On Thursday night, I gave a talk at the St. Louis Mid-County Library in Clayton, Missouri.

The room had around 35 people. Most weren’t scientists. Just curious.

I started with the basics: what is a neuron? What is a receptor? From there, I moved into circuits and models like REBUS, and then to neuroplasticity, critical periods, and how these ideas are shaping modern psychedelic research. I also briefly touched on work happening at WashU and the kinds of data we can get from human studies, animal models, and cellular systems.

The most interesting part of the night came at the very end. During the Q&A, I got questions about therapy, depression, and subjective experience.

But people kept coming back to one slide…

It compared LSD, psilocin, and THC across a range of receptors (Ray, 2010). From a neuroscience perspective, this kind of profile isn’t especially surprising. But it doesn’t match how people intuitively think about drugs.

LSD and psilocin show measurable binding affinity across a wide range of serotonin receptors, and extend into dopaminergic, adrenergic, and other systems. The profile is broad and distributed. In contrast, THC is much more selective.

That contrast is stark.

One person asked whether each receptor corresponded to a specific effect. Another wondered if a single receptor might map onto a specific disease.

That way of thinking is very intuitive. It’s how we’re taught to understand biology: break a system into parts, assign each part a function, and then map effects onto those functions. One receptor, one role. One target, one outcome.

The reality is much more complex. Receptors don’t usually map cleanly onto single effects, and most drugs interact with multiple targets rather than just one.

THC highlights a different kind of organization.

Its primary targets, CB1 and CB2, are part of the endocannabinoid system. While this system has its own complexity, its receptor footprint is much narrower. And that narrower footprint makes the system feel more intuitive.

If a drug acts through a small number of receptors, it’s natural to wonder whether each receptor corresponds to a specific effect, or even a specific disease. The system feels more legible, more decomposable.

Psychedelics break that intuition. Rather than acting through a small set of targets, they engage many receptors across multiple systems at once.

The 5-HT2A receptor is often treated as the central player, and it clearly contributes to both the subjective effects of psychedelics and neuroplasticity (Vollenweider et al., 1998; Ly et al., 2018). But it doesn’t operate in isolation. Other receptors and systems are part of that picture.

When you take a psychedelic, you are not just activating a single receptor. You are shifting a whole system. This makes them harder to study and points to a deeper question:

When a drug affects many targets at once, what actually matters?

References

1. Ray TS. Psychedelics and the human receptorome. PLoS One, 2010.

2. Vollenweider FX et al. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport, 1998.

3. Ly C et al. Psychedelics promote structural and functional neural plasticity. Cell Reports, 2018.

Subscribe now

This past month, I taught a short course on antidepressant mechanisms. Preparing for it brought me back to a question that has shaped my scientific interests: how does a negative psychological state become so persistent that it reshapes the way a person thinks, feels, and experiences the world?

Teaching this course clarified something for me: depressive states do not just arise. They consolidate.

In this essay, I trace how that consolidation unfolds biologically and how the brain becomes locked into rigid patterns of maladaptive thinking and behavior. I then turn to emerging treatments that are reshaping our understanding of how quickly those patterns can shift.

Depression and biology

Major depressive disorder affects hundreds of millions of people worldwide, making it one of the most common and disabling psychiatric conditions. Yet despite its prevalence, depression does not present in a uniform way.

Clinically, depression is a heterogeneous disorder affecting mood, cognition, motivation, sleep, and bodily state. Two individuals can meet diagnostic criteria while sharing few overlapping symptoms. This variability reflects the many biological pathways that can converge on a similar outward state.

In practice, psychiatrists diagnose depression using the DSM-5, which defines disorders based on reported symptoms rather than underlying biological markers. At present, no biomarker is sufficiently precise or reliable to be used diagnostically. Efforts to move toward biologically informed frameworks are underway, a topic I have written about previously¹.

This symptom-based framework has been invaluable for standardizing care, but it leaves open a deeper question: which biological changes underlie depression?

To understand why depression persists even when external circumstances improve, we have to move from symptoms to mechanisms. In neuroscience, depression is studied not only as a cluster of symptoms but as a state of the brain. Researchers ask how changes at the level of cells, circuits, and systems give rise to persistent alterations in mood, motivation, and behavior.

Because many of these processes cannot be directly manipulated in humans, much of this work relies on animal models to isolate components of depressive states. In rodents, chronic stress alters responses to reward, disrupts stress hormones, and weakens connections between neurons. These changes mirror several features of human depression².

