Over the last few years, the psychedelic medicine field undergone a rebrand. The term gaining traction across the industry and in funding circles is neuroplastogen. The premise is that the therapeutic value of psychedelics resides in their ability to promote neural plasticity, and the subjective psychedelic experience is an artifact that can be engineered away. Early clinical and preclinical data provide some support to this narrative.
Nonetheless, whether the psychedelic experience is necessary for therapeutic benefit remains an active debate in the field. I spent years researching experience-dependent myelination and brain plasticity at the bench, and from that vantage the mechanistic case for how experience interacts with pharmacological plasticity remains underdeveloped. Developing it could change how neuroplastogens are deployed clinically.
Pharmacology and two pathways to plasticity
Classical psychedelics (psilocybin, LSD, DMT) promote structural neuroplasticity (Ly et al., 2018) through a signaling cascade that begins at the serotonin 5-HT2A receptor. Where and how they engage that receptor turns out to be critical.
Intracellular 5-HT2A. Vargas et al., in David Olson’s lab at UC Davis, showed that psychedelics access intracellular pools of 5-HT2A receptors on the Golgi apparatus inside cortical neurons (Vargas et al., 2023). Because psychedelics are lipophilic, they passively diffuse across cell membranes; serotonin cannot. This difference in access, “location bias,” helps explain why endogenous serotonin doesn’t produce psychedelic effects despite activating the same receptor class. The slightly acidic Golgi compartments may even trap psychedelics, establishing sustained intracellular signaling that serotonin never achieves. Downstream, the cascade activates TrkB (the BDNF receptor), mTOR, and AMPA receptors: the canonical plasticity pathway (Vargas et al., 2023).
TrkB direct-binding. In 2023, Castrén’s group in Helsinki showed that LSD and psilocin bind directly to TrkB with affinities roughly 1,000-fold higher than conventional antidepressants like fluoxetine. The neuroplasticity and antidepressant-like effects depended on TrkB binding and BDNF signaling but were independent of 5-HT2A activation. Meanwhile the head-twitch response in mice (the behavioral proxy for hallucinogenic effects) depended on 5-HT2A and was independent of TrkB (Moliner et al., 2023).
That the plasticity pathway and the hallucinogenic pathway are dissociable at the molecular level is both surprising and clinically fortuitous. It is the scientific foundation on which the neuroplastogen industry rests.
Plasticity without the trip
Tabernanthalog (TBG), a non-hallucinogenic neuroplastogen from Olson’s lab, is the clearest proof of concept. A 2025 Nature Neuroscience paper showed that TBG promotes cortical neuroplasticity through the same biochemical pathway as classic psychedelics (5-HT2A → TrkB → mTOR → AMPA), but as a partial agonist, activating the receptor just enough for plasticity without crossing the hallucinogenic threshold (Aarrestad et al., 2025). TBG also doesn’t induce the glutamate burst or immediate early gene activation, processes that appear tied to the hallucinogenic properties rather than the plasticity-promoting effects (Aarrestad et al., 2025).
Clinical development is moving fast. At least one non-hallucinogenic neuroplastogen has shown rapid, durable antidepressant effects in a Phase 1b trial for MDD, roughly 50% symptom improvement by day 8, sustained over a month after the last dose (BusinessWire, 2025). In preclinical comparisons, these compounds have produced dendritic spine growth and functional plasticity comparable to or exceeding ketamine, psilocybin, and DMT (BusinessWire, 2025; ACS Chemical Neuroscience, 2025).
A take-home neuroplastogen pill could bypass the 6-8 hour supervised sessions and regulatory complexity that make psychedelic-assisted therapy hard to scale. For patient access, that would be a genuine advance.
What about experience?
An assumption that is easily buried in the “plasticity over experience” framing is that enhanced plasticity is itself therapeutic. But enhanced neuroplasticity may simply mean enhanced susceptibility to whatever is happening during the period of elevated plasticity. Neurons that fire together wire together, but which neurons? That is determined by experience, even mundane experience.
