Episode 34: Understanding & Conquering Depression | Huberman Lab

Key Takeaways

  • Pain and pleasure system is a scale: if you overwhelm the pleasure system, you will set yourself up for anhedonia (lack of enjoyment) and depression
  • Daily EPA above 1,000mg per day can be beneficial for mood and offset inflammatory pathways
  • Depression interventions to change biological function: exercise, ingesting EPAs, reducing inflammation, Selective serotonin reuptake inhibitors (SSRIs)
  • Ketamine and psilocybin take unique paths but focus on rewiring circuitry to function better in the future
  • The ketogenic diet has been explored for potential relief of depressive symptoms by modulating GABBA – particularly in those who do not respond to pharmaceutical treatment


Dr. Andrew Huberman, Ph.D. is a Professor of Neurobiology and Ophthalmology at Stanford University School of Medicine. His lab focuses on neural regeneration, neuroplasticity, and brain states such as stress, focus, fear, and optimal performance.

In this episode of Huberman Lab, Dr. Huberman explains major depression at the biological and physiological level, treatments to prevent and treat depression, the chemical systems altered in depression, and a review of preventive lifestyle interventions.

Host: Andrew Huberman (@hubermanlab)

Pleasure-Pain Scale

  • The pleasure system is the same pathway that modulates mental anguish and pain
  • When we pursue anything that we think will bring us pleasure, we experience a release of dopamine
  • Dopamine is the molecule of craving and drive
  • As we experience pleasure there’s a tilt on the scale of pain-pleasure and we crave more of the thing that brought us pleasure
  • If we remain in constant pursuit of pleasure, we’ll achieve less dopamine release every time while the amount of pain increases
  • To reset the balance, enter states of boredom which might even increase anxiety
  • Always be cautious of any state of mind or body that leads to any significant increase in dopamine release
  • Pain relievers can help people with emotional pain
  • A lot of people with depression are more sensitive to physical pain


  • Characterized by lows – in contrast to bipolar depression, which has a manic state followed by a crash
  • Depression affects us on a conscious level and subconscious (sleep, appetite, hormone)
  • Major depression impacts 5% of the population
  • Depression is the 4th largest cause of disability
  • There’s a significant challenge in diagnosing depression because the tool used to diagnose is language
  • Criteria of possible depression: grief, 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 to depression: norepinephrine, serotonin, dopamine
  • Norepinephrine relates to the lethargy and exhaustion
  • Dopamine relates to the anhedonia
  • Serotonin relates to the grief, guilt, and more cognitive effects of depression

Sleep & Depression

  • The architecture of sleep is disrupted during depression
  • The pattern of activity in the brain during sleep is disrupted
  • Sleep marker of depression: early waking without being able to fall back asleep
  • 9 pm peak in cortisol is signature of depression

Popular Pharmaceutical Treatments  

  • Tricyclic antidepressants & MAO inhibitors increase norepinephrine in the brain
  • Side effects: impact libido, appetite, digestion, blood pressure
  • Selective serotonin reuptake inhibitor (SSRI): prevent serotonin from being wiped up by synapse; increase the efficacy of serotonin at the synapse not the amount of serotonin
  • Side effects: only works in about 1/3 of depression patients and can take about two weeks to kick in

Hormones & Stress

  • 20% of people with depression have low thyroid function
  • There are symptoms of hormonal dysfunction that can make people more susceptible to depression or make underlying depression worse
  • Women may experience symptoms of depression during the menstrual cycle, pre- and post-menopausal, post-partum
  • One of the best things you can do to stave off depression is control stress levels and particularly long term stress
  • There is a genetic disposition to stress – particularly a gene that regulates how much serotonin is in the brain under conditions of stress
  • Genetic disposition doesn’t mean you will get depression, but it will take far fewer bouts of intense stress to induce depression
  • The more closely related you are to someone with major depression, the more likely you are to get major depression

Exercise For Depression

  • Exercise increases the norepinephrine in the body
  • Regular exercise is a protective behavior of depression and can alleviate symptoms of depression
  • Double-edged sword of exercise & depression: exercise can be protective and alleviate symptoms but depending on how far along you are, apathy can take over and inhibit you from moving at all
  • People with depression can’t access circuits of happiness, motivation, movement, etc. in the same way people without depression can
  • Exercise has a positive effect on the tryptophan-serotonin pathway by sequestering pro-depressive effects on the pathway, essentially limiting bad pathway
  • Exercise dose: 150-180 minutes exercise per week

Inflammation, Nutrition & The Immune System

  • There is an abundance of evidence pointing to excessive inflammation as a precursor or exacerbator of depression
  • People who are depressed have more of an appetite for carbohydrates because they are trying to get more tryptophan which is eventually converted into serotonin
  • Supplement to limit inflammation and relieve some symptoms of major depression: increase intake of essential fatty acids – critical threshold level: 1,000 mg EPA (not DHA, read more here)
  • The phosphocreatine system in the brain has been shown to be involved in the regulation of mood pathways
  • Creatine (monohydrate): improve mood and symptoms of major depression (dose 1g – 5g)
  • A caveat with creatine supplementation: shown to increase mania in people who are already manic – but this same thing could be helpful for people with major depression (not bipolar)
  • Keto diet has been explored for potential relief of depressive symptoms by modulating gabba – particularly in those who do not respond to pharmaceutical treatment

NMDA Receptor As Therapeutic Target

  • Ketamine and PCP act as antagonists, blocking NMDA receptor  
  • Dissociation induced by PCP and ketamine may lead to shifts in circuity and plasticity so depression doesn’t feel as heavy
  • Ketamine changes the spines of neurons in the prefrontal cortex
  • People who are depressed and take ketamine experience separateness from grief and emotions
  • Take ketamine with psychiatrist guiding experience
  • Ketamine may be increasing neuroplasticity through dissociative states

Psilocybin For Depressive Disorder

  • Significant improvement in depressive symptoms, mood, and affect in 50-70% of study participants who received psilocybin treatment
  • Read more: Recent study on the clinical use of psilocybin for the treatment of depression
  • It’s critical to have a highly trained guide and medical monitoring devices where relevant
  • There are common themes to psilocybin experience that lead to a therapeutic outcome, but people can have different experiences and still benefit
  • Microdosing effects don’t seem to be as impactful as bigger sessions given several weeks apart
  • Ketamine versus psilocybin: ketamine is about dissociating from oneself during the experience; psilocybin is about diving into oneself
  • MDMA breakthroughs are for trauma, not depression
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Notes By Maryann

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