Biological Psychiatry
November 29, 2014
Yasmin Schmid, Florian Enzler, Peter Gasser et al.
425 citations
In a double-blind, placebo-controlled crossover study, 200 μg of lysergic acid diethylamide (LSD) given to 16 healthy subjects produced pronounced alterations in consciousness lasting 12 hours, including visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization. LSD increased subjective well-being, happiness, closeness to others, openness, and trust, and decreased prepulse inhibition (PPI) of the acoustic startle response, a measure of sensorimotor gating. It also significantly increased blood pressure, heart rate, body temperature, pupil size, and plasma levels of cortisol, prolactin, oxytocin, and epinephrine. All adverse effects subsided within 72 hours, with no severe acute adverse effects observed. LSD produces empathogenic mood effects similar to methylenedioxymethamphetamine and alters sensorimotor gating in a human model of psychosis, supporting its potential use in psychotherapy and translational psychiatric research.
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.
Social Cognitive and Affective Neuroscience
October 4, 2013
Cédric M. Hysek, Yasmin Schmid, Linda D. Simmler et al.
356 citations
MDMA (ecstasy) enhances emotional empathy and prosocial behavior in men but impairs recognition of negative emotions like fear, anger, and sadness, especially in women. In a placebo-controlled, double-blind crossover trial with 32 healthy volunteers, MDMA increased explicit and implicit emotional empathy on the Multifaceted Empathy Test and boosted prosocial choices on the Social Value Orientation test in men. It did not affect cognitive empathy but worsened identification of negative facial expressions on the Face Emotion Recognition Task, particularly in women. MDMA also raised plasma cortisol, prolactin, and oxytocin levels, markers linked to social behavior. These effects may explain MDMA's recreational sociability and its potential therapeutic use in psychotherapy for social dysfunction or PTSD.
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.
Proc Natl Acad Sci U S A
January 28, 2019
Katrin H. Preller, Adeel Razi, Peter Zeidman et al.
303 citations
LSD alters communication within brain pathways that filter sensory information, according to a brain imaging study. Using a double-blind, placebo-controlled design with 25 healthy participants, researchers found that LSD increased signaling from the thalamus to the posterior cingulate cortex—an effect dependent on serotonin 2A receptor activation—and decreased signaling from the ventral striatum to the thalamus independently of those receptors. These changes in directed connectivity within cortico-striato-thalamo-cortical loops support the thalamic filter model of psychedelic action, which proposes that psychedelics disrupt the gating of sensory information to the cortex. The findings advance understanding of how psychedelics alter consciousness and may inform development of new therapeutics.
Nat Neurosci
October 24, 2022
Alex C. Kwan, David E. Olson, Katrin H. Preller et al.
291 citations
This review synthesizes the neurobiology of psychedelic drugs, which are serotonin 2A receptor agonists that alter perception, cognition, and mood. It covers the chemistry of diverse psychoactive molecules, their potency and pharmacokinetics, and the roles of serotonin receptors and downstream signaling pathways. The review describes effects on neuronal spiking in cortical and subcortical regions, transcriptional changes, and structural plasticity. Neuroimaging findings highlight impacts on association cortices and thalamocortical connectivity, informing theories of psychedelic action. The authors integrate knowledge across chemical, molecular, neuronal, and network levels to explain acute and enduring behavioral effects.
Current topics in behavioral neurosciences
January 1, 2016
Katrin H. Preller, Franz X. Vollenweider
285 citations
Psychedelics produce altered states of consciousness marked by changes in sensory perception, mood, thought, and sense of self. This review describes three primary dimensions of these states—oceanic boundlessness, anxious ego-dissolution, and visionary restructuralization—along with 11 lower-order factors, all measurable by the APZ-OAV questionnaire. The dynamic nature of psychedelic experiences is highlighted, with subjects progressing through stages along a perception-hallucination continuum. Acute effects on sensory perception, emotion, cognition, creativity, and time perception are reviewed, along with neural mechanisms. Non-pharmacological factors like demographics, genetics, personality, mood, and setting influence the experience, and long-term effects are discussed. Neuroscientific models of psychedelic states are presented.
Journal of Neuroscience
November 30, 2020
Danilo de Gregorio, Argel Aguilar‐valles, Katrin H. Preller et al.
