Biological Psychiatry
April 26, 2014
Rainer Kraehenmann, Katrin H. Preller, Milan Scheidegger et al.
325 citations
Psilocybin significantly reduced anxiety and depression symptoms in 67% of participants after just one treatment session. Utilizing functional magnetic resonance imaging, the study revealed heightened activity in the amygdala, indicating a strong serotonergic influence on emotional processing. Participants reported improved mood and cognitive flexibility, suggesting that psychedelics can effectively alter internal mental states. With a placebo group for comparison, these findings underscore the potential of psilocybin in clinical psychology and psychiatry as a groundbreaking treatment for mood disorders, reshaping conventional approaches to mental health care.
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.
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.
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.
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.
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.
CNS drugs
December 1, 2023
Niloufar Pouyan, Farnaz Younesi Sisi, Alireza Kargar et al.
12 citations
A review of 28 clinical studies with 477 participants examined how lysergic acid diethylamide (LSD) affects reward processing, using the National Institute of Mental Health's Research Domain Criteria (RDoC) framework. LSD produced dose-dependent mood improvement in 20 short-term and 3 long-term studies. Its subjective and neural effects were linked to the 5-HT2A receptor. Animal studies suggested LSD could mildly reinforce conditioned place preference without aversion and reduce responsiveness to other rewards. Findings on reward learning were inconsistent but hinted at potential enhancements in associative learning. Reward valuation measures indicated possible reductions in effort expenditure for other reinforcers. The review identified areas for future research but noted limitations including diverse study designs not initially RDoC-oriented and potential bias from open-label human studies.
The international journal of neuropsychopharmacology
December 28, 2024
Michael J Mueller, Helena D Aicher, Dario A Dornbierer et al.
10 citations
A new pharmaceutical formulation combining pure DMT and harmine produced ayahuasca-like psychological effects lasting 2-3 hours in 31 healthy male volunteers, with consistent drug levels and no serious adverse events. DMT reached peak plasma concentrations of 22.1 ng/mL, while buccal harmine reached 32.5 ng/mL in a sustained-release profile but caused no distinguishable subjective effects on its own. All drug conditions were safe and well tolerated, suggesting the formulation could reduce risks and improve therapeutic outcomes for mental health disorders.
Journal of Psychoactive Drugs
March 6, 2019
Ansgar Rougemont-Bücking, Henrik Jungaberle, Milan Scheidegger et al.
6 citations
Among 4,475 young adult men in Switzerland, those who used psychedelics in the past year showed no significant difference in mental health (depressive symptoms, overall mental health, perceived stress, life satisfaction) compared to those who used no drugs. In contrast, users of MDMA, psychostimulants, and cannabis had poorer mental health. These effects were influenced by stressful life events and past family functioning. The findings suggest that some men may use substances to cope with life adversity, and the lack of a negative mental health association with psychedelics warrants further research in both men and women.
European Neuropsychopharmacology
September 1, 2015
Katrin H. Preller, Thomas Pokorny, Rainer Krähenmann et al.
6 citations
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NeuroImage
June 1, 2025
Dila Suay, Helena D Aicher, Micheal Kometer et al.
4 citations
A psychedelic formulation combining DMT and harmine, inspired by ayahuasca, altered brain responses to faces in 30 healthy men. It increased early visual reactivity (P1 wave) and disrupted face-structural encoding (N170 wave) for all face types. Crucially, it reduced the neural distinction between self and other faces in the P300 wave, while familiar-face processing remained stable. Harmine alone did not produce these effects. The findings suggest psychedelics can reorganize self-related neural dynamics, potentially promoting cognitive flexibility and offering therapeutic benefits for conditions involving rigid self-focus, such as depression and social anxiety.
Translational psychiatry
October 10, 2025
Wolfgang Emanuel Zürrer, Lionel Wettstein, Helena D Aicher et al.
3 citations
Salvinorin A, the main psychoactive compound in Salvia divinorum, shows therapeutic potential for pain, addiction, and stroke in animal models, but its side effects—including anxiety, motor and cognitive impairment—may limit clinical use. A systematic review and meta-analysis of 82 studies found anti-nociceptive, anti-inflammatory, neuroprotective, and anti-addictive effects, though depression results were inconsistent. Doses ranged from 0.1 to 10 mg/kg, with rapid onset and a half-life of about one hour. Sixteen structurally distinct analogues were identified with potentially improved safety and pharmacokinetic profiles. Findings support further development of analogues to overcome the side effect profile.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
July 9, 2025
Angela Äbelö, John W Smallridge, Robin von Rotz et al.
3 citations
The psychedelic compound DMT is often taken with harmine, a monoamine oxidase inhibitor, as in ayahuasca, but how harmine alters DMT's effects was not well understood. In a study of 16 healthy adults, six combinations of buccal DMT (0-120 mg) and harmine (0-180 mg) were given. Harmine increased DMT's bioavailability and prolonged its absorption, leading to higher and more sustained blood levels. The intensity of subjective psychedelic effects rose with dose, and harmine potentiated these effects at higher DMT doses. A mathematical model captured these relationships and individual variability, offering a foundation for more personalized dosing in psychedelic therapy.