Although animal models cannot capture subjective experience, they provide experimental access to circuits, genes, and molecular pathways that would otherwise be inaccessible in living humans.

This shift from symptoms to mechanisms is essential if we want to understand how depressive states take hold and how they might be loosened. Without it, we cannot explain why some treatments act slowly, why others act rapidly, or why depression can be so resistant to change.

Brain circuits and depressive states

Depression does not reside in a single brain region. It reflects changes in how regions communicate. In neuroscience, it is often more useful to think in terms of circuits: patterns of ongoing exchange between brain areas that coordinate perception, emotion, memory, and behavior. When those exchanges become persistently biased, negative signals are amplified and regulatory processes weaken, reinforcing patterns of rumination and threat sensitivity.

The cortico-limbic circuit offers one example. This network includes limbic structures such as the amygdala and hippocampus, which generate emotional and stress-related signals. It also contains regions of the prefrontal cortex that help interpret and regulate those signals. Under typical conditions, these regions remain in dynamic balance.

In depression, that balance can shift. Prefrontal regulation becomes less effective while the limbic system exerts greater influence, reducing flexibility and reinforcing negative bias³.

Depression is therefore not simply a reaction to circumstance. It reflects patterns of neural communication that become increasingly rigid over time, helping to explain both its persistence and its resistance to change. From this perspective, depression begins to look less like a chemical imbalance and more like a stabilized brain state.

Theories of depression

Describing altered circuits tells us where communication has shifted, but not why a depressive state persists. Explaining persistence requires more than anatomy. It requires a hypothesis for how biological changes consolidate over time.

Biological theories of depression have shifted away from moment-to-moment chemical signaling and toward mechanisms of plasticity and structural change. Walking through these theories with my students made the shift especially clear.

The monoamine hypothesis

The monoamine hypothesis proposed that depression arises from reduced signaling by modulatory neurotransmitters such as serotonin, norepinephrine, and dopamine. The idea was straightforward: if depression reflected a deficiency in these molecules, restoring them should relieve symptoms.

Antidepressants alter monoamine levels within hours, yet clinical improvement typically emerges only after weeks of continuous treatment. This temporal gap suggests that neurotransmitter levels alone cannot explain sustained recovery. Likewise, manipulating monoamine signaling does not reliably induce or resolve depression⁴.

Rather than invalidating the hypothesis, these limitations reframed it. Monoamines shape how brain circuits function in real time, but sustained antidepressant effects appear to depend on longer-term changes in circuit structure and plasticity.

The neurotrophic hypothesis

As attention shifted beyond moment-to-moment chemical signaling, a different biological framework emerged. The neurotrophic hypothesis emphasizes how depression alters brain plasticity and structure over time⁵.

This hypothesis proposes that chronic stress and prolonged exposure to stress hormones such as cortisol reduce neurotrophic support. Central to this process is brain-derived neurotrophic factor (BDNF), a protein that supports synaptic strength and neuronal connectivity.

When BDNF signaling declines, the brain’s capacity for plasticity narrows in regions involved in learning, memory, and emotional regulation. Structural consequences can follow, including loss of dendritic branches and spines, as well as weakening of connections between neurons in the hippocampus and prefrontal cortex⁶.

This reframes depression not as a static chemical imbalance, but as a dynamic disorder of maladaptive plasticity. Over time, the brain’s capacity to adapt diminishes, stabilizing negative emotional patterns. From the inside, this often feels like being stuck in the same thought loops, even when life changes.

From this perspective, the delayed effects of traditional antidepressants begin to make sense. Although these medications rapidly alter neurotransmitter levels, their therapeutic impact depends on slower processes of synaptic remodeling. Recovery becomes less about correcting a chemical deficit and more about restoring the brain’s capacity for flexibility, allowing established emotional patterns to be updated.

Psychedelics and depression

Over the past decade, renewed research into psychedelic medicine has produced growing evidence that these compounds can reduce depressive symptoms across multiple conditions. What distinguishes psychedelics is not only the magnitude of their antidepressant effects but also their speed.

In a randomized clinical trial published in The New England Journal of Medicine, Goodwin and colleagues administered a single dose of synthetic psilocybin to individuals with treatment-resistant depression. Within 24 hours, participants showed large reductions in depressive symptoms, with improvements that persisted for several weeks after a single administration⁷.

Rapid antidepressant effects have also been reported in other trials of psilocybin^8–10, as well as other psychedelics including LSD¹¹ and, more recently DMT¹².