258 citations
A renewed interest in hallucinogens for treating psychiatric disorders has emerged. Preclinical and clinical studies have confirmed ketamine's efficacy for depression. Emerging evidence points to psilocybin and LSD's therapeutic properties and their ability to modulate functional brain connectivity. MDMA, an entactogen, has shown usefulness for post-traumatic stress disorder. This review summarizes the pharmacology of hallucinogenic compounds, highlighting differences between psychedelic and nonpsychedelic hallucinogens and entactogens, and describes their behavioral effects in animals and humans. Together, these data substantiate the potential of these compounds for treating mental diseases.
The International Journal of Neuropsychopharmacology
June 14, 2017
Thomas Pokorny, Katrin H. Preller, Michael Kometer et al.
202 citations
A single dose of psilocybin (0.215 mg/kg) increased emotional empathy in healthy adults but did not affect cognitive empathy or moral decision-making. The rise in implicit emotional empathy correlated with psilocybin-induced changes in the meaning of percepts. These results suggest psilocybin selectively enhances emotional empathy, likely through serotonin 2A/1A receptor activation, which may inform treatments for impaired social cognition.
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.
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.
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.
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.
Biol Psychiatry Cogn Neurosci Neuroimaging
December 20, 2019
Anya K. Bershad, Katrin H. Preller, Royce Lee et al.
95 citations
A very low dose of LSD (13 μg) alters brain connectivity in circuits involved in emotion, even though it produces negligible subjective changes. In healthy young adults, the dose increased amygdala connectivity with the right angular gyrus, right middle frontal gyrus, and cerebellum, while decreasing connectivity with the postcentral and superior temporal gyri. Effects on positive mood were weak and variable, but increases in positive mood correlated with stronger amygdala–middle frontal gyrus connectivity. These preliminary findings suggest that sub-perceptual doses of LSD can modulate limbic brain networks, though further research with repeated dosing is needed to clarify any potential antidepressant effects.
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.
Schizophrenia Bulletin
August 5, 2020
Pantelis Leptourgos, Martin Fortier-Davy, Robin Carhart‐Harris et al.
88 citations
A multidisciplinary working group reviewed evidence on the similarities and differences between hallucinations induced by psychedelics and those occurring in schizophrenia-spectrum disorders, examining data from pharmacology, brain imaging, phenomenology, and anthropology. The authors highlight both shared features and distinct characteristics across these scales, and attempt to integrate findings using computational approaches. They conclude with recommendations for future research, emphasizing the need for further study to clarify the relationship between these types of hallucinations.
International Review of Psychiatry
July 4, 2018
Frederick S. Barrett, Katrin H. Preller, Mendel Kaelen
85 citations
Music listening has been used consistently from the beginning of therapeutic psychedelic research to guide experiences during the acute effects of psychedelic drugs. Recent findings indicate that music can support meaning-making, emotionality, and mental imagery after psychedelic administration, and suggest it plays an important role in facilitating positive clinical outcomes. This review examines the history, current research, and future directions of music in psychedelic therapy, arguing for more detailed and rigorous investigation into music's contribution to treating psychiatric disorders within this novel framework.
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.
Pharmacopsychiatry
January 20, 2021
Lea J. Mertens, Katrin H. Preller
63 citations
Classical psychedelics such as psilocybin and LSD were studied in the 1950s and 1960s for substance-assisted psychotherapy and are now being reexamined. Modern clinical research provides new evidence for their safety and efficacy in treating substance use disorders and unipolar depression. This review outlines shared pathological mechanisms of these conditions, summarizes current literature on psychedelics' effects, and discusses clinical trials since 2011. Results are promising, but most trials lack methodological rigor for firm conclusions. Larger, blinded, randomized controlled trials with clear patient groups and endpoints are needed. Therapeutic mechanisms remain unknown, and hypotheses from preclinical and human studies require testing.
Neuroscience & Biobehavioral Reviews
December 6, 2019
Jasmine T. Ho, Katrin H. Preller, Bigna Lenggenhager
61 citations
The body continuously shapes cognition through sensory input and self-referential processing. In healthy individuals, predictive coding integrates multisensory information to form a coherent sense of self. Psychiatric disorders often involve distorted perceptions of the bodily self, linked to disrupted integration and updating of multisensory systems. Changes in functional connectivity between somatomotor and high-level association networks in these disorders may be remediated by 5-HT2A receptor agonism via psychedelics. Psychedelic experiences alter bodily self-awareness, suggesting a central role for the bodily self. The article proposes that psychedelic-induced desynchronization of predictive coding involves modulation of somatomotor, sensorimotor, and high-level association networks, potentially correcting aberrant bodily self-perceptions.