Neuroplasticity and Psychedelics: How They Rewire the Brain

What the claim is, and where it comes from

"Psychedelics rewire the brain" has become a stock phrase in coverage of psilocybin and LSD therapy. Behind it is a body of laboratory work, much of it from the past decade, showing that psychedelics make neurons grow new branches and connections. The research is real and some of it is elegant. Most of it was done in cells in dishes and in rodents, and the step to people has barely been taken.

This article walks through that evidence in order, from cells to animals to humans, and is careful about which is which. It does not cover whether psychedelic therapy works for depression: the psilocybin for depression page covers the clinical trials, and the depression trials listing shows what is recruiting.

What "neuroplasticity" can mean

Neuroplasticity is an umbrella term for the brain changing its structure or function. In this literature it usually means one of four narrower things, measured in quite different ways:

• Structural growth: more dendritic branches or more dendritic spines, the small protrusions where most excitatory synapses sit. Seen down a microscope, so almost only in cells and animals.
• Synapse number or strength: counted with labelled proteins or measured electrically in brain slices. Again mostly animal work.
• Molecular signals: levels of growth factors such as brain-derived neurotrophic factor (BDNF). Measurable in human blood, but blood levels may not reflect the brain.
• Network change: altered connectivity between brain regions on fMRI or EEG. Measurable in humans, but it says nothing directly about synapses.

When a headline says a drug "promotes neuroplasticity", it is worth asking which of these was measured, in what, and for how long.

The cell and animal evidence

Ly et al., 2018: the psychoplastogen paper

A University of California, Davis team led by David Olson treated rat cortical neurons with a range of psychedelics. DMT, psilocin, LSD, DOI and MDMA all promoted the growth of neuron branches, and the cells also gained spines and synapses. LSD and DOI increased dendritic branching in fruit fly larvae, and a single dose of DMT raised spine density in the prefrontal cortex of rats 24 hours later, to a similar extent as the same dose of ketamine. (Cell Reports, 2018) The authors coined the term psychoplastogen for compounds with this effect, and linked the growth to TrkB, mTOR and 5-HT2A signalling. (Cell Reports, 2018)

Shao et al., 2021: watching spines grow in living mice

A Yale team imaged the same dendrites in the frontal cortex of living mice over weeks. One dose of psilocybin increased spine size and density by about 10%, mostly by making new spines faster. The change appeared within 24 hours and persisted a month later, and psilocybin also eased a stress-related behaviour. (Neuron, 2021)

Critical periods

A 2023 Johns Hopkins study in mice found that psilocybin, LSD, ketamine, MDMA and ibogaine all reopened a developmental window for learning social reward, and that the window stayed open for a time proportional to how long each drug's effects last in humans. (Nature, 2023)

A first look in a larger brain

In pigs, a single dose of psilocybin raised a marker of synaptic density (SV2A) by about 9% in the hippocampus and 6% in the prefrontal cortex a week later. (International Journal of Molecular Sciences, 2021)

Ketamine as the reference point

Much of this work is framed against ketamine, the anaesthetic whose rapid antidepressant effect had already been linked to new dendritic spines in the rat prefrontal cortex. (Cell Reports, 2018) Ly and colleagues found the psychedelics they tested matched or exceeded ketamine's effect on neuron growth in culture, and that both act through the mTOR pathway. (Cell Reports, 2018) Esketamine, a form of ketamine, is FDA-approved as a nasal spray for treatment-resistant depression. (U.S. Food and Drug Administration, Drugs@FDA, 5 Mar 2019; U.S. Food and Drug Administration, Drugs@FDA, 2026) The ketamine therapy guide covers how that works in practice.

How long the window lasts

In the mouse spine study the new structure was still present a month after one dose. (Neuron, 2021) In the critical period study, the open window lasted longer for drugs with longer acute effects, and the authors argue this gives a mechanistic reason to take the period after treatment seriously. (Nature, 2023) That argument is often repeated as fact for humans; it is an extrapolation from mice.

These findings are consistent across labs and species. They are also mostly in young or stressed rodents at controlled doses, measured in specific cell types. None of that guarantees the same thing happens in an adult human taking a single dose.

The mechanism debate: 5-HT2A or TrkB?

The hallucinogenic effects of classic psychedelics run through the serotonin 5-HT2A receptor. (Pharmacological Reviews, 2016) Whether their plasticity effects do as well is disputed, and the answer matters for drug design.

