Pharmacology, biochemistry, and behavior • August 1, 2026 • Mengyang He, Zhifei Shi, Ruijie Zhan et al.
Depression involves multiple dysfunctions across brain systems, including emotional-cognitive circuits, stress hormone regulation, neurotransmitter systems, and neuroplasticity. This review argues that the BDNF/CREB signaling pathway acts as a central hub connecting these systems. It explains how genetic variations, stress-related epigenetic changes, and microRNA regulation affect this pathway, which in turn influences brain plasticity, stress toxicity, and neurotransmitter balance. The review also describes how antidepressants like ketamine, rTMS, and SSRIs work by activating this pathway, supporting its potential as a biomarker and treatment target. Limitations and future directions integrating multiomics and neuroimaging are discussed, reconceptualizing depression as a network disorder centered on BDNF/CREB signaling.
Translational Psychiatry • July 11, 2026 • Moira G. Semple, Sarah E. Mennenga, Ryan Smith et al.
Ketamine and MDMA, compounds known as psychoplastogens, show therapeutic potential for mood and trauma-related disorders, but their molecular mechanisms are not fully understood. In a study analyzing blood samples from 20 ketamine-treated participants and saliva samples from 16 MDMA-treated participants, DNA methylation changes were examined using a Brain-Epigenome-Wide Association Study targeting brain-relevant genes. Ketamine was associated with 405 significantly altered genes and 169 functional networks, while MDMA was linked to 346 altered genes and 183 networks. Both compounds converged on pathways related to neuroplasticity and neuroimmune regulation, suggesting they induce peripheral epigenetic changes that engage molecular pathways relevant to psychiatric health.
Figshare • July 10, 2026 • José Alexandre Salerno, Elizabeth R. Dominguez, Karina Karmirian et al.
A brief 24-hour exposure to the serotonergic psychedelic DMT increases proliferation of human neural stem cells derived from induced pluripotent stem cells. The effect was concentration-dependent, with half-maximal effect at 59.7 nM. DMT treatment also altered trophic gene expression, decreasing neurotrophin-3 while increasing nerve growth factor and brain-derived neurotrophic factor (BDNF) transcripts and intracellular BDNF protein. After DMT was removed, the primed stem cells formed larger neurospheres, with progenitor and early neuronal marker composition matching controls by day 10. These findings demonstrate that brief DMT exposure engages proliferative and neurotrophin-associated responses in human neural stem cells at concentrations consistent with those reported for DMT-induced plasticity in other systems.
Frontiers in Psychiatry • July 9, 2026 • Alqassem Y. Hakami
Ketamine, a drug that rapidly alters brain connections, shows promise for treating both treatment-resistant depression and substance use disorders, particularly alcohol and cocaine addiction. When combined with psychotherapy, small-to-moderate Phase 2 trials found it reduced cravings and increased days of abstinence. However, results vary widely due to differences in dosing, comparison treatments, and follow-up lengths, and effects on preventing relapse have been inconsistent. Ketamine works by blocking NMDA receptors and boosting synaptic plasticity, which may help disrupt harmful reward memories. While supervised use causes only temporary side effects, the drug carries a clear risk of misuse, especially without supervision. Larger, longer studies are needed before it becomes standard care.
Expert review of neurotherapeutics • July 1, 2026 • Stephen Rush, Henry A Nasrallah
Treatment-resistant depression may stem from impaired neural adaptability rather than a simple chemical imbalance. This expert review synthesizes research showing a shift from monoamine-based models of depression toward frameworks centered on neuroplasticity, synaptic growth, glutamatergic signaling, and brain network dysfunction. The authors describe how treatments such as ketamine, neuromodulation, and psychedelics may work by reopening windows of plasticity and recalibrating dysfunctional neural networks, representing a paradigm shift in antidepressant development. The review is a conceptual synthesis, not treatment guidelines, and prospective studies are needed to validate and apply these mechanistically informed models clinically.
Pharmacology, biochemistry, and behavior • June 30, 2026 • Lucie Ladislavová, Viera Kútná, Kristýna Mazochová et al.