I’ve thought about this for a long time, because my research concerned the role of experience in brain development and the damage done by social isolation and sensory deprivation, work that builds on what we understand about critical periods. The core insight: plasticity without the right experiential input is underdetermined. An open critical period isn’t intrinsically therapeutic. It’s closer to a vulnerability window that requires the proper environment to guide development.
Context, then, is clinically important. Give someone a plasticity-enhancing drug and let them go about their day, commuting, scrolling, ruminating, and what determines which circuits get reinforced? Quite possibly the default mode network, shaped by existing habits and environment. Without deliberate experiential input during the plastic window, the therapeutic potential may go underutilized, reinforcing existing patterns rather than establishing new ones.
The psychedelic experience might function as a pattern-interrupt, destabilizing existing network configurations before or as the plastic window opens. If so, the relevant mechanism isn’t the subjective content of the experience but the network-level disruption it produces, and the real question becomes whether neuroplastogens achieve comparable disruption through pharmacology alone.
Notably, the Castrén group acknowledged in their TrkB paper that psychedelic-induced plasticity at the network and behavioral level depends on environmental input, and that the therapeutic potential may lie in combining plasticity with environmental support rather than plasticity alone (Moliner et al., 2023).
Psychiatry has long organized itself around two philosophically divergent camps: pharmacological treatment, where the patient is largely a passive recipient of biochemistry, and psychotherapy, where change comes through active experiential engagement. Psychedelic-assisted therapy was interesting precisely because it loosened this distinction, the drug opens a window and the therapeutic process fills it. Neuroplastogens have an opportunity to bridge these camps rather than collapse back into the purely pharmacological one, but only if clinical protocols are designed to leverage the plastic window with intentional experiential input.
What I’m curious about
Glial effects. The neuroplastogen literature focuses almost entirely on neuronal plasticity. But 5-HT2A receptors are expressed on astrocytes and microglia, and glial responses to experience are mechanistically distinct from neuronal ones. Whether neuroplastogens drive meaningful glial plasticity matters for sustained therapeutic benefit.
Condition-specificity. Neuroplastogens may work well for acute depression with identifiable circuit-level deficits, where structural plasticity could restore hypoconnectivity regardless of experiential content. For complex PTSD and addiction, where progress means dismantling entrenched learned associations, it’s worth investigating whether experiential disruption during the plastic window adds clinical benefit beyond structural plasticity alone.
Whether the psychedelic experience is therapeutically necessary is not a new question. But the field has debated it largely at the level of phenomenology and clinical correlation. What’s needed is a framework grounded in what we already know about critical periods and experience-dependent plasticity, one that could help design clinical protocols to maximize the therapeutic value of these plastic windows, whether or not the psychedelic experience is part of them.
Disclaimer
The views expressed here are my own and don’t represent any employer.
References
[1] Vargas et al., Science, 2023. “Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors.” https://doi.org/10.1126/science.adf0435
[2] Moliner et al., Nature Neuroscience, 2023. “Psychedelics promote plasticity by directly binding to BDNF receptor TrkB.” https://doi.org/10.1038/s41593-023-01316-5
[3] Aarrestad et al., Nature Neuroscience, 2025. “The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation.” https://doi.org/10.1038/s41593-025-02021-1
[4] Ly et al., Cell Reports, 2018. “Psychedelics Promote Structural and Functional Neural Plasticity.” https://doi.org/10.1016/j.celrep.2018.05.022
[5] Phase 1b clinical results for a non-hallucinogenic neuroplastogen in MDD, October 2025. https://www.businesswire.com/news/home/20251028780846/en/
[6] Preclinical characterization of a non-hallucinogenic neuroplastogen, ACS Chemical Neuroscience, October 2025. https://www.businesswire.com/news/home/20251016580429/en/