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.
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.
NeuroImage
August 1, 2019
Lukasz Smigielski, Milan Scheidegger, Michael Kometer et al.
261 citations
A single dose of psilocybin (315 μg/kg) combined with a 5-day mindfulness retreat altered brain connectivity in the default mode network, particularly decoupling the medial prefrontal and posterior cingulate cortices. This decoupling correlated with the subjective experience of ego dissolution during meditation. The extent of ego dissolution and brain connectivity changes predicted improvements in psycho-social functioning four months later. The findings suggest that psilocybin-assisted meditation facilitates neurodynamic changes in self-referential networks, linking altered self-experience to lasting behavioral changes.
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.
Sci Rep
October 24, 2019
Lukasz Smigielski, Michael Kometer, Milan Scheidegger et al.
174 citations
In a mindfulness group retreat setting, the acute and sustained effects of psilocybin were characterized and predicted. The study examined how individuals responded to the psychedelic during and after the retreat, identifying factors that influenced the strength and duration of the experience. Results showed that certain psychological and contextual variables predicted more profound acute responses, which in turn were associated with greater long-term improvements in well-being. The findings suggest that psilocybin's effects in a group mindfulness context are shaped by individual differences and the retreat environment, offering insights into optimizing therapeutic use.
PLOS global public health
January 1, 2022
José Carlos Bouso, Óscar Andión, Jerome J Sarris et al.
115 citations
A large global survey of over 10,800 ayahuasca users from more than 50 countries found that acute physical adverse effects, primarily vomiting, occurred in 69.9% of participants, with 2.3% needing medical attention. Adverse mental health effects in the weeks or months after use were reported by 55.9% of the sample, but about 88% of those viewed these effects as part of a positive growth or integration process; around 12% sought professional support. Physical adverse effects were linked to older age at first use, having a physical health condition, higher lifetime and recent use, a prior substance use disorder diagnosis, and using ayahuasca in unsupervised settings.
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 Affective Disorders Reports
February 6, 2021
Jerome Sarris, Daniel Perkins, Lachlan Cribb et al.
72 citations
Among 1,571 people who reported depression and 1,125 who reported anxiety at the time of consuming ayahuasca, 78% of those with depression said their symptoms were 'very much' improved (46%) or 'completely resolved' (32%), while 70% of those with anxiety reported 'very much' improvement (54%) or complete resolution (16%). Greater improvement was linked to mystical experiences, more ayahuasca sessions, and personal psychological insights. A small minority—2.7% with depression and 4.5% with anxiety—reported worsened symptoms. The authors note this cross-sectional survey cannot establish treatment efficacy and call for randomized controlled trials.
Neuropharmacology
November 1, 2018
Henrik Jungaberle, Sascha Thal, Andrea Zeuch et al.
70 citations
A review of 77 studies with 9876 participants examined how psychedelics and entactogens relate to positive psychology—the study of healthy functioning, well-being, and eudaemonia. The substances produced acute and long-term effects on mood, well-being, prosocial behaviors, empathy, cognitive flexibility, creativity, openness, value orientations, nature-relatedness, spirituality, self-transcendence, and mindfulness-related capabilities. Evidence is preliminary due to methodological restrictions. Longitudinal data on both positive and adverse effects are lacking, so more rigorous, standardized measures from positive psychology should be applied in less biased populations with prospective longitudinal designs to assess the benefit-risk ratio.
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.
Molecules
April 22, 2021
Paul Cumming, Milan Scheidegger, Dario Dornbierer et al.
45 citations
Hallucinogens such as LSD, psilocybin, and mescaline are being re-evaluated for their psychotherapeutic potential. This narrative review covers in vitro and ex vivo binding studies and molecular imaging using PET or SPECT. Early PET work with [11C]-MBL showed that most specific binding is to serotonin 5-HT2A receptors, but interactions with 5-HT1A receptors and other pathways may contribute to the unique experiences. Other important factors include blood-brain barrier permeability, metabolism, and active metabolites. Only a few PET or SPECT studies of radiolabeled hallucinogens exist, most recently using [11C]Cimbi-36. Hybrid imaging combining PET with fMRI is expected to advance future research.
Human Brain Mapping
August 21, 2020
Lukasz Smigielski, Michael Kometer, Milan Scheidegger et al.
42 citations
A placebo-controlled, double-blind experiment with 17 participants found that psilocybin, a serotonin receptor agonist, alters self-perception by disrupting the brain's ability to distinguish between self- and other-related stimuli. Participants performed a verbal self-monitoring task while brain activity was recorded. Psilocybin reduced accuracy in identifying whether auditory feedback was their own voice or another's, and it eliminated the typical difference in electrical brain patterns (P300) between self and other stimuli. This effect was linked to changes in the anterior cingulate and insular cortex. The strength of this brain change correlated with feelings of unity and altered meaning. The findings suggest that serotonin signaling modulates how the brain processes self-referential information, offering insight into self-disturbances in mental health conditions.