Chronic microdosing of psilocin (0.05 or 0.075 mg/kg) in adult male Wistar rats over five weeks did not alter locomotor activity, depressive-like behavior, sociability, or novelty seeking, and did not increase cell proliferation in the dentate gyrus of the hippocampus. A small anxiogenic effect was detected in the Elevated Plus Maze. The findings suggest that, under this dosing schedule, psilocin microdosing produces limited behavioral effects and does not enhance hippocampal progenitor proliferation.
Asian Journal of Medical Sciences • June 30, 2026 • Raja Suhail Shounthoo, Ajaiz Rasool, Athar Un Nisa Quraishi et al.
Ketamine, a dissociative anesthetic developed in the 1960s, is experiencing a resurgence as a treatment for depression and pain. Unlike standard antidepressants that target monoamine systems, ketamine works by modulating glutamate, a key neurotransmitter, and enhancing synaptic plasticity. It shows rapid antidepressant effects in treatment-resistant depression and effectiveness for both acute and chronic pain. However, significant concerns remain about long-term safety, lack of standardized protocols, and potential for misuse. This review examines ketamine's expanding roles in anesthesia, psychiatry, and pain medicine, highlighting its mechanisms, clinical uses, safety issues, and gaps in current evidence.
Zenodo (CERN European Organization for Nuclear Research) • June 28, 2026 • Giulio Ruffini, Francesca Castaldo
Immersive algorithmic art may enhance neural plasticity through the same computational mechanism as psychedelics: sustained, structured prediction-error signaling. The brain's modeling engine generates predictions of sensory input; mismatches drive model updating via synaptic plasticity. Algorithmic art maximizes these errors while keeping stimuli in a compressible, emotionally rewarding "Goldilocks zone," creating a self-reinforcing loop of engagement, prediction error, plasticity, model updating, and positive valence. The hypothesis is formalized within Kolmogorov Theory, connected to the REBUS model, and supported by convergent evidence from psychedelic neuroimaging and predictive-coding electrophysiology. A translational pathway combining closed-loop EEG-driven algorithmic art with cognitive behavioral therapy for adolescent depression is outlined.
J Psychopharmacol • June 28, 2026
In a mouse model of posttraumatic stress disorder, a single dose of psilocybin reduced fear responses to a conditioned cue measured 1, 6, and 7 days later. Psilocybin also reversed the fear conditioning-induced reductions in neuroplasticity in the hippocampus and medial prefrontal cortex, increasing dendritic branches and spine density, upregulating GluR1 and synapsin-1, enhancing brain-derived neurotrophic factor and mammalian target of rapamycin signaling, and promoting neurogenesis. These results suggest that psilocybin may have therapeutic potential for PTSD and other disorders involving fear memory by restoring neuroplasticity in these brain regions.
Zenodo (CERN European Organization for Nuclear Research) • June 24, 2026 • Ramiro Solis
The brain's ability to rewire itself declines with age, but why remains unclear. This paper examines whether the compound N,N-dimethyltryptamine (DMT) helps maintain neuroplasticity, and whether its decline contributes to age-related loss of cognitive flexibility. DMT promotes synaptic growth and neurogenesis in animals, and levels are reportedly highest during development. However, evidence is mixed: one study finds DMT concentrations comparable to serotonin, while another finds it undetectable in rat brain. DMT's affinity for the sigma-1 receptor is three orders of magnitude higher than physiological concentrations, and a key finding about intracellular 5-HT2A receptor binding has not been replicated. The paper does not claim the hypothesis is established, but proposes a research program to test whether DMT depletion causes lost plasticity or is incidental.
Nature Neuroscience • June 1, 2023 • Rafael Moliner, Mykhailo Girych, Vera Kovaleva et al. • 439 citations
Psychedelics such as LSD and psilocin produce fast and lasting antidepressant effects by directly binding to the TrkB receptor, the receptor for brain-derived neurotrophic factor (BDNF). These compounds bind to TrkB with affinities 1,000 times higher than other antidepressants like fluoxetine and ketamine, and they interact with a distinct but partially overlapping site within the transmembrane domain of TrkB dimers. In mice, the neuroplasticity and antidepressant-like effects of psychedelics depend on TrkB binding and endogenous BDNF signaling, not on serotonin 2A receptor activation. However, LSD-induced head twitching requires serotonin 2A activation and is independent of TrkB binding. This suggests that high-affinity TrkB positive allosteric modulators without serotonin 2A activity could retain antidepressant benefits without hallucinogenic effects.
