Zenodo (CERN European Organization for Nuclear Research)
February 28, 2026
Kshirsagar Pankaj*, Misal Shivdarshan, Dr. Giri Ashok
About one-third of people with major depressive disorder or bipolar depression do not get better with standard antidepressants, a condition called treatment-resistant depression. Ketamine and esketamine, which modulate the glutamate system by blocking NMDA receptors, can produce rapid antidepressant effects within hours when given intravenously at low doses. Esketamine nasal spray is approved for treatment-resistant depression and major depression with suicidal thoughts, based on clinical trials. These drugs offer a new approach focused on neuroplasticity rather than the older monoamine theory, but they require monitoring for side effects such as dissociation, sedation, and potential for misuse. Long-term safety and effective maintenance strategies still need to be established.
Progress in Neuro-Psychopharmacology and Biological Psychiatry
February 27, 2026
Chris H. Miller, Angela Hickman, Caitlin Baten et al.
2 citations
Ketamine, originally developed as an anesthetic, has emerged as a novel treatment for major depressive disorder (MDD) and treatment-resistant depression (TRD). Its antidepressant properties were discovered serendipitously, leading to FDA approval for TRD and MDD with suicidal ideation. The drug acts primarily as an NMDA receptor antagonist, triggering a paradoxical AMPA-mediated glutamate surge that promotes synaptogenesis and neuroplasticity. Intravenous ketamine and intranasal esketamine differ in dosing, bioavailability, and onset. Common adverse effects include dissociation, sedation, and hypertension. Efficacy studies show mixed-to-positive results, with non-inferiority to established treatments like electroconvulsive therapy. Future research aims to develop predictive markers for personalized medicine.
Journal of Psychopharmacology
February 27, 2026
Claire T. Roberts, Mathieu Seynaeve, Anna O. Ermakova et al.
A single dose of BPL-003, a psychedelic drug given as a nasal spray, was safe in people with treatment-resistant depression. Depression scores dropped quickly and stayed lower for 12 weeks, suggesting the drug may help this hard-to-treat condition. Larger controlled trials are needed.
International Journal of Molecular Sciences
February 26, 2026
James Chmiel, Filip Rybakowski
Antidepressant response to psychedelic-assisted therapies depends more on what happens during the dosing session and how the therapeutic context shapes that experience than on static patient characteristics. Across 48 studies, greater emotional breakthrough, mystical experiences, and insight consistently predicted larger and more durable symptom reductions, while anxiety-dominant states attenuated benefit. A stronger therapeutic alliance and music perceived as resonant predicted both meaningful acute experiences and later clinical gains. Baseline factors such as PTSD comorbidity sometimes weakened outcomes, extensive prior psychedelic use was linked to smaller incremental benefits, and demographics were generally uninformative. Biological markers of increased neural flexibility and plasticity also correlated with better outcomes.
Psychiatry and Clinical Neurosciences
February 26, 2026
Kengo Yonezawa, M. Hirata, Hiroaki Takano et al.
1 citation
Psilocybin, a classic psychedelic compound, is being reexamined as a treatment for psychiatric disorders after decades of legal restrictions. Clinical trials report therapeutic effects for major depressive disorder, depressive symptoms in life-threatening illnesses, and some substance use disorders, with phase III trials for depression underway. Short-term side effects are generally mild and transient, but long-term effects need investigation. Neuroimaging research, mainly using MRI and EEG, is limited and focused on MDD, though ongoing trials include broader studies. Regulatory frameworks vary; controlled use is permitted in Switzerland, parts of the US, Canada, and Australia. Challenges remain, including the need for larger blinded trials and standardized protocols.
American Journal of Geriatric Psychiatry
February 24, 2026
Rachel Fremont, Amelia Karim, Tanya Peguero Estevez et al.
