Neuroscientist On How To Achieve A Calm State & Rewire An Anxious Brain | Nolan Williams PT 1
Neuroscientist Nolan Williams discusses how depression stems from loss of perceived control in specific brain circuits, particularly involving the dorsolateral prefrontal cortex and subgenual anterior cingulate. He explores cutting-edge treatments including transcranial magnetic stimulation (TMS), psychedelics, and ibogaine, arguing that psychiatry is evolving toward circuit-based understanding rather than chemical imbalance models.
Summary
Nolan Williams, a neuroscientist at Stanford, explains that depression fundamentally involves dysfunction in brain circuits controlling perceived control and mood regulation. When people experience social defeat stress or loss of control, the left dorsolateral prefrontal cortex (involved in control perception) goes offline while the subgenual anterior cingulate (sadness region) becomes hyperactive. This dysfunctional circuit pattern can be trained into the brain through repeated experiences, particularly early life trauma, creating a predisposition to depression that becomes increasingly resistant to treatment.
Williams presents the evolution of psychiatry in three eras: Psychiatry 1.0 focused on thought content and psychotherapy; Psychiatry 2.0 emphasized pharmacology and the flawed 'chemical imbalance' theory; and Psychiatry 3.0 adopts circuit-based thinking that bridges neurology and psychiatry. He clarifies that SSRIs likely work not by restoring serotonin levels but by upregulating brain-derived neurotrophic factor (BDNF), enabling neuroplasticity and circuit change over weeks, not days.
Williams describes his accelerated TMS approach (SAINT) as a non-invasive technique that can rapidly restore normal signaling directionality between brain regions. Research shows that in depressed individuals, the sadness circuit often leads the control circuit (reversed causality), but after successful stimulation, normal dominance is restored. Patients frequently report regaining volition and ability to engage in previously difficult activities like therapy or exercise.
Regarding psychedelics, Williams notes that psilocybin shows efficacy in treatment-resistant depression, with about one-third of patients experiencing clinically relevant benefit at 25mg doses. However, the full psychoactive experience appears necessary—lower doses don't produce the same results. He emphasizes the psychological risks of disappointment and hopelessness when psychedelics fail to help treatment-resistant patients.
Williams also discusses ibogaine, an African plant extract that uniquely upregulates both BDNF and glial-derived neurotrophic factor (GDNF). Veterans with PTSD and traumatic brain injury have reported symptom improvements after ibogaine treatment. Stanford conducted the first neuroimaging study of ibogaine's effects, partnering with treatment clinics in Mexico to circumvent cardiac risk concerns through prophylactic medication.
The host and Williams explore interconnections between brain, gut, and heart, discussing how COVID-19 exacerbated depression through loss of control and isolation. They debate whether depression is fundamentally about perceived loss of control or involves multiple distinct subtypes currently lumped under one diagnosis. Williams emphasizes the importance of early intervention and behavioral techniques (exercise, diet, therapy) before resorting to intensive neurostimulation or psychedelic interventions.
About this episode
<p>In today’s 2-part episode we’re digging into the real cause for depression and exploring how psychedelics and magnetic transcranial magnetic stimulation are helping to solve this problem?</p><p>If anxiety and depression have become one of your biggest roadblocks and challenges stay tuned, this conversation is aimed at helping you find ways to rewire your brain and get back to chasing fulfillment.</p><p>This episode with neuroscience expert, Nolan Williams, is an eye opening crash course for discovering what’s possible with psilocybin and MDMA, breaking down psychiatry 3.0 and understanding what mental health is and how depression has become one of the four leading health factors that significantly increases the risks for heart attack.</p><p><br /></p><p><strong>NOLAN WILLIAMS QUOTES:</strong></p><p>“Depression is now one of the four leading risk factors for having a heart attack.”</p><p>“You can have physical things that happen in the heart from things that happen in the brain.”</p><p>“I’m a very agnostic tool builder. I really don’t care what the social perception of the tool is, [...] if it’s safe for the patient, and it’s acceptable for the patient, and it’s something I would suggest to my mother, brother, or spouse, and the risk benefit is right, then we’ll look at it.”</p><p><br /></p><p><strong>Follow Nolan Williams:</strong></p><p>Website: <a href="https://bsl.stanford.edu/" target="_blank">https://bsl.stanford.edu/</a> </p><p>Twitter: <a href="https://twitter.com/NolanRyWilliams" target="_blank">https://twitter.com/NolanRyWilliams</a> </p><p>Instagram: <a href="https://www.instagram.com/stanford_bsl/" target="_blank">https://www.instagram.com/stanford_bsl/</a> </p><p><br /></p><p>SPONSORS:</p><p><a href="mailto:[email protected]" target="_blank">[email protected]</a></p><p><br /></p><p><strong><em>***Are You Ready for EXTRA Impact?***</em></strong></p><p>If you’re ready to find true fulfillment, strengthen your focus, and ignite your true potential, the Impact Theory subscription was created just for you.</p><p>Want to transform your health, sharpen your mindset, improve your relationship, or conquer the business world? This is your epicenter of greatness. </p><p>This is not for the faint of heart. This is for those who dare to learn obsessively, every day, day after day.