Dr. Nolan Williams on Brain Stimulation, Psychedelics and Rewiring Depression Circuits

High-Level Overview

Andrew Huberman talks with Dr. Nolan Williams, a triple board-certified psychiatrist and neurologist at Stanford who directs the Stanford Brain Stimulation Lab. Williams studies transcranial magnetic stimulation (TMS), a technique that uses magnetic pulses to excite or quiet specific brain circuits, and combines it with emerging treatments such as ketamine, psilocybin, MDMA and ibogaine. The conversation maps the circuitry of depression, from a brain-heart pathway that runs through the prefrontal cortex and vagus nerve, to the idea that depression happens when an emotional conflict-detecting region runs ahead of the brain's control center. Williams explains his lab's accelerated TMS protocol, which in trials puts many severely depressed patients into remission within days.

The discussion then moves through the pharmacology, history and safety of psychedelics and related drugs, including a surprising finding that ketamine's antidepressant effect depends on the opioid system. They also cover SSRIs and the chemical imbalance debate, cannabis and psychosis risk, alcohol's harms, and a sleep-deprivation and light therapy for depression. The tone is curious, technical and measured, with Huberman frequently translating ideas and Williams repeatedly stressing that these treatments belong under strict medical supervision. The conversation flows from brain circuits, to specific treatments and their evidence, to practical reflections on behavior, sleep and the future of psychiatry.

The Discussion Explores:

• Why depression is so disabling and why emergency psychiatry has so few tools
• The brain-heart connection and left-right balancing of mood in the prefrontal cortex
• The prefrontal cortex as the governor of the cingulate, and how TMS restores that order
• Ketamine's surprising dependence on the opioid system
• SSRIs, the chemical imbalance idea, and the shift to circuit-based psychiatry
• MDMA for PTSD, psilocybin for depression, and the role of letting go
• Ibogaine, 5-MeO-DMT and ayahuasca research, plus cannabis and alcohol risks
• Sleep deprivation triple therapy and Stanford's accelerated TMS protocol

Deep Dive into Main Ideas

Depression's Scope and the Emergency Gap

Williams describes depression as a range of presentations: some people mainly lose interest, some are anxious and overactive, others are slowed with no motivation. His lab works with colleagues at Cornell to find brain-imaging biotypes that separate these. He calls depression the most disabling condition worldwide, noting that moderate depression is as disabling as an acute heart attack and severe depression as disabling as untreated terminal cancer. The American Heart Association recently added depression as the fourth major risk factor for coronary artery disease, alongside high blood pressure, high cholesterol and diabetes, and people are more likely to become depressed after a heart attack.

He points out a paradox: in cardiology, the more acute a patient's situation, the more tests and treatments become available, but in psychiatry, as someone goes from depressed to suicidal and into an emergency setting, the number of treatments on average goes down and there are no tests. Trained in both neurology and psychiatry, he set out to engineer fast, brain-based treatments for these high-acuity situations.

The Brain-Heart Pathway and Hemispheric Balance of Mood

Williams explains that TMS uses Faraday's law to induce electrical current in brain tissue directly under a magnetic coil. When his team stimulates the left dorsolateral prefrontal cortex (DLPFC), the signal travels to the anterior cingulate, insula and amygdala, then to the nucleus tractus solitarius and down the vagus nerve to the heart. Heart rate drops about 10 beats per minute within a second of each two-second train of pulses and drifts back up during the pause. Stimulating visual or motor cortex doesn't do this. He stresses that the heart rate drop is mainly a marker that they've hit the right network, not the mechanism of improvement; slowing the heart alone, for instance with a beta blocker, is unlikely to treat depression.

He cites Mike Fox at Harvard, who mapped strokes onto the human connectome and found that strokes causing depression all connect to the left DLPFC, while lesions causing mania connect to the right. Exciting the left side or inhibiting the right is antidepressant, suggesting the hemispheres balance mood. Huberman frames depression as a loss of control over the hinge between alert and calm states. Williams adds that behavioral tools like meditation, mindfulness and exercise work well for mild depression, but that there is a volitional threshold: as depression worsens, thoughts become semi-voluntary and these approaches lose traction, with catatonia as the extreme.