Frontiers in Psychiatry
August 2, 2021
Nicolas Langlitz, Erika Dyck, Milan Scheidegger et al.
35 citations
Psychedelics may act as non-specific amplifiers that help people reconnect with their values, or they might specifically promote liberal and anti-authoritarian views, as recent studies suggest. The return of psychedelics from counterculture to mainstream science has diversified their users and uses. This article argues for a moral psychopharmacology that brings pharmacological and neuroscientific research into conversation with historical and anthropological scholarship on the full range of moral and political views linked to psychedelic use. The work highlights the cultural plasticity of drug action and has implications for designing psychedelic therapies, while also questioning whether other psychoactive drugs have similarly rich moral and political dimensions.
Frontiers in psychiatry
January 1, 2023
Helena D Aicher, Michael J Mueller, Dario A Dornbierer et al.
34 citations
A standardized formulation combining the monoamine oxidase inhibitor harmine (100 mg orodispersible tablet) with incremental intranasal N,N-dimethyltryptamine (DMT, up to 100 mg) produced a psychedelic experience in 31 healthy male subjects, as measured by the 5D-ASC rating scale. The experience was characterized by psychological insights, emotional breakthroughs, and low scores on challenging experiences. Participants reported personal and spiritual significance and mainly positive persisting effects at 1- and 4-month follow-ups. No changes in trait personality, psychological flexibility, general well-being, or increases in psychopathology were observed. The formulation appears well tolerated and may support psychotherapy, but further studies in patients are needed.
Frontiers in pharmacology
January 1, 2023
Dario A Dornbierer, Laurenz Marten, Jovin Mueller et al.
32 citations
Ayahuasca, an Amazonian plant medicine containing DMT and harmine, shows promise for mental health disorders but its oral use causes gastrointestinal side effects and unpredictable drug levels. This study tested new ayahuasca-analogue formulations in 10 healthy men: an oral capsule of purified DMT and harmine versus a combined oromucosal harmine tablet with intranasal DMT spray. The combined buccal/intranasal route significantly reduced variations in systemic exposure and attenuated common side effects like nausea, vomiting, and diarrhea compared to traditional oral ayahuasca. All preparations were well tolerated. This approach may enable safer, patient-friendly DMT/harmine administration for affective disorders.
Cellular and molecular life sciences : CMLS
September 10, 2024
Klemens Egger, Helena D Aicher, Paul Cumming et al.
30 citations
The potent hallucinogen N,N-dimethyltryptamine (DMT) alters perception, mood, and cognition, presumably through agonism at serotonin 5-HT1A/2A/2C receptors in the brain. DMT is nearly inactive orally due to rapid first-pass metabolism, but co-administration with β-carbolines or synthetic MAO-A inhibitors—as in the Amazonian brew ayahuasca—greatly increases its bioavailability and duration of action. The synergistic effects of DMT and MAOIs may promote neuroplasticity, which presumably underlies their promising therapeutic efficacy in clinical trials for depression, addiction, and post-traumatic stress disorder. Neuroimaging reveals alterations in brain activity, functional connectivity, and network dynamics during DMT-induced altered states.
Psychoactives
April 16, 2024
Daniel Meling, Rebecca Ehrenkranz, Sandeep M. Nayak et al.
26 citations
Psychedelic research has returned after a period of suppression, but media coverage now often overstates benefits as much as it once overstated risks. The actual evidence is more mixed than commonly portrayed, so conclusions about effectiveness remain preliminary. Poor communication may mislead patients and misinform policy. This article reviews studies on psychedelics for depression, noting that effect sizes for other depression treatments—cognitive behavioral therapy, mindfulness, SSRIs, and ketamine—have decreased over time as trials improved. The authors suggest the same may happen for psychedelics: larger, better-controlled trials will likely show smaller, more realistic benefits. Clear communication is essential to set public expectations and guide policy.
The International Journal of Neuropsychopharmacology
August 10, 2022
Anne Weigand, Matti Gärtner, Milan Scheidegger et al.
22 citations
Activity in the pregenual anterior cingulate cortex (pgACC) during emotional stimulation can predict how well a single intravenous infusion of ketamine will relieve depression symptoms in people with major depressive disorder. In 24 patients, pgACC activity was linked to an increase in glutamate in the same brain region 24 hours after the infusion, and this glutamate increase was associated with greater symptom improvement. The findings suggest pgACC activity may serve as a neuroimaging biomarker for early treatment response to ketamine.
European Neuropsychopharmacology
March 8, 2017
Oliver G. Bosch, Michael M. Havranek, A Baumberger et al.
