Exploring serotonin 5-HT2A receptors, BDNF, TrkB signaling, non-hallucinogenic psychoplastogens, and one of the most intriguing questions in modern neuroscience
Biotech International Institute (BII)
The Next Frontiers in Neuroscience — Tuesday, October 20, 2026
Introduction: Can the Brain Change Without the Psychedelic Experience?
For decades, psychedelic compounds attracted attention primarily because of their powerful effects on perception, consciousness, and subjective experience.
But modern neuroscience is investigating something potentially just as important.
What happens to the brain at the cellular level when certain psychedelic compounds interact with neuronal signaling pathways?
Research suggests that some psychedelic compounds can influence processes associated with neuroplasticity — the nervous system's ability to modify its structure, function, and connections.
In experimental systems, researchers have observed changes involving dendritic growth, synaptic structures, intracellular signaling, and neurotrophic pathways.
These findings have raised an important scientific question.
Are the molecular processes associated with neuroplasticity inseparable from the psychedelic experience, or can scientists investigate and potentially influence those processes independently?
This question has implications for neuroscience, drug discovery, and the future investigation of neurological and psychiatric conditions.
At Biotech International Institute, it is particularly relevant to our research-stage interests in psilocybin/fungi-inspired small molecules and post-dependency brain adaptation.
But answering it requires distinguishing three different things:
1. A compound's activity at a biological receptor.
2. The cellular changes associated with that activity.
3. The subjective and clinical outcomes that may follow.
These are related questions, but they are not interchangeable.
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1. Neuroplasticity: The Brain's Ability to Adapt
Neuroplasticity describes the nervous system's capacity to change in response to activity, experience, learning, and biological conditions.
These changes can involve several processes.
Some connections between neurons become stronger.
Others weaken.
New dendritic spines may form.
Existing synaptic structures may be remodeled.
Neural circuits may change their patterns of activity.
These processes are important to learning, memory, adaptation, and recovery from certain forms of neurological disruption.
However, neuroplasticity is not automatically beneficial.
Plasticity can also contribute to maladaptive learning, persistent fear responses, chronic pain sensitization, and substance-related behavioral patterns.
This distinction is important because simply increasing a plasticity-related marker does not establish that a compound produces beneficial neurological change.
The biological context determines what those changes may mean.
2. The Serotonin 5-HT2A Receptor
One of the central molecular targets in classic psychedelic neuroscience is the serotonin 5-HT2A receptor.
This receptor belongs to a family of G protein-coupled receptors involved in cellular signaling.
It is found in several tissues and is particularly important in cortical neuronal signaling.
Classic psychedelics such as psilocin, the active metabolite of psilocybin, interact with 5-HT2A receptors.
Activation of these receptors contributes to the altered perception, cognition, and subjective experience associated with psychedelic compounds.
But scientists have discovered that receptor activation alone does not explain every biological effect.
Different compounds may interact with the same receptor while producing different downstream responses.
Some compounds may activate particular signaling pathways more strongly than others.
Others may differ in cellular access, receptor localization, or the duration and character of signaling.
This raises a fundamental pharmacology question:
Why can two compounds interact with the same receptor yet produce different cellular outcomes?
The answer may involve much more than whether a compound binds to the receptor.
3. A Major Discovery: Receptor Location May Matter
In 2023, researchers led by Maxemiliano Vargas and David Olson published an influential study in Science.
The study investigated why certain psychedelic compounds promote neuronal growth in experimental models while other serotonin receptor agonists do not produce comparable effects.
Using molecular and genetic approaches, the researchers identified an important role for intracellular 5-HT2A receptors.
Their findings suggested that access to receptors located inside neurons helps explain some psychedelic-associated structural plasticity responses.
This was a significant observation.
It indicated that receptor location can influence biological outcomes.
A compound that activates receptors at the cell surface may not necessarily produce the same response as a compound capable of reaching intracellular receptor populations.
The researchers described this concept in terms of location-dependent receptor signaling.
For small-molecule discovery, the implications are intriguing.
Chemical structure affects properties such as membrane permeability.
Those properties can influence which receptor populations a molecule reaches.
And that may affect downstream cellular responses.
The location of receptor engagement may matter alongside the identity of the receptor itself.
However, these experiments do not establish that selectively activating intracellular receptors produces beneficial clinical outcomes in humans.
That question requires additional evidence.
4. BDNF: A Molecule Associated With Neural Adaptation
Another important area of research involves brain-derived neurotrophic factor, commonly called BDNF.
BDNF is a signaling protein involved in neuronal development, synaptic function, and activity-dependent plasticity.
It interacts with a receptor known as TrkB, or tropomyosin receptor kinase B.
BDNF-TrkB signaling can influence intracellular pathways involved in neuronal growth and synaptic remodeling.
These pathways have attracted interest because they help regulate how neural connections respond to experience and biological activity.
Some psychedelic-related experiments have identified relationships between neuroplasticity-associated responses and signaling pathways involving BDNF, TrkB, mTOR, and AMPA receptors.