These studies converge on a similar conclusion: under controlled conditions, psychedelics can produce rapid and sustained antidepressant effects.

Unlike conventional antidepressants, which typically require weeks of continuous treatment¹³, improvements following psychedelic administration often emerge within hours or days of a single dose. This difference in timescale is not trivial. It suggests that the biological processes underlying recovery may shift far more rapidly than previously assumed.

Psychedelics are not simply new tools added to an existing framework. They function as a stress test of prevailing models, revealing gaps in our understanding of how depressive states emerge, stabilize, and how rapidly those configurations can change.

Reopening the brain’s capacity for change

If depression reflects a brain that has narrowed its capacity to adapt, what happens when that capacity is suddenly reopened?

Neurobiologically, classical psychedelics exert their subjective effects primarily through activation of the 5-HT2A receptor. Blocking this receptor abolishes hallucinations¹⁴ and prevents plasticity-promoting effects in neurons¹⁵.

Moreover, a human neuroimaging study conducted at Washington University in St. Louis found that psilocybin can temporarily disrupt brain network organization¹⁶. This destabilization may weaken rigid patterns of thought and perception, creating an opportunity for entrenched cognitive and emotional states to reorganize¹⁷.

At the level of subjective experience, this loosening of brain network organization is accompanied by profound shifts in perception, emotion, and self-related processing. These internally generated experiences are not incidental; they coincide with evidence of enhanced neuroplasticity that appears to extend beyond the acute psychedelic experience.

Work from Gül Dölen’s lab has shown that several psychoactive compounds, including MDMA, psilocybin, LSD, ketamine, and ibogaine, can reopen windows of social learning in adult mice, with the duration of this plasticity scaling with the typical length of the subjective effects in humans¹⁸. These findings suggest that psychedelics may temporarily reopen critical periods of plasticity in adulthood.

Although direct evidence in humans remains limited, these findings raise the possibility that psychedelics create a transient window in which rigid beliefs and maladaptive emotional patterns become more open to revision. This window may be especially powerful when supported by therapeutic context and integration, consistent with findings from clinical trials of psychedelic-assisted psychotherapy¹⁹.

Psychedelics appear to operate on two levels at once. Neurobiologically, they open a temporary period of increased plasticity. Psychologically, they generate powerful subjective experiences that can restore the flexibility needed to revise maladaptive emotional patterns. Together, these processes may help explain both the speed of their effects and why set and setting so strongly shape long-term outcomes.

Conclusion

Rather than a single defect or imbalance, depression can be understood as a state that consolidates over time. Stress, vulnerability, and experience reshape biology, gradually narrowing neural flexibility and reinforcing maladaptive patterns of thought and behavior.

While this essay has focused on psychedelics, they are not the only interventions capable of producing rapid antidepressant effects. Electroconvulsive therapy, ketamine, and transcranial magnetic stimulation have all demonstrated meaningful clinical improvement^20–22. Although these treatments differ mechanistically, they share an important feature: the ability to interrupt stabilized brain states and create conditions for rapid reorganization.

A single psychedelic experience can produce enduring antidepressant effects. But the experience alone is not the whole story. Psychedelics appear to create a temporary window in which new interpretations, emotional patterns, and behaviors can emerge. Whether those shifts endure depends not only on the acute effects, but on what follows.

More broadly, psychedelics highlight something fundamental about the brain: the capacity for change is intrinsic to our biology. Psychedelics do not create this ability but reveal it. Seen this way, depression looks less like failure and more like constrained flexibility. Change becomes less about correcting a defect and more about restoring the capacity to adapt.

Selected references

The references below highlight literature cited in this essay for readers who want to explore the science in more detail.

1. Krentzman O. The Future of Mental Health Diagnosis. Medium, 2020.

2. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature, 2008.

3. Mayberg S. Limbic-cortical dysregulation: a proposed model of depression. Journal of Neuropsychiatry and Clinical Neurosciences, 1997.

4. Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science, 2012.

5. Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Archives of General Psychiatry, 1997.

6. McEwen BS, Morrison JH. The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron, 2013.

7. Goodwin GM et al. Single-dose psilocybin for a treatment-resistant episode of major depression. New England Journal of Medicine, 2022.

8. Carhart-Harris RL et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry, 2016.

9. Davis AK et al. Effects of psilocybin-assisted therapy on major depressive disorder. JAMA Psychiatry, 2021.

10. Weintraub MJ et al. Psilocybin-assisted cognitive behavioral therapy for major depressive disorder: a pilot trial. Journal of Affective Disorders, 2026.