22 citations
Gamma-hydroxybutyrate (GHB), a drug used for narcolepsy and abused recreationally, has prosexual effects in healthy men. In two double-blind, placebo-controlled experiments, GHB increased subjective sexual arousal and desire, and made sexually neutral images of people seem arousing. Brain scans showed that GHB boosted activity in reward regions like the nucleus accumbens when viewing erotic pictures, and increased connectivity between the nucleus accumbens and the ventromedial prefrontal cortex. The findings indicate GHB enhances hedonic sexual functioning and lowers the threshold for perceiving erotic cues by sensitizing mesolimbic reward pathways.
Frontiers in Psychology
April 3, 2023
Daniel Meling, Milan Scheidegger
17 citations
Psychedelics are psychoactive substances whose effects involve changes in biochemistry, brain activity, and subjective experience, but how these levels relate is debated. Two current views are the integration view and the pluralistic view. This article proposes an enactive perspective that re-evaluates the molecule-brain-experience relationship. It applies the concept of autonomy to the causal link between the drug and brain activity, and dynamic co-emergence to the link between brain activity and experience. This enactive view emphasizes interdependence and circular causality across multiple levels, supporting and enriching the pluralistic view by offering a principled account of how layered processes interact. It has implications for understanding causality in psychedelic therapy and research.
Frontiers in pharmacology
January 1, 2023
Klemens Egger, Frederik Gudmundsen, Naja Støckel Jessen et al.
17 citations
Co-administration of harmine with DMT in rats increased brain DMT levels by inhibiting its metabolism to indole-3-acetic acid, yet no significant occupancy of serotonin 5-HT2A receptors by DMT was detected, even at brain DMT concentrations up to 11.3 µM. Low doses of DMT and/or harmine did not significantly alter brain glucose metabolism as measured by [18F]FDG-PET. These preliminary findings suggest that the role of MAO-A inhibition in potentiating DMT's psychedelic effects may be more complex than previously assumed, and further dose-response studies are needed.
Journal of Psychopharmacology
September 27, 2024
Daniel Meling, Klemens Egger, Jovin Mueller et al.
15 citations
In a double-blind, placebo-controlled study over a 3-day meditation retreat, 40 experienced meditators received either DMT-harmine or a placebo. Those who took DMT-harmine reported greater mystical-type experiences, non-dual awareness, and emotional breakthrough during the acute substance effects, and greater psychological insight one day later after adjusting for baseline differences. Mindfulness and compassion did not differ significantly between groups. At one-month follow-up, the DMT-harmine group rated their experience as more personally meaningful, spiritually significant, and well-being-enhancing than the placebo group. The findings suggest specific synergistic effects of DMT-harmine during meditation.
Scientific reports
March 26, 2024
Berit Singer, Daniel Meling, Matthias Hirsch-Hoffmann et al.
15 citations
Brain activity patterns during meditation shift after a psilocybin-assisted retreat, especially when open-monitoring meditation is practiced. Using functional MRI and a topological data analysis method (Mapper), researchers compared experienced meditators who received psilocybin or placebo over five days. The psilocybin group showed a link between positive derealization—an altered perception that can foster insight—and a greater geometric distance between open-monitoring meditation and resting-state brain activity, as measured by optimal transport distance. This suggests that combining psilocybin with open-monitoring practice enhances meta-awareness and insight. The findings point to possible brain markers for synergistic effects between mindfulness and psychedelics.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
March 1, 2025
Klemens Egger, Javier Jareño Redondo, Jovin Müller et al.
14 citations
Ayahuasca contains DMT and harmine, but their interactions are not fully understood. In a single-blind, randomized, two-arm, factorial dose-finding study with 16 healthy participants, each received six dose combinations of DMT (0-120 mg) and harmine (0-180 mg) via a transmucosal delivery system. All combinations produced dose-dependent subjective effects lasting 4-5 hours, with peak DMT and harmine levels reaching 33 ng/mL and 49 ng/mL, respectively. The interaction was bidirectional: harmine reduced DMT metabolism, while DMT altered harmine pharmacokinetics. The formulation had a favorable safety profile, supporting further testing for affective disorders.
January 1, 2021
Milan Scheidegger
14 citations
Ayahuasca, a traditional indigenous brew, shows promise in transforming mental health treatment. In a sample of 150 participants, 80% reported significant improvements in depression and anxiety after just two sessions with a trained psychotherapist. This aligns with the growing interest in psychedelics as medicine, suggesting a paradigm shift in psychology. Concurrently, cannabis and cannabinoid research is providing insights into biochemical mechanisms, enhancing our understanding of these substances' therapeutic potential. Such findings may redefine how we approach mental health and leadership in therapeutic settings.