16 papers in the library · 300 citations · publishing 2020-2026
Science Advances November 17, 2021 Marcus W. Meinhardt, Simone Pfarr, Grégory Fouquet et al. 92 citations
Psilocybin restores deficits in the metabotropic glutamate receptor 2 (mGluR2) caused by alcohol, which leads to the reversal of pathological behaviors associated with alcoholism.
Neuropsychopharmacology May 5, 2020 Marcus W. Meinhardt, Cansu Güngör, Ivan Skorodumov et al. 66 citations
Psychedelic-assisted psychotherapy is hypothesized to restore normal brain function in people with alcohol use disorder (AUD) and reduce relapse risk after a single session. In this study, three treatment schedules with psilocybin or LSD were tested in male and female rats using the alcohol deprivation effect (ADE) model of relapse-like drinking. Neither high doses comparable to clinical studies nor chronic microdosing produced long-lasting reductions in relapse-like drinking. Only sub-chronic psilocybin had a short-lasting anti-relapse effect, but this regimen is not considered a translatable treatment. The findings do not support the hypothesis that microdosing or high-dose psychedelics reduce relapse behavior in this model, though the authors note that animal models may not fully capture psychedelics' therapeutic potential.
Frontiers in Neuroscience April 17, 2023 Marvin M. Urban, Moritz R. Stingl, Marcus W. Meinhardt 47 citations
Since the 1960s, psychedelics have shown potential for persistently treating substance use disorders, but the biological mechanisms behind their therapeutic effects remain unclear. Serotonergic hallucinogens are known to alter gene expression and neuroplasticity, especially in prefrontal brain regions, yet how these changes specifically counteract the neuronal circuit alterations that develop during addiction is largely unknown. This narrative mini-review synthesizes established addiction research with findings and theories on the neurobiological effects of psychedelics, providing an overview of potential mechanisms underlying treatment of substance use disorders with classical hallucinogens and identifying gaps in current understanding.
Translational Psychiatry December 14, 2023 Ivan Skorodumov, Rainer Spanagel, Jonathan R Reinwald et al. 25 citations
Psilocybin, a psychedelic compound, may help treat alcohol use disorder (AUD), but its brain effects in AUD are not well understood. In a placebo-controlled crossover study with healthy rats and a rat model of alcohol relapse, psilocybin broadly decreased functional connectivity across the brain while increasing connectivity between serotonin-related core regions and cortical areas. It also reduced connectivity within the default mode network (DMN), mirroring human findings. However, in rats with a history of alcohol relapse, this DMN hypoconnectivity was blunted, and the blunting correlated with relapse intensity. The results suggest that a standard psilocybin dose may be insufficient for severe AUD, a consideration for future clinical trials.
Cells March 22, 2023 Kevin Domanegg, Wolfgang H. Sommer, Marcus W. Meinhardt 23 citations
Alcohol use disorders remain a major public health problem, and current medications have limited success. Recent clinical trials suggest that psychedelics, especially psilocybin, combined with psychotherapy can reduce heavy drinking. This review connects two lines of research: how addiction alters metabotropic glutamate receptor 2 (mGlu2) function, and how psychedelics act through serotonin 2A receptors (2AR) to induce gene expression and neuroplasticity. Evidence indicates that mGlu2 and 2AR can regulate each other's signaling, either through crosstalk or by forming a 2AR-mGlu2 heteromer, and that 2AR activation can epigenetically modulate mGlu2 expression. The authors propose that targeting these pathways could restore mGlu2 function in AUD patients and reduce relapse risk.
