Research Updates

Clinical Research

RCTs

• Psilocybin therapy alters personality in alcohol dependence | Psilocybin-assisted therapy significantly reduced neuroticism, increased extraversion and openness, and lowered impulsiveness in individuals with alcohol use disorder, with impulsiveness reduction linked to lower alcohol consumption. Double-blind, placebo-controlled clinical trial with 84 participants. Am J Psychiatry
• Psilocybin therapy improves emotional empathy in depression | Psilocybin therapy significantly increased emotional empathy, particularly towards positive stimuli, in individuals with major depressive disorder, with effects lasting at least two weeks. Randomized, placebo-controlled clinical trial with 51 participants. Mol Psychiatry
• Psilocybin therapy reduces depression in frontline clinicians | Single-dose psilocybin therapy significantly reduced depressive symptoms in clinicians who experienced psychological distress from frontline work during the COVID-19 pandemic, with trends toward improvement in burnout and PTSD symptoms. Randomized, double-blind clinical trial with 30 participants. JAMA Netw Open
• Effects of LSD with SSRI Paroxetine | Pre-administration of the SSRI paroxetine did not reduce LSD’s pleasant effects but lowered negative effects such as anxiety and nausea while increasing LSD blood concentrations due to CYP2D6 inhibition. Randomized, double-blind, cross-over Phase I trial with 23 healthy participants. Clin Pharmacol Ther

Non-randomized trials

• Psilocybin for severe treatment-resistant depression | A single dose of psilocybin significantly reduced depressive symptoms in patients with severe treatment-resistant depression, with greater response linked to specific subjective aspects of the psychedelic experience. Open-label clinical trial with 12 participants. Am J Psychiatry
• Long-term effects of psilocybin on depression | A single 25 mg dose of psilocybin led to a longer-lasting antidepressant effect compared to 10 mg and 1 mg doses, with a median time to depressive relapse of 189 days versus 43 and 21 days, respectively. Observational follow-up study of a randomized controlled trial with 66 participants over 52 weeks. J Clin Psychiatry
• Single-dose psilocybin for alcohol use disorder | A single psilocybin dose significantly reduced alcohol consumption, heavy drinking days, and craving while increasing self-efficacy over 12 weeks, despite individual variations in drug metabolism. Open-label clinical trial with 10 participants. J Psychopharmacol
• Psilocybin vs. escitalopram: 6-month depression outcomes | At 6 months, both psilocybin therapy and escitalopram led to sustained antidepressant effects, but psilocybin therapy showed greater improvements in psychosocial functioning, connectedness, and meaning in life. Observational follow-up of a phase 2, double-blind, randomized, controlled trial with 59 participants. EClinicalMedicine

Other Clinical Studies

• Serotonin dysfunction in Parkinson’s and impulse control | Patients with Parkinson’s disease and impulse control disorders exhibited serotonergic dysfunction, including increased serotonin transporter (SERT) availability in the putamen and pallidum and elevated 5-HT2A receptor binding in inhibitory control regions. Prospective case-control PET study with 45 participants. Brain
• Higher 5-HT2A binding linked to neuroticism | Higher 5-HT2A receptor binding was associated with increased neuroticism traits such as depression, anxiety, self-consciousness, and stress vulnerability, independent of cortisol awakening response. PET imaging study with 80 healthy participants. Br J Psychiatry
• Impulsivity linked to serotonin transporter and 5-HT2A | Higher non-planning impulsivity was associated with increased 5-HT2A receptor binding in key brain regions, suggesting a role of serotonergic neurotransmission in impulsivity. Double-tracer PET study with 26 healthy individuals. Int J Mol Sci
• Serotonin receptor genes linked to substance use risk | Genetic variants in the genes for 5-HT2A and 5-HT2B receptors (HTR2A and HTR2B) were significantly associated with increased risk of substance use disorder. Case-control genetic association study with 496 SUD patients and 496 controls. Ann Med
• Psychedelics for opioid use: community perspectives | Many Reddit users reported that psychedelics helped reduce opioid cravings, manage withdrawal symptoms, and address underlying mental health issues, while others remained skeptical. Qualitative study analyzing 151 posts from two Reddit communities. Addiction