11. Daldegan-Bueno D et al. LSD microdosing for major depressive disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 2026.

12. Erritzoe D et al. A short-acting psychedelic intervention for major depressive disorder. Nature Medicine, 2026.

13. Cipriani A et al. Comparative efficacy and acceptability of 21 antidepressant drugs. The Lancet, 2018.

14. Vollenweider FX et al. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport, 1998.

15. Ly C et al. Psychedelics promote structural and functional neural plasticity. Cell Reports, 2018.

16. Siegel JS et al. Psilocybin desynchronizes the human brain. Nature, 2024.

17. Carhart-Harris RL, Friston KJ. REBUS and the anarchic brain. Pharmacological Reviews, 2019.

18. Nardou R et al. Psychedelics reopen the social reward learning critical period. Nature, 2023.

19. Johnson M, Richards W, Griffiths R. Human hallucinogen research: guidelines for safety. Journal of Psychopharmacology, 2008.

20. UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders. The Lancet, 2003.

21. Berman RM et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 2000.

22. O’Reardon JP et al. Efficacy and safety of transcranial magnetic stimulation in major depression. Biological Psychiatry, 2007.

Subscribe now

One of my most memorable classes at Berkeley was Genetic Factors in Neuropsychology, taught by Dr. Linda Isaac. It was my first semester taking upper-level courses, and I was missing a prerequisite, but eager to enroll anyway. I emailed Dr. Isaac, explained my interest, and she made an exception. I enrolled.

The lecture was in Birge Hall, on the opposite end of campus from the Perception class I had just before. I remember running up Campanile Way from one class to the next, late and curious, always trying to get a good seat.

That class stayed with me for several reasons. It was the first time I had seen what serious, open-ended scientific discourse could look like in a small lecture hall. Students regularly raised their hands to question and even challenge the material, and those exchanges often unfolded into thoughtful discussions. That dynamic alone was new and exciting.

Beyond the classroom culture, the material itself was fascinating. The central premise was simple but unsettling: specific genetic factors have been linked to neuropsychiatric conditions strongly enough that an entire course could be built around them. Running beneath the course was a persistent question: how much of our biology is shaped by chance rather than choice?

The class felt different from anything I had taken before. It wasn’t focused solely on describing psychiatric disorders as they appear clinically, but on understanding the biological factors that precede them. We talked about genetics not just as an explanation for disease, but as a way of understanding how vulnerability exists long before symptoms ever appear.

Underlying all of it was a way of thinking Dr. Isaac emphasized repeatedly. She called it supervenience: the idea that to understand complex phenomena, you first have to understand the most basic level on which they rest. In biology, that meant starting from molecules and genes before jumping to behavior or diagnosis. This first principles way of thinking has shaped how I approach science.

Over the course of the semester, we moved through a wide range of neuropsychiatric conditions, but one category stood out more than the rest. I found myself especially drawn to personality disorders and to the questions they raised about vulnerability and control.

Those questions stopped feeling abstract once we began examining how genetic risk is regulated at a molecular level. We learned that genetic code is fixed, but its expression is not. Through epigenetic mechanisms, genes can be silenced or amplified in response to environmental influences over time. In that framework, risk is not a verdict, but a process.

Depression became the clearest example of how biological vulnerability and environment interact. There are genetic factors that contribute to risk, but depression is also a disorder in which environment plays an undeniable role. Experiences such as chronic stress, trauma, and early-life adversity can influence how genes are expressed, shaping vulnerability at a biological level.

Seen this way, depression is neither purely genetic nor simply a reaction to circumstance. It’s a disorder that emerges at the intersection of inherited susceptibility and lived experience. That complexity helps explain why depression is difficult to predict, why it often hides in plain sight, and why its course varies so widely between individuals.

This February, I’ll be co-teaching a course on antidepressant mechanisms at WashU. Understanding genetic risk changes how suffering is seen. It calls for compassion grounded in the recognition that inherited vulnerability is real. At the same time, when genetic susceptibility is shaped by environment, knowledge becomes leverage. It reveals where influence is possible and how adaptive change can begin.

Four years later, I had finally become fully integrated, just in time to return to the United States. Once again, I had to adjust to a new environment, one I had been absent from during critical years of development.

Drifting years

Back in the United States, I never found my footing academically. My grades weren’t great, and I didn’t feel at home in either the Italian or American curriculum. Science and math didn’t capture my interest back then.