• TrkB. A Helsinki group reported in 2023 that LSD and psilocin bind directly to TrkB, the receptor for BDNF, with roughly 1,000-fold higher affinity than other antidepressants. In mice, the plasticity and antidepressant-like effects depended on that binding and not on 5-HT2A, while the head-twitch response, a rodent proxy for hallucinogenic effect, needed 5-HT2A. (Nature Neuroscience, 2023)
• 5-HT2A not needed for behaviour. A Maryland study found that blocking 5-HT2A and 5-HT2C receptors with ketanserin did not stop psilocybin reversing stress-induced anhedonia in mice, or strengthening their hippocampal synapses. (Proceedings of the National Academy of Sciences, 2021)
• 5-HT2A essential. The Yale group found in 2025 that knocking out 5-HT2A receptors in the mouse frontal cortex abolished psilocybin's effects on stress-related behaviour and on spine growth. (Nature, 2025) Olson's group had earlier shown that blocking 5-HT2A stopped the growth in cultured neurons and argued that the relevant receptors sit inside the cell rather than on its surface. That could explain why serotonin itself does not trigger the same growth. (Cell Reports, 2018; Science, 2023)

These results come from different methods, brain regions and behavioural tests, so they may not be in direct conflict. What they show is that the mechanism is not settled.

Non-hallucinogenic analogues

If plasticity can be separated from the trip, a drug could be given without hours of supervision. Olson's group designed tabernanthalog, a simplified, water-soluble relative of ibogaine. In rodents it promoted structural plasticity, reduced alcohol- and heroin-seeking and had antidepressant-like effects, without the hallucinogenic or toxic profile the authors wanted to avoid. (Nature, 2021) The Helsinki TrkB findings point the same way. (Nature Neuroscience, 2023)

These are animal results. Whether a non-hallucinogenic compound helps people, and whether the subjective experience is part of how psychedelic therapy works, are open questions. A Basel trial now recruiting gives DMT under propofol anaesthesia to people with depression precisely to test whether the conscious experience is needed. (ClinicalTrials.gov, 2025)

What has been shown in humans

Very little that measures plasticity directly.

• BDNF in blood. A Maastricht study found that single low doses of LSD (5 and 20 micrograms) raised plasma BDNF hours later in healthy volunteers compared with placebo. (ACS Pharmacology & Translational Science, 2021) A 2025 meta-analysis of 29 studies of ketamine, esketamine, LSD, psilocybin, ayahuasca, DMT, MDMA and others found no evidence that these drugs raise peripheral BDNF in humans, and better-controlled studies reported smaller effects. (Molecular Psychiatry, 2025)
• Synaptic density. A Copenhagen team used PET to measure SV2A in 15 healthy people before and a week after psilocybin. There was no statistically significant overall increase; people dosed in a therapy-like room had larger increases and more intense experiences than those dosed in an MRI scanner. (Translational Psychiatry, 2026) The subgroups were small.
• Brain networks. After psilocybin therapy for depression, response correlated with greater integration between brain networks, a change escitalopram did not produce. (Nature Medicine, 2022) In 12 healthy volunteers, the number of significant resting-state connections rose at one week and one month after a high dose. (Scientific Reports, 2020) These are changes in connectivity, not counts of synapses.

So the honest summary for humans is: network changes have been seen, a molecular marker has not held up across studies, and the one direct synaptic measure so far was not significant overall.

Theories that link brain and mind

The most cited framework is REBUS, proposed by Robin Carhart-Harris and Karl Friston in 2019. It argues that psychedelics relax the weight the brain gives to high-level beliefs, letting bottom-up information revise them, and that with the right intention and care this could loosen entrenched patterns in mental illness. (Pharmacological Reviews, 2019) It is a theory that organises the findings, not a finding itself.

What this means for a person

Laboratory plasticity is a reason scientists take psychedelics seriously as medicines. It is not evidence that a retreat or a single dose will "rewire" anyone in a predictable direction. Plasticity, if it occurs in humans, is not inherently good: it is a capacity for change, and the studies above suggest context may shape what changes. (Translational Psychiatry, 2026)

That is a reason to take setting, preparation and support seriously. The integration practices article covers the weeks after an experience, and the screening checklist helps check whether a programme screens for the risks that matter, including psychosis history and medicines. Anyone on a prescribed medicine should discuss changes with their prescriber, not alter it to make a psychedelic "work better".