medRxiv Preprint Server
April 19, 2026
Cameron C. Glick, Saad Pirzada, Shaun Quah et al.
preprint
A scalable, low-burden behavioral intervention using ultra-brief, remotely delivered meditation was tested in a randomized controlled trial with multimodal outcome assessment under real-world conditions. The intervention aimed to address rising subclinical mental health symptoms, though the abstract does not report specific findings or effect sizes.
medRxiv Preprint Server
April 17, 2026
Chiranth Bhagavan, Orwa Dandash, Olivia Carter et al.
preprint
Psilocybin, a classic psychedelic, acutely alters brain functional connectivity, and these changes are linked to therapeutic doses and subjective effects. Some evidence indicates that such changes persist beyond the acute drug administration period. However, the effects of lower doses on sustained connectivity changes remain unclear.
medRxiv Preprint Server
April 1, 2026
Jiawei Zhu, Zhenfu Wen, Yonghao Cao et al.
preprint
A wearable mindfulness meditation brain-computer interface (MM-BCI) system that provides real-time neurofeedback can reduce carsickness severity. In a 10-week randomized controlled trial, 60 carsickness-susceptible individuals practiced mindfulness meditation with either real MM-BCI neurofeedback or sham feedback during car rides and at home. Those receiving real feedback showed significantly reduced carsickness severity at post-intervention and at a one-month follow-up, assessed during regular car riding without any task or feedback. At baseline, susceptible participants had a reduced aperiodic exponent in occipito-parietal cortex compared to non-susceptible controls. MM-BCI training increased this exponent toward non-susceptible levels, and the degree of neural normalization correlated with symptom improvement.
medRxiv Preprint Server
March 27, 2026
Brooke L. Sevchik, S. Parker Singleton, Analiese Lahey et al.
preprint
A living systematic review and meta-analysis of six randomized controlled trials with 286 participants found that MDMA-assisted therapy reduces PTSD symptoms more than control conditions (Hedges' g = -0.71). More dosing sessions and higher cumulative doses were linked to larger effects. MDMA also led to higher response (risk ratio 1.35) and remission (risk ratio 2.25) rates. Most studies had low risk of bias per Cochrane guidelines, though issues like expectancy and functional unblinding remain. The evidence was rated low certainty using GRADE, and the authors note more trials are needed.
medRxiv Preprint Server
February 23, 2026
Fernando A. Wilson, Eric L. Garland
preprint
Opioid misuse causes widespread harm, and Mindfulness-Oriented Recovery Enhancement (MORE) has been shown to be an effective treatment for it. However, the cost-effectiveness of this intervention has not yet been determined.
medRxiv Preprint Server
January 14, 2026
Gaia Zin, Guy Nagels, Jeroen Van Schependom et al.
preprint
Disruption of the balance between excitatory and inhibitory neural processes is thought to play a role in multiple sclerosis (MS), but no fMRI-based method has been available to measure this balance in MS. This paper introduces a novel fMRI technique for assessing E/I balance in people with MS, addressing a gap left by traditional electrophysiological measures.
medRxiv Preprint Server
January 13, 2026
Deniz Yilmaz, Lena Deller, Johanna Spaeth et al.
preprint
Schizophrenia spectrum disorders (SSD) involve pervasive disturbances in how the brain processes internal bodily signals—a function called interoception. In a cross-sectional observational study, 53 people with SSD and 60 matched healthy controls completed a heartbeat counting task and EEG recordings. People with SSD showed altered subjective interoceptive awareness, including impaired regulation and negative bodily appraisal, along with elevated depersonalization. Their interoceptive accuracy was marginally lower, and their heartbeat evoked potentials were attenuated, especially during the heartbeat counting task, over centro-parietal regions. Depersonalization was the most consistent correlate of clinical severity. These findings suggest interoceptive dysfunction is a central, trait-like feature of SSD.
medRxiv Preprint Server
December 16, 2025
Derek Newman, Charlotte Maschke, George A. Mashour et al.
preprint
Propofol anesthesia can cause either the expected suppression of brain activity or a transient paradoxical excitation. EEG measures of signal complexity and entropy, specifically Type I and Type II complexity on the Complexity–Entropy Causal Plane (CECP), distinguish these divergent neural trajectories. The findings suggest that paradoxical excitation is reflected in both types of complexity, that the CECP separates excitation from suppression, and that baseline EEG complexity is linked to how susceptible a person is to propofol.