After high school, I didn’t get into any four-year colleges, so I enrolled at community college and chose Italian as my major because it was the path of least resistance since I already spoke the language.

Community college felt unmotivating, especially as I started a social media marketing company called Round Meadow Media with my friend Dom. As the business began to generate income, school felt even less meaningful.

Eventually, I dropped out to pursue marketing and start a podcast with my friend Alec called The Mindful Guys. We interviewed people, raised money for charity, and explored different ways of thinking.

Teachers along the way

One afternoon at my local herb shop, Jonathan, the head herbalist, introduced me to a gentleman at the counter. “This is Tim,” he said. “He’s a neuroscientist. You should have him on your podcast.”

Tim agreed and invited us to Joshua Tree. We drove to the desert and spent the afternoon interviewing him among his chickens and gardens. We camped out under the stars that night, surrounded by stillness.

That experience changed me. Dr. Tim Delorey engaged us on topics like consciousness, theory of mind, epigenetics, and psychedelics. Tim treated my questions as worth asking, my ideas as worth exploring. This was the first time that a scientist took my ideas and interests seriously.

Through our conversations, it became apparent that my curiosity about the mind and consciousness could be pursued with rigor.

Returning to school

I decided to return to community college. My goal was to understand the mind from first principles, starting with cells. So I changed my focus of study to biology.

One day, my biology professor, Danielle Amoroso, told me about an upcoming Holotropic Breathwork workshop led by Michael Stone, a former student of Stan Grof.

A week later, under glistening stars in Venice Beach, I participated in the workshop.

Holotropic Breathwork is a structured breathing practice designed to induce altered states of consciousness.

For two hours, I breathed rhythmically to music that built in intensity. The session was physically and psychologically demanding.

When the session ended, there was an integration circle. A man in the back raised his hand. His voice shook as tears streamed down his face. He shared that he had made contact with his mother, who had died only a week earlier. “She told me everything will be okay,” he said.

I was only 20 years old, but that moment etched itself into my mind.

In its aftermath, I applied to four-year universities to study neuroscience, hoping to ground my questions about altered states in rigorous science, and was accepted to UC Berkeley.

Becoming a scientist

Arriving at Berkeley was surreal.

My goal remained to research the mind and consciousness. Emails to professors and postdocs disappeared into the void. After countless attempts, a graduate student in Dr. Aaron Fisher’s lab invited me to help with her dissertation research.

The following semester, I enrolled in The Biology of Learning, a course taught by Dr. Linda Wilbrecht. I went to every office hour, asking Linda questions about consciousness, breathwork, and psychedelics, topics far beyond the course material.

By the end of the semester, Linda invited me to join her lab, where I was trained in mouse behavioral and circuit neuroscience and eventually led my own project.

At the same time, I embarked on an honors thesis project to design a breathwork study. With guidance from Drs. David Presti and Dacher Keltner, my thesis titled The Cognitive, Psychological, and Physical Effects of Wim Hof’s Breathing Method: An Exploratory Study found that breathwork increased awareness, awe, and physical sensations such as tingling compared to the control group.

My undergraduate training built a foundation in cognitive science and neuroscience, but offered few chances to connect rodent research with questions of consciousness.

There was no doubt that I wanted to pursue a PhD in Neuroscience to explore the mechanistic underpinnings of consciousness.

Graduate school: a full circle moment

In 2021, a visit to Washington University in St. Louis made my grad school choice clear. The Midwest felt like a place where I could thrive.

At WashU, I rotated through multiple labs before joining Dr. Jordan McCall’s lab. Jordan offered an environment where I could build upon the skills I developed in Linda’s lab, but this time applying them to the questions I have been after all along.

Now, in my fourth year of the Neuroscience PhD program, I study the mechanistic underpinnings of altered states through behavioral pharmacology. Specifically, I research how psychedelics change brain function, leading to shifts in physiology, perception, and behavior that could underlie their therapeutic potential.

My early curiosity about consciousness has grown into a scientific career, but the questions remain: What is consciousness? What is its neurobiological basis? And how can we use this knowledge to better serve humanity? At the core of it all, that’s what my research is about.

The mystery of the future

My journey into neuroscience has been non-linear, shaped by failure, detours, and many unexpected turns. Those challenges have imbued my path with deep personal meaning.

I’m starting this Substack now because I’ve reached a point where thinking privately no longer feels sufficient.

Moving forward, I’ll be writing about the ideas that pull at me, especially psychedelics and consciousness, subjects that continue to fuel my passion for science.

Thanks for reading, and welcome.