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F. Vollenweider

Phenomenology, Structure, and Dynamic of Psychedelic States

December 27, 2016 / Papers, Psychology, Publications / By / ,

Abstract

Classic serotonergic hallucinogens or psychedelics produce an Altered States of Consciousness (ASC) that is characterized by profound alterations in sensory perception, mood, thought including the perception of reality, and the sense of self. Over the past years, there has been considerable progress in the search for invariant and common features of psychedelic states. In the first part of this review, we outline contemporary approaches to characterize the structure of ASCs by means of three primary etiology-independent dimensions including Oceanic Boundlessness, Anxious Ego Dissolution, and Visionary Restructuralization as well as by 11 lower order factors, all of which can be reliably measured by the Altered State of Consciousness questionnaire (APZ-OAV). The second part sheds light on the dynamic nature of psychedelic experiences. Frequently, psychedelic subjects progresses through different stages over time and levels of changes along a perception-hallucination continuum of increasing arousal and ego dissolution. We then review in detail the acute effects of psychedelics on sensory perception, emotion, cognition, creativity, and time perception along with possible neural mechanisms underlying them. The next part of this review outlines the influence of non-pharmacological factors (predictors) on the acute psychedelic experience, such as demographics, genetics, personality, mood, and setting, and also discusses some long-term effects succeeding the acute experience. The last part presents some recent concepts and models attempting to understand different facets of psychedelic states of consciousness from a neuroscientific perspective.

Preller, K. H., & Vollenweider, F. X. (2016). Phenomenology, Structure, and Dynamic of Psychedelic States. 10.1007/7854_2016_459

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Serotonergic Hallucinogen-Induced Visual Perceptual Alterations

November 30, 2016 / DMT, LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / ,

Abstract

Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT), are famous for their capacity to temporally and profoundly alter an individual’s visual experiences. These visual alterations show consistent attributes despite large inter- and intra-individual variances. Many reports document a common perception of colors as more saturated, with increased brightness and contrast in the environment (“Visual Intensifications”). Environmental objects might be altered in size (“Visual illusions”) or take on a modified and special meaning for the subject (“Altered self-reference”). Subjects may perceive light flashes or geometrical figures containing recurrent patterns (“Elementary imagery and hallucinations”) influenced by auditory stimuli (“Audiovisual synesthesia”), or they may envision images of people, animals, or landscapes (“Complex imagery and hallucinations”) without any physical stimuli supporting their percepts. This wide assortment of visual phenomena suggests that one single neuropsychopharmacological mechanism is unlikely to explain such vast phenomenological diversity. Starting with mechanisms that act at the cellular level, the key role of 5-HT2A receptor activation and the subsequent increased cortical excitation will be considered. Next, it will be shown that area specific anatomical and dynamical features link increased excitation to the specific visual contents of hallucinations. The decrease of alpha oscillations by hallucinogens will then be introduced as a systemic mechanism for amplifying internal-driven excitation that overwhelms stimulus-induced excitations. Finally, the hallucinogen-induced parallel decrease of the N170 visual evoked potential and increased medial P1 potential will be discussed as key mechanisms for inducing a dysbalance between global integration and early visual gain that may explain several hallucinogen-induced visual experiences, including visual hallucinations, illusions, and intensifications.

Kometer, M., & Vollenweider, F. X. (2016). Serotonergic Hallucinogen-Induced Visual Perceptual Alterations. 10.1007/7854_2016_461
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Effects of serotonin 2A/1A receptor stimulation on social exclusion processing

April 18, 2016 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Social ties are crucial for physical and mental health. However, psychiatric patients frequently encounter social rejection. Moreover, an increased reactivity to social exclusion influences the development, progression, and treatment of various psychiatric disorders. Nevertheless, the neuromodulatory substrates of rejection experiences are largely unknown. The preferential serotonin (5-HT) 2A/1A receptor agonist, psilocybin (Psi), reduces the processing of negative stimuli, but whether 5-HT2A/1A receptor stimulation modulates the processing of negative social interactions remains unclear. Therefore, this double-blind, randomized, counterbalanced, cross-over study assessed the neural response to social exclusion after the acute administration of Psi (0.215 mg/kg) or placebo (Pla) in 21 healthy volunteers by using functional magnetic resonance imaging (fMRI) and resting-state magnetic resonance spectroscopy (MRS). Participants reported a reduced feeling of social exclusion after Psi vs. Pla administration, and the neural response to social exclusion was decreased in the dorsal anterior cingulate cortex (dACC) and the middle frontal gyrus, key regions for social pain processing. The reduced neural response in the dACC was significantly correlated with Psi-induced changes in self-processing and decreased aspartate (Asp) content. In conclusion, 5-HT2A/1A receptor stimulation with psilocybin seems to reduce social pain processing in association with changes in self-experience. These findings may be relevant to the normalization of negative social interaction processing in psychiatric disorders characterized by increased rejection sensitivity. The current results also emphasize the importance of 5-HT2A/1A receptor subtypes and the Asp system in the control of social functioning, and as prospective targets in the treatment of sociocognitive impairments in psychiatric illnesses.