</p><p><strong>* New episodes delivered ad-free</strong></p><p>* Unlock the gates to a treasure trove of wisdom from inspiring guests like Andrew Huberman, Mel Robbins, Hal Elrod, Matthew McConaughey, and many, many, more</p><p>* Exclusive access to Tom’s AMAs, keynote speeches, and suggestions from his personal reading list</p><p>* You’ll also get access to an<strong> <em>5 additional podcasts</em> </strong>with hundreds of archived Impact Theory episodes, meticulously curated into themed playlists covering health, mindset, business, relationships, and more:</p><p>*<a href="https://podcasts.apple.com/us/podcast/legendary-mindset/id1683397827?itsct=podcast_box&itscg=30200&ls=1&at=1000l3anZ" target="_blank"><strong>Legendary Mindset</strong></a><strong>:</strong> Mindset & Self-Improvement</p><p>*<a href="https://podcasts.apple.com/us/podcast/money-mindset/id1683397173?itsct=podcast_box&itscg=30200&ls=1&at=1000l3anZ" target="_blank"><strong>Money Mindset</strong></a><strong>: </strong>Business & Finance</p><p>*<a href="https://podcasts.apple.com/us/podcast/relationship-theory/id1683229040?itsct=podcast_box&itscg=30200&ls=1&at=1000l3anZ" target="_blank"><strong>Relationship Theory:</strong></a> Relationships</p><p>*<a href="https://podcasts.apple.com/us/podcast/health-theory/id1683215287?itsct=podcast_box&itscg=30200&ls=1&at=1000l3anZ" target="_blank"><strong>Health Theory</strong></a><strong>: </strong>Mental & Physical Health</p><p>*<a href="https://podcasts.apple.com/us/podcast/power-ups/id1683398038?itsct=podcast_box&itscg=30200&ls=1&at=1000l3anZ" target="_blank"><strong>Power Ups:</strong></a> Weekly Doses of Short Motivational Quotes </p><p><br /></p><p><strong>*****Subscribe on Apple Podcasts: </strong><a href="https://apple.co/3PCvJaz" target="_blank">https://apple.co/3PCvJaz</a>*****</p><p><br /></p><p><strong>Subscribe on all other platforms</strong> (Google Podcasts, Spotify, Castro, Downcast, Overcast, Pocket Casts, Podcast Addict, Podcast Republic, Podkicker, and more) : <a href="https://impacttheorynetwork.supercast.com/" target="_blank">https://impacttheorynetwork.supercast.com/</a></p><p> </p><p>Learn more about your ad choices. Visit <a href="https://megaphone.fm/adchoices" target="_blank">megaphone.fm/adchoices</a></p><p>See Privacy Policy at <a href="https://art19.com/privacy" rel="noopener noreferrer" target="_blank">https://art19.com/privacy</a> and California Privacy Notice at <a href="https://art19.com/privacy#do-not-sell-my-info" rel="noopener noreferrer" target="_blank">https://art19.com/privacy#do-not-sell-my-info</a>.</p>
Key Insights
- Williams argues that depression involves a specific circuit dysfunction where the control region (dorsolateral prefrontal cortex) goes offline during loss-of-control experiences, trainable into pathological patterns through repeated stress or trauma.
- The researcher claims that SSRIs' antidepressant effects likely stem from upregulating BDNF and promoting neuroplasticity over weeks, not from acutely increasing serotonin levels as historically marketed.
- Williams presents evidence that ketamine's antidepressant effects require opiate system activation—when opiate receptors are blocked, ketamine loses efficacy despite maintaining its dissociative effects.
- The neuroscientist argues that normal brain function requires the control circuit to signal ahead of the sadness circuit in time, but in ~70% of depressed individuals studied, this temporal relationship reverses—a pattern that normalizes after successful TMS treatment.
- Williams contends that treatment-resistant depression may not be a single disorder but multiple distinct circuit abnormalities currently lumped under one diagnosis, similar to how Parkinson's disease was later disaggregated into subtypes.
- The researcher claims that psilocybin's antidepressant benefits only emerge at full psychoactive doses (25mg), with sub-threshold doses producing no clinical benefit, suggesting the perceptual/psychological experience may be mechanistically necessary.
- Williams argues that psychedelics may access intracellular 5-HT2A receptors inaccessible to serotonin, potentially representing evolved receptors for endogenous compounds like DMT or lipophilic psychedelics.
- The neuroscientist claims that ibogaine uniquely upregulates both BDNF and glial-derived neurotrophic factor (GDNF), explaining its exceptional efficacy in addiction interruption across multiple studies.
- Williams presents data showing that neurostimulation can reproducibly decelerate heart rate by engaging parasympathetic control circuits, demonstrating direct brain-heart mechanistic pathways.
- The researcher argues that depression exacerbation during COVID resulted from multiple compounding factors—isolation reducing perceived control, social media creating emotional distance, and poor diet/exercise disrupting gut-brain signaling.
- Williams contends that early intervention before severe depression emerges (e.g., post-trauma prophylaxis) could prevent symptomatic episodes, yet psychiatry remains largely reactive rather than preventative due to practical constraints.
- The neuroscientist claims that volition and sense of agency return when depression circuits are corrected, with patients reporting capacity to engage in previously insurmountable therapeutic work immediately after TMS, suggesting control perception directly enables behavioral change.
Topics
Transcript
We all live inside of a simulation created by our brains. As such, your brain is without a doubt the most important thing in your life. Everything in your life is downstream of your brain. When your brain is functioning well, you're free to grow and chase your dreams. But if something goes wrong in your brain, everything in your life suffers. That's why I am really excited about today's guest, Nolan Williams. Nolan is at the forefront of brain research, specifically your brain as it relates to anxiety and depression. In today's episode, we explore how things can go wrong for any of us, what to do when there's a glitch in our personal matrix, and some of the…
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