Cell
April 30, 2026
Hermany Munguba, Anisul Arefin, Ryota Hasegawa et al.
4 citations
Ketamine's rapid antidepressant effects depend on mu-opioid receptors (MORs) located on somatostatin-expressing interneurons in the medial prefrontal cortex. Chronic stress causes these interneurons to become hypertrophic, leading to excessive inhibition of pyramidal neurons, a disruption that ketamine reverses. By identifying GPCRs enriched in these interneurons through RNA sequencing, the authors validate several antidepressant targets and show that activating multiple GPCRs synergistically produces potent antidepressant-like effects with fewer side effects. This approach offers a general strategy for discovering GPCR-based treatments for brain disorders.
Pharmaceuticals (Basel, Switzerland)
April 24, 2026
Pietro Carmellini, Alessandro Cuomo, Maria Beatrice Rescalli et al.
Depression likely arises from a mix of two interacting biological problems: imbalances in monoamine neurotransmitters (like serotonin) and disruptions in glutamate signaling that impair the brain's ability to adapt and form new connections. These two systems can combine in different ways across individuals, helping explain why some people respond to standard antidepressants while others do not. Rapid-acting treatments such as ketamine work by directly targeting the glutamate system to boost synaptic plasticity, offering faster relief, especially for treatment-resistant depression. A framework called the 'monoamine-glutamate continuum' may guide future precision psychiatry by matching treatments to each person's specific neurobiological profile.
Journal of psychoactive drugs
April 23, 2026
Brayan Jonas Mano-Sousa, Maria Clara Gama Fontes, Ana Clara Anacleto Gonçalves et al.
In people with treatment-resistant depression, ayahuasca—a traditional Amazonian psychedelic—rapidly reduces suicidal thoughts and depressive symptoms. A systematic review of five studies found consistent evidence of these effects, attributed to the synergistic action of β-carbolines and DMT. Neurobiologically, ayahuasca promotes neuroplasticity by upregulating Brain-Derived Neurotrophic Factor and decreasing Default Mode Network activity, enabling profound introspection and emotional processing. Despite promising results, large-scale, rigorous longitudinal studies are needed to establish safe clinical guidelines.
Current Issues in Molecular Biology
April 18, 2026
Christopher S. Gondi, Manu Gnanamony, Tarun P. Gondi et al.
Psychedelics such as LSD, psilocybin, and MDMA show promise for treating autism spectrum disorder by promoting neuroplasticity—the brain's ability to change and adapt. These substances modulate serotonin 5-HT2A receptors and interact with other serotonergic, dopaminergic, and glutamatergic pathways, leading to structural and functional brain changes that may enhance social behavior and emotional regulation. Studies indicate psychedelics can reduce symptoms of treatment-resistant depression and PTSD, and for autism specifically, may improve psychological flexibility, reduce distress, and enhance social interaction. However, their use requires careful monitoring and ethical oversight due to intense experiences and altered states of consciousness.
Journal of affective disorders
April 15, 2026
Gia Han Le, Sabrina Wong, Danica E Johnson et al.
4 citations
Ketamine and esketamine rapidly reduce depression in people with treatment-resistant depression and bipolar depression, but the synaptic mechanisms behind dosing and durability are unclear. This review of 61 clinical and 17 preclinical studies found that a single 0.5 mg/kg intravenous infusion produces antidepressant effects peaking at 24 hours and fading over 2-3 days. Early neurophysiological changes appear within 3-8 hours, consolidate by 24 hours, and are rarely detected beyond 3 days. Twice-weekly and thrice-weekly dosing produce comparable four-week outcomes, and weekly maintenance reduces relapse risk. Ketamine may open a plasticity window lasting about 2-3 days, and aligning dosing intervals with this window could optimize durability while minimizing drug exposure.
