Psychopharmacology
September 13, 2007
Olivia Carter, Felix Hasler, John D. Pettigrew et al.
150 citations
Binocular rivalry, where each eye sees a different image and perception alternates between them, was slowed by psilocybin (215 µg/kg) in ten healthy adults. Pretreatment with ketanserin (50 mg), a 5-HT2A receptor blocker, prevented most of psilocybin's hallucinogenic symptoms but did not reverse the slowing of rivalry switching or the drug's negative-type symptoms such as reduced arousal and vigilance. These findings link slower binocular rivalry switching to subjective levels of arousal and attention, and suggest that psilocybin's effect on rivalry is not mediated by the 5-HT2A receptor.
European Neuropsychopharmacology
January 22, 2016
Thomas Pokorny, Katrin H. Preller, Rainer Kraehenmann et al.
148 citations
Psilocybin dose-dependently induces an altered state of consciousness with changes in perception, mood, thought, and self-awareness, mainly through 5-HT2A receptor activation. In a double-blind, within-subject study with 36 healthy participants, the partial 5-HT1A agonist buspirone (20 mg) significantly reduced psilocybin-induced (170 µg/kg) visual hallucinations and, at a trend level, feelings of oceanic boundlessness, derealization, and depersonalization. The non-hallucinogenic 5-HT2A/1A agonist ergotamine (3 mg) had no effect. These results suggest that modulating 5-HT1A receptor activity may help treat visual hallucinations in psychiatric and neurological disorders.
Journal of Psychopharmacology
May 1, 2000
Matthias E. Liechti, Franz X. Vollenweider
144 citations
MDMA (Ecstasy) moderately increases blood pressure and heart rate, slightly elevates body temperature, and produces a range of short-term side effects in humans. Pretreatment with the serotonin uptake inhibitor citalopram (40 mg i.v.) reduced all these physiological changes except for body temperature, in a double-blind placebo-controlled study of 16 healthy volunteers. These findings suggest that MDMA's physiological effects in humans are partially due to its interaction with the serotonin carrier and subsequent release of serotonin.
Dialogues in Clinical Neuroscience
December 31, 2001
Franz X. Vollenweider
127 citations
A review of brain imaging and behavioral studies finds that classic hallucinogens like psilocybin and dissociative anesthetics like ketamine produce overlapping psychotic syndromes marked by increased activity in the prefrontal cortex and changes in temporoparietal, striatal, and thalamic regions, suggesting a common final pathway. Both drug classes disrupt sensory gating in rats by acting on serotonin 5-HT(2) receptors in cortico-striato-thalamic circuitry, indicating that disruption of cortico-subcortical processing leading to sensory overload of the cortex is a shared feature of these psychoses. In contrast, the entactogen MDMA produces positive mood and activates prefrontolimbic and paralimbic structures while deactivating the amygdala and thalamus.
Neuropsychopharmacology
January 26, 2005
Olivia Carter, John D. Pettigrew, Felix Hasler et al.
122 citations
Binocular rivalry, where each eye sees a different image and perception alternates between them, is influenced by psilocybin. In 12 healthy volunteers, both low (115 µg/kg) and high (250 µg/kg) doses of psilocybin significantly reduced the rate and rhythmicity of perceptual alternations 90 minutes after administration, compared to placebo. Over time, switch rates increased, with some exceeding pretest levels at 360 minutes, though mean phase duration did not significantly differ from placebo. Drug-induced changes in rivalry phase durations corresponded to altered states of consciousness measured by the 5D-ASC scale. The findings implicate serotonergic pathways and support a brainstem oscillator's role in perceptual rivalry and psychosis symptoms.
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.
Cerebral Cortex
August 8, 2012
André Schmidt, Andreea O. Diaconescu, Michael Kometer et al.
110 citations
Using dynamic causal modeling and Bayesian model selection on data from a double-blind, placebo-controlled, crossover ketamine study, the authors investigated how the NMDA-receptor antagonist ketamine reduces mismatch negativity (MMN) amplitudes. Guided by a predictive coding framework that unifies adaptation and model adjustment theories, they compared models allowing different expressions of neuronal adaptation and synaptic plasticity. Results replicated that both adaptation and short-term plasticity are necessary for MMN generation. Ketamine significantly affected synaptic plasticity but not adaptation, with a selective effect on the forward connection from left primary auditory cortex to superior temporal gyrus. This model-based estimate of ketamine's effect on synaptic plasticity correlated with ratings of ketamine-induced impairments in cognition and control, suggesting a concrete mechanism linking ketamine effects on MMN to drug-induced psychopathology.