Preller, K. H., Pokorny, T., Hock, A., Kraehenmann, R., Stämpfli, P., Seifritz, E., … & Vollenweider, F. X. (2016). Effects of serotonin 2A/1A receptor stimulation on social exclusion processing. Proceedings of the National Academy of Sciences, 201524187. http://dx.doi.org/10.1073/pnas.1524187113

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Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience

January 22, 2016 / Mushrooms / Psilocybin, Neuroscience, Papers, Publications / By / , , ,

Abstract

The mixed serotonin (5-HT) 1A/2A/2B/2C/6/7 receptor agonist psilocybin dose-dependently induces an altered state of consciousness (ASC) that is characterized by changes in sensory perception, mood, thought, and the sense of self. The psychological effects of psilocybin are primarily mediated by 5-HT2A receptor activation. However, accumulating evidence suggests that 5-HT1A or an interaction between 5-HT1A and 5-HT2A receptors may contribute to the overall effects of psilocybin. Therefore, we used a double-blind, counterbalanced, within-subject design to investigate the modulatory effects of the partial 5-HT1A agonist buspirone (20 mg p.o.) and the non-hallucinogenic 5-HT2A/1A agonist ergotamine (3 mg p.o.) on psilocybin-induced (170 µg/kg p.o.) psychological effects in two groups (n=19, n=17) of healthy human subjects. Psychological effects were assessed using the Altered State of Consciousness (5D-ASC) rating scale. Buspirone significantly reduced the 5D-ASC main scale score for Visionary Restructuralization (VR) (p<0.001), which was mostly driven by a reduction of the VR item cluster scores for elementary and complex visual hallucinations. Further, buspirone also reduced the main scale score for Oceanic Boundlessness including derealisation and depersonalisation phenomena at a trend level (p=0.062), whereas ergotamine did not show any effects on the psilocybin-induced 5D-ASC main scale scores. The present finding demonstrates that buspirone exerts inhibitory effects on psilocybin-induced effects, presumably via 5-HT1A receptor activation, an interaction between 5-HT1A and 5-HT2A receptors, or both. The data suggest that the modulation of 5-HT1A receptor activity may be a useful target in the treatment of visual hallucinations in different psychiatric and neurological diseases.

Pokorny, T., Preller, K. H., Kraehenmann, R., & Vollenweider, F. X. (2016). Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience. European Neuropsychopharmacology. http://dx.doi.org/10.1016/j.euroneuro.2016.01.005
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The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity

August 22, 2015 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybin’s effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. We therefore analyzed our previous fMRI data using dynamic causal modeling and used Bayesian model selection to infer how psilocybin modulated effective connectivity within the visual–limbic–prefrontal network during threat processing. First, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. Second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. These findings may have important implications for the treatment of mood and anxiety disorders.

Kraehenmann, R., Schmidt, A., Friston, K., Preller, K. H., Seifritz, E., & Vollenweider, F. X. (2015). The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity. NeuroImage: Clinical. https://dx.doi.org/10.1016/j.nicl.2015.08.009
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Psilocybin-induced spiritual experiences and insightfulness are associated with synchronization of neuronal oscillations

August 1, 2015 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , ,

Abstract

Rationale

During the last years, considerable progress has been made toward understanding the neuronal basis of consciousness by using sophisticated behavioral tasks, brain-imaging techniques, and various psychoactive drugs. Nevertheless, the neuronal mechanisms underlying some of the most intriguing states of consciousness, including spiritual experiences, remain unknown.

Objectives

To elucidate state of consciousness-related neuronal mechanisms, human subjects were given psilocybin, a naturally occurring serotonergic agonist and hallucinogen that has been used for centuries to induce spiritual experiences in religious and medical rituals.