1 citation
In an open-label clinical trial, a single intravenous infusion of ketamine (0.5 mg/kg) was safe and well tolerated in 13 patients with mild cognitive impairment and major depressive disorder. No serious adverse events occurred. Depression severity, measured by the Montgomery-Asberg Depression Rating Scale, dropped from a mean of 27.4 before treatment to 5.7 at 24 hours after the infusion—a large-magnitude improvement. For 8 of the 13 patients, this improvement persisted for up to one month, with a mean score of 12.1 and at least a 50% reduction. These findings suggest ketamine may be effective for depression in this population, but larger randomized controlled trials are needed to confirm efficacy and assess cognitive effects.
J Affect Disord
February 23, 2026
Xiaofeng Lan, Zitao Wu, Chengyu Wang et al.
In a randomized controlled trial, adolescents with major depressive disorder who received repeated esketamine infusions showed changes in multiple peripheral inflammatory markers compared to those who received a placebo. The treatment was associated with reductions in certain inflammatory markers, suggesting that esketamine may influence immune system activity in this population. The findings indicate a potential link between the antidepressant effects of esketamine and its impact on inflammation, though the exact relationship requires further investigation.
Research Square
February 23, 2026
Rotem Petranker, Norman Farb, Omer A. Syed et al.
Repeated low doses of psilocybin were safe and well tolerated in adults with major depressive disorder but did not show greater antidepressant effects than placebo. In a randomized, double-blind trial, 39 participants received either 2 mg psilocybin or placebo weekly for four weeks. Both groups reported similar reductions in depression scores on the PHQ-9 (psilocybin: -5.4; placebo: -6.0) and other measures. The microdose-first group showed slightly more improvement on a dysfunctional attitudes scale than the placebo-first group. No serious adverse events occurred, and symptom reductions continued during an open-label phase. Trial participation itself contributed to clinically meaningful improvement.
Journal of Clinical Medicine
February 20, 2026
Vassilis Martiadis, Fabiola Raffone, Serena Testa et al.
7 citations
Intranasal esketamine provides rapid symptom relief for treatment-resistant depression when standard antidepressants fail, but its real-world effectiveness depends on organizational and multidisciplinary factors beyond pharmacology. This narrative review synthesizes clinical and real-world evidence to propose a phase-based integration framework that specifies complementary roles for psychiatry, nursing, and psychotherapy across pre-treatment assessment, induction, session delivery, post-session integration, and maintenance phases. The framework emphasizes safety, continuity of care, and patient-centred monitoring, with measurable implementation indicators. While evidence supports esketamine's efficacy in reducing depressive symptoms, anhedonia, and suicidality, prospective implementation studies are needed to evaluate clinical effectiveness, feasibility, and cost-effectiveness of the proposed multidisciplinary approach.
Psychiatry Research
February 19, 2026
Trisha Menon, Andy Lu, Akhilan Arulmozhi et al.
Ketamine, esketamine, repetitive transcranial magnetic stimulation (rTMS), and electroconvulsive therapy (ECT) are associated with reductions in suicidal ideation in people with major depressive disorder. The strongest evidence from randomized controlled trials supports rapid, short-term effects, particularly for ketamine and esketamine. Further research is needed to characterize the durability of these antisuicidal effects and to determine whether reductions in suicidal ideation translate into reduced severity of suicidal behavior.
AJN American Journal of Nursing
February 19, 2026
Liz Braun, Alison Colbert
Ketamine, initially approved as an anesthetic in 1970, is increasingly used off-label for treatment-resistant depression, anxiety, and posttraumatic stress disorder. Its S-enantiomer, esketamine (Spravato), received FDA approval for treatment-resistant depression in 2019. Clinical applications include intranasal esketamine, IV infusions, ketamine-assisted psychotherapy, and at-home therapy, with varying oversight. The regulatory landscape remains fragmented, evidence is evolving, and vulnerable patients seek relief. This article provides clinical information for nurses advising patients about ketamine and discusses regulatory, ethical, and nursing implications.
medRxiv
February 19, 2026
Amanda Gow, Emily Shih, Ryan Reid et al.
Under Oregon's regulated psilocybin program, adults who consumed an average of 27.8 mg of psilocybin showed significant improvements in depression, anxiety, and well-being 30 days after a session, including those concurrently using psychiatric medication. Of 88 participants (median age 43, 52% male, 64.8% with prior psychedelic experience), two reported symptoms of hallucinogen persisting perception disorder one day after the session, but none at 30 days. The findings suggest that legal psilocybin services can produce clinically meaningful mental health benefits.