Case Studies

• Psilocybin therapy for methamphetamine dependence | A patient with daily methamphetamine use remained abstinent for 3 months after inpatient withdrawal management followed by a single psilocybin-assisted therapy session, reporting improved mental health and self-esteem. Case report. Front Psychiatry
• Ibogaine reduced multiple sclerosis lesions | Ibogaine treatment led to significant reductions in brain lesions and structural neural changes in MS patients, suggesting potential neuroregenerative effects. Case report of two MS patients undergoing ibogaine treatment, assessed using MRI and neuroimaging. Front Immunol
• Low-dose MDMA for neuropathic pain relief | Repeated low-dose MDMA treatment was associated with sustained pain relief in a patient with neuropathic pain following chemotherapy. Case report of a 64-year-old male patient treated with LSD and MDMA. Front Psychiatry

Preprints

• Psilocybin for repetitive mild head injuries | Psilocybin reduced neuroinflammation, restored vascular function, decreased tau accumulation, and enhanced neuroplasticity in a rat model of repetitive mild head injury. Preclinical study using adult female rats. bioRxiv (Preprint)
• Psilocybin and mindfulness for healthcare burnout | Psilocybin-assisted group therapy combined with mindfulness-based stress reduction (MBSR) led to significantly greater reductions in depression and burnout symptoms among frontline healthcare providers compared to MBSR alone, with no serious adverse events. Randomized controlled trial with 25 participants. medRxiv (Preprint)

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Preclinical Research

In vivo

• Brain imaging classifies psychedelics by their effects | Machine learning-based analysis of brain-wide c-Fos expression in mice successfully classified psychedelic and psychoactive drugs, distinguishing psilocybin from other compounds based on distinct neural activity patterns. Nat Commun
• Ibogalogs reduce neuropathic pain through receptor crosstalk | Ibogalogs induced significant pain relief in neuropathic mice by activating 5-HT2A receptors and engaging crosstalk with mGlu2 receptors, with pain relief enhanced by sub-threshold doses of both receptor agonists. Biomed Pharmacother
• Non-hallucinogenic doses increase motivation in mice | Low doses of 2,5-dimethoxy-4-propylamphetamine (DOPR) increased motivation in low-performing mice without inducing hallucinogenic effects, suggesting potential therapeutic applications for amotivated states. Neuropharmacology
• How stress and sex influence psilocybin’s effects | Psilocybin reduced anxiety-like behaviors in mice, but its effects were diminished by acute stress, particularly in males, while stress had a lesser impact on females. Neuropharmacology
• Psilocybin reduces stress-induced depression in rats | Early intervention with psilocybin significantly reduced stress-induced depression-like behaviors and cognitive impairment in rats exposed to chronic stress, likely through HPA axis regulation via the endocannabinoid system. Prog Neuropsychopharmacol Biol Psychiatry
• Psychoplastogens induce antidepressant-like effects in mice | Ibogainalog and ibogaminalog induced antidepressant-like activity in naïve and depressed mice through 5-HT2A receptor activation, suggesting a role in antidepressant treatment. Prog Neuropsychopharmacol Biol Psychiatry
• Psychedelic DOI reduces cocaine reward in rats | (-)-DOI, a 5-HT2A receptor agonist, significantly reduced cocaine intake and motivation in male rats, with effects blocked by a 5-HT2A antagonist, indicating serotonin receptor involvement. Psychopharmacology (Berl)
• How DOM and lisuride affect brain activity in rats | DOM and lisuride both altered neuronal oscillations in the nucleus accumbens of freely moving rats, but DOM uniquely disrupted fast-spiking interneuron activity and low gamma power, which may explain its hallucinogenic properties. Eur J Pharmaco
• Psilocybin effects in serotonin transporter knockout mice | Psilocybin's effects on behavior and cognition were absent in serotonin transporter knockout mice, highlighting the importance of 5-HTT in mediating psilocybin's acute effects. Psychopharmacology (Berl).
• How 5-HT1A receptors modulate 5-MeO-DMT effects | 5-MeO-DMT analogs activated 5-HT2A and 5-HT1A receptors, inducing psychedelic-like behaviors in mice, with 5-HT1A activation dampening 5-HT2A-mediated head-twitch responses. ACS Chem Neurosci
• Benzodiazepine reduces psilocin's antidepressant effects | Administration of benzodiazepine lorazepam administration before psilocin reduced its antidepressant-like efficacy and duration in rats, suggesting that lorazepam interferes with psilocin's effects. Psychedelic Med
• Ayahuasca reduces ischemic stroke-induced inflammation | Ayahuasca treatment after ischemic stroke modulated oxidative stress and neuroinflammation in the prefrontal cortex, hippocampus, and hypothalamus of rats but did not improve neurological or behavioral outcomes. Behav Brain Res.
• Effects of DOI on Cocaine Motivation in Rats | (-)-DOI dose-dependently reduced cocaine intake and motivation in male rats, with effects blocked by a 5-HT2A antagonist. Pharmacol Rep
• New PET tracer for 5-HT2A imaging | [18F]R91150 successfully targeted 5-HT2A receptors in the cortex and forebrain of rodents, demonstrating good specificity and stability for PET imaging in rodents. Eur J Med Chem
• PET imaging of pimavanserin at 5-HT2A/2C receptors | Pimavanserin exhibited significantly higher affinity for 5-HT2A receptors in the cortex than for 5-HT2C receptors in the choroid plexus of non-human primates, with moderate displacement at 5-HT2C sites. J Cereb Blood Flow Metab
• Psilocybin alters brain connectivity in mice | Diffusion MRI revealed psilocybin-induced structural changes in the hippocampus, striatum, and frontal cortex in male mice at 24 and 72 hours post-injection. AJNR Am J Neuroradiol