Methods

In this double-blind, placebo-controlled study, 50 healthy human volunteers received a moderate dose of psilocybin, while high-density electroencephalogram (EEG) recordings were taken during eyes-open and eyes-closed resting states. The current source density and the lagged phase synchronization of neuronal oscillations across distributed brain regions were computed and correlated with psilocybin-induced altered states of consciousness.

Results

Psilocybin decreased the current source density of neuronal oscillations at 1.5–20 Hz within a neural network comprising the anterior and posterior cingulate cortices and the parahippocampal regions. Most intriguingly, the intensity levels of psilocybin-induced spiritual experience and insightfulness correlated with the lagged phase synchronization of delta oscillations (1.5–4 Hz) between the retrosplenial cortex, the parahippocampus, and the lateral orbitofrontal area.

Conclusions

These results provide systematic evidence for the direct association of a specific spatiotemporal neuronal mechanism with spiritual experiences and enhanced insight into life and existence. The identified mechanism may constitute a pathway for modulating mental health, as spiritual experiences can promote sustained well-being and psychological resilience.

Kometer, M., Pokorny, T., Seifritz, E., & Vollenweider, F. X. (2015). Psilocybin-induced spiritual experiences and insightfulness are associated with synchronization of neuronal oscillations. Psychopharmacology, 1-14. https://dx.doi.org/10.1007/s00213-015-4026-7

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The Effect of 5-HT2A/1a Agonist Treatment On Social Cognition, Empathy, and Social Decision-making

March 28, 2015 / Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , , , ,

Abstract

Social cognition is a crucial factor influencing development, progress, and treatment of psychiatric disorders. However, social cognition skills are insufficiently targeted by current treatment approaches. In particular, patients suffering from depression show an increased negative reaction to social exclusion and deficits in empathy. The 5HT-1A/2A receptor agonist psilocybin has previously been shown to reduce the neural response to negative emotional stimuli. However, it is not known if this extends to negative social interaction and whether 5HT-1A/2A receptor stimulation induces changes in empathy. Given the clear need for improved treatment of socio-cognitive functioning in psychiatric disorders, it is important to better understand the neuronal and neuromodulatory substrates of social cognition.

In a double-blind, randomized, cross-over design we therefore investigated the neural response to ostracism after the acute administration of psilocybin (0.215mg/kg) and placebo in healthy volunteers using fMRI. Furthermore, we assessed cognitive and emotional empathy using the Multifaceted Empathy Test.

The neural response to social exclusion in the ACC – a brain region associated with ‘social pain”- was reduced after psilocybin administration compared to placebo. Furthermore, emotional empathy was enhanced after treatment with psilocybin while no significant differences were found in cognitive empathy.

These results show that the 5HT-1A/2A receptor subtypes play an important role in the modulation of socio-cognitive functioning and therefore may be relevant for the treatment of social cognition deficits in psychiatric disorders. In particular, they may be important for the normalization of empathy deficits and increased negative reaction to social exclusion in depressed patients.

Preller, K. H., Pokorny, T., Krähenmann, R., Dziobek, I., Stämpfli, P., & Vollenweider, F. X. (2015). The Effect of 5-HT2A/1a Agonist Treatment On Social Cognition, Empathy, and Social Decision-making. European Psychiatry, 30, 22. http://dx.doi.org/10.1016/S0924-9338(15)30017-1
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Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects

November 29, 2014 / LSD, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / By / , , , , , ,

Abstract

Background

After no research in humans for >40 years, there is renewed interest in using lysergic acid diethylamide (LSD) in clinical psychiatric research and practice. There are no modern studies on the subjective and autonomic effects of LSD, and its endocrine effects are unknown. In animals, LSD disrupts prepulse inhibition (PPI) of the acoustic startle response, and patients with schizophrenia exhibit similar impairments in PPI. However, no data are available on the effects of LSD on PPI in humans.

Methods

In a double-blind, randomized, placebo-controlled, crossover study, LSD (200 μg) and placebo were administered to 16 healthy subjects (8 women, 8 men). Outcome measures included psychometric scales; investigator ratings; PPI of the acoustic startle response; and autonomic, endocrine, and adverse effects.

