknown. In healthy subjects given a single ketamine dose, blood oxygenation level-dependent (BOLD) reactivity to negative emotional pictures increased specifically in the pregenual anterior cingulate cortex, not in a posterior control region. The increase was greater in subjects with low ability to use distraction during negative experiences. Ketamine may attenuate pathological increased self-focus during negative experiences.
British Journal of Clinical Pharmacology
December 11, 2015
Matthias E. Liechti, Boris B. Quednow, Evangelia Liakoni et al.
57 citations
Gamma-hydroxybutyrate (GHB) produced mixed stimulant-sedative effects in healthy men, with higher doses causing more sedation and dizziness but no changes in heart rate or blood pressure. Plasma exposure to GHB rose disproportionately with dose—a 40% greater increase than expected from dose alone—indicating nonlinear pharmacokinetics. The psychotropic effects were closely tied to plasma concentrations, and no acute tolerance developed over time.
iScience
May 19, 2023
Andres Ort, John W Smallridge, Simone Sarasso et al.
47 citations
Classical psychedelic drugs like psilocybin induce profound changes in consciousness, including heightened sensory-emotional awareness and arousal, accompanied by increased spontaneous EEG signal diversity. By combining Transcranial Magnetic Stimulation (TMS) with EEG, this work shows that psilocybin creates a state of increased chaotic brain activity, which is not due to altered complexity in causal interactions between brain regions. The study also maps regional effects of psilocybin on TMS-evoked activity, identifying changes in frontal brain structures that may relate to the phenomenology of psychedelic experiences.
EClinicalMedicine
March 14, 2025
Raoul Bitar, Simon Halm, Christina Rossgoderer et al.
42 citations
A randomized controlled trial investigated whether psilocybin-assisted therapy could reduce relapse in patients with alcohol use disorder. The study compared psilocybin therapy against a control condition, finding that the psilocybin group showed a significantly lower rate of heavy drinking days over the follow-up period. The results suggest that psilocybin, when combined with psychotherapy, may be a promising intervention for relapse prevention in alcohol dependence, though further research is needed to confirm these findings.
Psychoneuroendocrinology
July 17, 2015
Oliver G. Bosch, Christoph Eisenegger, Jürg Gertsch et al.
42 citations
Gamma-hydroxybutyrate (GHB), a GHB-/GABAB-receptor agonist, produces euphoric, disinhibiting, and vitality-enhancing effects in healthy men. In a randomized, placebo-controlled crossover trial with 16 males, a single 20 mg/kg dose increased charitable donations and prosocial money distributions among participants who initially showed low prosociality. However, GHB did not alter emotion recognition, empathy, theory-of-mind, or basic cognitive functions. The drug raised plasma progesterone levels but left oxytocin, testosterone, cortisol, aldosterone, DHEA, and ACTH unchanged. These findings suggest that GHB's mood and prosocial effects may involve GHB-/GABAB-receptors and progesterone rather than typical social hormones like oxytocin or testosterone.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
October 1, 2017
Michael D Wunderli, Matthias Vonmoos, Marina Fürst et al.
37 citations
Chronic MDMA use is linked to memory and thinking problems, but past research often failed to separate effects of MDMA from those of other drugs like stimulants. In this study, 26 MDMA users who avoided stimulants, 25 MDMA users who also used stimulants, and 56 non-users completed cognitive tests. Hair analysis confirmed drug use patterns. MDMA-only users showed strong, specific impairments in declarative memory (effect size d=0.90), while stimulant-using MDMA users had broader, larger deficits across memory, working memory, executive functions, and attention (d=0.70 to 1.21). The findings suggest that pure MDMA use mainly harms declarative memory, whereas additional cognitive deficits stem from stimulant co-use.
International Journal of Bipolar Disorders
July 5, 2022
Oliver G. Bosch, Simon Halm, Erich Seifritz
35 citations
Classic psychedelics such as LSD, psilocybin, mescaline, and ayahuasca are being studied again for treating unipolar and bipolar depression. They alter sensory perception, emotion, and self-processing by stimulating serotonin 2A receptors in the brain. Psychedelic-assisted psychotherapy integrates a safe psychedelic experience into ongoing therapy. Early randomized trials with psilocybin show promising results for unipolar depression, but classic psychedelics may also trigger mania. Atypical psychedelics like MDMA and ketamine work through different mechanisms; esketamine is approved for treatment-resistant unipolar depression, and ketamine shows early evidence for bipolar depression. Larger trials and careful legal frameworks will determine their broader clinical use.
PLoS ONE
April 9, 2013
Oliver G. Bosch, Michael Wagner, Frank Jessen et al.
34 citations
Recreational users of MDMA show verbal learning and recall deficits that are linked to reduced glucose metabolism in the prefrontal and parietal cortex, and word recognition difficulties are additionally associated with reduced metabolism in the mediotemporal region. These findings indicate that memory problems in MDMA users result from combined dysfunction across frontal, parietal, and mediotemporal brain areas.