In 2018, a team at UC Davis published a finding that shifted the scientific perception of psychedelics. Psilocybin, LSD, DMT, and their derivatives cause measurable growth of dendrites (the neuronal branches that receive signals) and synaptic spines in cortical neurons, with an amplitude comparable to that of BDNF (brain-derived neurotrophic factor, the primary neuronal growth protein) (PubMed). This was no longer about mystical trips. It was structural biology, observable under a microscope.
Since then, research has accelerated. Clinical trials are multiplying across depression, post-traumatic stress, and addiction. And the central question has evolved: can we retain the neuroplastic effect without the hallucination? In March 2026, an Italian team published a concrete answer.
The mechanism: synaptogenesis driven from within
To understand why these molecules interest aging researchers, we first need to understand how they act on neurons. And the answer is not what anyone expected.
The turning point came in 2023. A study published in Science demonstrated that serotonergic psychedelics do not act primarily through 5-HT2A receptors on the neuronal surface (the ones that trigger hallucinations), but through the same receptors located inside the cell (PubMed). Psilocybin, DMT, and LSD, due to their lipophilicity, cross the cell membrane and bind to 5-HT2A receptors on the endoplasmic reticulum. These intracellular receptors trigger a signaling cascade profoundly different from that of surface receptors.
The distinction is fundamental. Surface receptors activate pathways responsible for sensory alteration (visual hallucinations, time distortion, ego dissolution). Intracellular receptors trigger a different sequence: BDNF production, TrkB activation (the BDNF receptor), then mTOR stimulation in its role of local protein synthesis. The result: new dendrites appear, new synaptic spines form, neural circuits reconnect.
This mechanism is fast. Time-lapse microscopy studies show an increase in dendritic spine density within 24 hours of a single dose of psilocybin or DMT. And lasting: some structural effects persist for several weeks after a single administration. A study published in Cell in 2021 further showed that psychedelics bind directly to the TrkB receptor, the same receptor activated by BDNF, suggesting a direct neurotrophic effect not solely mediated through serotonin (PubMed).
Psychedelics produce measurable dendritic growth under microscopy within 24 hours of a single dose.
Ketamine's convergent pathway
Ketamine takes a different road to the same destination. It is not a serotonergic psychedelic: it is an NMDA glutamate receptor antagonist. By blocking these receptors, it causes a "glutamatergic rebound" that activates AMPA receptors, stimulates BDNF release, and triggers the same mTOR-dependent synaptogenesis cascade in the prefrontal cortex (PubMed).
The fact that two pharmacologically distinct classes (serotonergic and glutamatergic) converge on the same final pathway (BDNF → TrkB → mTOR → synaptogenesis) reinforces the idea that this pathway is a fundamental lever of brain plasticity, not an artifact specific to one molecular family.
The clinical landscape: between breakthroughs and setbacks
Ketamine: the only authorized molecule
Ketamine is the only molecule in this family with marketing authorization for a psychiatric indication. Esketamine (Spravato, the S-enantiomer of ketamine) has been FDA-approved since 2019 for treatment-resistant depression. Its antidepressant effects appear within hours, where SSRIs (selective serotonin reuptake inhibitors, the most prescribed antidepressant class) require four to six weeks. This speed of action is directly attributable to the synaptogenesis it induces in the prefrontal cortex.
The limitation: the effect fades within days to weeks, requiring repeated administration. Ketamine does not "cure" depression. It opens a plasticity window that other interventions (psychotherapy, lifestyle changes) can exploit.
Psilocybin: promising results, modest cohorts
Psilocybin has reached the phase 2 trial stage. A trial published in the New England Journal of Medicine in 2021 compared two doses of psilocybin to six weeks of escitalopram in 59 patients with moderate-to-severe depression. Both treatments produced comparable reductions in depression scores, but psilocybin showed superior improvements on secondary endpoints: well-being, emotional connectivity, social functioning (PubMed).