Results

Administration of LSD to healthy subjects produced pronounced alterations in waking consciousness that lasted 12 hours. The predominant effects induced by LSD included visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization phenomena. Subjective well-being, happiness, closeness to others, openness, and trust were increased by LSD. Compared with placebo, LSD decreased PPI. LSD significantly increased blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine. Adverse effects produced by LSD completely subsided within 72 hours. No severe acute adverse effects were observed.

Conclusions

In addition to marked hallucinogenic effects, LSD exerts methylenedioxymethamphetamine-like empathogenic mood effects that may be useful in psychotherapy. LSD altered sensorimotor gating in a human model of psychosis, supporting the use of LSD in translational psychiatric research. In a controlled clinical setting, LSD can be used safely, but it produces significant sympathomimetic stimulation.

Schmid, Y., Enzler, F., Gasser, P., Grouzmann, E., Preller, K. H., Vollenweider, F. X., … & Liechti, M. E. (2014). Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects. Biological psychiatry. https://dx.doi.org/doi:10.1016/j.biopsych.2014.11.015
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Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers

April 26, 2014 / Depressive Disorders, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Background
The amygdala is a key structure in serotonergic emotion-processing circuits. In healthy volunteers, acute administration of the serotonin 1A/2A/2C receptor agonist psilocybin reduces neural responses to negative stimuli and induces mood changes toward positive states. However, it is little-known whether psilocybin reduces amygdala reactivity to negative stimuli and whether any change in amygdala reactivity is related to mood change.

Methods
This study assessed the effects of acute administration of the hallucinogen psilocybin (.16 mg/kg) versus placebo on amygdala reactivity to negative stimuli in 25 healthy volunteers using blood oxygen level-dependent functional magnetic resonance imaging. Mood changes were assessed using the Positive and Negative Affect Schedule and the state portion of the State-Trait Anxiety Inventory. A double-blind, randomized, cross-over design was used with volunteers counterbalanced to receive psilocybin and placebo in two separate sessions at least 14 days apart.

Results
Amygdala reactivity to negative and neutral stimuli was lower after psilocybin administration than after placebo administration. The psilocybin-induced attenuation of right amygdala reactivity in response to negative stimuli was related to the psilocybin-induced increase in positive mood state.

Conclusions
These results demonstrate that acute treatment with psilocybin decreased amygdala reactivity during emotion processing and that this was associated with an increase of positive mood in healthy volunteers. These findings may be relevant to the normalization of amygdala hyperactivity and negative mood states in patients with major depression.

Kraehenmann, R., Preller, K. H., Scheidegger, M., Pokorny, T., Bosch, O. G., Seifritz, E., & Vollenwieder, F. X. (2014). Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers. Biological Psychiatry. http://dx.doi.org/10.1016/j.biopsych.2014.04.010
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Spatiotemporal Brain Dynamics of Emotional Face Processing Modulations Induced by the Serotonin 1A/2A Receptor Agonist Psilocybin

July 16, 2013 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

Emotional face processing is critically modulated by the serotonergic system. For instance, emotional face processing is impaired by acute psilocybin administration, a serotonin (5-HT) 1A and 2A receptor agonist. However, the spatiotemporal brain mechanisms underlying these modulations are poorly understood. Here, we investigated the spatiotemporal brain dynamics underlying psilocybin-induced modulations during emotional face processing. Electrical neuroimaging analyses were applied to visual evoked potentials in response to emotional faces, following psilocybin and placebo administration. Our results indicate a first time period of strength (i.e., Global Field Power) modulation over the 168–189 ms poststimulus interval, induced by psilocybin. A second time period of strength modulation was identified over the 211–242 ms poststimulus interval. Source estimations over these 2 time periods further revealed decreased activity in response to both neutral and fearful faces within limbic areas, including amygdala and parahippocampal gyrus, and the right temporal cortex over the 168–189 ms interval, and reduced activity in response to happy faces within limbic and right temporo-occipital brain areas over the 211–242 ms interval. Our results indicate a selective and temporally dissociable effect of psilocybin on the neuronal correlates of emotional face processing, consistent with a modulation of the top-down control.

Bernasconi, F., Schmidt, A., Pokorny, T., Kometer, M., Seifritz, E., & Vollenweider, F. X. (2013). Spatiotemporal brain dynamics of emotional face processing modulations induced by the serotonin 1A/2A receptor agonist psilocybin. Cerebral Cortex, bht178. 10.1093/cercor/bht178
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