Nolan Williams, M.D., (@NolanRyWilliams) is a triple board-certified psychiatrist, neurologist, and professor of psychiatry and behavioral sciences at Stanford School of Medicine. He is also the Director of the Stanford Brain Stimulation Lab.
In this episode, Andrew Huberman & Nolan Williams discuss clinical applications for brain stimulation, behavioral protocols, and novel drug treatments to halt and reverse mental health disorders, including depression and post-traumatic stress disorder. They discuss the neural circuits behind mood and mood control, dive deep into the history, use, and safety of psychedelics, and review behavioral approaches to mental health disorders.
Host: Andrew Huberman (@hubermanlab)
Depression can manifest in different ways: loss of interest, anxiety, overactive, underactive, low motivation – and much more
Depression is really a combination of a few disorders – closely related to anxiety, mania, etc.
 “Depression is the most disabling condition worldwide. What’s interesting about depression is it’s both a risk factor for other illnesses and it makes other medical and psychiatric illnesses worse.” – Dr. Nolan Williams
Criteria of possible depression: grief, a threshold to cry (when you didn’t previously cry), anhedonia (lack of enjoyment), guilt, confabulation, self-deprecation that doesn’t align with reality, vegetative symptoms, decreased appetite
At least three major chemical pathways in the brain relate the depression: norepinephrine, serotonin, dopamine
Treatment for depression can be difficult because there are no scans or quantitative tests to measure
Stimulating the vagus nerve seems to alleviate depressive symptoms and improve mood
Behavioral interventions like meditation, mindfulness, exercise, and breathwork stimulate DLP and help with depression
Studies on heart rate variability (HRV) indicate that lower is associated with mild to moderate depression
Simply reducing the heart rate won’t improve depression but there are regulatory networks and features of the ability to control the nervous system which help
A good therapist tries to identify beliefs and whether they’re flexible or fixed then helps find a new explanation for things to integrate into the memory system
The left dorsolateral prefrontal cortex (DLP) is connected to depression and also happens to be the area of the brain related to heart rate variability (note, the right DLP is associated with mania)
The DLP is the governor of how we interpret physiological signals and spontaneous thoughts
Depression is now the fourth highest risk factor for coronary heart disease (along with high blood pressure, high cholesterol, and diabetes)
The risk of having depression after a heart attack is higher
Transcranial magnetic stimulation (TMS) restores governance of left DLP which helps re-regulate over time and improve depression
TMS is about recalibrating a circuit and fixing it like arrhythmia in the heart, pushing back on serotonin theory because it’s focused on circuitry, not neurotransmitters
TMS works in 1-5 days post-treatment
We have persistent memories attached to negative emotion which may have served us in certain settings (e.g., a combat veteran in battle should jump at noises because it’s protective but becomes harmful back home)
Psychedelics are really too powerful to use recreationally, they need to be done under supervision because they put you in vulnerable states
Psychedelics allow you to enter into a highly plastic state and reconsolidate memory which may drive a therapeutic effect
Untethering from autonomic arousal/letting go is key to therapeutic effect through psychedelics
Ketamine: level of dissociation appears correlated with antidepressant effect – but dissociation is necessary but not sufficient
Antidepressant effects of ketamine last 1-2 weeks; dosing and cycling matter in longevity of therapeutic effect
In studies with naltrexone and ketamine, there was a dramatic blocking of antidepressant effect when naltrexone was present even when the dissociation level was the same – the opioid receptor may have a role in mood regulation
Research shows there’s no direct link between serotonin levels and depression, but SSRIs may still be effective but through a different mechanism (note, this was information already known in the psychiatric world but seems new to press and lay people)
SSRIs take a while to work which points to the possibility that it may not be as simple as recirculating serotonin
MDMA has effects on the dopamine system; psilocybin is a serotonergic agent
Psilocybin has been successful in about 50-75% of people for relief of symptoms in treatment-resistant depression
MDMA in clinical settings appears to have anti-PTSD effects in about 2/3 of people after 1-3 sessions, with benefits lasting for years
Despite previous research, MDMA does not have neurotoxic effects in the 1-3 dose range
Ibogaine is an alkaloid extracted from a tree in Africa; it is sacramentally used in the Gaban tradition
Ibogaine is an atypical psychedelic – it does not elicit visual perceptual differences in the external world, but it enables you to re-experience memories as a third party
Ibogaine is a 24-36 hour experience and very difficult to go through; it’s the most potent and riskiest psychedelic because it has contraindications with cardiac conditions
Ayahuasca is a combination of plants from the Amazon that produces psychedelic effects, being explored as an antidepressant agent
  • Brazilian prisoner study: prisoners were given ayahuasca and the recidivism rate was lower in the intervention group than the control
Early use (age 12-14) of potent cannabis can exacerbate psychotic episodes later in life
CBD in high doses is anti-psychotic in schizophrenic patients – the problem is we’ve bred CBD out of cannabis and make very potent strains
THC on the flipside is pro-psychotic and pro-epileptic
Before prefrontal maturation (under 25 years old), don’t use marijuana – after 25, it is safer
Alcohol imposes a huge amount of personal risk and societal risk but for some reason, we don’t see it as a drug
It’s likely that we’ll see alcohol become less prevalent in the future just like we saw cigarettes evolve
Paradoxically, sleep deprivation can improve symptoms of depression – but the foundation of good health is to get good quality sleep 80% of the time
The theory behind sleep deprivation therapy is it shifts your circadian rhythm back to regulation
Sleep deprivation therapy needs to be done under medical supervision because it is pro-anxiety
For most people, a regular light/dark cycle and sleep rhythm is beneficial for good mental health
For good sleep, there are only two things you should do in the bedroom: (1) sleep; (2) sex – don’t look at your phone, don’t watch TV, don’t eat, etc.
Articles
  • Adjunctive triple chronotherapy (combined total sleep deprivation, sleep phase advance, and bright light therapy) rapidly improves mood and suicidality in suicidal depressed inpatients: An open-label pilot study (Journal of Psychiatric Research)
  • Development of a rational scale to assess the harm of drugs of potential misuse (The Lancet)
Books
  • Breaking Open the Head: A Psychedelic Journey into the Heart of Contemporary Shamanism (by Daniel Pinchbeck)
Other Resources
  • Brain Stimulation Lab – Ongoing & Upcoming Studies
  • Magnus Medical