But an increase in BDNF-related signaling is not equivalent to improved memory, better cognition, or recovery from neurological disease.
The timing, location, intensity, and downstream consequences of signaling all matter.
5. Could Psychedelic Compounds Interact Directly With TrkB?
A particularly interesting 2023 study, published in Nature Neuroscience by Moliner and colleagues, investigated whether psychedelic compounds interact directly with the TrkB receptor.
The researchers reported that LSD and psilocin bound to TrkB in their experimental systems.
They also found that certain plasticity-related effects and antidepressant-like behavioral responses in mice depended on TrkB-associated signaling.
Importantly, their experimental findings suggested that some TrkB-associated plasticity responses could be distinguished from 5-HT2A-dependent behavioral responses.
This created an intriguing scientific possibility.
Perhaps some molecular effects associated with psychedelic compounds could be investigated separately from the receptor mechanisms most directly associated with altered perception.
However, the experiments do not establish that the subjective psychedelic experience is unnecessary for therapeutic benefit in humans.
Human treatment responses may involve psychological, behavioral, interpersonal, and biological processes that are difficult to separate.
The study helped open a research direction.
It did not settle the clinical question.
6. Enter the Non-Hallucinogenic Psychoplastogens
The term psychoplastogen refers to compounds investigated for their capacity to promote certain forms of structural or functional neural plasticity.
Researchers are exploring compounds designed to retain particular plasticity-associated properties without producing the full range of subjective effects associated with classic psychedelics.
One example is tabernanthalog, or TBG.
TBG is an experimental compound investigated for neuroplasticity-related activity.
In a 2025 study published in Nature Neuroscience, researchers examined how TBG influenced cortical neuronal plasticity in rodent experiments.
The investigators reported that non-hallucinogenic psychoplastogens could promote plasticity through pathways involving 5-HT2A, TrkB, mTOR, and AMPA receptor signaling.
Their findings also connected TBG-induced cortical spine formation with sustained antidepressant-like behavioral effects in their experimental model.
These results are important because they suggest that some molecular processes associated with psychedelic-related plasticity may be investigated using compounds that do not produce comparable hallucinogenic-like effects in standard preclinical assessments.
But there are important limitations.
Animal behavioral models do not fully reproduce human subjective experience.
Non-hallucinogenic classification in preclinical experiments does not establish the complete psychological effects of a molecule in humans.
And antidepressant-like responses in rodents are not proof of clinical antidepressant efficacy.
TBG and related compounds remain subjects of ongoing investigation.
7. Why This Does Not Settle the Debate
The relationship between psychedelic experiences and lasting therapeutic outcomes remains controversial.
One scientific perspective emphasizes molecular and cellular mechanisms.
From this perspective, receptor signaling and neuroplasticity may be central drivers of certain longer-lasting biological effects.
Another perspective emphasizes the subjective experience.
Changes in emotional processing, psychological insight, perception, and the therapeutic environment may contribute to outcomes observed in human studies.
These perspectives are not necessarily mutually exclusive.
Both may contribute under different conditions.
A 2026 review in Nature Medicine, titled The Science of Psychedelic Medicine, examines this tension between preclinical evidence involving non-hallucinogenic analogs and clinical findings associating subjective experiences with treatment responses.
The review also discusses two potentially complementary processes: acute changes in neural network dynamics and subsequent plasticity-related changes.
The central question remains unresolved.
Can the molecular mechanisms be separated from the experience in a way that preserves meaningful clinical benefit?
Preclinical research suggests that certain biological responses can be separated experimentally.
Whether that separation produces effective and safe human treatments remains to be determined.
8. Why the Difference Between Cellular Plasticity and Clinical Recovery Matters
A molecule may increase dendritic spine formation in a laboratory model.
That is a measurable cellular observation.
But it does not demonstrate that a person will experience improved cognition, emotional stability, neurological recovery, or reduced symptoms.
Several additional questions must be answered.
Are the new or modified synaptic connections functional?
Do they improve the activity of relevant neural circuits?
Are the changes sustained?
Are they beneficial within the biological context being studied?
Could increased plasticity reinforce maladaptive learning instead?
Are there safety risks associated with broad activation of neural signaling?
Does the effect reproduce in human-relevant systems?
Ultimately, can a carefully designed clinical study establish a meaningful benefit?
This is why neuroscience requires multiple levels of evidence.
Molecular signaling is important.
Cellular plasticity is important.
Neural network function is important.
But clinical outcomes require their own validation.
9. Mycophorol™ and BII's Interest in Neurotrophic Signaling
At Biotech International Institute, Mycophorol™ represents our research-stage psilocybin/fungi-inspired small-molecule platform.
Its proposed research direction includes neurotrophic-pathway questions, neuronal adaptation, and neural-resilience biology.
The emerging literature involving 5-HT2A, BDNF, TrkB, and related signaling systems provides useful scientific context for this research area.
It also raises important questions for future candidate evaluation.
Does a defined molecule interact with a relevant receptor or signaling pathway?