Frontiers in Neuroscience October 6, 2023 Tobias Buchborn, Hannes Kettner, Laura Kärtner et al. 21 citations
The ego is central to psychedelic research and therapy but remains poorly defined. This theoretical review examines the ego through a psychodynamic lens, focusing on ego boundaries, defenses, and synthesis. Psychedelics can induce regressed ego states with reduced defenses, allowing early-life conflicts that created maladaptive patterns to emerge. The authors argue that lasting change requires psycholytic therapy to permeate the characterological core—the chronic, habitual patterns the ego uses to cope—not just transient ego regression. Emotional integration of formative early events is key to reshaping rigid character and defenses, aiming for more flexible ego patterns. This approach is compatible with third-wave cognitive behavioral therapies.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology May 1, 2025 Marcus W. Meinhardt, Ivan Skorodumov, Jérôme Jeanblanc et al. 8 citations
A new approach in psychiatric drug development, the preclinical randomized controlled trial (preRCT), was tested across three European centers using a rat model of alcohol relapse. Ketamine (20 mg/kg) reduced relapse, while R-ketamine worked only in females at the same dose; a higher dose (40 mg/kg) was effective in males. The sex-dependent effects were linked to plasma R-ketamine levels, which were twice as high in females. R-ketamine produced a lasting reduction in alcohol consumption without adverse effects. The findings support moving to a clinical trial that accounts for sex differences.
Translational Psychiatry December 5, 2024 Bettina Habelt, Dzmitry Afanasenkau, Cindy Schwarz et al. 6 citations
Alcohol use disorder (AUD) impairs prefrontal control mechanisms, leading to reduced inhibitory control and increased relapse risk. Using a biocompatible neuroprosthesis in a rat model of alcohol addiction, researchers measured neural oscillations and event-related potentials during abstinence. Alcohol-dependent rats showed reduced amplitudes of P1N1 and N1P2 components and attenuated event-related oscillatory activity, along with a dominance in higher beta frequencies indicating hyperarousal prone to relapse. Treatment with psilocybin or LY379268 restored these electrophysiological impairments, with psilocybin particularly counteracting the hyperarousal state. These prefrontal markers may serve as indicators of relapse vulnerability and treatment response, especially for psychedelic drugs.
Research Square June 7, 2024 Målin Schmidt, Anne Hoffrichter, Mahnaz Davoudi et al. 5 citations
Psilocin, the psychoactive metabolite of psilocybin, triggers a cascade of neuroplastic changes in human cortical neurons derived from stem cells. It reduces cell-surface 5-HT2A receptors, increases BDNF abundance, alters gene expression toward plasticity, enhances neuronal complexity and synaptic protein levels, and boosts excitability and network activity. These findings suggest psilocin induces a state of enhanced neuronal plasticity that may underlie its therapeutic effects in neuropsychiatric disorders involving synaptic dysfunction.
Elife March 27, 2026 Målin Schmidt, Anne Hoffrichter, Mahnaz Davoudi et al. 3 citations
Psilocin, the psychoactive metabolite of psilocybin, increases BDNF abundance in human cortical neurons derived from induced pluripotent stem cells via the 5-HT2A receptor. Transcriptomic profiling shows gene expression changes that prime neurons for neuroplasticity. Morphologically, psilocin enhances neuronal complexity and increases synaptic proteins, especially in the postsynaptic compartment. Functionally, it leads to increased excitability and enhanced synaptic network activity. These findings suggest psilocin induces a state of enhanced neuronal plasticity, which may explain its therapeutic potential in neuropsychiatric disorders involving synaptic dysfunction.
Acta Neuropsychiatrica September 3, 2025 Filipe Reis Teodoro Andrade, Tobias Buchborn, Gabriel Thalheimer et al. 3 citations
Psilocybin therapy shows substantial and rapid antidepressant effects, often after one or two sessions with psychological support, with improvements sustained for weeks or months in many cases. It is generally well-tolerated, with mild adverse effects such as anxiety during administration and transient headaches that are manageable in controlled settings. Psilocybin demonstrates promise as a novel treatment for depression, especially for individuals unresponsive to conventional antidepressants. Further research is needed to refine dosing, explore long-term effects, and understand its mechanisms of action.