medRxiv Preprint Server
December 5, 2025
Gabriel Loewinger, Mats J. Stensrud, Sandeep M. Nayak et al.
preprint
Functional unmasking (unblinding) in clinical trials for mental health treatments, especially with psychedelics, can bias results because participants often know they received the active drug due to its unmistakable acute effects. This undermines confidence that outcomes reflect true therapeutic properties rather than placebo-like effects. A counterfactual conceptualization formalizes the shortcomings of existing solutions like dose-response and active controls, and shows how modern causal inference approaches can isolate effects free of this contamination. Feedback mechanisms between perceived benefits and expectancies can make traditional methods obscure or exaggerate therapeutic benefits. The proposal motivates trial designs and statistical methods to mitigate the impacts of functional unmasking.
medRxiv Preprint Server
May 26, 2025
Nathan J. Wellington, Bonnie L. Quigley, Ana P. Bouças et al.
preprint
A six-week course of oral ketamine produced substantial and persistent changes in gene expression in 23 people with PTSD. Short-term effects included suppression of inflammation and antimicrobial activity; long-term effects shifted toward sustained immune regulation, inflammation remodulation, and tissue repair. Over four weeks, the number of genes whose activity changed rose by 37%, the magnitude of expression changes increased 6.5-fold, and pathway activity strengthened 8.8-fold. Key immune and inflammatory pathways modulated included interferon alpha/beta signaling, IL-17 signaling, cytokine storm signaling, neutrophil degranulation, and antimicrobial peptide signaling. Central regulators such as IL-6, IL-1β, IFI27, IL-10, CXCL8, SOCS1/3, and CAMP were implicated. These molecular changes point to mechanisms underlying ketamine's long-term therapeutic effects and suggest avenues for personalized maintenance therapy to prevent relapse.
medRxiv Preprint Server
March 2, 2025
Bonnie L. Quigley, Emerald Orr, Sophie Kafka et al.
preprint
In a 6-week open-label trial of low-dose oral ketamine for PTSD, blood samples from 25 participants showed a small but significant decrease in both BDNF and VEGF-A levels after treatment, with a positive correlation between the two biomarkers. This suggests ketamine's effects may involve a reciprocal interaction between BDNF and VEGF-A, offering potential insight into a biological mechanism for PTSD symptom reduction. Novel relationships between FKBP51, serotonin, and clinical scales were also observed. No significant changes in immune cytokines were detected, possibly because half the participants had low-grade inflammation and half did not.
medRxiv Preprint Server
January 30, 2024
Lauren N. Swanson, Lila S. Jones, Jose Muñoz Aycart et al.
preprint
Repeated at-home ketamine treatments are effective for reducing symptoms of depression, generalized anxiety, and social anxiety, and they appear safe with limited adverse effects and low tendency for long-term use.
medRxiv Preprint Server
July 3, 2023
Eric A. Miller, Houtan Totonchi Afshar, Jyoti Mishra et al.
preprint
Ketamine helps some patients with treatment resistant depression, but reliable methods for predicting which patients will respond are lacking.
medRxiv Preprint Server
June 28, 2023
Mohammad Ali Shenasa, Houtan Totonchi Afshar, Eric A. Miller et al.
preprint
Cannabis use may weaken the antidepressant effects of ketamine and repetitive transcranial magnetic stimulation (rTMS). The antidepressant effects of these treatments rely on long-term potentiation and synaptic plasticity, but cannabis activates CB1 receptors, which can impair synaptic plasticity. This suggests that cannabis use might reduce the effectiveness of ketamine and rTMS for depression treatment.
medRxiv Preprint Server
September 23, 2021
Nirmaljot Kaur, Siva Naga S. Yarrarapu, Abhishek R. Giri et al.
preprint
Ketamine, a dissociative anesthetic that blocks glutaminergic NMDA receptors, can rapidly relieve depression. While previously used in outpatient settings for treatment-resistant depression, this work demonstrates its usefulness for managing depression in the intensive care unit (ICU), expanding the settings where this rapid antidepressant effect can be applied.
medRxiv Preprint Server
June 13, 2021
Rui Du, Kun Niu, Guofang Lu et al.
