Serotonergic Psychedelics in Neural Plasticity

Torregrossa and colleagues situate serotonergic psychedelics within a long history of human use and shifting terminology, from early labels such as "psychotomimetics" to contemporary descriptors including "psychoplastogens," which emphasise these compounds' capacity to drive neural plasticity. The introduction summarises converging evidence that classical psychedelics—tryptamines, ergolines, and phenethylamines—promote structural and functional changes at synapses, and notes that affinity for the serotonin 2A (5-HT2A) receptor is strongly correlated with subjective hallucinogenic effects. It also highlights that many psychedelics interact with additional receptor subtypes (for example 5-HT1A, 5-HT2C and dopaminergic receptors), and that intracellular signalling pathways implicated in plasticity (notably TrkB/BDNF and mTOR) may be engaged by these drugs. The paper sets out to review the evidence that classical serotonergic psychedelics induce neuritogenesis, spinogenesis and synaptogenesis in vitro and in vivo, and to consider molecular and circuit mechanisms that could link these neuroplastic effects to therapeutic potential for psychiatric disorders. Rather than re‑reviewing psychedelic pharmacology exhaustively, Torregrossa and colleagues focus specifically on how these compounds affect neural structure and function and on open questions about mechanism, spatial specificity, and the relationship between hallucinogenic and plasticity-related effects.

The extracted text does not include a Methods section or an explicit description of search strategy, inclusion criteria, or study selection. From the content and organisation, the article appears to be a narrative review synthesising findings from cellular, animal, and some large-animal studies rather than a systematic review or meta-analysis with a reported literature search.

The review organises empirical findings by compound class and summarises cellular, synaptic, circuit-level, and some behavioural data linking psychedelics to neuroplasticity. DMT and derivatives: DMT, an active component of ayahuasca, promotes neurite outgrowth and increases dendritic spine density in cultured rat cortical neurons after 24 h exposure. A single high systemic dose (10 mg/kg) increased synaptic density on prefrontal cortical pyramidal neurons in adult rats and raised frequency and amplitude of spontaneous excitatory postsynaptic currents ex vivo. By contrast, chronic intermittent low-dose DMT (1 mg/kg) reduced prefrontal spine density in female but not male rats, indicating dose- and sex-dependent effects. Mechanistically, DMT-induced plasticity is reported to be blocked by ketanserin (a 5-HT2A antagonist), by ANA-12 (a TrkB antagonist), and by rapamycin (an mTOR inhibitor), implicating 5-HT2A, TrkB/BDNF, and mTOR signalling. DMT also agonises the sigma-1 receptor, which may modulate calcium signalling and synaptic function. The methoxylated analogue 5‑MeO‑DMT altered oscillatory activity in multiple brain regions and produced effects that in some cases persisted in 5-HT2A knockout mice but were prevented by 5-HT1A antagonism, suggesting state-dependent engagement of 5-HT1A receptors and complex receptor-state interactions. In vitro and organoid data implicate 5‑MeO‑DMT in modulation of proteins involved in long-term potentiation, spine formation and cytoskeletal dynamics. Ibogaine and analogues: Ibogaine binds multiple targets including NMDA, κ- and µ-opioid, 5-HT2A and sigma-2 receptors; it is metabolised to noribogaine, which attains higher and more persistent plasma levels and, in culture, increases dendritic arbor complexity whereas parent ibogaine did not. High doses of ibogaine (≥50 mg/kg) produce cerebellar Purkinje cell degeneration in rats, while a therapeutic dose is cited at about 40 mg/kg, highlighting a narrow safety margin. To retain prosynaptogenic properties while reducing hallucinogenicity and cardiotoxicity, researchers developed tabernanthalog (TBG), a non-hallucinogenic analog that increases dendritic complexity and spine formation in vitro and in vivo; TBG’s effects are blocked by ketanserin, implicating 5-HT2A signalling. A single TBG dose reversed anxiety-like behaviours, cognitive inflexibility and sensory-processing deficits in mice subjected to unpredictable mild stress and partially restored stress-induced spine loss and electrophysiological abnormalities in inhibitory interneurons. Psilocybin: Psilocybin is rapidly converted to psilocin, which binds several 5-HT receptors. In cultured rat cortical neurons, psilocin increased dendritic arbor complexity and spine density. A single psilocybin dose in mice increased formation of dendritic spines on layer 5 pyramidal neurons in medial frontal cortex; the new spines were reported to be as stable as control spines, and spine head size was increased, consistent with synaptic strengthening. In pigs, a single dose produced persistent increases in presynaptic SV2A density in hippocampus and prefrontal cortex, and other mouse data indicate an increased AMPA/NMDA ratio at specific hippocampal synapses, signifying enhanced synaptic strength. LSD: Recent cellular work shows that 24 h LSD exposure increases dendritic arbor complexity, spine density and synaptic marker co-localisation (VGLUT1/PSD95) in cultured cortical neurons; brief exposures of 15 min–6 h were later shown to be sufficient to elicit similar morphological effects. At the circuit level, in vivo electrophysiology indicates LSD modulates firing patterns of reticular thalamic GABAergic neurons and disinhibits thalamocortical relay neurons in the mediodorsal thalamus. LSD’s neuroplastic effects are reported to be ketanserin-sensitive, indicating 5-HT2A involvement despite LSD’s broader receptor binding profile. DOI (a phenethylamine): Transient (1 h) DOI exposure enlarges dendritic spine size in cultured neurons, while longer treatments enhance neurite complexity and growth-cone dynamics. In mouse frontal cortex DOI increases density of stubby and thin spines on layer 2/3 pyramidal neurons and enhances long-term potentiation at corresponding synapses. DOI reduces low-frequency cortical oscillations and alters the timing relationship between pyramidal firing and local field potentials; these effects are blocked by a 5-HT2A antagonist. DOI-induced spinogenesis and synaptogenesis require TrkB, 5-HT2A and mTOR signalling, and depend on kalirin-7, a spine morphogenesis regulator. A single DOI dose can induce epigenetic changes at enhancer regions that persist for at least a week, suggesting a substrate for lasting effects. Ketamine (comparative): Although not serotonergic, ketamine also drives rapid synaptogenesis and spinogenesis; cultured neurons show increased spine and synapse formation within 15 min of exposure. In vivo, ketamine increases spine density in medial prefrontal cortex and hippocampus, partially restores stress- or corticosterone-induced spine loss, and enhances spine formation observed by in vivo imaging. Functional plasticity resembling homeostatic upscaling has also been reported. Importantly, ketamine’s prosynaptogenic and behavioural antidepressant effects engage BDNF/TrkB and mTOR signalling, indicating convergence with some molecular pathways implicated in serotonergic psychedelic-induced plasticity.

