Biomedicines
September 5, 2020
Ana Sofia Vargas, Ângelo Luís, Mário Barroso et al.
121 citations
A systematic review with meta-analysis of clinical trials found that psilocybin significantly reduces symptoms of depression and anxiety in patients with life-threatening diseases. Analyzing data from 92 patients, the intervention group showed a significant decrease in depression scores on the Beck Depression Inventory and in both trait and state anxiety scores on the State-Trait Anxiety Inventory. The results suggest psilocybin may be effective for conditions resistant to standard treatments or where pharmacotherapy is not yet approved, and it may also have potential as a first-line treatment given its safety profile.
Biomedicines
November 15, 2024
83 citations
Mindfulness and meditation practices, particularly Mindfulness-Based Stress Reduction (MBSR), improve emotional regulation and brain structure, reduce anxiety, and enhance stress resilience. These practices induce neuroplasticity, increase cortical thickness, reduce amygdala reactivity, and improve brain connectivity and neurotransmitter levels. MBSR enhances brain regions involved in emotional processing and sensory perception, improves psychological outcomes such as anxiety and depression, and exhibits unique mechanisms of pain reduction compared to placebo. Future research should focus on diverse populations and naturalistic settings to better understand and optimize these benefits.
Biomedicines
October 9, 2024
Piotr Kawczak, Igor Feszak, Tomasz Bączek
50 citations
Esketamine, the (S)-enantiomer of ketamine, is more potent than arketamine, offering three times stronger analgesic effects and 1.5 times greater anesthetic efficacy. It provides smoother anesthesia with fewer side effects and is used clinically for its neuroprotective, bronchodilatory, and antiepileptic properties. Approved by the FDA and EMA in 2019, esketamine is prescribed alongside SSRIs or SNRIs for treatment-resistant depression. Arketamine, the (R)-enantiomer, shows potential for treating neurological disorders like Alzheimer's, Parkinson's, and multiple sclerosis, with possible antidepressant and anti-inflammatory benefits. Esketamine is already in clinical use, while arketamine requires further research on safety, efficacy, and dosing.
Biomedicines
February 5, 2023
Erika Plazas, Nicoletta Faraone
40 citations
Indole alkaloids from magic mushrooms are promising alternatives to synthetic drugs for treating neuropsychiatric disorders like depression, anxiety, and PTSD. These compounds have a rich history and broad biological properties, with the indole heterocycle being significant in drug discovery. The review reports the physicochemical and pharmacological characteristics of these alkaloids, highlighting their potential as safe and effective therapeutic agents.
Biomedicines
February 18, 2020
Candace R. Lewis, Katrin H. Preller, B. Blair Braden et al.
27 citations
Psilocybin, the psychoactive compound in psilocybe mushrooms, primarily affects serotonin 2A receptors, which are highly expressed in the cingulate cortex. In healthy adults (n = 55) given oral psilocybin at low (0.160 mg/kg) or high (0.215 mg/kg) doses, greater thickness of the rostral anterior cingulate predicted higher subjective ratings on emotional sub-scales of the Five-Dimensional Altered State of Consciousness questionnaire, after controlling for sex and age. The caudal and posterior cingulate did not show this effect. These findings suggest that individual differences in brain structure, specifically cingulate cortex thickness, contribute to the wide variability in subjective psychedelic experiences, extending the traditional set and setting hypothesis.
Biomedicines
March 7, 2023
Hans O Kalkman
16 citations
Depression involves an infection-like inflammation in the brain driven by activation of microglial Toll-like receptors and the enzyme glycogen synthase kinase-3β (GSK3β). GSK3β shifts the balance between the pro-inflammatory transcription factor NFκB and the neuroprotective, anti-inflammatory transcription factor NRF2. Tricyclic antidepressants work by activating GS-coupled microglial receptors, raising cAMP, and activating protein kinase A, which inhibits GSK3β. Other antidepressant principles—cannabinoid receptor-2 activation, opioid μ receptor agonists, 5HT2 agonists, valproate, ketamine, and vagus nerve stimulation—also inhibit GSK3β. Screening for NRF2 activation in microglial cells with TLR-activated GSK3β activity could accelerate discovery of novel antidepressants.
Biomedicines
June 25, 2023
Wen-Chien Chen, Tzong-Shi Wang, Fang-Yu Chang et al.
12 citations
Ketamine, a drug abused for its psychedelic effects, alters movement differently depending on a mouse's age, strain, and dose. Adolescent and adult male mice from two strains, C57BL/6J and BALB/c, were given ketamine at 0, 25, or 50 mg/kg after a 30-minute baseline. In C57BL/6J mice, both age groups showed significantly increased distance traveled and speed after ketamine, but BALB/c mice did not. The higher dose delayed the onset of hyperlocomotion compared to the lower dose. Adolescent C57BL/6J mice showed greater locomotor activation than adults, a difference not seen in BALB/c mice. These results indicate that sensitivity to ketamine's effects on movement is biologically determined.
Biomedicines
April 26, 2022
Anna Szilágyi, Barbara Takács, Réka Szekeres et al.
10 citations
A study tested whether N’N-dimethyltryptamine (DMT), a psychedelic compound, could protect the retina from damage caused by ischemia (restricted blood flow) followed by reperfusion. Because DMT is rapidly broken down by monoamine oxidase A (MAO-A), it was given alongside harmaline (a MAO-A inhibitor found in the Amazonian brew ayahuasca). In rats whose eye blood flow was blocked for 60 minutes and then restored for 7 days, harmaline alone protected the retina from injury. Surprisingly, adding DMT counteracted that protection. The two drugs had opposing effects on proteins involved in cell death, inflammation, tissue breakdown, and oxidative stress. The results suggest harmaline may have therapeutic potential for ischemic eye diseases, while DMT's effects on eye ischemia warrant caution.