The Prefrontal Cortex as Coach, the Cingulate as Player

Using the Stroop task, in which people must name a word's ink color rather than read the word, Williams shows that different sub-regions of the left DLPFC handle distinct functions. Inhibiting one area slows people on the task; inhibiting another, connected to the dorsal anterior cingulate, increased trait hypnotizability in work with David Spiegel. The mood-relevant area sits lower and more lateral, connected to the subgenual anterior cingulate, which processes emotional conflict. Huberman proposes that the prefrontal cortex governs rules, or beliefs, such as I'm not good enough, and that therapy helps people perform a kind of Stroop task on those beliefs. Williams agrees that cognitive behavioral therapy identifies fixed beliefs and helps integrate alternative explanations.

The key finding from his lab: in depressed people, cingulate activity precedes the DLPFC in time, while in healthy people the DLPFC leads. Effective treatment flips that timing back. Huberman sums it up as the coach telling the player what to do rather than the reverse, and Williams agrees that restoring order correlates with improvement. He likens TMS to exercise for this brain region, and says patients once told they weren't trying hard enough in therapy come back after treatment saying they can finally understand their therapy books. Several patients who remitted early in the five-day protocol reported unusually mindful experiences, like sitting on a beach fully present for an hour.

Ketamine and the Opioid System

Ketamine is a dissociative anesthetic now used for depression, and Williams says dissociation seems necessary but not sufficient for its antidepressant effect. In a crossover study, his team gave the same patients ketamine with either placebo or 50 milligrams of naltrexone, an opioid receptor blocker. The antidepressant effect was dramatically blocked with naltrexone, though the dissociative trip felt identical. That challenged both the idea that ketamine works purely through the glutamate system and the idea that the psychedelic experience alone produces the benefit. He links this to other findings: an opioid blocker stops TMS's pain-relieving effect, and patients with depression need roughly triple the opioid dose after knee replacement. He notes opioids may relieve emotional pain transiently but are pro-depressant over time.

Both men flag that researchers are designing psychedelic analogs without hallucinogenic effects, and that separating the experience from the underlying biology is crucial. Williams says a single ketamine infusion's benefit lasts about a week and a half on average.

SSRIs and Psychiatry 3.0

Williams says SSRIs clearly help a subset of people with depression, OCD, anxiety and panic, but because they take weeks to work, their benefit probably comes from plasticity changes such as increased BDNF rather than serotonin levels alone. He says the recent headline that depression isn't a serotonin deficiency, or chemical imbalance, isn't new to psychiatry. He frames the field in stages: psychiatry 1.0 focused on family and early experience, 2.0 on chemical imbalance, and 3.0 on circuits. Both earlier framings can tell patients something is missing in them.

Circuit-focused treatment, he argues, is empowering because it presents depression as recalibratable, like fixing an arrhythmia or a broken leg. Rapid TMS works in one to five days without adding serotonin, and imaging shows TMS, ketamine and psilocybin converge on the same change: reduced connectivity between the subgenual cingulate and the default mode network, essentially unpairing a negative mood system from the brain's self-representation. Patients who relapse have told him they'll never think about suicide again because they know the treatment can get them well.

MDMA, Psilocybin and Letting Go

Williams explains that brains hold onto negative memories for evolutionary reasons, like veterans whose battlefield reflexes are maladaptive at home, and that psychedelics may open a plastic state in which memories can be re-experienced and reconsolidated. In clinical trials, one to a few MDMA sessions produced clinically significant PTSD improvement in about two-thirds of people, with effect sizes comparable to antacids for heartburn, and earlier trials suggested benefits lasting years in some. For psilocybin in depression, open-label studies show half to two-thirds of people improve, and blinded trials about a third. He describes himself as agnostic about tools but insistent on well-designed trials, noting that blinding is hard and ketamine plus naltrexone might serve as an active placebo.

On MDMA safety, they discuss a Science paper claiming MDMA neurotoxicity whose monkeys, the group later admitted, had actually been given methamphetamine, a study of Latter-day Saints who used only MDMA and showed no cognitive differences, and neuropsychological testing in early trials that found no harm, suggesting little apparent risk in a few clinical doses. Huberman relays a colleague's suggestion that post-MDMA fatigue may reflect a prolactin rebound after a dopamine surge. On why letting go matters in psychedelic sessions, Williams compares it to exposure and response prevention for OCD; his first patient, afraid of draining his car battery, lost the compulsion after they left the lights on for an hour and the car still started. Huberman shares his own knock-on-wood habit, and Williams explains that clinical scales define normal as a range above zero; something becomes a diagnosis only when it impairs functioning.