preprint
A meta-analysis of ten trials with 705 patients examined ketamine for post-traumatic stress disorder (PTSD). Ketamine did not increase PTSD prevalence (risk ratio 0.86, 95% CI 0.61 to 1.20). For short-duration PTSD (months), ketamine showed a small symptom-scale difference (mean difference 2.45, 95% CI 1.33 to 3.58). For chronic PTSD (years), ketamine reduced symptoms (mean difference −3.66, 95% CI −7.05 to −0.27), with greater benefit when treatment lasted more than one week. The authors recommend avoiding ketamine for short-term PTSD but suggest it as a new therapy for chronic PTSD, noting potential to improve arousal, avoidance, and dissociative symptoms, while calling for more research.
medRxiv Preprint Server
April 20, 2021
Anand S. Patil, Ahish Chitneni, Suhani Dalal et al.
preprint
Ketamine infusions may reduce pain for some patients with treatment-resistant Complex Regional Pain Syndrome (CRPS), but the evidence is limited by small studies and varying protocols. This systematic review examined clinical studies on ketamine use for CRPS and found that while some patients experience pain relief, the quality of evidence is low, and more rigorous research is needed to confirm effectiveness and determine optimal dosing and duration of treatment.
medRxiv Preprint Server
February 22, 2021
Jessica R. Gilbert, Christina S. Galiano, Allison C. Nugent et al.
preprint
A single intravenous infusion of ketamine rapidly reduces depressive symptoms in people with treatment-resistant major depressive disorder. In a double-blind, crossover, placebo-controlled study with 19 depressed individuals and 15 healthy volunteers, magnetoencephalographic recordings were taken before and six to nine hours after drug or placebo infusion while participants performed an emotional face attention task. Dynamic causal modeling revealed that ketamine accelerated GABA and NMDA transmission in the early visual cortex, sped NMDA transmission in the fusiform cortex, and slowed NMDA transmission in the amygdala.
medRxiv Preprint Server
February 21, 2021
Jinsong Tang, Qiuxia Wu, Chang Qi et al.
preprint
Long-term, non-medical use of ketamine is associated with reduced gray matter in the dorsal prefrontal cortex, and this study investigated whether similar cortical thinning occurs. Chronic ketamine users showed cortical thickness abnormalities compared to non-users, suggesting that recreational ketamine use may lead to structural brain changes beyond gray matter volume loss. The findings indicate potential neurotoxic effects of sustained illicit ketamine use on brain health, as observed through MRI scans.
medRxiv Preprint Server
November 12, 2020
Indie C. Garwood, Sourish Chakravarty, Jacob Donoghue et al.
preprint
Ketamine, an anesthetic and psychoactive drug, produces alternating patterns of brain activity: bursts of gamma oscillations (30-50 Hz) and slow oscillations (0.1-10 Hz). A hidden Markov model (HMM) was applied to brainwave data from two non-human primates and nine human subjects receiving anesthetic doses of ketamine. The model revealed distinct states corresponding to gamma bursts and slow oscillations, with intermediate states. Mean gamma burst durations were 2.5 seconds (non-human primate 1), 1.2 seconds (non-human primate 2), and 2.7 seconds (humans). Mean slow oscillation durations were 1.6 seconds, 0.7 seconds, and 2.8 seconds, respectively. This framework provides quantitative constraints for understanding how ketamine alters states of consciousness.
medRxiv Preprint Server
August 31, 2020
Steven Pennybaker, Brian J Roach, Susanna L Fryer et al.
preprint
Older age is associated with slower and less durable antidepressant responses to intravenous ketamine in veterans with treatment-refractory depression. The study found that age-related declines in neuroplasticity may attenuate ketamine's mechanism of action, which involves glutamatergic signaling and synaptogenesis. Older patients took longer to achieve a clinically meaningful reduction in depression symptoms and were more likely to relapse sooner after the infusion series ended. The findings suggest that age is a key patient characteristic influencing the speed and durability of ketamine's antidepressant effects.
medRxiv Preprint Server
June 17, 2026
Danny Nacker, Luise Kalus, Anil K. Seth et al.
preprint
Supervised stroboscopic light stimulation (SLS) was safe, tolerable, and feasible in adults with depressive symptoms, but efficacy was not established. In a staged program, 31 participants tested 11 SLS parameter sets; no severe adverse reactions occurred, and mean discomfort was low (0.49 out of 10). A subsequent randomized trial assigned 84 participants to four weekly 31-minute sessions of SLS or a low-phenomenology control. Retention was 83.3% (70 of 84 participants), with higher retention in the intervention arm (39 of 42) than the control arm (31 of 42). Exploratory depressive-symptom changes suggested a possible signal on the BDI-II but do not confirm efficacy. The next step is a Phase 2a feasibility trial with a locked protocol.