Biomedicines
September 28, 2023
Hans O. Kalkman
8 citations
Ketamine is a racemic mixture of S-ketamine and R-ketamine, each with distinct pharmacological activities. S-ketamine blocks NMDA channels and acts as an opioid μ-receptor agonist, while R-ketamine binds to σ1-receptors and is believed to act as an agonist. In patients with major depressive disorder, S-ketamine nasal spray shows clear antidepressant activity, but compared to intravenous racemic ketamine, its response rate, duration of action, and anti-suicidal activity appear less pronounced. The σ1-activity of R-ketamine may enhance pathways through which S-ketamine produces antidepressant effects and provide its own antidepressant activity, potentially explaining the superior effect of racemic ketamine over S-ketamine alone.
Biomedicines
March 6, 2025
Ping-Cheng Shih, I-Shiang Tzeng, Yi-Chyan Chen et al.
1 citation
Gastrodin, a compound from the traditional herbal medicine Gastrodia elata, counteracts ketamine-induced disruptions in Rho signaling, cytoskeletal dynamics, and cell migration. In B35 and C6 cells, gastrodin reversed ketamine's effects on cell mobility inhibition, F-actin condensation, and the modulation of Rho pathway proteins including RhoGDI1, RhoA, CDC42, Rac1, ROCK1, NWASP, MLC2, PFN1, and cofilin-1. Similar modulations of Rho signaling were observed in the prefrontal cortex of Sprague Dawley rats. These findings suggest gastrodin may act as a comprehensive regulator of cellular signaling, with potential implications for neuronal function and cancer metastasis.
Biomedicines
July 6, 2026
Kasper Buczma, Katarzyna Kamińska, Kaja Kasarełło et al.
Psilocybin, a serotonergic hallucinogen, shows therapeutic promise for treatment-resistant depression, but its multi-organ safety profile remains unclear. This narrative review of preclinical studies, clinical data, and case reports found limited and heterogeneous evidence, with rare adverse events often confounded by polysubstance use and uncertain dosing. Biologically plausible mechanisms via serotonergic receptor activation warrant further investigation, yet controlled clinical data do not consistently indicate intrinsic multi-organ toxicity. The review highlights critical gaps in understanding psilocybin's organ-specific safety and calls for systematic evaluation.
Biomedicines
June 1, 2026
Masaru Tanaka
Antidepressant efficacy, especially for rapid-acting agents like ketamine and esketamine, depends on coordinated phases of synaptic plasticity and neuronal excitability. Induction occurs through NMDAR and AMPAR signaling, consolidation involves TrkB, eEF2K, and SV2A to stabilize changes, and maintenance relies on intrinsic excitability governed by Kv7, HCN, and GIRK potassium channels that prevent relapse. The proposed Induction-Consolidation-Maintenance (ICM) framework links these phases to distinct therapeutic windows and candidate biomarkers such as SV2A PET, EEG, and fMRI, offering a hypothesis-generating roadmap for future studies rather than validated clinical tools.
Biomedicines
May 23, 2026
Dominik Jucha, Michał Klimas, Dominika Wiśniewska et al.
About 25% of people with bipolar disorder experience drug-resistant depression, where standard treatments fail. This paper reviews augmentation strategies and polypharmacotherapy for treatment-resistant bipolar depression. Atypical antipsychotics show limited efficacy and high side effects. Ketamine produces the fastest and strongest antidepressant effect with low risk of switching to mania. Pramipexole shows long-term promise but carries high risk of mania and impulse control disorders. Celecoxib, as anti-inflammatory therapy, significantly improved response and remission rates compared to escitalopram alone. Memantine showed only early, short-term benefit. The authors conclude that rational polypharmacotherapy targeting glutamatergic and inflammatory pathways is most promising, with ketamine having the greatest clinical potential.
Biomedicines
February 25, 2026
Alice Melani, Giorgia Papini, Marco Bonaso et al.
Psychedelics are gaining renewed scientific interest as breakthrough therapies for mental disorders, with ayahuasca and its active component DMT showing particular promise. DMT acts primarily as a serotonin 5-HT2A receptor partial agonist, while 5-MeO-DMT has higher affinity for 5-HT1A receptors; both foster neuroplasticity and reorganize brain networks involved in perception, cognition, and mood. Current evidence offers an optimistic outlook for treatment-resistant depression and major depressive disorder, with four phase II studies of 5-MeO-DMT and one of DMT for TRD, plus two phase II studies of DMT fumarate for MDD. Evidence for other mental disorders remains preliminary.
Biomedicines
February 21, 2026
Maximiliano Ganado, Carmen Rubio, Javier Pérez-villavicencio et al.
Psychedelic effects are not solely driven by serotonin receptors. The compound salvinorin A, from Salvia divinorum, produces altered consciousness by directly activating kappa opioid receptors (KORs), bypassing serotonin entirely. This review synthesizes evidence from lab studies, animal models, and human brain imaging. Salvinorin A triggers a specific signaling pathway (β-arrestin bias) that causes rapid receptor desensitization, disrupts thalamocortical communication, suppresses dopamine activity in reward circuits, and fragments large-scale brain networks. Despite being a potent opioid agonist, it has low abuse potential because its aversive effects and dopamine suppression prevent positive reinforcement. Understanding opioid receptor mechanisms expands psychedelic neuroscience beyond serotonin-focused models and may guide development of treatments for depression, addiction, and chronic pain.