Episode 93: Dr. Nolan Williams – Psychedelics & Neurostimulation for Brain Rewiring | Huberman Lab

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Key Takeaways

  • Evolution of psychiatry: phase I – must be something genetic or how you were raised; phase II – must be a chemical imbalance or something chemically missing
  • There’s actually a decrease in the level of activity in the brain on psychedelics, but the connectivity in regions increases
  • We’re all taught to retain some level of control in our day-to-day lives – part of the therapeutic effect of psychedelics is about untethering, letting go, and letting the system assume a natural state you’ve been fighting
  • Mental health disorders exist on a range; you may not reach a clinical level of OCD but you may have some tendencies or habits
  • “If you can rid yourself of all to social and cultural constructions and re-examine these if we just discovered these today, we’d say that [psychedelics] are a huge breakthrough in psychiatry.” – Dr. Nolan Williams
  • Psychedelics allow you to enter into a highly plastic state and reconsolidate memory which may drive a therapeutic effect
  • Anti-psychotic therapeutic effects of cannabis are from the CBD and not the THC – the problem is we have potent strains now heavy with THC and low in CBD
  • Transcranial magnetic stimulation (TMS) has the potential to send a signal to the prefrontal cortex and use the brain’s own communication style to get it out of a depressive state – you’re tapping into core circuitry with minimal side effects (unlike tinkering neurotransmitters)


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)

Overview Of Depression

  • 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

Physiology Of Depression

  • 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

Psychedelics & Emerging Treatments For Depression

  • 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

Marijuana & Alcohol

  • 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

Sleep Deprivation

  • 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.


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