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.
NeuroImage
July 12, 2017
Candace R. Lewis, Katrin H. Preller, Rainer Kraehenmann et al.
105 citations
Psilocybin, the active compound in psychedelic mushrooms, acts on serotonin receptors. In a placebo-controlled, double-blind study with 58 healthy participants, two oral doses of psilocybin (0.160 mg/kg and 0.215 mg/kg) were given. After adjusting for global brain perfusion, psilocybin increased relative perfusion in right frontal and temporal regions and the anterior insula, while decreasing it in left parietal and temporal cortices and left subcortical regions. However, absolute perfusion was reduced across frontal, temporal, parietal, and occipital lobes, and in bilateral amygdalae, anterior cingulate, insula, striatal regions, and hippocampi. The findings show consistency with both the hyperfrontal hypothesis and recent studies showing decreased perfusion, depending on analysis method.
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.
Biological Psychiatry
December 4, 2010
Michael Kometer, B. Rael Cahn, David Andel et al.
101 citations
The hallucinogenic compound psilocybin, which activates 5-HT2A/1A serotonin receptors, alters how the brain processes visual information. In a placebo-controlled experiment with 17 healthy volunteers, psilocybin dose-dependently reduced the N170 brain response, especially when viewing incomplete object figures, while slightly enhancing the P1 component over occipital areas. The reduction in N170-related brain activity in the right extrastriate and posterior parietal regions correlated with the intensity of visual hallucinations. These findings point to a central role of 5-HT2A/1A receptors in visual processing and suggest that a diminished N170 response may be a key mechanism underlying visual hallucinations.
Journal of Pharmaceutical and Biomedical Analysis
August 26, 2002
Felix Hasler, Daniel Bourquin, Rudolf Brenneisen et al.
100 citations
After oral doses of psilocybin (212 ± 25 µg/kg body weight), the metabolite psilocin appears in urine, peaking at 870 µg/L between 2 and 4 hours. Within 24 hours, 3.4 ± 0.9% of the dose is excreted as free psilocin. Adding beta-glucuronidase doubles measured psilocin levels, indicating partial excretion as psilocin-O-glucuronide, though 18 ± 7% of unconjugated psilocin decomposes during incubation. Enzymatic hydrolysis extends detectability in urine.
Neuroscience Letters
February 13, 2008
Jiřı́ Wackermann, Marc Wittmann, Felix Hasler et al.
95 citations
Psilocybin, a hallucinogenic substance, alters the internal representation of time by increasing the loss rate of the internal duration representation. In two double-blind, placebo-controlled experiments—one with 12 subjects receiving graded doses and another with 9 subjects receiving a very low dose—participants repeatedly reproduced time intervals between 1.5 and 5 seconds. The parameter kappa from the 'dual klepsydra' model was used to assess effects. At 90 minutes after intake, psilocybin significantly increased kappa, indicating a higher loss rate of internal time representation. These findings may relate to qualitative changes in subjective time during altered states of consciousness.
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.
Journal of Psychoactive Drugs
June 1, 2002
Franz X. Vollenweider, Matthias E. Liechti, Alex Gamma et al.
92 citations
Since the mid 1990s, MDMA has been increasingly used recreationally as 'Ecstasy' by young people in Europe and the United States, yet systematic data on its psychological and neurobiological effects have been scarce. The authors conducted several studies in healthy human volunteers using placebo-controlled within-subject designs, standardized psychometric ratings, and neuropsychological tests to characterize the acute, short-term, and prolonged effects of MDMA. They also used specific receptor antagonists and Positron Emission Tomography to explore the neurotransmitter systems and functional neuroanatomy involved. This summary covers MDMA's acute effects on psychological and cognitive measures, information processing, and regional brain activity in healthy volunteers.
Journal of Clinical Psychopharmacology
February 1, 2001
Alex Gamma, Alfred Buck, Thomas Berthold et al.
84 citations
Regular polytoxic Ecstasy users show higher levels of depressiveness than non-users, but their brain activity during a sustained-attention task does not differ from controls. Mood was assessed with the Hamilton Rating Scale for Depression and the EWL Mood Rating Scale, while regional cerebral blood flow was measured using positron emission tomography. Both groups performed equally on the cognitive task. The heightened depressiveness in Ecstasy users is consistent with previous studies and may relate to serotonergic hypofunction from repeated MDMA consumption, but the study cannot rule out that these mood differences existed before Ecstasy use.