Torregrossa and colleagues interpret the convergent evidence as supporting a model in which multiple psychedelics—DMT, LSD, DOI and others—as well as ketamine, can reconfigure neuronal networks by promoting dendritic branching and formation of new dendritic spines, thereby adding synaptic connections that may persist or be pruned in activity-dependent ways. They propose that such structural remodelling could underlie the persistence of symptomatic improvements reported in clinical studies of psychedelics for conditions such as addiction, depression, anxiety, obsessive-compulsive disorder and post-traumatic stress disorder. The authors emphasise that 5-HT2A receptor signalling is widely implicated in both hallucinogenic and neuroplastic effects, but they note that it is unlikely to be the sole pathway. They discuss evidence that 5-HT1A, 5-HT2C, dopaminergic receptors and sigma receptors can contribute, and highlight intracellular convergence on TrkB/BDNF and mTOR pathways as a common molecular substrate linking psychedelics and ketamine to prosynaptogenic outcomes. Torregrossa and colleagues also draw attention to findings that complicate simplistic mappings between receptor occupancy and therapeutic or plasticity outcomes—for example, studies where 5-HT2A antagonism did not abolish behavioural effects or where receptor density changes do not parallel synaptogenesis. Key limitations and open questions are underscored. The authors indicate that it remains unclear whether induced spine dynamics are localised to particular dendritic domains or inputs, whether new synapses are functionally stronger and how different psychedelics differ in spatiotemporal patterns of plasticity across cell types. Safety concerns are noted for certain compounds (for example ibogaine’s narrow therapeutic-to-neurotoxic window), and the review highlights the need to dissociate hallucinogenic effects from plasticity when developing therapeutics, as exemplified by non-hallucinogenic analogues such as tabernanthalog. They call for multidisciplinary research—combining chemistry, molecular and cellular neuroscience, synaptic physiology and clinical studies—to resolve mechanistic questions and to determine how hallucinogenic and neuroplastic actions interact to produce therapeutic benefit.