Is pathway engagement measurable?
Does compound exposure produce reproducible cellular responses?
Are those responses dose-dependent?
Do biological changes reflect the proposed mechanism rather than cellular stress or off-target activity?
Are the observed effects supported by appropriate functional measurements?
BII has not established that Mycophorol™ produces psychedelic-independent plasticity, activates TrkB, improves cognition, or treats neurological disease.
Those outcomes cannot be inferred from published studies of other compounds.
For BII, the appropriate objective is to investigate defined chemistry and mechanistic questions before considering stronger conclusions.
10. NeuroReset™ and the Biology of Post-Dependency Adaptation
NeuroReset™ represents BII's research-stage psilocybin/cannabinoid small-molecule direction associated with post-dependency recovery biology.
This research area is particularly complex because substance-use-related adaptation involves multiple interacting biological systems.
These may include reward circuitry, stress response, associative learning, emotional processing, neuroimmune signaling, and synaptic plasticity.
Some substance-related behavioral patterns involve deeply learned associations between environmental cues and rewarding or aversive experiences.
Recovery may involve the development of alternative behavioral responses and changes in how neural circuits process those cues.
This raises a scientifically interesting possibility.
Could a better understanding of plasticity-related pathways eventually help researchers investigate how persistent maladaptive neural patterns change?
But that question should not be confused with a treatment claim.
Increased plasticity is not automatically beneficial.
It may be influenced by environmental conditions and behavioral experiences.
And cellular changes do not establish that a compound prevents relapse or improves recovery.
For NeuroReset™, the responsible research path involves defining the investigational candidates, clarifying their pharmacology, selecting appropriate models, and investigating safety and biological relevance.
The platform has not been demonstrated to treat addiction or prevent relapse.
11. The Role of Cannabinoid Signaling in a Multi-Pathway Research Strategy
NeuroReset™ also includes cannabinoid-related scientific questions.
Cannabinoid receptor systems interact with neuronal and immune processes and have been investigated in relation to stress biology, synaptic function, reward processing, and neuroimmune signaling.
But cannabinoid receptor activity and serotonin-related psychedelic mechanisms should not be treated as interchangeable.
CB1, CB2, and 5-HT2A are different receptor systems with different pharmacological and physiological properties.
A multi-pathway research approach would need to determine which targets are relevant to the specific hypothesis.
If multiple compounds or pathways are involved, possible interactions and safety risks must also be evaluated.
For BII, the goal is not to assume that combining biological mechanisms necessarily produces better outcomes.
The goal is to investigate whether a scientifically defined approach produces meaningful, reproducible findings.
12. What Scientists Still Need to Discover
Despite advances, fundamental questions remain.
Which cellular changes are most important for beneficial neural adaptation?
How much of psychedelic-associated plasticity depends on 5-HT2A activation?
What roles do intracellular receptor populations play?
How does BDNF-TrkB signaling interact with other pathways?
Which molecular responses can be separated from altered perception?
Does this separation matter for human clinical outcomes?
Can scientists guide plasticity toward beneficial rather than maladaptive circuit changes?
And how do individual biology, psychological context, and environmental conditions influence the consequences?
These are not minor details.
They may determine whether a promising molecular finding eventually becomes a useful medical intervention.
13. The Next Frontier May Be Precision in Neural Plasticity
One of the most compelling developments in this field is the shift from asking whether a compound increases plasticity to asking what type of plasticity it produces.
Where does the change occur?
Which neural circuits are affected?
How long does it last?
Does it involve new synaptic structures, altered signaling, or changes in network activity?
Does the change support adaptive learning?
Could it strengthen an unwanted neural response?
Can the effect be produced reproducibly at acceptable exposure levels?
Precision in neuroscience requires understanding more than whether a molecular signal increases or decreases.
It requires connecting that signal to cellular function, circuit behavior, safety, and ultimately meaningful outcomes.
This is a challenging scientific goal.
But it is also one of the reasons psychedelic-related neurobiology has become such an important area of contemporary research.
Closing Thought: Can We Separate the Mechanism From the Experience?
The most exciting aspect of modern psychedelic neuroscience may not be the psychedelic experience itself.
It may be the opportunity to understand how particular molecules influence the biological processes involved in neural adaptation.
Research involving intracellular 5-HT2A receptors, BDNF-TrkB signaling, and non-hallucinogenic psychoplastogens suggests that some cellular processes can be investigated separately from classic psychedelic-like effects.
However, the relationship between those processes and meaningful human therapeutic outcomes remains unresolved.
For Biotech International Institute, this research provides a scientific foundation for asking better questions about fungi-inspired small molecules and recovery-related neurological biology.
It does not provide evidence that our investigational platforms have already achieved those effects.
The scientific opportunity lies in understanding the difference.
Could future neuroscience learn to influence specific forms of neural plasticity without requiring the full psychedelic experience?
The answer is still being investigated.
And that is precisely what makes the question worth studying.
Research-stage. Built for validation.
Mechanism first. Validation always.
Biotech International Institute
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