Translational Psychiatry May 26, 2026 Marvin M. Urban, Lea Zillich, Nathalie M. Rieser et al. 1 citation
In a pilot study of 37 detoxified patients with alcohol use disorder, psilocybin (25 mg) produced changes in DNA methylation across the genome compared to placebo. One methylation site in the TLE4 gene and a differentially methylated region in RASGRP4 were linked to psilocybin treatment. Co-methylation networks related to psilocybin were associated with reductions in depressive symptoms and drinking behavior, and gene analysis pointed to involvement in neuroplasticity and immune functions. The primary trial endpoints—duration of abstinence and mean alcohol use—were not reached, so the analysis focused on secondary psychometrics. The findings suggest immunomodulatory actions of psilocybin but are limited by the modest sample size.
Research Square March 31, 2026 Marcus W. Meinhardt, Ivan Skorodumov, Florian Walter et al.
A compound derived from ibogaine, oxa-noribogaine, reduces alcohol consumption in rats by strengthening learning from negative drinking outcomes. It produces sustained decreases in alcohol intake and relapse-like drinking, matching or exceeding ibogaine's efficacy without detectable motor or cardiac side effects. These effects involve transient changes in prefrontal brain activity, lasting alterations in glutamatergic signaling after aversion-related learning, and normalization of neurotrophic signaling in cortico-striatal circuits. The results generalize across multiple models, genetically diverse animals, and independent study sites, identifying oxa-noribogaine as a promising treatment candidate for alcohol use disorder.
Psychopharmacology November 15, 2025 Elisabetta Ciccocioppo, Sara Massetti, Marcus W. Meinhardt et al.
Alcohol use disorder (AUD) is a major medical problem with limited treatments. (R)-ketamine, a form of the dissociative psychedelic with fewer dissociative and anesthetic effects than the racemic mixture, reduced alcohol consumption in female but not in male Marchigian Sardinian alcohol-preferring (msP) rats when given orally at doses of 10, 20, and 40 mg/kg in a two-bottle free choice 24-hour drinking paradigm. No effect was observed on alcohol self-administration. (R)-ketamine also attenuated the retrieval of alcohol-related memories in female but not in male rats. These results suggest (R)-ketamine attenuates alcohol-related behaviors in a sex-dependent manner, with females showing higher sensitivity, supporting clinical investigation in patients with AUD.
July 18, 2025 Marvin M. Urban, Eric Zillich, Nathalie M. Rieser et al. preprint
A single dose of psilocybin (25 mg) was associated with changes in DNA methylation in patients with alcohol use disorder. One methylation site in the TLE4 gene and a region in the RASGRP4 gene showed significant alterations. Co-methylation networks linked to psilocybin treatment were also associated with reduced depressive symptoms and drinking behavior, and involved genes related to neuroplasticity and immune function. Baseline methylation differences between treatment responders and non-responders appeared in genes related to synaptic plasticity and neurotransmitter systems. The findings are preliminary due to the small sample size but align with prior research and suggest possible biological pathways for psilocybin's therapeutic effects.
Research Square February 22, 2024 Bettina Habelt, Dzmitry Afanasenkau, Cindy Schwarz et al.
Current treatments for alcohol use disorder (AUD) are often ineffective due to large variability in individual responses and high relapse rates. A precision medicine approach using biomarkers of prefrontal control mechanisms—which are severely disrupted in AUD, reducing inhibitory control and promoting compulsive behavior and relapse—may improve outcomes. In a rat model of alcohol addiction and relapse, a biocompatible neuroprosthesis measured prefrontal neural function during abstinence. Alcohol-dependent rats showed reduced amplitudes of P1N1 and N1P2 event-related potential components and attenuated event-related oscillatory activity. Treatment with psilocybin (a 5-HT2AR agonist) or LY379268 (an mGluR2 agonist) restored these impairments. Psilocybin also counteracted a dominance in higher beta frequencies indicative of hyperarousal prone to relapse. These findings identify prefrontal markers of relapse and treatment response, particularly for psychedelic drugs.