TMS, psilocybin, and ketamine for treating depression

Depression is the most disabling condition worldwide, yet treatment options have been limited and slow for decades. In this Huberman Lab Essentials episode, Andrew Huberman speaks with Dr. Nolan Williams, a neurologist and psychiatrist at Stanford University, about emerging therapies reshaping the field: from transcranial magnetic stimulation to psychedelics.

Depression as a brain circuit problem

Williams pushes back on the "chemical imbalance" narrative popularized by SSRI antidepressants. His research frames depression as fundamentally a circuit problem: the left dorsolateral prefrontal cortex fails to properly regulate the subgenual anterior cingulate, which generates negative mood states. When that regulation breaks down, negative thoughts dominate the brain's self-representation.

SSRIs work for a meaningful subset of patients, but not immediately and probably not for the reason originally assumed. Their effects most likely stem from induced neuroplasticity rather than correcting a serotonin deficit.

Transcranial magnetic stimulation: the SAINT protocol

The SAINT protocol (now called SNT), developed at Stanford, reorganizes TMS delivery to compress the equivalent of seven and a half months of conventional treatment into five days. The principle is spaced learning theory: stimulate the prefrontal cortex every hour, ten times per day, for five consecutive days.

Results are striking: between 60 and 90 percent of patients reach full remission within one to five days, without medication. Some have maintained remission for years. Williams describes the signal sent to the brain as simple but profound: "turn on, stay on, remember to stay on."

Psilocybin for depression

Psilocybin produces an overall decrease in brain activity alongside an increase in global connectivity between regions that normally do not communicate. In blinded trials, roughly a third of depressed patients achieve significant improvement; in open-label studies, the figure rises to half or two thirds.

Most notably, the connectivity change produced by psilocybin in brain networks mirrors precisely what the SNT protocol produces with TMS, suggesting a shared mechanism: decoupling negative mood states from the self-representation.

MDMA for PTSD

In controlled clinical settings, MDMA has shown in trials published in Nature Medicine that two thirds of participants with PTSD achieve clinically significant improvement after one or two assisted sessions. The effect lasts years in many cases, unlike ketamine whose antidepressant effect typically fades within a week and a half after a single infusion.

Ibogaine: the most potent psychedelic under study in veterans

Ibogaine, extracted from the root bark of the iboga tree in Central Africa, produces 24 to 36-hour sessions in which patients revisit early memories from a place of empathy and detachment. Williams calls it "ten years of psychotherapy in one night."

His group conducted the first complete neurobiological study in special operations personnel (Navy SEALs, Army Rangers), including cognitive assessments, clinical depression and PTSD scales, and neuroimaging before and after. Results are promising: soldiers carrying moral injuries report having found self-forgiveness and a new perspective. The primary risk is cardiac; pre-screening with an ECG reduces that risk substantially.

Ayahuasca and the Brazilian prison study

Ayahuasca combines two Amazonian plants: one containing DMT and one containing a reversible MAO inhibitor that allows DMT to cross the blood-brain barrier. A Brazilian study administered ayahuasca to prisoners and found that the recidivism rate in the treated group was statistically significantly lower than in the control group.

Psychiatry 3.0

Williams describes a paradigm shift: from psychiatry 1.0 (psychoanalysis) to 2.0 (chemical imbalance) to 3.0 (recalibrable circuits). This new framework is empowering because it positions depression as something fixable — analogous to a cardiac arrhythmia or a broken bone — rather than a lifelong sentence rooted in childhood experience or brain chemistry.