Journal of Psychopharmacology
August 1, 2022
Javier Hidalgo Jiménez, José Carlos Bouso
34 citations
DMT, a potent psychedelic naturally produced by many plants and animals including humans, may play significant roles in mammalian physiology. This review integrates historical and recent evidence to address ongoing debates about DMT's relevance. Arguments dismissing endogenous DMT are often based on obsolete data or misleading assumptions. Evidence strongly suggests DMT functions as a neurotransmitter, neuromodulator, hormone, and immunomodulator, and is important in pregnancy and development. Key experiments are proposed to definitively determine DMT's specific physiological roles.
Brain Network and Modulation
July 1, 2023
Javier Hidalgo Jiménez
2 citations
DMT is a naturally occurring psychedelic with potent subjective effects and preliminary evidence for antidepressive, anxiolytic, and antiaddictive properties. Its effects arise from neuromodulation of glutamatergic, monoaminergic, and cholinergic systems, causing acute shifts in brain networks including visual, auditive, and default-mode networks. Top-down cognitive processing becomes restricted while bottom-up processing is enhanced. DMT also induces neuroplasticity via sigma 1 receptor, BDNF, TrkB, and 5-HT2A, which may underlie therapeutic benefits. This review updates the neuromodulatory mechanisms of DMT, covering molecular targets, changes in cortical function and structure, neuroplasticity, and therapeutic relevance and risks.
Neuroscience and Biobehavioral Reviews
June 1, 2026
Javier Hidalgo Jiménez, Karl Kristjan Kaup, Jaan Aru
1 citation
Psychedelics such as LSD and NBOH produce complex, heterogeneous effects on brain cells, challenging the idea that they simply increase cortical excitability. A systematic review of 23 in vitro and 26 in vivo electrophysiological studies found that these compounds modulate both excitatory and inhibitory processes in a cell-type- and compartment-specific manner, with biphasic, dose-dependent, and context-sensitive responses. Activation of 5-HT2A receptors triggers intricate calcium signaling, downregulating excitatory currents and firing rates in many neurons while enhancing glutamate release and activating a subset of projection fibers. Modulation of presynaptic and extrasynaptic GluN2B-containing NMDA receptors appears central to these effects.
bioRxiv (Cold Spring Harbor Laboratory)
March 23, 2026
Marco Taddei-Tardón, Lidia Medina-Rodríguez, Jessica L Maltman et al.
Serotonergic psychedelics, including tryptamines, phenethylamines, and ergolines, promote structural and transcriptional changes in neurons through an integrated signaling network involving the 5-HT2A receptor and TrkB. Using a neural stem cell-derived model, the study shows that TrkB silencing blocks dendritogenesis induced by psychedelics, ketamine, and TrkB agonists, while 5-HT2A silencing selectively impairs psychedelic-induced plasticity. Most compounds increase synaptogenesis and immediate-early gene expression, though psilocin and the phenethylamines DOI and Ariadne show ligand-specific differences. Lactate production, dependent on 5-HT2A and both Gq/11 and Gi/o protein signaling, also occurs. These results establish a platform for dissecting psychedelic action.
Molecular Psychiatry
July 16, 2026
Marco Taddei-Tardón, Lidia Medina-Rodríguez, Jessica L Maltman et al.
Serotonergic psychedelics recruit an integrated 5-HT2A-TrkB signaling network that drives neuroplastic changes. Using a neural stem cell-derived in vitro model, a panel of tryptamines, phenethylamines, and ergolines was tested alongside ketamine and TrkB agonists. TrkB silencing abolished dendritogenic responses to all tested compounds, while 5-HT2A receptor silencing selectively impaired psychedelic-induced plasticity. Most compounds increased synaptogenesis and induced c-Fos and Egr-2 expression, with ligand-specific differences for psilocin, DOI, and Ariadne. Gq/11 or Gi/o protein coupling differentially modified neuroplastic and transcriptional responses. Psychedelics also induced a 5-HT2A receptor-dependent lactate response sensitive to disruption of either Gq/11 or Gi/o coupling.