Frontiers in Psychiatry
April 13, 2026
Craig F. Ferris
Psychiatric drug development has stagnated for decades, with treatments for depression, schizophrenia, and PTSD offering only partial relief—remission rates of 30-40% for treatment-resistant depression and 60-70% of schizophrenia patients experiencing persistent symptoms. A paradigm shift proposes that mental illness stems from breakdowns in the brain's sensory filtering mechanisms, which gate irrelevant stimuli. The cerebellum is identified as a critical hub for bottom-up sensory gating, housing over half the brain's neurons and showing disrupted connectivity during PTSD symptom provocation. Psychedelic drugs may recalibrate these filters by disrupting entrenched filtering architectures and reopening plasticity windows. This framework extends predictive processing theory with a specific neural substrate and suggests novel therapeutic targets.
bioRxiv (Cold Spring Harbor Laboratory)
April 12, 2026
Ibrahim A. Akkouh, Jordi Requena Osete, N. W. Steen et al.
Activating GABA-A receptors with muscimol, a non-classic psychedelic, suppresses inflammatory signaling and promotes neuroplasticity in human cortical spheroids and astrocytes derived from patients with schizophrenia. Inflammatory stimulation triggered interferon-responsive gene programs, with astrocytes acting as key mediators. Muscimol reduced proinflammatory cytokine secretion, attenuated interferon signaling, and upregulated neuroplasticity-related genes such as NTRK2 and ELK1. It also restored impaired glutamate uptake in schizophrenia-derived astrocytes. These effects depended on GABA-A receptor activation. Proteomic analyses of spheroids and human brain tissue confirmed baseline dysregulation of GABAergic and neurotrophin signaling in schizophrenia, supporting the therapeutic potential of targeting astrocyte GABAergic signaling to restore neural homeostasis.
Preprints.org
April 7, 2026
Luis Miguel Gallardo
preprint
Altered states of consciousness (ASC) are a universal human capacity for accessing and transforming the subconscious mind, employed through diverse contemplative, somatic, pharmacological, ritual, and technological modalities. This review synthesizes evidence from over 25 disciplines, finding converging neurobiological mechanisms including default mode network suppression, autonomic regulation, and neuroplasticity. Clinical evidence is strongest for MDMA-assisted therapy in PTSD (67% response rate in Phase 3 RCTs), psilocybin for treatment-resistant depression (60-70% response), EMDR for trauma, mindfulness for depression relapse and anxiety, and neurofeedback for ADHD and anxiety. Transpersonal modalities like Life Between Lives hypnotherapy show preliminary evidence for existential distress but lack rigorous controlled trials. The review proposes an integrative framework positioning ASC as a spectrum from subconscious to superconscious, with diverse modalities as complementary vehicles for consciousness transformation.
Neuroscience
April 6, 2026
Fernando Minauro-Sanmiguel, Hector Vargas-Perez
Mitochondrial dysfunction is a key driver of Alzheimer's disease, fueling neuroinflammation, synaptic failure, and energy collapse. Emerging preclinical evidence suggests that classic hallucinogens like psilocybin, LSD, DMT, and mescaline may restore mitochondrial integrity by activating serotonin 2A and sigma-1 receptors. In experimental models, these pathways enhance mitochondrial biogenesis, reduce oxidative stress, and preserve ER-mitochondrial coupling. DMT and 5-MeO-DMT specifically engage sigma-1 receptors at mitochondria-associated membranes, improving calcium homeostasis and cellular resilience. However, evidence for clinical efficacy in Alzheimer's remains limited and largely preclinical. This framework is presented as a hypothesis-generating model, emphasizing that neuropsychiatric safety, patient selection, and translational feasibility must be carefully addressed.
JOURNAL OF ADVANCE AND FUTURE RESEARCH
April 1, 2026
Ashish Yadav, Ravina Yadav
Depression involves impaired brain neuroplasticity, and brain-derived neurotrophic factor (BDNF) is a key marker of this process. A meta-analysis of 20 studies with 1504 participants found that BDNF levels significantly increase after antidepressant treatment, with a moderate effect size of 0.62. Higher BDNF levels correlated with greater improvement in depression scores. Before treatment, depressed patients had markedly lower BDNF than healthy individuals; after treatment, levels improved but remained slightly lower. Chronic stress and depression are linked to neuronal atrophy in the hippocampus and prefrontal cortex. Emerging treatments like ketamine and non-invasive brain stimulation (transcranial magnetic stimulation) may enhance neuroplasticity and offer faster relief.