Neuroplasticity and BDNF: why psychedelics are called psychoplastogens
What are psychoplastogens, how psychedelics bind to the TrkB receptor, and what this changes in the understanding of depression. A review of studies from Nature Neuroscience and Science.
For decades, psychiatry has described depression mainly as a neurotransmitter imbalance disorder. Data from the last several years have shifted the focus elsewhere: towards the connections between neurons and the protein that maintains those connections. When it became clear in 2023 that psychedelics bind directly to the receptor of this protein, the term psychoplastogens emerged. This article explains what these studies have shown, where their scope ends, and why the popular description of psychoplastogens as a completely new class of substances is less accurate than it seems. You will not find any dosage sizes or practical tips here: the substances described are used exclusively in clinical settings and under medical supervision, and the decision to treat depression lies with the specialist. All numbers come from specific studies and describe their participants, not the reader.
KEY INFORMATION
• LSD and psilocybin bind directly to the TrkB receptor, with an affinity a thousand times higher than other antidepressants (Moliner et al., Nature Neuroscience, 2023).
• The effects of psychedelics on neurotrophic signaling and behavior in mice depended on binding to TrkB, not on the 5-HT2A receptor.
• Depression is associated with a reduction in the volume of the prefrontal cortex and hippocampus and with a loss of synapses in these areas (Duman and Aghajanian, Science, 2012).
• Esketamine is the first FDA-approved antidepressant of a new class (Kim et al., New England Journal of Medicine, 2019).
What is neuroplasticity and what connects it to depression?
Neuroplasticity is the ability of the nervous system to change its structure and functioning in response to experience. In the context of depression, it primarily concerns its structural dimension, meaning the number and durability of synaptic connections, rather than the concentration of transmitters in the synaptic cleft.
Basic and clinical research shows that depression is associated with a reduction in the volume of brain areas regulating mood and cognitive processes, including the prefrontal cortex and hippocampus, as well as with a loss of synaptic connections in these areas. Antidepressants can block or reverse these losses, although typical preparations have limited effectiveness, and the response may take weeks or months.
From these observations, the synaptogenic hypothesis has emerged: depression is described not only as a transmission disorder but also as a disease of lost connections, with the goal of treatment being their restoration. The authors of this proposal emphasize the importance of homeostatic control over connections in circuits responsible for mood. This shift in focus explains why researchers began to look for substances that act on the structure of synapses rather than solely on the availability of neurotransmitters. The practical consequences of this shift are discussed more broadly in the text about the 5-HT2A receptor and the activation of brain plasticity.
What is BDNF and why does the brain need it?
BDNF, or brain-derived neurotrophic factor, is a protein first isolated in 1982. Since then, extensive data has been gathered indicating its role in brain development, physiology, and pathology, and independently of these functions, it is considered essential for the molecular mechanisms of synaptic plasticity.
The way it works is more important than the name itself. Activity-dependent changes in the central nervous system occur, as is assumed, because BDNF modifies synaptic transmission, particularly in the hippocampus and neocortex. These are precisely the areas affected by the aforementioned loss of synapses in depression, and this is where the connection between the two threads arises.
However, this relationship is not straightforward, and it is worth noting before BDNF becomes a marketing slogan. Pathological levels of BDNF-dependent plasticity are associated with epilepsy and the persistence of chronic pain, so more does not always mean better. At the same time, the trophic properties of this protein are a starting point for seeking therapies in neurodegenerative diseases and neuropsychiatric disorders (Binder and Scharfman, Growth Factors, 2004). The protein acts through the TrkB receptor, which is the hero of the next section.
What did the study on the direct binding of psychedelics to TrkB show?
A study published in 2023 in Nature Neuroscience showed that lysergic acid diethylamide and psilocybin, the active metabolite of psilocybin, bind directly to TrkB, the receptor for BDNF. The affinity turned out to be a thousand times higher than the affinity of other antidepressants, and the binding site lies in the transmembrane domain of the receptor dimers.
The authors also showed that the binding sites of psychedelics and classical antidepressants are distinct, although they partially overlap. However, the strongest conclusion concerns the causal relationship. The impact of psychedelics on neurotrophic signaling, plasticity, and behavior resembling antidepressant action in mice depended on binding to TrkB and on the enhancement of endogenous BDNF signaling, rather than on the activation of the serotonin receptor 5-HT2A.
The separation of these two pathways has a consequence that the authors state directly. The head-shaking induced by LSD in mice, which is a behavioral equivalent of psychedelic action, depended on 5-HT2A and did not depend on binding to TrkB. Since the therapeutic effect and the psychedelic effect run along separate paths, it may be possible to separate them in the molecule as well. The authors suggest that positive allosteric modulators of TrkB with high affinity and devoid of activity towards 5-HT2A could retain the antidepressant potential of psychedelics without the hallucinogenic effect.
Are psychoplastogens really a separate class of substances?
The popular description states that psychoplastogens act completely differently than traditional antidepressants. However, the same study from 2023 undermines the sharpness of this division, and that in the introductory sentence. The authors remind of their own earlier report, according to which pharmacologically diverse antidepressants, including fluoxetine and ketamine, act precisely through binding to TrkB.