Science • February 16, 2023 • 467 citations
Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-HT2ARs is essential for psychedelic-induced cortical plasticity, but it is unclear why some 5-HT2AR agonists promote neuroplasticity while others do not. Using molecular and genetic tools, the authors demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics, explaining why serotonin does not engage similar plasticity mechanisms. This work emphasizes location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology • January 1, 2023 • Abigail E Calder, Gregor Hasler • 303 citations
Classic psychedelics like LSD, psilocybin, and ayahuasca may help treat depression, anxiety, and addiction, with clinical improvements lasting months or years. The leading theory is that these drugs rapidly and persistently stimulate neuroplasticity. This review examines evidence that psychedelics promote neuroplasticity, including dendritogenesis, synaptogenesis, neurogenesis, and plasticity-related gene expression, particularly in the prefrontal cortex and hippocampus. It also considers the doses required—hallucinogenic versus microdoses—and how long neuroplastic changes last. The authors discuss consequences for patients and healthy individuals and identify key research questions for future study.
Nat Med • April 11, 2022 • 432 citations
A single dose of psilocybin therapy increased global brain integration in people with depression, with effects lasting for weeks. The brain's regions communicated more broadly and flexibly after treatment, a pattern linked to reduced depressive symptoms. This neural change suggests psilocybin may help reorganize brain networks that become rigid in depression.
Translational psychiatry • November 8, 2021 • Manoj K Doss, Michal Považan, Monica D Rosenberg et al. • 343 citations
Psilocybin therapy increased cognitive flexibility for at least four weeks in 24 patients with major depressive disorder, though these improvements were not linked to antidepressant effects. One week after treatment, glutamate and N-acetylaspartate concentrations decreased in the anterior cingulate cortex (ACC), and functional connectivity dynamics increased between the ACC and posterior cingulate cortex. Surprisingly, larger increases in this neural flexibility were associated with smaller gains in cognitive flexibility. Baseline brain connectivity from the ACC predicted cognitive flexibility improvements, with greater baseline connectivity linked to better baseline flexibility but less improvement. The findings suggest that while some increase in neural dynamics may help shift from rigid states, larger persisting increases may be less beneficial.
Frontiers in Psychiatry • September 10, 2021 • Cato M. H. de Vos, Natasha L. Mason, Kim P. C. Kuypers • 259 citations
A review of 16 preclinical and 4 clinical studies (20 total) shows that a single dose of a psychedelic—such as ayahuasca, DMT, psilocybin, or LSD—rapidly alters molecular, neuronal, synaptic, and dendritic plasticity mechanisms. These changes include increased expression of plasticity-related genes and proteins like Brain-Derived Neurotrophic Factor (BDNF) and greater dendritic complexity that outlasts the drug's acute effects. Repeated administration directly stimulates neurogenesis and elevates BDNF mRNA levels for up to a month. The evidence suggests these neuroplasticity adaptations parallel and may underlie the antidepressant, anxiolytic, and antiaddictive clinical effects of psychedelics.
Scientific reports • February 10, 2020 • Frederick S Barrett, Manoj K Doss, Nathan D Sepeda et al. • 375 citations
A single 25 mg/70 kg dose of psilocybin temporarily reduced negative affect and amygdala response to negative facial expressions one week later in twelve healthy volunteers, while positive affect and prefrontal cortex responses to emotional conflict increased. One month later, negative affect and amygdala reactivity returned to baseline, but positive affect remained elevated and trait anxiety was lower. The number of resting-state functional connections across the brain increased from baseline to both one week and one month after dosing. These preliminary findings suggest psilocybin may enhance emotional and brain plasticity, with negative affect as a potential therapeutic target.
Neuroimage • May 25, 2019 • 249 citations
Psilocybin alters how the brain dynamically explores its repertoire of resting-state networks, increasing the flexibility and range of network configurations. This suggests the drug shifts brain dynamics toward more variable and less constrained patterns of functional connectivity, which may underlie its profound effects on consciousness and perception. The findings indicate that psilocybin expands the brain's capacity to transition between different network states, potentially explaining its therapeutic applications in mental health by disrupting rigid patterns of thought.