Progress in Neuro-Psychopharmacology and Biological Psychiatry
February 18, 2026
Dimitri Henriques Daldegan-Bueno, C Donegan, Rachael L. Sumner et al.
1 citation
Taking very low doses of LSD (8 micrograms) repeatedly over a short period may temporarily improve mood in people with depression, though the effect needs confirmation in controlled experiments. The drug's behavior in the body was measured in this group, and no evidence of tolerance or increased sensitivity appeared, even when the dose was gradually increased.
Molecular Psychiatry
February 18, 2026
Marie Huc, Sara Siddiqi, Mysa Myers et al.
1 citation
Esketamine, a fast-acting antidepressant, improves depression in both sexes among adults with treatment-resistant depression. However, females showed greater overall improvement and higher odds of treatment response than males toward the end of four-week trials, regardless of whether they received esketamine or placebo. Females also experienced more pronounced reductions in sadness, detachment, and neurovegetative symptoms at certain time points. In contrast, males showed a significant reduction in sadness symptoms two days after esketamine. These findings indicate that sex assigned at birth influences the trajectory and symptom profile of antidepressant response, highlighting its importance for personalized treatment strategies.
Medical Science Monitor
February 18, 2026
Łukasz Grabarczyk, Sophia Rebekka Wolfermann, Hubert Oniszczuk et al.
Conventional antidepressants work in only about half of patients with treatment-resistant depression (TRD). Ketamine, a fast-acting NMDA receptor antagonist, offers an alternative. This non-systematic review of preclinical and clinical evidence found that both ketamine and esketamine show efficacy across several TRD subpopulations, including geriatric, psychiatric, neurologic, oncologic, pediatric, and obstetric patients. Key challenges include psychotomimetic effects, abuse potential, and cardiovascular side effects. Preliminary data on arketamine suggest possible longer-lasting benefits with fewer adverse effects. However, many findings come from very small samples, highlighting the need for larger trials to establish definitive safety and efficacy.
Research Square
February 17, 2026
Zofia Winczewska, Magdalena Górska‐ponikowska, Wiesław Jerzy Cubała
Ketamine at 25 ng/mL increased the viability of mouse hippocampal HT22 neuronal cells exposed to hydrogen peroxide, but only at the highest concentration tested (1000 µM H₂O₂). At that level, cell viability rose from 12% (±1.63%) without ketamine to 38% (±9.12%) with ketamine. This suggests a protective, nonlinear effect that depends on the intensity of oxidative stress, activating only at critical H₂O₂ overload typical of severe depression. The findings indicate a threshold antioxidant mechanism that may contribute to ketamine's antidepressant action and inform future predictive models for individualized treatment.
BJPsych Open
February 16, 2026
Zeina Beidas, Anya Ragnhildstveit, Adam Blackman et al.
1 citation
This is a protocol for a phase II trial testing whether very low doses of psilocybin (2 mg, a microdose) can safely and effectively treat major depressive disorder. Forty adults with MDD will receive either psilocybin or a placebo once weekly for four weeks, then all will receive psilocybin for another four weeks. The trial will measure changes in depression symptoms, mood, well-being, attention, creativity, mindfulness, and pro-sociality. Results will be published regardless of outcome. The findings are expected to guide future research on dose regimens, effect sizes, and the role of expectancy bias, and to inform debates about sub-threshold versus threshold doses of psilocybin.
International Journal of Innovative Technologies in Social Science
February 16, 2026
Aleksandra Lejman, Rafał Bednarczyk, Natalia Bednarczyk et al.