In vitro & Chemistry

• Blocking CB1-5HT2A reduces cannabis side effects | Small molecules were designed to disrupt the heteromerization between cannabinoid CB1 and serotonin 5HT2A receptors in vitro, developing tools for in vivo studies. J Med Chem
• Psilocin analogs and 5-HT2A receptor activation | Psilocin analogs with hydroxyl groups at the 4th and 5th positions exhibited stronger 5-HT2A receptor activation and psychedelic-like effects, while those at the 6th and 7th positions had reduced activity. Eur J Med Chem
• Serotonergic psychedelics modulate glutamate release | Serotonergic psychedelics (psilocin, LSD, and DMT) rapidly modulated glutamate release in cultured primary rat cortical neurons, showing drug-specific effects on synaptic vesicle pools and short-term plasticity. J Neurochem
• Cannabidiol modulates 5-HT2A receptor activity | CBD inhibited 5-HT2A receptor activity by acting as a negative allosteric modulator, reducing Gq activation in HEK 293 cells and rat primary cortical neurons. Cell Signal
• Receptor activation insights for drug development | Study of 5-HT2A receptor interactions with serotonin and psilocin provides new insights into receptor activation and conformational states, aiding in the development of targeted drugs for neurological disorders. FEBS Lett

Preprints

• Psilocybin's impact on pyramidal cell types | Psilocybin increased dendritic spine density in pyramidal cells of rodents and required 5-HT2A receptor activation to affect stress-related behavior and structural plasticity in the medial frontal cortex. bioRxiv (preprint)
• Psilocybin modulates gene expression in neurons | Psilocybin induced time-dependent and cell-type-specific changes in gene expression in rat cortical neurons, especially in excitatory and GABAergic neurons, potentially contributing to its long-lasting effects on neural circuits and behavior. bioRxiv (preprint)
• Psychedelic exposure alters gene splicing in neurons | Psilocybin induces long-lasting, cell-type-specific changes in alternative splicing in the medial prefrontal cortex, affecting gene expression and neuronal function for at least a month. bioRxiv (preprint)
• Psychedelic phenethylamine modifies glial proteins | The psychedelic phenethylamine analogue induces glial protein modifications in human astrocyte cultures, via transglutaminase 2-mediated monoaminylation, suggesting new mechanisms for psychedelic effects. bioRxiv (preprint)

