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.
The Journal of neuroscience : the official journal of the Society for Neuroscience
November 8, 2023
Lindsay P Cameron, Joseph Benetatos, Vern Lewis et al.
88 citations
Serotonergic psychedelics like psilocybin and LSD activate serotonin 5-HT2A receptors in cortical brain regions, altering perception, cognition, and emotions. Their ability to promote neuroplasticity—forming new neural connections and rewiring networks—is thought to underlie therapeutic potential for depression, anxiety, and substance use disorders. These compounds also interact with other serotonin receptor subtypes (5-HT1A, 5-HT2C) and neurotrophin receptors, adding complexity to their effects. Research is exploring nonhallucinogenic derivatives that retain therapeutic benefits without intense psychedelic experiences, potentially reducing adverse reactions. The review also discusses psychedelics as substrates for post-translational protein modification as part of their mechanism.
J Neurosci
November 1, 2022
Steven F. Grieco, Eero Castrén, Gitte M. Knudsen et al.
83 citations
Psychedelic drugs are being reexamined as treatments for brain disorders, with hundreds of clinical trials underway by 2022. Emerging evidence suggests these drugs may produce lasting therapeutic effects by inducing structural and functional neural plasticity. The work reviews basic and clinical research on mechanisms, including receptor binding, gene expression, dendritic changes, and effects on microcircuitry and brain-wide circuits. It also outlines unmet clinical needs and unanswered neuroscience questions for future study.
Trends in neurosciences
November 1, 2024
Cecilia Anna Brunello, Cecilia Cannarozzo, Eero Castrén
29 citations
Antidepressant drugs, including slow-acting types, fast-acting ketamine, and psychedelics, all promote neuronal plasticity through activation of BDNF signaling via its receptor TRKB, though each drug targets different cells. The authors propose that some antidepressants may directly bind to TRKB and allosterically enhance BDNF signaling. Activating TRKB in parvalbumin-containing interneurons disinhibits cortical networks and reopens a juvenile-like window of plasticity. This rewiring of faulty neural circuits, combined with environmental input, may explain clinical antidepressant effects. This hypothesis could guide development of new treatments.
Biological psychiatry
February 1, 2025
Cassiano Ricardo Alves Faria Diniz, Ana Paula Crestani, Plinio Cabrera Casarotto et al.
15 citations
Antidepressants such as fluoxetine and ketamine bind to the p75 neurotrophin receptor (p75NTR) and trigger its proteolysis by α- and γ-secretase, leading to p75NTR nuclear localization. These drugs also enhance brain plasticity and extinction memory in mice and rats, and these effects depend on p75NTR signaling. The authors propose that antidepressants co-opt both the BDNF/TrkB and proBDNF/p75NTR systems to promote activity-dependent synaptic competition and brain remodeling.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
January 1, 2024
Zack Blumenfeld, Kallol Bera, Eero Castrén et al.
10 citations
Many antidepressants work by entering cells and binding to targets inside the cytoplasm or organelles, contrary to the traditional view that they act only at extracellular sites on cell surface proteins. The ability of a drug to cross membranes depends on its charge and lipid solubility, described by parameters LogP, pKa, and LogD at pH 7.4. Some antidepressants have an unusually large volume of distribution, reflecting both binding to membranes and trapping inside acidic organelles. For SSRIs and SNRIs, the exact cellular compartment where they engage their target transporters remains unknown. Rapidly acting antidepressants like ketamine and psychedelics also rely on these intracellular mechanisms, an area termed location-biased or inside-out pharmacology.
Neuroscience applied
January 1, 2024
Drummond E-Wen Mcculloch, Juan Pablo Lopez, Christina Dalla et al.
2 citations
Classical psychedelic drugs like psilocybin and LSD stimulate the serotonin 2A receptor and are being investigated for clinical effects in brain disorders. Experts at the ECNP 'New Frontiers meeting' in March 2023 identified key knowledge gaps in psychedelic mechanisms, including the need for appropriate behavioral models, dose optimization, molecular mechanisms, sex differences, and effects on neurotransmitter release and brain activity. The meeting highlighted the importance of preclinical and neuroimaging research to address these gaps.