If so, then psychedelics have not discovered a new mechanism but hit the same target much more accurately. The difference is not a separate class of action, but affinity, and that by three orders of magnitude. This is a more modest thesis than the revolution proclaimed in popular texts, but it better corresponds to the data and explains why the authors call TrkB the common primary target of antidepressants.
Additionally, there is a difference in speed. Ketamine, an NMDA receptor antagonist, induces a rapid antidepressant response within hours in individuals for whom typical medications have failed, and in basic research, it quickly induces synaptogenesis and reverses synaptic deficits caused by chronic stress. Typical medications require weeks or months. The development of this thread can be found in a separate text about ketamine and esketamine in depression therapy.
| Substance | What has been shown | Source |
|---|---|---|
| Typical antidepressants | Limited effectiveness, response delayed by weeks or months | Duman and Aghajanian, 2012 |
| Fluoxetine | Acts through binding to the TrkB receptor | Moliner et al., 2023 |
| Ketamine | Response within hours in treatment-resistant cases; induces synaptogenesis and reverses deficits from chronic stress | Duman and Aghajanian, 2012 |
| Esketamine | First FDA-approved antidepressant of a new class | Kim et al., 2019 |
| LSD and psilocybin | Binding to TrkB with an affinity a thousand times higher than other antidepressants; effect independent of 5-HT2A | Moliner et al., 2023 |
What do these discoveries mean for clinical practice?
For now, less than the headlines suggest, but the direction is clear. Of the substances discussed here, esketamine has the status of a registered antidepressant, described in the literature as the first FDA-approved antidepressant of a new class. The other substances remain subjects of clinical research conducted under strictly defined protocols.
The best-documented area outside of depression is addictions. In a double-blind study, 95 individuals diagnosed with alcohol dependence were randomly assigned to psilocybin or diphenhydramine, combining drug administration with psychotherapy in both groups. Over thirty-two weeks, the percentage of days of heavy drinking was 9.7 percent in the psilocybin group compared to 23.6 percent in the control group, and no serious adverse events were reported among participants receiving psilocybin (Bogenschutz et al., JAMA Psychiatry, 2022).
The second example shows both promise and its limits. In an open pilot study involving 15 smokers, psilocybin was combined with cognitive-behavioral therapy. After a year, biological confirmation of abstinence was obtained for ten participants, and in a long-term follow-up, on average after thirty months, for nine (Johnson et al., American Journal of Drug and Alcohol Abuse, 2017). These are encouraging results, but they come from a study without a control group and on a small number of individuals, so they do not carry the weight of evidence of efficacy. Both protocols combined the administration of the substance with structured therapy, which no home use replicates. The thread of the plasticity window after the session is developed in the text about afterglow and the neuroplasticity window.
Frequently Asked Questions
What are psychoplastogens?
These are substances that induce rapid structural plasticity, meaning changes in the connections between neurons. The term has been adopted for psychedelics and ketamine, but research from 2023 shows that fluoxetine also acts through the same TrkB receptor. The difference lies more in the binding strength than in a separate mechanism.
What is BDNF and why is it important?
BDNF is brain-derived neurotrophic factor, a protein isolated in 1982, considered essential for the molecular mechanisms of synaptic plasticity. Activity-dependent changes in the central nervous system are attributed to BDNF modifying synaptic transmission, particularly in the hippocampus and neocortex. However, its pathological levels are associated with epilepsy and chronic pain.
How do psychedelics affect BDNF and neuroplasticity?
LSD and psilocybin bind directly to TrkB, the receptor for BDNF, in the transmembrane domain of its dimers. The impact on neurotrophic signaling, plasticity, and behavior in mice depended on this binding and the enhancement of endogenous BDNF signaling, rather than on the activation of the 5-HT2A receptor. The affinity was a thousand times higher than that of other antidepressants.
Is ketamine also a psychoplastogen?
Ketamine is an NMDA receptor antagonist and induces a rapid antidepressant response within hours in individuals for whom typical medications have failed. In basic research, it quickly induces synaptogenesis and reverses synaptic deficits caused by chronic stress. It also binds to the TrkB receptor, similar to fluoxetine.
Is there already a registered drug from this group?
Yes, it is esketamine, described in the literature as the first FDA-approved antidepressant of a new class, used in treatment-resistant depression. The other substances discussed in this article remain subjects of clinical research and are not approved for use outside of research protocols conducted under medical supervision.
Do psychedelics help with addictions?
The data is promising but early. In a double-blind study of 95 individuals with alcohol dependence, the percentage of days of heavy drinking was 9.7 percent after psilocybin with psychotherapy compared to 23.6 percent in the control group. An open study involving 15 smokers yielded ten confirmed abstinences after a year. Both protocols combined the substance with structured therapy.
This article is for informational and educational purposes. It describes clinical studies in which the substance is administered under medical supervision after participant qualification; self-use of these conditions does not replicate. These substances are controlled in Poland under the Act on Counteracting Drug Addiction. If you have suicidal thoughts, call the free, 24-hour numbers 116 123 or 800 70 2222. In case of life-threatening situations: 112.
Author: Michał Waluk · Published: 2026-08-09 · Updated: 2026-08-11
