G protein-coupled receptors (GPCRs) represent key drug targets, with approximately 30%-40% of all medications acting on these receptors. Recent advancements have uncovered the complexity of GPCR signaling, including biased signaling, which allows selective activation of specific intracellular pathways-primarily mediated by G proteins and β-arrestins. Among aminergic GPCRs, the serotonin 5-HT_2A receptor has garnered attention for its potential to generate therapeutic effects without adverse outcomes, such as hallucinations, through biased agonism. This review delivers a comprehensive overview of 5-HT_2A receptor-biased signaling and its significance in developing safer mental health therapeutics, particularly for depression and anxiety. We provide a critical evaluation of methodologies for assessing biased signaling, spanning from traditional radioligand binding assays to advanced biosensor technologies. Furthermore, we review structural studies and computational modeling that have identified key receptor residues modulating biased signaling. We also highlight novel biased ligands with selective pathway activation, presenting a promising avenue for developing targeted antidepressant therapies without psychedelic effects. Additionally, we explore the 5-HT_2A receptor's role in memory processes and stress response regulation. Ultimately, advancing our understanding of 5-HT_2A receptor-biased signaling could drive the development of next-generation GPCR-targeted therapies, maximizing therapeutic efficacy while minimizing side effects in psychiatric treatment.

Neurons are believed to be non-proliferating cells. However, neuronal stem cells are still present in certain areas of the adult brain, although their proliferation diminishes with age. Just as with other cells, their proliferation and differentiation are modulated by various mechanisms. These mechanisms are foundational to the strategies developed to induce neuronal proliferation and differentiation, with potential therapeutic applications for neurodegenerative diseases. The most common among these diseases are Parkinson's disease and Alzheimer's disease, associated with the formation of β-amyloid (Aβ) aggregates which cause a reduction in the number of neurons. Compounds such as LiCl, 4-aminothiazoles, Pregnenolone, ACEA, harmine, D2AAK1, methyl 3,4-dihydroxybenzoate, and shikonin may induce neuronal proliferation/differentiation through the activation of pathways: MAPK ERK, PI3K/AKT, NFκB, Wnt, BDNF, and NPAS3. Moreover, combinations of these compounds can potentially transform somatic cells into neurons. This transformation process involves the activation of neuron-specific transcription factors such as NEUROD1, NGN2, ASCL1, and SOX2, which subsequently leads to the transcription of downstream genes, culminating in the transformation of somatic cells into neurons. Neurodegenerative diseases are not the only conditions where inducing neuronal proliferation could be beneficial. Consequently, the impact of pro-proliferative compounds on neurons has also been researched in mouse models of Alzheimer's disease.