Ibogaine, 5-MeO-DMT and Ayahuasca

Ibogaine comes from the root bark of the iboga shrub, used sacramentally by the Bwiti in Gabon, and Williams recommends Daniel Pinchbeck's book Breaking Open the Head for background. Unlike psilocybin or LSD, it doesn't cause visual changes with eyes open; with eyes closed, people review life memories with detached empathy for themselves and others, sometimes described as ten years of psychotherapy in a night. It can last 24 to 36 hours, has no recreational appeal, and carries cardiac risk, which his team reduced by screening electrocardiograms. His lab is running the first full neurobiological study of veterans, including former Navy SEALs and Army Rangers, who took ibogaine in Mexico for PTSD, traumatic brain injury and depression. Early reports are dramatic, with no cardiac events, and many describe forgiving themselves for moral injuries. Some also take 5-MeO-DMT from the Sonoran Desert toad in a separate session.

Ayahuasca combines a DMT-containing plant with one containing a reversible MAO inhibitor that lets DMT survive digestion. Williams says studies suggest it's safe, including in children exposed in Amazonian traditions, and describes a Brazilian study in which prisoners given ayahuasca had significantly lower recidivism than controls, while cautioning that he is not recommending psychedelics for prisoners. He argues that stripped of the 1960s cultural baggage, these drugs would be seen as potential breakthroughs, but insists they are too powerful for recreational use and must stay under strict medical supervision.

Cannabis, Alcohol and Relative Risk

On cannabis, Williams says the key is the ratio of THC to CBD. CBD is anti-epileptic and appears antipsychotic at high doses; he cites the Charlotte's Web strain and GW Pharmaceuticals' trials for severe childhood epilepsies. THC is pro-psychotic and pro-epileptic, and very high doses can land people in psychiatric units until it clears. Breeding has pushed THC up and CBD out. Referring to a Lancet Psychiatry report Huberman mentions linking early potent cannabis use to later psychosis, Williams says cause isn't established but, as a parent, he wouldn't want a teenager using it before prefrontal maturation around 25, while being unconcerned about a healthy 30-year-old trying it.

He cites David Nutt's analysis of combined personal and societal harm, which ranked alcohol as the most dangerous drug, ahead of heroin and cocaine, with psilocybin at the other end. He predicts institutions will eventually treat alcohol the way they now treat smoking, while noting the cancer story is harder to tell. Huberman adds that removing alcohol from campuses would likely improve decision-making.

Sleep, Light and Stanford's Accelerated TMS

One night of sleep deprivation relieves depression temporarily, but the benefit vanishes after sleep. Williams describes a triple therapy developed with a Stanford colleague named Greg, combining sleep deprivation, a circadian phase shift and bright light exposure, which produced durable antidepressant effects in trials. He warns that it must be done with professionals, since sleep deprivation increases anxiety, and that it's underused partly because there's no billing code. For everyday mood, he recommends regular sleep and wake times, CBT for insomnia, limiting light from screens at night, and keeping the bedroom for sleep and intimacy only.

He closes with the history of TMS, from Mark George's insight at NIH to FDA clearance around 2008, and his lab's Stanford Neuromodulation Therapy, originally called SAINT. It combines three improvements: theta-burst stimulation that mimics hippocampal rhythms, spaced learning with sessions every hour for ten hours a day over five days, amounting to about 90 minutes of actual stimulation and roughly seven and a half months' worth of standard dosing, and precise targeting of each person's DLPFC-cingulate subcircuit using brain scans. Between 60 and 90 percent of patients reach full remission within one to five days, depending on the trial, with some staying well for a year to four years, and he says patients don't report the numbness or sexual side effects some experience on SSRIs. The treatment has FDA clearance through Magnus Medical, and his lab is recruiting about a thousand patients for trials, with sham-group participants able to access the real treatment later.

Conclusion

Nolan Williams presents depression as a problem of circuits that can be recalibrated rather than a permanent flaw or chemical deficit. When the brain's emotional conflict center runs ahead of the prefrontal cortex, people lose control over their moods, and effective treatments, whether targeted TMS, psilocybin or ketamine, seem to restore the right order and unpair negative emotion from the sense of self. He's enthusiastic but rigorous: psychedelics show real promise for PTSD and depression, yet their mechanisms are still being untangled, ketamine turns out to depend on the opioid system, and none of these tools belong outside medical supervision. For everyday listeners, the practical takeaways are to protect sleep regularity, use exercise and mindfulness for milder low moods, and seek help early, because depression is treatable and people can recover.

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