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Reviews and Editorials

Meta-analyses and Systematic Reviews

• Structural neural plasticity evoked by rapid-acting antidepressant interventions | This review highlights how rapid-acting antidepressant treatments, including ketamine and psychedelics, trigger dendritic spine growth in cortical neurons, suggesting a role for structural neural plasticity in restoring excitatory synaptic function in major depressive disorder. Nat Rev Neurosci
• Effects of psychoplastogens on blood levels of brain-derived neurotrophic factor (BDNF) in humans: a systematic review and meta-analysis | This meta-analysis found no evidence that neuroplastogens, including ketamine, psilocybin, and LSD, elevate peripheral BDNF levels in humans, suggesting that peripheral BDNF may not serve as an informative marker of rapid neuroplasticity changes. Mol Psychiatry
• The intensity of the psychedelic experience is reliably associated with clinical improvements: A systematic review and meta-analysis | This review and meta-analysis found a significant positive correlation between the intensity of mystical psychedelic experiences and clinical improvements, especially for mood disorders, with stronger effects observed in controlled clinical settings. Neurosci Biobehav Rev
• Effects of psychedelics on neurogenesis and broader neuroplasticity: a systematic review | This review examines how various psychedelics, including tryptamines, entactogens, and cannabinoids, affect neurogenesis and brain plasticity, offering insights into their potential therapeutic roles for neuropsychiatric disorders. Molecular Medicine
• Serotonergic underpinnings of obsessive-compulsive disorder: a systematic review and meta-analysis of neuroimaging findings | This review and meta-analysis examine the serotonergic dysfunctions in obsessive-compulsive disorder (OCD), revealing lower serotonin transporter binding in specific brain regions, which provides evidence of serotonin system involvement in OCD pathophysiology. Psychiatry Clin Neurosci
• Neurobiological mechanisms of antidepressant properties of psilocybin: a systematic review of blood biomarkers | This review investigates the neurobiological mechanisms underlying the antidepressant effects of psilocybin, focusing on blood biomarkers associated with its therapeutic properties. Prog Neuropsychopharmacol Biol Psychiatry
• A systematic review of participant diversity in psychedelic-assisted psychotherapy trials | This review evaluates the reporting, representation, and analysis of sociodemographic characteristics in randomized controlled trials of psychedelic-assisted psychotherapy, highlighting significant underrepresentation of Black and Hispanic participants. Psychiatry Res
• A systematic review of study design and placebo controls in psychedelic research | This review examines the methodologies used in randomized controlled trials of psychedelic-assisted psychotherapy, highlighting the need for improved blinding, reporting, and inclusion of active placebos to reduce bias in psychedelic research. Psychedelic Med (New Rochelle)

Reviews

• Modifying informed consent to help address functional unmasking in psychedelic clinical trials | This review explores the use of modified informed consent to improve masking in psychedelic clinical trials, while also addressing ethical risks and the potential for better treatment efficacy evaluation. JAMA Psychiatry
• Benefits and challenges of ultra-fast, short-acting psychedelics in the treatment of depression | This review examines the potential benefits and challenges of using ultra-fast, short-acting psychedelics like 5-MeO-DMT and DMT for treating depression, highlighting their rapid effects and the need for further research on treatment duration and efficacy. Am J Psychiatry
• Toward translatable biomarkers of psychedelic-induced neuroplasticity | This review discusses the challenge of measuring psychedelic-induced structural plasticity in humans and highlights new advances in imaging technologies that may lead to the identification of biomarkers for neuroplasticity. Am J Psychiatry
• Psychedelic-assisted treatment for substance use disorder: a narrative systematic review | This review explores the efficacy and safety of psychedelic-assisted treatments for substance use disorders, highlighting psilocybin's potential for alcohol use disorder and the need for further research to optimize these interventions. Addiction
• Investigating novel pharmacological strategies for treatment-resistant depression: focus on new mechanisms and approaches | This review explores emerging treatments for treatment-resistant depression (TRD), including glutamatergic antagonists, opioid system modulators, and psychedelics like psilocybin, while emphasizing the need for further research and personalized approaches. Expert Opin Drug Discov
• Serotonergic psychedelics as potential therapeutics for post-COVID-19 syndrome (or Long COVID): a comprehensive review | This review discusses how serotonergic psychedelics, through their effects on inflammation, neuroplasticity, and other mechanisms, may offer potential therapeutic benefits for alleviating the symptoms of post-COVID-19 syndrome. Prog Neuropsychopharmacol Biol Psychiatry
• The potential of non-psychedelic 5-HT2A agents in the treatment of substance use disorders: a narrative review of the clinical literature | This review explores the role of 5-HT2A receptor-targeting non-psychedelic agents in treating substance use disorders, highlighting mixed results and comparing these agents with psychedelic counterparts. Expert Opin Pharmacother

Editorials

• Could psychedelics be fine-tuned to relieve anxiety but skip the ‘trip’? | This article explores the potential for psychedelics to be optimized for treating anxiety without inducing the hallucinogenic experiences. Nature
• Treatment expectancies and psilocybin vs escitalopram for depression | This research letter discusses how treatment expectancies may influence the relative efficacy of psilocybin compared to escitalopram in the treatment of major depressive disorder. JAMA Psychiatry

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