"Psychedelics cause neuroplasticity" gets thrown around regularly. But do we really know how they cause such plasticity? Underneath this global phenomenon lie at least three separate, still weakly connected models.
The first model is DMN disruption. After psilocybin intake, the prefrontal cortex decouples from the posterior cingulate cortex (a region thought to be the center of the Self) during a glutamate surge triggered by 5-HT2A receptor activation (Carhart-Harris et al., 2012, 2016). That cortical desynchronization is the signature everyone sees on the scan, and it is also what produces ego dissolution. For a long time, this was treated as the main cause of the plasticity mechanism itself. Still, this disruption resolves within hours, while the clinical benefit lasts for weeks, so disruption alone cannot be the whole story of plasticity. What seems to matter is what happens next: the acute disruption opens a high-plasticity window in which the brain rewires itself based on neural activity occurring during the psychedelic state, and that new configuration is what persists (Barrett et al., 2020; Daws et al., 2022). So it is not the DMN desynchronizing that drives lasting change, but rather the resynchronization afterward, the brain reorganizing into a new architecture once it comes back online.
The second model operates purely at the cellular level, with no network topology involved, and has been observed in rodents and cultured neurons, not yet in humans. 5-HT2A receptor activation indirectly triggers TrkB receptors, and that drives new dendritic spines and structural plasticity at the level of the neuron itself (Vargas et al., 2023). There is also a competing route to the same outcome: psychedelics can bind directly and allosterically to TrkB, producing the same spinogenesis and arbor complexity even when 5-HT2A receptors are blocked (Moliner et al., 2023). Two different molecular paths, same physical result, new spines growing on the dendrites of cortical neurons within about 24 hours.
The third model could bridge the first two, and it is the one that ties the acute network event to the lasting structural one. Under normal conditions, different brain regions are segregated and specialized, without much cross-talk. Under psilocybin, those normally isolated regions start communicating with each other, creating unexpected connections and installing new routes of communication throughout the brain (Roseman et al., 2014; Petri et al., 2014). That cross-network integration is itself a form of plasticity, distinct from DMN disruption and distinct from the cellular TrkB story. In a treatment-resistant depression cohort, it is this decrease in modularity, not DMN suppression on its own, that correlates with symptom improvement (Daws et al., 2022).
“When a paper or a pitch deck invokes ‘neuroplasticity’ to explain durable benefit, ask which of the three models it actually measured.”
There is already a rodent test of whether the trip itself is even necessary for the cellular story. Tabernanthalog (TBG) is a non-hallucinogenic iboga analog, developed specifically to keep the plasticity-promoting chemistry of psychedelics while dropping the subjective trip. In rodents, TBG grows the same new cortical spines that the hallucinogenic compound 5-MeO-DMT does, through the same 5-HT2A, TrkB, mTOR, and AMPA pathway, but without the glutamate burst and immediate early gene activation that normally accompany the psychedelic state (Aarrestad et al., 2025). Erase those new spines afterward and the antidepressant-like effect disappears, the first time that spine growth has been shown to be necessary for a serotonergic compound's effect rather than ketamine's. So in rodents, you can get the spine growth without the trip. What that doesn't tell us is whether you can also get it without the network-level changes seen on human fMRI (DMN disruption and reduced modularity), since nobody has scanned TBG or a similar compound in humans.
When a paper or a pitch deck invokes "neuroplasticity" to explain durable benefit, ask which of the three it actually measured. Only one, reduced modularity, has ever been shown to track who gets better, in Daws's depressed cohort (Daws et al., 2022). What's still untested is whether the network-level story (DMN disruption and reduced modularity) causes the TrkB-driven spine growth, or whether the two just happen together after a dose without one driving the other. Nobody has shown that spine growth happens in humans at all, either.
That gap is partly closable, and there is a study underway to close part of it. SYNVEST (NCT06512220) is measuring synaptic density directly, via SV2A-PET, in treatment-resistant depression patients before and after psilocybin, alongside clinical outcome. If synaptic density change tracks who responds, that is the first direct human evidence that spine-level plasticity matters clinically, not just in rodents. What it won't tell us is whether that spine-level change is connected to the modularity story at all, since SYNVEST isn't collecting the fMRI data that would show that. Lyons et al. (2026) is the closest thing to that link so far, and it used white matter diffusivity, not spines, in healthy volunteers, not patients. The two halves of the question, does spine growth predict outcome, and is spine growth the same phenomenon as reduced modularity, are still being tested by different studies, in different populations, with different tools.
References
- Carhart-Harris, R.L. et al. (2016). Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences, 113(17), 4853–4858.
- Roseman, L., Leech, R., Feilding, A., Nutt, D.J., & Carhart-Harris, R.L. (2014). The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers. Frontiers in Human Neuroscience, 8, 204.
- Petri, G., Expert, P., Turkheimer, F., Carhart-Harris, R.L., Nutt, D.J., Hellyer, P.J., & Vaccarino, F. (2014). Homological scaffolds of brain functional networks. Journal of the Royal Society Interface, 11(101), 20140873.
- Barrett, F.S., Doss, M.K., Sepeda, N.D., Pekar, J.J., & Griffiths, R.R. (2020). Emotions and brain function are altered up to one month after a single high dose of psilocybin. Scientific Reports, 10, 2214.
- Daws, R.E., Timmermann, C., Giribaldi, B., Sexton, J.D., Wall, M.B., Erritzoe, D., Roseman, L., Nutt, D., & Carhart-Harris, R. (2022). Increased global integration in the brain after psilocybin therapy for depression. Nature Medicine, 28, 844–851.
- Vargas, M.V. et al. (2023). Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science, 379(6633), 700–706.
- Moliner, R. et al. (2023). Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nature Neuroscience, 26(6), 1032–1041.
- Lyons, N. et al. (2026). Human brain changes after first psilocybin use. Nature Communications, 17, 3977.
- Schartner, M.M., Carhart-Harris, R.L., Barrett, A.B., Seth, A.K., & Muthukumaraswamy, S.D. (2017). Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin. Scientific Reports, 7, 46421.
- Aarrestad, I.K., Cameron, L.P., Fenton, E.M. et al. (2025). The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation. Nature Neuroscience, 28(9), 1919–1931.