Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity

Stress-related neuropsychiatric disorders such as depression, post-traumatic stress disorder (PTSD), and substance use disorder (SUD) are associated with atrophy and dysfunction of neurons in the prefrontal cortex (PFC). Olson outlines that classic serotonergic psychedelics and a broader class of compounds he terms psychoplastogens can produce rapid and sustained behavioural improvements after only one or a few doses, in contrast to traditional daily-administered neurotherapeutics. One mechanistic hypothesis proposed to explain these durable effects is that psychedelics catalyse structural and functional neuroplasticity in the PFC, restoring synaptic connectivity and thereby repairing pathological circuits that control mood, fear and reward. This perspective sets out to review current biochemical knowledge of how psychedelics and related psychoplastogens promote neuronal growth. Olson summarises preclinical and some clinical evidence that various psychoplastogens (including LSD, psilocin, DMT, DOI, MDMA, ibogaine, ketamine and nonhallucinogenic analogues such as tabernanthalog) induce neuritogenesis, spinogenesis and synaptogenesis, and then focuses on the signalling pathways and unresolved questions linking receptor activation to long-lasting changes in cortical structure and function. The aim is to identify molecular targets and experimental gaps that must be addressed to design improved, potentially nonhallucinogenic, neuroplasticity-promoting therapeutics.

Olson synthesises a body of in vitro and in vivo studies showing that diverse psychoplastogens promote rapid and, in many cases, long-lasting increases in cortical neuronal structure and function. Early work with the phenethylamine DOI demonstrated transient increases in dendritic spine size and, with longer treatments, increased spine density in cultured cortical neurons. Subsequent studies extended these findings across chemical classes: tryptamines (for example DMT and psilocybin), ergolines (LSD), dissociatives (ketamine) and nonhallucinogenic analogues (tabernanthalog, TBG) all produce neuritogenesis, spinogenesis and synaptogenesis in rodent cortical cultures, and single in vivo doses can increase PFC spine density and excitatory synaptic activity measured long after drug clearance. Two-photon imaging experiments show increased spine formation rates after single doses of both hallucinogenic and nonhallucinogenic psychoplastogens, and some compounds (for example TBG) can rescue stress-induced spine loss and normalise cortical activity. Cross-species effects, including reports in Drosophila, are noted but species differences in receptor sequences and trafficking complicate translation. Mechanistically, Olson emphasises that psychoplastogens appear to converge on a core set of downstream effectors required for structural plasticity: AMPA receptors, TrkB (the receptor for brain-derived neurotrophic factor, BDNF) and mTOR, the latter being a key kinase that drives production of plasticity-related proteins. The prevailing model is that psychoplastogens provoke a cortical glutamate ‘‘burst’’, activating AMPA receptors, triggering BDNF secretion, engaging TrkB and activating mTOR; positive feedback between BDNF and glutamate may sustain the pathway. However, the author stresses substantial uncertainty about whether a large glutamate surge is essential. Alternative explanations developed for ketamine’s effects include homeostatic synaptic upscaling and selective blockade of NMDA receptors on GABAergic interneurons to disinhibit pyramidal neurons; these mechanisms do not require a single large glutamate pulse. For ketamine and scopolamine, causal roles for BDNF have been demonstrated using inducible BDNF knockouts and the Val66Met BDNF polymorphism, whereas comparable causal genetic manipulations have not yet been reported for serotonergic psychedelics, although psychedelics do increase cortical BDNF expression and immediate early genes linked to plasticity. At the receptor and proximal signalling level, Olson focuses on the 5-HT2A receptor as the primary mediator of classical serotonergic psychedelic effects and many psychoplastogenic actions. Evidence reviewed includes correlations between 5-HT2 receptor affinity and human hallucinogenic potency, blockade of hallucinations by 5-HT2 antagonists such as ketanserin, and genetic knockout studies in mice where loss of 5-HT2A abolishes the head-twitch response (HTR) and prevents DOI-induced increases in spine density. Pharmacokinetic limitations of antagonists (for example poor brain penetration of ketanserin) are discussed as a caveat to some in vivo pharmacology. Olson also notes that serotonin itself does not reproduce the structural plasticity seen with psychedelics, and that species-specific receptor sequence differences can affect ligand binding and receptor trafficking. The author then describes the complexity and context dependence of 5-HT2A receptor signalling. Canonically, 5-HT2A couples to Gq to activate phospholipase C (PLC), IP3 production and intracellular calcium increases; many psychedelics act as partial agonists at this axis. Other pathways may be engaged, including phospholipase A2 (PLA2) activation (potentially involving Gi/o, Gβγ and G12/13), ERK, JAK2 and GSK3β, plus β-arrestin-dependent effects. Importantly, different ligands show functional selectivity or biased agonism, and the same receptor can form heteromeric complexes with metabotropic glutamate, dopamine, cannabinoid and other serotonin receptors. Olson discusses the debated 5-HT2A–mGlu2 heterodimer as a possible mediator of presynaptic glutamate release and subsequent BDNF upregulation, but concludes that its role in psychoplastogenic effects is unresolved, especially because some nonhallucinogenic psychoplastogens do not appear to activate this heterodimer. To disentangle hallucinogenic from psychoplastogenic actions, Olson highlights two experimental advances. First, molecular sensors of 5-HT2A conformation have been engineered: an intracellularly fused circularly permuted GFP variant dubbed psychLight whose fluorescence change in HEK293T cells correlates with human hallucinogenic potency. Notably, psychLight distinguishes hallucinogenic from nonhallucinogenic PLC-activating ligands but does not currently predict psychoplastogenicity. Second, phosphoproteomic and transcriptomic profiling efforts show that different 5-HT2A ligands produce distinct phosphoproteomic and gene expression signatures, suggesting that multi-omic fingerprints might ultimately separate hallucinogenic and neuroplasticity-promoting compounds; Olson cautions that many more ligands across diverse scaffolds need to be characterised before firm signatures can be defined. Finally, he summarises medicinal chemistry and phenotypic screening efforts to generate nonhallucinogenic psychoplastogens such as TBG, which in preclinical models repairs stress-damaged circuitry and produces enduring behavioural effects after a single dose.

Olson concludes that 5-HT2A receptor signalling underlying psychedelic-induced neuroplasticity is highly complex and depends both on the ligand and the cellular milieu. To determine which downstream pathways are necessary for psychoplastogenic effects, the author calls for systematic use of pharmacological and genetic perturbations in neurons, together with high-throughput phenotypic assays that can quantify neuroplasticity. Key remaining questions include whether 5-HT2 receptor localisation confers cell-type specificity to psychoplastogenic actions and whether psychedelics stimulate growth in non-neuronal cells expressing these receptors. Resolving these uncertainties is presented as essential for rational design of improved neuroplasticity-promoting therapeutics, including nonhallucinogenic analogues.