Proc Natl Acad Sci U S A • January 28, 2019 • 303 citations
LSD alters communication within brain pathways that filter sensory information, according to a brain imaging study. Using a double-blind, placebo-controlled design with 25 healthy participants, researchers found that LSD increased signaling from the thalamus to the posterior cingulate cortex—an effect dependent on serotonin 2A receptor activation—and decreased signaling from the ventral striatum to the thalamus independently of those receptors. These changes in directed connectivity within cortico-striato-thalamo-cortical loops support the thalamic filter model of psychedelic action, which proposes that psychedelics disrupt the gating of sensory information to the cortex. The findings advance understanding of how psychedelics alter consciousness and may inform development of new therapeutics.
Cell Reports • June 1, 2018 • Calvin Ly, Alexandra C. Greb, Lindsay P. Cameron et al. • 1,158 citations
Serotonergic psychedelics, like ketamine, can robustly increase the growth of neurons and their connections (neuritogenesis and spinogenesis) in the prefrontal cortex, both in lab dishes and in living animals. These structural changes are accompanied by more synapses and enhanced function, as shown by microscopy and electrophysiology. The effects appear to arise from stimulation of TrkB, mTOR, and 5-HT2A signaling pathways, which may explain the clinical effectiveness of these compounds. The findings highlight the therapeutic potential of psychedelics and identify several chemical scaffolds for developing fast-acting, safe antidepressants that promote brain plasticity.
Sci Rep • October 13, 2017 • 590 citations
In patients with treatment-resistant depression, a single dose of psilocybin combined with psychological support reduced depressive symptoms and altered brain activity and connectivity. Functional MRI scans before and after treatment showed decreased blood flow in the temporal cortex, including the amygdala, and increased resting-state functional connectivity within the default-mode network. Reduced amygdala blood flow correlated with fewer depressive symptoms. Changes in connectivity between the ventromedial prefrontal cortex and inferior lateral parietal cortex, as well as between the parahippocampus and prefrontal cortex, predicted treatment response at five weeks. These brain changes differ from the drug's acute effects and suggest a 'reset' of neural circuits.
Hum Brain Mapp • May 6, 2016 • 333 citations
A single dose of LSD increased brain entropy—the unpredictability of neural activity—across sensory and higher-order networks in 19 healthy adults. These entropy shifts, measured during resting-state fMRI, predicted lasting increases in the personality trait openness two weeks later. The predictive effect was strongest when participants listened to music and reported experiences of ego dissolution during the drug's acute effects. The findings suggest that psychedelic-induced changes in brain dynamics and subjective experience can forecast enduring personality change.
Neural Plasticity • January 1, 2016 • Chuan-chih Yang, Alfonso Barrós‐loscertales, Daniel Pinazo et al. • 284 citations
Forty days of mindfulness meditation training in 13 novice meditators altered functional connectivity in brain networks linked to self-referential thought and emotion regulation. During meditation, internal consistency increased in the precuneus and temporoparietal junction but decreased in frontal regions, and connectivity between the dorsal anterior cingulate cortex and anterior insula was reduced. After training, resting-state connectivity between the pregenual anterior cingulate and dorsomedial prefrontal cortex decreased. Participants also reported significantly reduced depression and anxiety scores. These results suggest that meditation may produce antidepressant effects through neuroplastic changes in brain networks underlying affective disorders.
PLoS ONE • September 2, 2014 • Marwan N. Baliki, Ali Mansour, Alex T. Baria et al. • 539 citations
Chronic pain reorganizes the brain's default mode network (DMN). Using resting-state functional magnetic resonance imaging, patients with chronic back pain, complex regional pain syndrome, and knee osteoarthritis all showed reduced connectivity between the medial prefrontal cortex and posterior DMN regions, alongside increased connectivity to the insular cortex proportional to pain intensity. Multiple DMN regions, especially the medial prefrontal cortex, exhibited increased high-frequency oscillations and decreased phase locking with parietal attention-processing regions. Both phase and frequency changes correlated with pain duration in osteoarthritis and chronic back pain patients. These findings suggest chronic pain reflects maladaptive neural dynamics across different pain types.