Two doses. Not six weeks of daily intake. This dosing asymmetry is what makes psilocybin so pharmacologically interesting: a punctual intervention that produces lasting structural changes in neural circuits.
MDMA: the regulatory setback
MDMA has had a more turbulent path. After promising phase 3 results for severe post-traumatic stress disorder (PubMed), the FDA denied approval in 2024, citing methodological shortcomings (blinding difficulties, incomplete safety data). This setback illustrates an essential point: the evidence base, while growing rapidly, remains below what conventional pharmacology demands. Media enthusiasm should not be confused with regulatory validation.
The subjective experience: side effect or therapeutic mechanism?
Preclinical data support the dissociation. But human clinical data complicate the picture.
In trials for depression and anxiety, the intensity of the psychedelic experience is one of the most robust predictors of therapeutic outcomes. The MEQ (Mystical Experience Questionnaire), developed at Johns Hopkins, measures four dimensions of the psilocybin experience. Participants who exceed a threshold score (what researchers call a "complete mystical experience") show substantially greater reductions in anxiety and depression at six months (PubMed). In treatment-resistant depression, it is specifically the mystical component of the experience (not its overall intensity) that mediates the antidepressant response (Frontiers).
A result published in Nature in 2024 adds a mechanistic dimension to this correlation. Using high-temporal-resolution EEG and fMRI, researchers showed that the degree of neural desynchronization induced by psilocybin, directly linked to the opening of the plasticity window, correlates with the intensity of the subjective experience (Nature). This is not a statistical coincidence: it is a biological link between the phenomenal experience and the neuroplastic mechanism.
This tension has fueled a formal debate. In 2021, ACS Pharmacology & Translational Science published two opposing papers: Yaden and Griffiths (Johns Hopkins) argue that the subjective effects of psychedelics are necessary for their enduring therapeutic effects; Olson (UC Davis) holds the opposite view (ACS). The disagreement remains unresolvable in current human trials: it is practically impossible to pharmacologically block the subjective experience while preserving the drug's activity in human patients.
On "bad trips", the reality is more nuanced than their reputation. Studies measuring experiences of fear, confrontation with death, or feelings of identity dissolution show that these, when navigated in a supported setting and followed by an integration phase, do not neutralize therapeutic benefits and can generate a transformative process through emotional confrontation. But the idea that any difficult experience is automatically beneficial after integration is an oversimplification: lasting adverse reactions exist, primarily in unsupported contexts. The clinical literature does not recommend deliberately inducing distress.
This debate does not undermine the relevance of non-hallucinogenic analogues, it reinforces it. If the subjective experience contributes to the therapeutic effect, it does so through a psychological mechanism (insight, emotional integration, meaning-making) that is difficult to standardize, reproduce, and ensure safety at clinical scale. A compound that achieves the same neuroplasticity through purely pharmacological means would represent a clinical advance regardless of who is right in this debate.
Two strategies to separate the trip from the effect
Whatever the outcome of this debate, two strategies aim to produce the neuroplastic effect without the hallucinogenic experience. They rely on very different pharmacological rationales.
Strategy 1: modify the molecule (structural analogues)
This is the pioneering approach from David Olson's team at UC Davis. In 2021, his laboratory synthesized tabernanthalog (TBG), a structural analogue of ibogaine. TBG produces dendritic growth comparable to classical psychedelics in mouse cortical neurons, reduces depressive and addictive-type behaviors, and triggers no head-twitch response (the standard hallucination marker in rodents) (PubMed).
The principle: modify the chemical structure to favor intracellular penetration while reducing affinity for surface 5-HT2A receptors. Several companies (Delix Therapeutics, Gilgamesh Pharmaceuticals) are now developing entire libraries of molecules based on this model.
Structural analogues (new molecule) and controlled kinetic release (same molecule, different speed): two distinct pharmacological paths to separate neuroplasticity from hallucination.