Esketamine nasal spray, the first novel mechanism treatment for treatment-resistant depression in decades, has an acceptable safety profile under clinical supervision. Common adverse effects such as dissociation and sedation resolve within two hours, and blood pressure elevations normalize within 1.5 hours without intervention. Pre-approval concerns about bladder cystitis, cognitive decline, and abuse were not confirmed: no cystitis occurred despite years of exposure, cognitive function remained stable or improved, and misuse was rare (less than 0.01%). Serious adverse events were infrequent (less than 0.2% of sessions), mainly during initial treatments. Mortality rates matched background rates in treatment-resistant depression. Long-term studies up to 6.5 years found no organ damage, cognitive decline, or meaningful abuse problems.
Nat Med
February 16, 2026
David Erritzøe, Tommaso Barba, Tiffanie Benway et al.
4 citations
A single 21.5-mg intravenous dose of the psychedelic DMT, given with psychotherapeutic support, produced a rapid and significant reduction in depressive symptoms in adults with moderate-to-severe major depressive disorder. In a double-blind, placebo-controlled trial with 34 participants, those receiving DMT showed a greater decrease in depression scores at two weeks compared to placebo. Antidepressant effects persisted up to three months in an open-label phase. Adverse events were mostly mild to moderate, and no serious adverse events occurred.
Research square
February 12, 2026
Jenessa Johnston, Greg Jones, Shiyong Peng et al.
Rapid-acting antidepressants such as ketamine and psychedelics share common downstream effects on gene expression in human cortical neurons, despite targeting different initial receptors. Using stem cells from people with treatment-resistant depression and healthy volunteers, neurons were treated with several compounds. After 6 and 24 hours, gene activity was highly correlated across all drugs, converging on pathways related to inflammation, mTORC1 signaling, and cell growth. One compound, HNK, increased gene activity in excitatory neurons and decreased it in inhibitory neurons. These gene changes matched protein changes in spinal fluid from people given ketamine, supporting the model's relevance for studying antidepressant mechanisms.
Journal of Affective Disorders
February 12, 2026
Erica Kaczmarek, Nelson Rodriguez, Noah Chisamore et al.
Anhedonia, a core symptom of depression that often resists standard treatments, may be reduced by psilocybin-assisted psychotherapy (PAP). In a secondary analysis of a randomized, waitlist-controlled trial, 30 adults with treatment-resistant depression (major depressive disorder or bipolar II disorder) received one 25 mg dose of oral psilocybin plus psychotherapy. Anhedonia severity, measured by the Snaith-Hamilton Pleasure Scale, decreased significantly at the 2-week primary endpoint, with clinically meaningful improvements persisting at 3 and 6 months. The analysis adjusted for sex and age. These preliminary results suggest PAP could be a promising intervention for anhedonia in treatment-resistant depression, though larger placebo-controlled trials are needed to confirm the findings and clarify underlying mechanisms.
Journal of Psychedelic Studies
February 12, 2026
Matthew Hicks, Olivia Hicks, Ryan Bradley et al.
2 citations
Group psilocybin therapy is feasible for low-income adults with depression in Oregon's regulated psilocybin program. In an open-label study, 20 participants began treatment and 19 completed two psilocybin administration sessions one week apart, with preparation and integration sessions online. No severe adverse events occurred; participants rated satisfaction 4.8 out of 5, reporting moderate to high benefit and no harm. Exploratory outcomes showed a significant decrease in Hamilton Depression scores with a strong effect size (Cohen's d = 1.89), and all eight domains of the PROMIS-29 significantly improved with effect sizes from 0.667 to 1.774. Further research with comparator groups is warranted.
Research Square
February 11, 2026
Jack Swain, Davis Carter, Leonardo Vando
Among 374 adults with moderate-to-severe PTSD who completed six sessions of at-home, telehealth-supported ketamine-assisted therapy, PTSD symptoms improved substantially. Mean PCL-5 scores dropped from 51.1 at baseline to 28.3 after session 6, a 44.6% reduction. The clinical response rate was 79.7%, and 60.7% achieved remission. Suicidal ideation resolved completely in 75.9% of those who reported it at baseline. Depression and anxiety scores also declined by about half. Side effects occurred in 4.3% of participants. Controlled trials are needed to confirm causality.
Br J Psychiatry
February 10, 2026
Tor-Morten Kvam, Ivar W. Goksøyr, Justyna Rog et al.
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