Neuroreport
August 1, 2004
Olivia Carter, John D. Pettigrew, David C. Burr et al.
83 citations
The hallucinogenic drug psilocybin, which activates serotonin receptors, selectively impairs the ability to perceive coherent motion in random dot patterns, a task that relies on high-level global motion detectors, while leaving contrast sensitivity for drifting gratings, mediated by low-level detectors, unaffected. This pattern of visual processing deficits mirrors those seen in schizophrenia, suggesting psilocybin may serve as a pharmacological model for studying psychosis and the neural basis of visual perception.
Journal of Neuroscience
June 19, 2020
Lilian Weber, Andreea O. Diaconescu, Christoph Mathys et al.
82 citations
The auditory mismatch negativity (MMN) is reduced in schizophrenia and can also be reduced by NMDA receptor (NMDAR) antagonists, suggesting impaired predictive coding. This study tested the theory that perceptual inference depends on NMDAR-dependent hierarchical precision-weighted prediction errors (PEs). Using a hierarchical Bayesian model on single-trial EEG data from healthy volunteers given the NMDAR antagonist S-ketamine in a placebo-controlled, double-blind, within-subject design, the analysis showed that low-level PEs (about stimulus transitions) appear early (102-207 ms), while high-level PEs (about transition probability) appear later (152-199 and 215-277 ms). Ketamine significantly diminished high-level PE responses, indicating NMDAR antagonism disrupts inference on abstract statistical regularities and impairs hierarchical Bayesian inference about the world's statistical structure.
Neuroreport
January 1, 2000
Alex Gamma, Edi Frei, Dietrich Lehmann et al.
81 citations
People who regularly use Ecstasy show altered brain activity patterns, including increased theta, alpha, and beta power across the scalp, particularly with eyes open, as measured by EEG and brain tomography. They also report higher levels of state depressiveness, emotional excitability, and a trend toward increased state anxiety compared to non-users. These differences could stem from regular Ecstasy or other illicit drug use, or may have existed before drug use began.
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
December 3, 2019
Katrin H. Preller, Franz X. Vollenweider
67 citations
Hallucinogens and entactogens can modulate social processing, which is crucial for everyday functioning and often impaired in psychiatric disorders. This review of controlled human studies examines how these substances influence social cognition and identifies the neurobiological and neuropharmacological mechanisms involved. The authors highlight current knowledge gaps and suggest implications for hallucinogen-assisted treatments and the development of new medications targeting trans-diagnostic social cognition deficits.
Cerebral Cortex
June 10, 2021
Patricia Duerler, Silvia Brem, Gorka Fraga González et al.
64 citations
Psilocybin reduces brain responses to surprising tactile stimuli, altering the sense of body and self. In a combined EEG-fMRI study, psilocybin decreased activity in frontal regions, visual cortex, and cerebellum during unexpected touch, and reduced mismatch negativity signals at frontal electrodes. These changes were linked to altered body- and self-experience. The findings highlight the role of the 5-HT2A receptor system in processing unexpected bodily sensations and integrating them with self-awareness, which may inform treatments for psychiatric disorders involving distorted body perception.
The World Journal of Biological Psychiatry
March 1, 2010
Patrik Roser, Franz X. Vollenweider, Wolfram Kawohl
63 citations
Delta(9)-Tetrahydrocannabinol (THC), the main psychoactive component of cannabis, can cause psychomotor effects, psychotic reactions, and cognitive impairment similar to schizophrenia. These effects can be reduced by two other cannabinoids: cannabidiol (CBD) and SR141716. CBD, the second most abundant cannabis constituent, weakly antagonizes the CB(1) receptor, inhibits anandamide reuptake and hydrolysis, and has neuroprotective antioxidant activity. SR141716 is a potent and selective CB(1) receptor antagonist. Both can reverse many effects of CB(1) receptor agonists, suggesting antipsychotic properties. Experimental studies in animals, healthy volunteers, and schizophrenic patients support this, with a pharmacological profile similar to atypical antipsychotic drugs. This review presents preclinical and clinical studies on the potential antipsychotic effects of CBD and SR141716.
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.