Strategy 2: slow down the release (pharmacokinetics)
An Italian team led by Sara De Martin (University of Padua) published a radically different approach in the Journal of Medicinal Chemistry in March 2026. Rather than creating a new molecule, the researchers modified the release kinetics of psilocin (the active metabolite of psilocybin, the one that actually acts in the brain) (DOI).
Their compound, designated 4e (a fluorinated N-alkyl carbamate derivative), is designed to release psilocin slowly and sustainably, instead of the sharp spike produced by classical psilocybin. In mice, the results are clear: compound 4e produces brain psilocin levels that are lower but significantly longer-lasting than standard psilocybin, and the animals exhibit significantly fewer head-twitch responses.
The underlying idea is elegant: it is not psilocin itself that is hallucinogenic, but the concentration spike. A massive, sudden influx saturates surface 5-HT2A receptors and triggers the psychedelic experience. Slow, controlled release preferentially activates intracellular receptors (those that trigger synaptogenesis) without reaching the activation threshold of surface receptors.
This pharmacokinetic approach has a major conceptual advantage: it uses the same active ingredient whose neuroplastic efficacy is already documented. No new molecule to characterize. No new safety profile to establish from scratch. Just a modulation of delivery speed.
What this means for brain aging
Brain aging is not primarily a story of neuronal death. It is a story of lost connectivity. Neurons largely remain, but their connections thin out. Synaptic density declines. BDNF production drops. The dendritic tree simplifies, particularly in the prefrontal cortex (executive function, decision-making) and hippocampus (memory, spatial navigation).
This decline is not abstract. It manifests as what neuroscientists call "cognitive rigidity": difficulty integrating new information, modifying habits, adapting to novel contexts. It is not a loss of intelligence. It is a loss of plasticity.
Any molecule capable of restarting synaptogenesis in these specific regions holds theoretical potential against this decline. Psychedelics and their non-hallucinogenic analogues target precisely this mechanism. The fact that two dissociation strategies (structural and kinetic) have demonstrated feasibility in animals strengthens the hypothesis of a future application in aging neurology.
But clarity is needed about what is still missing. No clinical trial has tested these molecules for cognitive aging. Neuroplasticity data come primarily from murine models. The question of the therapeutic window (at what stage of decline to intervene, at what frequency, for how long) is entirely open. And the aging brain does not necessarily respond to neuroplastic stimuli the same way a young brain does.
What is established: the mechanism is identified, the dissociation between psychoactive and neurotrophic effects is confirmed by two independent approaches, and the first non-hallucinogenic compounds work in animals. Human trials are the next barrier. If the data hold, this class of molecules could become a tool for brain maintenance, much as physical exercise serves the cardiovascular system.
Frequently asked questions
References
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- Vargas MV, Dunlap LE, Dong C, et al. Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science. 2023;379(6633):700-706 (PubMed).
- Casarotto PC, Girber M, Bhatt S, et al. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell. 2021;184(5):1299-1313.e19 (PubMed).
- Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354 (PubMed).
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- Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27(6):1025-1033 (PubMed).
- Cameron LP, Tombari RJ, Lu J, et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature. 2021;589(7842):474-479 (PubMed).
- De Martin S, Mattarei A, Bhatt S, et al. Reversible N-Alkyl Carbamates as Slow-Release Prodrugs of Psilocin. J Med Chem. 2026;69(3):2145 (DOI).
- Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016;30(12):1181-1197 (PubMed).
- Carhart-Harris RL, Roseman L, Bolstridge M, et al. Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression. Front Pharmacol. 2017;8:974 (Frontiers).
- Siegel JS, Subramanian S, Perry D, et al. Psilocybin desynchronizes the human brain. Nature. 2024;632(8023):131-138 (Nature).
- Yaden DB, Griffiths RR. The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS Pharmacol Transl Sci. 2021;4(2):568-572 (ACS).
